Value-Based Care Cardiometabolic Health Dec 2012, Vol 1, No 3

DECEMBER 2012, VOL 1, NO 3

Value-Based Care Cardiometabolic Health

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F R O M T H E P U B L I S H E R S O F A M E R I CA N H E A LT H & D R U G B E N E F I T S

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CVD Pipeline: Novel Approaches to Modifying Lipids/Lipoproteins

Heart disease the leading cause of death in diabetic patients

A total of 16 new drug classes are in development

By Wayne Kuznar

By Mary Mosley

Photo © Jim Dowdalls/Photo Researchers, Inc

Interventions for Cardiovascular Risk Reduction in Type 2 Diabetes Must Be Multifactorial Boston, MA—Optimal cardiovascular (CV) risk reduction in patients with diabetes must be multifactorial, stated James R. Gavin III, MD, PhD, Clinical Professor of Medicine, Emory University, Atlanta, GA, at the 2012 Cardiometabolic Health Congress.

A great deal is known about CV disease (CVD) in diabetes, yet its prevention remains a paradox. No matter how well its risks are mitigated, the rates of CVD in the presence of diabetes remain higher than in its absence “in ways that simply make no sense,” Dr Gavin said.

Coronary heart disease (CHD) is the leading cause of death in patients with diabetes. Although there are a host of emerging risk factors for CHD that ulti-

Munich, Germany—A total of 16 novel classes of drugs are under development for the management of lipoprotein metabolism toward the prevention of cardiovascular disease (CVD), according to John J.P. Kastelein, MD, PhD, Academic Medical Center, University of Amsterdam, the Netherlands. Dr Kastelein reviewed several of these approaches at the 2012 European Society of Cardiology (ESC) Congress.

New Approaches to LDL-C Reduction Apolipoprotein (apo)-B mRNA antisense drugs, microsomal triglyceride transfer protein (MTP) inhibitors, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are promising new approaches to reducing low-density lipoprotein cholesterol (LDL-C), according to Dr Kastelein.

ApoB mRNA Antisense Drugs Mipomersen (Kynamro; Genzyme/Sanofi, Isis Pharmaceuticals) is an apoB mRNA antisense drug that has been studied in a trial Continued on page 11

Continued on page 6

Belly Fat Triples CV and All-Cause GLP-1 Agonism Holds Promise Mortality, Even with Normal Weight for Preventing Macrovascular

Disease in Type 2 Diabetes

By Mary Mosley Munich, Germany—The risk of cardiovascular (CV) and all-cause death is nearly 3 times higher in persons with normal weight who nevertheless have excess belly fat than in people who are overweight or obese with a high waist-to-hip ratio (WHR), according to new data presented by Karine Sahakyan, MD, PhD, MPH, a cardiologist at the Mayo Clinic, Rochester, MN, at the 2012 European

Society of Cardiology Congress.

The study data came from a large, nationwide, representative sample of the US population, “so we’re pretty confident about the results of this study,” said Dr Sahakyan.

Normal-Weight Central Obesity Is Deadly Nearly half (47.8%) of the people with a normal body mass index (BMI) Continued on page 13

By Wayne Kuznar Boston, MA—No glucose-lowering regimen has been shown to reduce macrovascular complications, such as myocardial infarction (MI) or stroke, but glucagon-like peptide (GLP)-1 agonism appears to have favorable effects on many surrogate markers for cardio-

Continued on page 10

INSIDE CARDIOMETABOLIC HEALTH . . . . .6 Controlling 4 risk factors cuts CHD rate in diabetes by 50% Data reveal potential cardioprotective role for DPP-4 inhibitors CVD MANAGEMENT . . . . . . . . . . . . . . .8 Third definition of MI presented at ESC PHS II: CV events in men not reduced with multivitamins EMERGING THERAPIES . . . . . . . . .10 Serelaxin reduces dyspnea in acute heart failure LCZ696 promising in heart failure with preserved EF

©2013 Engage Healthcare Communications, LLC

vascular disease (CVD), according to presenters at the 2012 Cardiometabolic Health Congress.

Although hyperglycemic states increase cardiovascular (CV) risk in a continuous manner, definitive evidence that glucose control decreases

OBESITY/OVERWEIGHT . . . . . . . . . .13 Behavioral interventions can result in weight loss HYPERTENSION . . . . . . . . . . . . . . . . .14 Three new prognostic markers in hypertension LIPID MANAGEMENT . . . . . . . . . . .15 Lipid therapy update DRUG UPDATES . . . . . . . . . . .18, 22 Belviq: New weight-loss Rx for overweight or obese patients Qsymia: Combination oral therapy for obese or overweight patients

FOR ADULT PATIENTS WITH TYPE 2 DIABETES TRADJENTA (LINAGLIPTIN) TABLETS: THE ONLY ONCE-DAILY 1-DOSE DPP-4 INHIBITOR

Focusing on what matters Improving glycemic control for adult patients with type 2 diabetes Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA has not been studied in combination with insulin.

a clinical trial. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. MACROVASCULAR OUTCOMES There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

Important Safety Information

ADVERSE REACTIONS

CONTRAINDICATIONS

Adverse reactions reported in ≼5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS USE WITH MEDICATIONS KNOWN TO CAUSE HYPOGLYCEMIA Insulin secretagogues are known to cause hypoglycemia.

The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

TRADJENTA delivers proven glycemic control Placebo-adjusted mean change in A1C at 24 weeks (%)

0

Significant A1C reductions from baseline at 24 weeks †

-0.2

-0.4

TRADJENTA monotherapy 1,2* (n=333) P<0.0001

-0.6

-0.8

TRADJENTA + metformin 2,3† (n=513) P<0.0001

-0.6% -0.7%

A randomized, double-blind, placebo-controlled, parallel-group study of adult patients with type 2 diabetes (aged 18-80) with insufficient glycemic control despite metformin therapy who were randomized to TRADJENTA 5 mg/day (n=524; mean baseline A1C=8.1%) or placebo (n=177; mean baseline A1C=8.0%) in combination with metformin ≥1500 mg/day for 24 weeks. Primary endpoint was change from baseline in A1C at 24 weeks. Results are adjusted for a 0.15% mean A1C increase for placebo and 0.5% mean decrease for TRADJENTA in add-on combination with metformin. 18.9% of patients in the placebo group required rescue therapy vs 7.8% of patients in the TRADJENTA group. Full analysis population using last observation on study.

*A randomized, multicenter, double-blind, placebo-controlled study of adult patients with type 2 diabetes (aged 18-80) who were randomized to TRADJENTA 5 mg/day (n=336; mean baseline A1C=8.0%) or placebo (n=167; mean baseline A1C=8.0%) for 24 weeks.

Primary endpoint was change from baseline in A1C at 24 weeks. 20.9% of patients in the placebo group required rescue therapy vs 10.2% of patients in the TRADJENTA group.

Results adjusted for a 0.3% mean A1C increase for placebo and 0.4% mean decrease for TRADJENTA monotherapy. Full analysis population using last observation on study.

TRADJENTA: Experience dosing simplicity No dose adjustment required, regardless of declining renal function or hepatic impairment4 TRADJENTA is primarily nonrenally excreted: 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing

ENTA J D A R T 30 5 MG # O QD Sig: i P ILLS x2 REF

One dose, once daily for adult patients with type 2 diabetes

TRADJENTA: A safety and tolerability profile demonstrated in more than 4000 patients In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure [1 per 538 person-years]) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (e.g., rifampin). Therefore, use of alternative treatments to TRADJENTA is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com Copyright © 2012 Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(03/12) TJ184308PROFB

milk, caution should be exercised when TRADJENTA is administered to a nursing woman.

The safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

TJ PROF ISI FEB132012 References: 1. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle H-J, Dugi K. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-267. 2. Data on file.

Boehringer Ingelheim Pharmaceuticals, Inc. 3. Taskinen M-R, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65-74. 4. Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther. 2011;28:447-459.

Please see brief summary of full Prescribing Information on the adjacent page.

Tradjenta™ (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

INDICATIONS AND USAGE TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

TRADJENTA has not been studied in combination with insulin.

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with pioglitazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in *5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyngitis (5.8% vs 5.5%). Adverse reactions reported in *2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in * 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).

Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to Table 1

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and *1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA. DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp or CYP3A4 inducer.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

OVERDOSAGE During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis.

Adverse Reactions Reported in *2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Monotherapy* n (%)

Nasopharyngitis Hyperlipidemia Cough Hypertriglyceridemia† Weight increased

Combination with SU n (%)

TRADJENTA Placebo n = 765 n = 458

Combination with Metformin# n (%) TRADJENTA Placebo n = 590 n = 248

– – – – –

– – – – –

7 (4.3) – – 4 (2.4) –

– – – – –

– – – – –

TRADJENTA Placebo n = 161 n = 84 1 (1.2) – – 0 (0.0) –

Combination with Metformin + SU n (%) TRADJENTA Placebo n = 791 n = 263

Combination with Pioglitazone n (%) TRADJENTA Placebo n = 259 n = 130

– – 19 (2.4)

– 7 (2.7) – – 6 (2.3)

–

– – 3 (1.1) – –

– 1 (0.8) – – 1 (0.8)

SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)

Copyright © 2011 Boehringer Ingelheim Pharmaceuticals, Inc. Revised: July 2011

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In This Issue Value-BasedCare Cardiometabolic Health

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Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1892 National Accounts Manager Zach Ceretelle zach@engagehc.com 732-992-1898 Executive Vice President Engage Managed Markets Chuck Collins ccollins@engagehc.com 732-992-1894 Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536 Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto

CARDIOMETABOLIC HEALTH Controlling 4 risk factors cuts CHD rate in diabetes by 50% Data reveal potential cardioprotective role for DPP-4 inhibitors More…..

CVD MANAGEMENT Third definition of MI presented at ESC 2012 PHS II: CV events in men not reduced with multivitamins More…..

EMERGING THERAPIES CVD pipeline: novel approaches to lipid therapy RELAX-AHF: Serelaxin reduces dyspnea in acute HF LCZ696 promising in HF with preserved EF More…..

OBESITY AND OVERWEIGHT Belly fat triples CV, all-cause mortality Behavioral interventions can result in weight loss

EDITOR-IN-CHIEF

Value-Based Care in Cardiometabolic Health provides a forum for payers, providers, and the entire cardiometabolic team to consider the cost-value issues particular to

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health, Philadelphia, PA

Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com T: 732-992-1892; F: 732-992-1881 Permission requests to reprint all or part of any article published in this publication should be addressed to editorial@engagehc.com.

Value-Based Care in Cardiometabolic Health, ISSN applied, is published 3 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Cardiometabolic Health is a trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Care in Cardiometabolic Health do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Cardiometabolic Health should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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VOL 1

NO 3

LIPID MANAGEMENT Lipid therapy update: HDL therapies fall short, LDL agents promising, 2 potential treatments for familial hypercholesterolemia HEALTH ECONOMICS CABG outcomes superior to PCI, cost-effective DRUG UPDATES Belviq: New weight-loss Rx for overweight or obese patients Qsymia: Combination oral therapy for obese or overweight patients CONTINUING EDUCATION Value-based treatment paradigm in CV and metabolic disorders

EDITORIAL BOARD

Mission Statement

cardiovascular and metabolic treatments. This unique focus is achieved through news coverage from major professional meetings and the literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

HYPERTENSION New prognostic markers for hypertension More…..

J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship University of Michigan, School of Public Health and Medicine, Ann Arbor

Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise PATIENT ADVOCACY Institute, Washington, DC William E. Fassett, BSPharm, MBA, Robert W. Dubois, MD, PhD DEPUTY EDITORS PhD, FAPhA Chief Science Officer Joseph D. Jackson, PhD Professor of Pharmacy Law & Ethics National Pharmaceutical Council Program Director, Applied Health Dept. of Pharmacotherapy, College of DC Washington, Economics and Outcomes Research, Pharmacy, Washington State University, HEALTH OUTCOMES RESEARCH Jefferson University School of Population Spokane, WA Jack E. Fincham, PhD, RPh Diana Brixner, RPh, PhD Health, Philadelphia Professor of Pharmacy Practice and Mike Pucci Professor & Chair, Dept. of Laura T. Pizzi, PharmD, MPH, RPh Sr VP Commercial Operations and Business Administration, School of Pharmacy Pharmacotherapy Associate Professor, Dept. of Pharmacy Development, PhytoChem Pharmaceuticals University of Missouri Executive Director, Outcomes Research Kansas City, MO Practice, Jefferson School of Pharmacy, Center, Director of Outcomes, Personalized Lake Gaston, NC Philadelphia Health Care Program, University of Utah, Walid F. Gellad, MD, MPH MEDICINE PERSONALIZED Salt Lake City Assistant Professor of Medicine, University AGING AND WELLNESS Amalia M. Issa, PhD, MPH of Pittsburgh, Staff Physician, Pittsburgh Eric G. Tangalos, MD, FACP, AGSF, CMD Joseph Couto, PharmD, MBA Professor and Chair VA Medical Center, Adjunct Scientist Clinical Program Manager Professor of Medicine Department of Health Policy and RAND Health Cigna Corporation, Bloomfield, CT Mayo Clinic, Rochester, MN Public Health Director, Program in Personalized Medicine Paul Pomerantz, MBA Steve Miff, PhD CANCER RESEARCH Executive Director & Targeted Therapeutics Senior Vice President Al B. Benson III, MD, FACP, FASCO Drug Information Association University of the Sciences, Philadelphia VHA, Inc., Irving, TX Professor of Medicine, Associate Director Horsham, PA Kavita V. Nair, PhD for Clinical Investigations PHARMACOECONOMICS J. Warren Salmon, PhD Associate Professor, School of Pharmacy Robert H. Lurie Comprehensive Cancer Josh Feldstein Professor of Health Policy & Administration University of Colorado at Denver, CO Center, Northwestern University, IL President & CEO School of Public Health Past Chair, NCCN Board of Directors CAVA, The Center for Applied Value Gary M. Owens, MD University of Illinois at Chicago Analysis, Inc., Norwalk, CT President, Gary Owens Associates Samuel M. Silver, MD, PhD, FASCO Raymond L. Singer, MD, MMM, CPE, Glen Mills, PA Professor of Internal Medicine Jeff Jianfei Guo, BPharm, MS, PhD FACS Hematology/Oncology Professor of Pharmacoeconomics & Andrew M. Peterson, PharmD, PhD Chief, Division of Cardiothoracic Surgery Assistant Dean for Research Pharmacoepidemiology, College of Dean, Mayes School of Healthcare Vice Chair, Department of Surgery for Associate Director, Faculty Group Practice Business and Policy, Associate Professor, Pharmacy, Univ of Cincinnati Quality & Patient Safety and Outreach University of Michigan Medical School Medical Center, OH University of the Sciences Lehigh Valley Health Network, PA Philadelphia, PA EMPLOYERS PHARMACY BENEFIT DESIGN RESEARCH & DEVELOPMENT Arthur F. Shinn, PharmD, FASCP Sarah A. Priddy, PhD Joel V. Brill, MD, AGAF, CHCQM Frank Casty, MD, FACP President, Managed Pharmacy Director, Competitive Health Analytics Chief Medical Officer, Predictive Chief Medical Officer Consultants, LLC, Lake Worth, FL Humana, Louisville, KY Health, Phoenix, AZ Senior VP, Clinical Development F. Randy Vogenberg, RPh, PhD Timothy S. Regan, BPharm, RPh, CPh Leslie S. Fish, PharmD Medical Science Principal, Institute for Integrated HealthExecutive Director, Strategic Accounts Vice President of Clinical Programs Endo Pharmaceuticals, Chadds Ford, PA care and Bentteligence, Sharon, MA Xcenda, Palm Harbor, FL Fallon Community Health Plan, MA Michael F. Murphy, MD, PhD Vincent J. Willey, PharmD John Hornberger, MD, MS Chief Medical Officer and Scientific ENDOCRINOLOGY Associate Professor, Philadelphia School of Cedar Associates, LLC Officer James V. Felicetta, MD Pharmacy, University of the Sciences CHP/PCOR Adjunct Associate Worldwide Clinical Trials Chairman, Dept. of Medicine Philadelphia, PA Menlo Park, CA King of Prussia, PA Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ David W. Wright, MPH Michael S. Jacobs, RPh SPECIALTY PHARMACY President, Institute for Interactive Patient Vice President, National Accounts Quang Nguyen, DO, FACP, FACE Atheer A. Kaddis, PharmD Truveris, Inc., New York, NY Adjunct Associate Professor, Endocrinology Care, Bethesda, MD Senior Vice President Touro University Nevada, College of Managed Markets/Clinical Services Matthew Mitchell, PharmD, MBA HEALTH & VALUE PROMOTION Osteopathic Medicine Diplomat Specialty Pharmacy, Flint, MI Manager, Pharmacy Services Craig Deligdish, MD SelectHealth, Salt Lake City, UT Hematologist/Oncologist James T. Kenney, Jr, RPh, MBA EPIDEMIOLOGY RESEARCH Oncology Resource Networks, Orlando, FL Paul Anthony Polansky, BSPharm, MBA Pharmacy Operations Manager Joshua N. Liberman, PhD Harvard Pilgrim Health Care Senior Field Scientist, Health Outcomes Executive Director, Research, Development Thomas G. McCarter, MD, FACP Wellesley, MA and PharmacoEconomics (HOPE) & Dissemination Chief Clinical Officer Endo Health Solutions, Chadds Ford, PA Sutter Health, Concord, CA Executive Health Resources, PA Michael Kleinrock Director, Research Development Christina A. Stasiuk, DO, FACOI Albert Tzeel, MD, MHSA, FACPE GOVERNMENT IMS Institute for Healthcare Informatics Senior Medical Director National Medical Director Kevin B. “Kip” Piper, MA, FACHE Collegeville, PA Cigna, Philadelphia, PA HumanaOne, Waukesha, WI President, Health Results Group, LLC Washington, DC Scott R. Taylor, BSPharm, MBA MANAGED MARKETS Executive Director, Industry Relations Jeffrey A. Bourret, RPh, MS, FASHP HEALTH INFORMATION TECHNOLOGY Geisinger Health System, Danville, PA Senior Director, Medical Lead, Payer and Kelly Huang, PhD Specialty Channel Strategy, Medical Affairs President, HealthTronics, Inc. Pfizer Specialty Care Business Unit, PA Austin, TX

DECEMBER 2012

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

5

Cardiometabolic Health

Interventions for Cardiovascular Risk Reduction... mately lead to atherosclerosis and vulnerable plaque, 9 modifiable risk factors account for 90% of the risk for myocardial infarction (MI) worldwide, said Dr Gavin.

Multifactorial Risk Factors As demonstrated in the INTERHEART study, these 9 risk factors are dyslipidemia, smoking, hypertension, diabetes, abdominal obesity, psychosocial factors, a low consumption of fruits and vegetables, excessive alcohol intake, and being inactive.

Therefore, for optimal CV risk reduction, interventions must be multifactorial, he argued.

“The greater the number of traditional risk factors, the greater the incidence of events, including definitive events [ie, death],” Dr Gavin noted. In patients with diabetes, the age-adjusted rate of CHD-related death increases from approximately 35 per 10,000 person-years with no CHD risk factors to >120 per 10,000 personyears with 3 risk factors. The corresponding rate in those without diabetes is ≤33%.

Therefore, another nagging paradox is that in the absence of additional discernible risk factors, diabetes alone is associated with increased rates of CVD events compared with CVD event rate in the absence of diabetes, Dr Gavin noted.

The multifactorial approach to preventing vascular disease in diabetes should include lifestyle intervention,

glucose lowering, lipid modification, and blood pressure (BP) lowering.

Lifestyle Changes Are Key Lifestyle changes have been shown to reduce the need for pharmacologic therapy, he said. Among patients with impaired glucose tolerance, fewer of those who were assigned to weight reduction and moderate-intensity physical activity for at least 150 minutes

Lifestyle intervention “is an essential platform upon which all other treatment interventions must be built, for any treatment to be successful.”

—James R. Gavin III, MD, PhD weekly required antihypertensive drug therapy and lipid-modifying drug therapy than those assigned to metformin or to placebo.

Exercise has been shown to reduce the risk of all-cause death and CV death among patients with diabetes, regardless of whether they are normotensive or hypertensive.

Dietary intervention has also reduced the rate of mortality in many primary prevention trials by reducing the rate of CVD events.

Despite the demonstrated benefits of lifestyle intervention, it is “not taken seriously enough or pursued consis-

tently or intensively enough to reduce vascular disease or provide CVD risk reduction in persons with diabetes,” Dr Gavin pointed out. “Despite this limitation, it is an essential platform upon which all other treatment interventions must be built, for any treatment to be successful.”

Beyond lifestyle interventions, early and comprehensive reduction of risk factors is needed to prevent vascular disease in diabetes, he said.

Early Glycemic Control The contribution of hyperglycemia to CVD in patients with type 2 diabetes was explored in the United Kingdom Prospective Diabetes Study (UKPDS) and offers “a compelling argument for early glucose control,” said Dr Gavin.

The UKPDS researchers uncovered a legacy effect of early glucose control on any macrovascular disease; 8.5 years after the trial was completed, patients who had early intensive glycemic control suffered 15% fewer MIs and had a 13% reduction in all-cause mortality compared with those patients assigned to less-intensive control.

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, a target hemoglobin (Hb) A1c level of <7% was associated with a significant reduction in the risk of nonfatal MI but a significant increase in CV death. There was no significant effect of achieving an HbA1c <7% on these end points in the Action in Diabetes and Vascular Disease trial and in

Continued from page 1

the Veterans Affairs Diabetes Trial.

The message is that an individualized, patient-centered approach is needed to achieve glycemic control, with looser targets for those with advanced CVD, Dr Gavin acknowledged.

Lipid Lowering Lipid lowering with atorvastatin did reduce the risk of a first CV event, including stroke, in patients with type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS). The number needed to treat to prevent 1 event was only 27, demonstrating the importance of lipid lowering in the prevention of CVD in patients with type 2 diabetes.

Blood Pressure Despite lipid lowering with a statin, patients with type 2 diabetes have a substantial residual risk of CHD events, he said, adding further credence to a multifactorial approach to reducing risk in this population. This approach includes lowering risk by controlling systolic BP; a relationship between systolic BP reduction and lower CV mortality is unequivocal.

Beyond early, aggressive, and comprehensive reduction of conventional CV risk factors, it is clear that other, less well-characterized features of the risk profile “must be defined and targeted to resolve the paradox of diabetes and excess CV disease,” said Dr Gavin. “Until we know more, we control well what we can.” ■

Control of 4 Risk Factors Would Slash CHD Rate in Diabetes by Half

By Wayne Kuznar Los Angeles, CA—More than half of all coronary heart disease (CHD) events in American patients with diabetes could be prevented with optimal control of risk factors, suggested Nathan Wong, PhD, MPH, Professor and Director, Heart Disease Prevention Program at the University of California, Irvine, at the 2012 American Heart Association meeting.

Only approximately 10% of the US population with diabetes has simultaneous control of blood glucose, blood lipids, and blood pressure (BP), said Dr Wong. In his statistical analysis, the proportion of CHD events among adults (aged ≥30 years) diagnosed with preventable diabetes was calculated using the United Kingdom Prospective Diabetes Study (UKPDS) CHD Risk Engine version 1.1. The UKPDS

6

Risk Engine was developed specifically in persons with type 2 diabetes, noted Dr Wong.

“One third of CHD events could be prevented from just achieving goal levels in risk factors not already at goal in a 10-year period.”

—Nathan Wong, PhD, MPH

The study population consisted of those individuals identified with type 2 diabetes and no preexisting CHD from the US National Health and Nutrition Examination Surveys (NHANES) 20072008. The impact of control of total

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

DECEMBER 2012

cholesterol, high-density lipoprotein cholesterol (HDL-C), systolic BP, and hemoglobin (Hb) A1c in all patients who are not controlled to goal levels was examined.

Control to goals was defined as simultaneous achievement of the following 4 parameters: • Total cholesterol, ≤170 mg/dL • HDL-C, ≥40 mg/dL in men; ≥50 mg/dL in women • Systolic BP ≤130 mm Hg • HbA1c ≤7.0%.

Preventable CHD events were calculated by subtracting the number of events prevented by controlling the 4 CHD risk factors from the number of events before risk factor control.

The overall 10-year baseline risk of the study population was estimated at 18%: 23.6% for men, 12.1% for women.

With control of all 4 risk factors to goal, 53.2% of CHD events could be prevented, said Dr Wong. With only nominal control of these risk factors (ie, a 25% reduction in total cholesterol, a 10% increase in HDL-C, a 10% decrease in systolic BP, and an absolute reduction of 1% in HbA1c), 34.7% of the events would have been prevented.

Control of single risk factors to goal would prevent 8% to 36.2% of events, with total cholesterol being the single most important risk factor to control.

“One third of CHD events could be prevented from just achieving goal levels in risk factors not already at goal in a 10-year period,” Dr Wong pointed out.

One weakness to the analysis is the lack of information on atrial fibrillation in NHANES, he said. ■

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Cardiometabolic Health

Several Antihypertensive Drug Combinations Increase the Risk for Incident Diabetes Lower systolic blood pressure reduces risk

By Wayne Kuznar Los Angeles, CA—Antihypertensive regimens that include a thiazide diuretic or a beta-blocker increase the risk for incident diabetes, according to an observational study presented at the 2012 American Heart Association meeting.

The risk was nearly doubled when both drug classes were used together compared with antihypertensive combinations that included neither, reported Rhonda Cooper-DeHoff, PharmD, Associate Professor, Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville.

To study the effect of prescribing combined antihypertensive drug classes on diabetes risk, her group conducted a nested case-control study among Kaiser Permanente members (aged 35-65 years) without diabetes at baseline.

Incident diabetes was defined as fasting glucose, ≥126 mg/dL; random glucose, ≥200 mg/dL; hemoglobin A1c, ≥7.0%; or prescription of any diabetes therapy. Ten age-matched controls with a fasting glucose of <126 mg/dL at the time of the case onset of diabetes were selected per case.

A total of 9097 cases of diabetes were matched with 90,495 controls.

When drug classes were considered separately, the prescription of a thiazide diuretic “imparted a 50% excess risk of diabetes,” said Dr CooperDeHoff. The adjusted odds of developing diabetes increased by 14% with prescription of a beta-blocker. No other drug class was associated with excess risk.

The prescription of a thiazide diuretic “imparted a 50% excess risk of diabetes….

Renin-angiotensin system– blocking combinations may be preferred in patients at high risk of diabetes.”

—Rhonda Cooper-DeHoff, PharmD

“The diabetes risk for a thiazide diuretic plus beta-blocker combination was stacked, meaning that we saw the full effect of both drugs added to-

gether,” she said. This combination increased the adjusted odds of incident diabetes by 87% compared with the nonuse of either of these 2 drug classes.

None of the combinations that included a blocker of the renin-angiotensin system showed an increased risk for diabetes. “Renin-angiotensin system–blocking combinations may be preferred in patients at high risk of diabetes,” Dr Cooper-DeHoff noted.

A separate analysis that she performed using the database from the Women’s Health Initiative Clinical Trials and Observational Study revealed an increased risk of incident diabetes among postmenopausal women who took ≥2 classes of drugs such as thiazide diuretics, beta-blockers, statins, and antidepressants compared with those who took only a single agent.

Lower Systolic BP Equals Lower Risk of Incident Diabetes An examination of data from a large, randomized trial comparing outcomes between antihypertensive therapy with the angiotensin receptor blocker losartan and the beta-blocker atenolol among patients with left-ventricular

hypertrophy revealed that patients with systolic blood pressure (BP) ≤130 mm Hg had a lower risk of developing diabetes than those with higher intreatment BPs, reported Peter M. Okin, MD, Director of Clinical Affairs and Associate Director of the Cardiac Graphics Laboratory, Weill Cornell Medical College, New York City.

His analysis of the Losartan Intervention for Endpoint Reduction (LIFE) trial included 7485 patients in the trial without diabetes at baseline. During a mean follow-up of 4.6 years, newonset diabetes was diagnosed in 520 patients (6.9%).

In a multivariate model, patients with systolic BP ≤130 mm Hg had a significant 38% lower risk of newonset diabetes compared with those with systolic BP ≥142 mm Hg. The risk for new-onset type 2 diabetes associated with in-treatment systolic BP of ≤130 mm Hg was independent of other risk factors for diabetes, notably the previously demonstrated decreased risk seen with losartan-based therapy and the in-treatment level of high-density lipoprotein cholesterol, said Dr Okin. ■

Encouraging Data Reveal Potential Cardioprotective Role for DPP-4 Inhibitors Los Angeles, CA—A new meta-analysis suggests that the use of dipeptidyl peptidase (DPP)-4 inhibitors to achieve glucose control in patients with type 2 diabetes may be cardioprotective.

“It is extremely unlikely that DPP4 inhibitors increase cardiovascular adverse events,” said Kari A.O. Tikkinen, MD, PhD, Senior Researcher, McMaster University, Ontario, Canada, and a coinvestigator of the metaanalysis. “The results suggest the possibility of substantial relative risk reduction in cardiovascular events, particularly myocardial infarction, with DPP-4 inhibitors.” The data were released at the 2012 American Heart Association meeting.

DPP-4 inhibitors enhance incretin action and improve glucose control by inhibiting glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide. Because of the low cardiovascular (CV) event rates in randomized controlled trials of DPP4 inhibitors, information on CV risk is

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limited. Using a prespecified protocol, Dr Tikkinen and colleagues performed a systematic review and metaanalysis of randomized clinical trials of DPP-4 inhibitors with follow-up of at least 12 weeks.

To identify the randomized controlled trials, they searched MEDLINE, EMBASE, the Cochrane Library, clini caltrials.gov, published systematic reviews/health technology assessment reports, and abstracts accepted for presentation at the American Diabetes Association and the European Association for the Study of Diabetes meetings. Eligible trials included a comparison of an incretin agent with a placebo, usual care, or other active agents for patients with type 2 diabetes and for which prespecified CV outcomes were reported.

A total of 55 studies were eligible— 42 studies of DPP-4 inhibitors and 13 of GLP-1 agonists. Of the 42 DPP-4 inhibitors trials, 19 investigated sitagliptin; 10, saxagliptin; 7, vildagliptin; and 6, alogliptin. The length of follow-

up was 12 to 104 weeks; 10 of the trials followed patients for more than 24 weeks; 93% of the trials had a low risk for bias.

“The results suggest the possibility of substantial relative risk reduction in cardiovascular events, particularly myocardial infarction, with DPP-4 inhibitors.”

—Kari A.O. Tikkinen, MD, PhD Some 110 major adverse cardiovascular events (MACE) were recorded in 24,215 trial participants. DPP-4 inhibitors reduced the risk of MACE by 49% (P = .004) and the risk of myocardial infarction by 72% (relative risk, 0.09-0.94). A 50% reduction in all-cause mortality with DPP-4 inhibitors was not significant, said Dr Tikkinen.

DECEMBER 2012

A difference in the effect of DPP-4 inhibitors was found between monotherapy, in which the risk of MACE was reduced by a nonsignificant 7%, and as add-on therapy, in which the risk of MACE was reduced by 54% (relative risk, 0.36-0.59).

There was no difference in treatment effects between study groups based on the duration of the trials, the type of control (active vs placebo), the risk of bias (low vs moderate vs high risk), or the type of DPP-4 inhibitor.

The number of events per study was too low to examine publication bias, he said. Only 4 of the studies adjudicated CV outcomes; in most of the studies, MACE were reported as adverse events.

The data are encouraging, said Dr Tikkinen, but confirmatory studies are necessary before DPP-4 inhibitors can be prescribed specifically to reduce the risk of CV events. Four large-scale randomized controlled outcomes trials with DPP-4 inhibitors are ongoing, he said. ■

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

7

CVD Management

Third Definition of Myocardial Infarction Presented at ESC 2012, Focusing on New High-Sensitivity Biomarkers

By Mary Mosley Munich, Germany—The Third Universal Definition of Myocardial Infarction, which was developed by 4 major cardiology societies, was presented at the 2012 Congress of the European Society of Cardiology (ESC),

by Kristian Thygesen, MD, Professor, Aarhus University Hospital, Denmark. Dr Thygesen is Cochair of the Global Myocardial Infarction Task Force that developed this document and was involved with developing the previous definitions.

The definition of myocardial infarction (MI) provides information for the diagnosis of patients, as well as end points in clinical trials, which have had tremendous heterogeneity of the definition of MI, thereby limiting the ability to appropriately compare outcomes data across trials. Standardizing the definition of MI for clinical trial end points is necessary, because these trials are used to develop clinical practice guidelines.

Focus on Biomarkers and Imaging The key drivers for updating the definition of MI are the increasingly sensitive markers of myocardial necrosis, especially troponin, and more refined imaging techniques, including electrocardiogram (ECG) changes.

“We have always had to go for a more biochemical approach,” said Dr Thygesen. “Biomarkers could detect necrosis, which was always difficult with an ECG. So, in this latest definition, the concept of MI has not

changed, but the diagnosis is now based on patient symptoms, ECG changes, highly sensitive biochemical markers, and information gleaned from various imaging techniques.”

“In this latest definition, the concept of MI has not changed, but the diagnosis is now based on patient symptoms, ECG changes, highly sensitive biochemical markers, and information gleaned from various imaging techniques.”

—Kristian Thygesen, MD

The third universal definition was developed jointly by the ESC, the American College of Cardiology (ACC), the American Heart Association (AHA), and the World Heart Federation. The first universal definition was developed in 2000 by the ESC and ACC because of the emerging role of biomarkers in accurately reflecting the pathology, and all 4 societies developed the second definition, which was published in 2007.

Notably, the third universal definition includes additions related to percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG)

surgery, cardiac and noncardiac surgery, and clinical trials. New definitions in the document include: • Definition to differentiate MI types 1 and 2 according to condition of the coronary arteries • New definition of MI in patients undergoing cardiac procedures (eg, transcatheter aortic valve implantation, ablation, MI), MI associated with noncardiac procedures, MI in the intensive care unit, and associated with heart failure (HF) • Definitions for clinical trial end points.

Updates in the document include: • Criteria of acute MI, including identification of intracoronary thrombus by angiography or autopsy • Information on elevations of cardiac troponin levels from myocardial injury • Definition of MI types 1, 2, 3, 4a, and 4b • ST-segment elevation criteria that are age- and sex-specific • Tabulation of MI types with multiples of the 99th percentile of troponin values • Definition of reinfarction, recurrent MI, and silent MI. “There has been some confusion about how to define MI, because the new biomarkers are so sensitive that they are seen in many conditions besides MI, thus a new way to put the new biomarkers into perspective was needed,” said Robert O. Bonow, MD, a member of the Global Myocardial In-

farction Task Force and spokesperson for the AHA. Dr Bonow is the Goldberg Distinguished Professor of Cardiology, Vice Chairman of the Department of Medicine and Director of the Center for Cardiovascular Innovation at Northwestern University Feinberg School of Medicine, Chicago, IL. Dr Bonow noted the possible concern of the overdiagnosis of MI, because the high-sensitivity biomarkers could be elevated in other conditions, such as HF or cardiomyopathies, where there may be a steady lowgrade, long-term release of troponin. In contrast, a suspected MI should have a pattern of troponin over time, where it increases and then decreases.

The Third Definition of MI will also be useful after PCI or CABG, because the standardized definition for the postprocedure level of troponin will help to distinguish between a true complication of the procedure and a standard type of change that occurs in the heart muscle after blood flow is restored.

In addition, this definition is important epidemiologically, stated Dr Bonow, so “good data can be developed in the United States and globally for the prevalence of MI,” and to help identify whether strategies to prevent MI are effective.

The Third Universal Definition of MI is being published simultaneously by the European Heart Journal, Journal of the American College of Cardiology, Circulation, Global Heart, and Nature Reviews Cardiology. ■

Alternative Anticoagulants to Warfarin Reduce Vascular Risk in Patients with NVAF

By Wayne Kuznar Los Angeles, CA—Several new drugs have recently entered the market as effective alternatives to warfarin for the treatment of patients with nonvalvular atrial fibrillation (NVAF).

The safety of dabigatran was also similar among those with and without diabetes in the RE-LY trial, said Harald Darius, MD, PhD, Director of the

RE-LY: Dabigatran Effective for Patients with NVAF Relative to warfarin, the direct thrombin inhibitor dabigatran etexilate (Pradaxa) is effective in preventing stroke and other adverse vascular outcomes in patients with diabetes and NVAF, as well as in nondiabetic patients with NVAF, based on results of a subanalysis of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial.

Dabigatran is effective in preventing stroke and other adverse vascular outcomes in patients with NVAF with and without diabetes.

Department of Medicine, Vivantes Neukölln Medical Center, Berlin, Germany, at the 2012 American Heart Association meeting.

Patients with NVAF who have diabetes have up to double the risk for a stroke compared with nondiabetic patients.

RE-LY was a global, phase 3 clinical trial of 18,113 patients, investigating whether dabigatran was as effective as open-label warfarin that was titrated to a dose to achieve a target international normalized ratio (INR) of 2.0 to 3.0 for stroke prevention. The trial enrolled patients with NVAF and at least 1 other known risk factor for stroke. Patients were followed for a minimum of 1 year.

Of the 18,113 patients, 4221 (23%) had diabetes on enrollment. This subanalysis compared the efficacy of dabigatran 150 mg twice daily or 110 mg

twice daily versus warfarin in patients with and without diabetes in the NVAF population (the 110-mg twicedaily dose is not approved by the US Food and Drug Administration [FDA]).

Patients with diabetes had a higher prevalence of vascular disease than those without diabetes, including hypertension, coronary artery disease, and peripheral vascular disease.

In the diabetic patients who were randomized to warfarin, INR was not as well controlled as in those without diabetes: the median time in the therapeutic range was 65% for patients with diabetes versus 68% for nondiabetics.

Nevertheless, among patients with NVAF, those with and without diabetes Continued on page 9

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DECEMBER 2012

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CVD Management Alternative Anticoagulants... Continued from page 8 derived similar relative benefits from dabigatran 150 mg or 110 mg compared with warfarin, reported Dr Darius.

The risk reduction of stroke and systemic embolism with dabigatran 150 mg twice daily relative to warfarin was 34% in patients without diabetes and 38% in those with diabetes.

The rates of ischemic stroke, vascular death, and death were all similarly reduced in the dabigatran arm relative to the warfarin arm in patients with and without diabetes.

Compared with nondiabetics, patients with diabetes had a 44% higher risk of major bleeding (P <.001), but only a nonsignificant lower increase in intracranial bleeding risk; no significant differences were seen in bleeding events between dabigatran and warfarin.

ROCKET AF Study: Rivaroxaban Also Effective in Patients with Diabetes and NVAF In the ROCKET AF trial, the relative efficacy and safety of rivaroxaban (Xarelto) was similar to warfarin in patients with and without diabetes, supporting its use as an alternative to warfarin for stroke prevention in patients with diabetes and NVAF, said Jonathan L. Halperin, MD, Robert and Harriet Heilbrunn Professor of Medicine at Mount Sinai School of Medicine, Director of Clinical Cardiology Services at the Zena and Michael A. Wiener Cardiovascular Institute at the Mount Sinai Medical Center, New York City.

More than 14,000 patients with NVAF were enrolled in ROCKET AF, of whom 5635 had diabetes. In patients with diabetes, the rates of primary events with rivaroxaban versus warfarin were 1.59 versus 2.15 per 100 patient-years, respectively; these were similar to the rates in patients without diabetes. The same was true for the rates of ischemic stroke and systemic embolism.

The rates of any major or nonmajor clinically relevant bleeding in patients with diabetes who received rivaroxaban were similar to those receiving warfarin, with a trend toward less frequent intracranial hemorrhage with rivaroxaban.

Apixaban Newest Therapy for NVAF At the 2012 European Society of Cardiology meeting, researchers presented a secondary analysis of data from the clinical trial ARISTOTLE, which showed that the oral factor Xa inhibitor apixaban (Eliquis) reduced the risk of stroke and systemic embolism by 21%, the risk of mortality by 11%, and the risk for bleeding by 31% relative to warfarin in patients with NVAF. The secondary analysis also looked at renal impairment in the pa-

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tient population, showing that patients with the greatest renal impairment had the most benefit with apixaban relative to warfarin, because of the higher risk of bleeding associated with the latter drug.

On December 28, 2012, the FDA approved apixaban for the risk reduction

of stroke and systemic embolism in patients with NVAF based on the safety and efficacy data from ARISTOTLE that showed fewer stroke events and reduced bleeding in patients taking apixaban compared with warfarin.

Apixaban was not studied in patients with prosthetic heart valves or

in patients with atrial fibrillation that is associated with a heart valve problem. These patients should therefore not use this medication. As with other FDA-approved anticoagulants, bleeding is the most serious risk with apixaban, although the incidence is lower than with warfarin. ■

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VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

9

Emerging Therapies

GLP-1 Agonism Holds Promise for Preventing... the risk of major CV events is missing, said Jorge Plutzky, MD, Director, Vascular Disease Prevention Program, Brigham and Women’s Hospital, Harvard Medical School, Boston.

As many as 80% of patients with type 2 diabetes will develop and possibly die from macrovascular disease.

Even impaired glucose tolerance increases the risk for atherosclerosis and death. “By the time that type 2 diabetes is diagnosed, there are already changes that are manifest in the vasculature,” Dr Plutzky said.

Although lower levels of hemoglobin A1c levels were associated with a lower risk of mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, this study also showed that intensive glucose lowering increased 5-year mortality compared with conventional glucose lowering. As for macrovascular disease, “there is conflicting evidence that achievement of glycemic control with antidiabetic therapy is associated with reductions in CV morbidity and mortality,” said Jaime A. Davidson, MD, FACP, FACE, President of Endocrine and Diabetes Associates of Texas, and Clinical Professor of Medicine, University of Texas Southwestern Medical School, Dallas.

Evidence from the United Kingdom Prospective Diabetes Study (UKPDS) suggests, however, that early diagnosis and intensive glucose control from the start are keys to long-term risk reduction in diabetes, said Dr Davidson.

Long-term follow-up of the UKPDS

cohort demonstrated a significant 15% to 33% reduction in the rate of MI within the intensive glycemic control group compared with the conventionally treated group.

“By the time that type 2 diabetes is diagnosed, there are already changes that are manifest in the vasculature.”

—Jorge Plutzky, MD Some common oral therapies for type 2 diabetes have adverse CV effects, said Dr Davidson, including the sulfonylureas and thiazolidinediones.

In particular, sulfonylureas that are not selective for KATP channels may have negative CV effects. In addition, sulfonylureas increase the risk for severe hypoglycemia, which is associated with increased risk for death.

Potential for CV Protection, Outcomes Studies in Progress Recent regulatory obligations for all diabetes medications include excluding excess risk in phase 2/3 clinical trials, especially in high-risk populations, that include predefined CV end points with independent blind adjudication being mandatory, said Benjamin Scirica, MD, MPH, of the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital.

Until now, guideline recommenda-

tions have been made in high-risk patients based on CV end points in clinical studies that enrolled less than 1000 patients. “We need better data in more patients and over a longer follow-up to appropriately evaluate the risks and benefits of antidiabetic agents,” he said. “Surrogate end points are not sufficient for such a prevalent and morbid disease.”

The incretin GLP-1 is secreted by enteroendocrine L cells. GLP-1 receptors are expressed at multiple sites in the body. Normal GLP-1 secretion is stimulated by food intake. Activation of GLP-1 receptors in the central nervous system promotes satiety and the reduction of appetite, and their activation in the pancreas enhances insulin secretion and insulin sensitivity. However, the release of GLP-1 is no longer intact in persons with type 2 diabetes, said Dr Plutzky.

GLP-1 receptors are also prominent in cardiac tissues. In animal models of cardiac function, GLP-1 receptor agonism leads to vasodilation, increased myocardial glucose uptake, attenuation of ischemic injury, limitation of infarct size, and improvements in stroke volume, cardiac output, ejection fraction, and systemic resistance.

The half-life of GLP-1 in circulation is less than 2 minutes, because it is rapidly degraded by the dipeptidyl peptidase (DPP)-4 enzyme.

In humans, incretin-based therapies in the form of GLP-1 receptor agonists and DPP-4 inhibitors have improved

Continued from page 1

peripheral blood flow in short-term studies in patients with type 2 diabetes, improved left ventricular function and short-term exercise capacity in patients

“We need better data in more patients and over a longer follow-up to appropriately evaluate the risks and benefits of antidiabetic agents.”

—Benjamin Scirica, MD, MPH with class II to III heart failure, and decreased the incidence of arrhythmias and improved glycemic control after coronary artery bypass graft surgery.

The potential for CV protection with the use of DPP-4 inhibitors and GLP-1 agonists is being tested in clinical studies. Incretin modulators and other antidiabetes agents are being studied in studies of CVD outcomes in more than 120,000 patients with type 2 diabetes. ■

CVD Management

PHS II: Cardiovascular Events in Men Not Reduced with Multivitamins US adults spend approximately $5 billion annually on supplements

By Mary Mosley Los Angeles, CA—Taking a multivitamin did not reduce myocardial infarction (MI), stroke, or cardiovascular (CV) death in older men in the first large-scale, long-term randomized controlled trial to address this question to date.

The results of the Randomized Trial of a Multivitamin in the Prevention of a Cardiovascular Disease in Men: The Physicians’ Health Study II (PHS II) were presented at the 2012 American Heart Association meeting by Howard D. Sesso, ScD, MPH, Associate Epidemiologist, Brigham and Women’s Hospital, and Associate Professor of Medicine, Harvard Medical School, and were published simultaneously (Gaziano JM, et al. JAMA. 2012;308: 1871-1880).

More than 33% of US adults take a

10

multivitamin supplement, spending approximately $5 billion annually, many with the notion that this may improve their CV health, making this an important study question. There is also concern among physicians that patients will take a multivitamin for a perceived CV benefit, but not take their prescribed medications.

Basic research has suggested that some of the components of a multivitamin may reduce the risk of CV disease, but observational studies have not demonstrated an association.

This PHS II study included 14,641 male, mostly white, physicians (aged ≥50 years) in the United States, who were randomized to a multivitamin or to placebo and were followed for a mean of 11.2 years. The adherence ranged from 77% at year 4 to 67% at

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

DECEMBER 2012

study end. A total of 2757 deaths occurred during follow-up and 1 major CV event was reported in 1732 participants.

“Except for age, no differences were seen in any subgroup for the effect of the multivitamin on CV events.”

—Howard D. Sesso, ScD, MPH The incidence of the combined primary end point of nonfatal MI, nonfatal stroke, and CV death was similar in both groups. A similar lack of effect was seen for total MI and stroke. A nonsignificant reduction was seen for CV death (hazard ratio [HR], 0.95) and for total mortality (HR, 0.94).

However, there was a 39% reduction in MI death, which had borderline significance (27 events in the active arm, 43 in the placebo arm; P = .048).

The study participants were fairly healthy at the start of the study, and many exercised, took aspirin, and had good diets.

“Except for age, no differences were seen in any subgroup for the effect of the multivitamin on CV events,” said Dr Sesso. In participants aged >70 years, there were fewer primary outcome events, which had a borderline significance (P = .04).

“The main reason for taking a multivitamin still remains to prevent vitamin and mineral deficiency,” said Dr Sesso, “however, the decision to take a multivitamin should also consider its modest beneficial effects on cancer.” ■

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Emerging Therapies

CVD Pipeline: Novel Approaches... of patients with familial hypercholesterolemia. In addition to statin therapy and ezetimibe, a once-weekly subcutaneous injection of 200 mg mipomersen reduced LDL-C by 28% compared with 5.2% with placebo at 28 weeks (2 weeks after the final dose). The LDL-C reduction continued to increase over time.

“This is the beginning of personalized therapy,” according to Dr Kastelein. Applying the approach of personalized medicine in CVD, drugs such as mipomersen have the potential to be used for the highest-risk patients, which are expected to prove cost-effective and confer a positive risk-benefit ratio in this patient population.

ApoB mRNA antisense drugs work by decreasing the synthesis of apoB, a component of atherogenic lipoproteins and a central player in the pathogenesis of atherosclerosis. ApoB synthesis is inhibited by destroying the RNA for apoB in the liver cell. In contrast, currently available drugs lower the concentration of apoB by increasing its clearance.

MTP Inhibitors The inhibition of the MTP limits the secretion of cholesterol and triglycerides from the intestine and the liver.

This results in lower levels of chylomicrons and very-low-density liproprotein, and leads to lower levels of LDL-C, total cholesterol, and triglycerides.

BMS-201038/AEGR-733. In a phase 2, open-label study in patients with familial hypercholesterolemia and high LDL-C levels, in addition to optimal lipid-lowering therapy, the use of 1-mg/kg dose of BMS-201038/ AEGR-733 reduced LDL-C by approximately 50%, triglycerides by approximately 65%, and non–high-density lipoprotein cholesterol (HDL-C) by 60% (Cuchel M, et al. N Engl J Med. 2007;356:148-156). Despite the proof of concept, a limiting factor to be ad-

dressed is the side effect of diarrhea that results from blocking chylomicrons in the intestine. Other studies with this compound are under way or were recently completed.

“This is the beginning of personalized therapy,” according to Dr Kastelein.

Applying the personalized medicine approach in CVD, drugs such as mipomersen have the potential to be used for the highest-risk patients.

PCSK9 Inhibitors A 20-week study of SAR236553 (also known as REGN727; Sanofi) showed a rapid reduction in LDL-C of approximately 60% at week 2 and sustained at week 12, with a 150-mg subcutaneous injection of SAR236553 every 2 weeks in patients with familial hypercholesterolemia. Further study with this compound is ongoing.

AMG 145 (Amgen) is an investigational monoclonal inhibitor of PCSK9 currently in phase 2 clinical trials. The inhibitor compound binds to PCSK9, a circulating protein produced by the liver, and prevents it from binding to LDL receptors in the liver, allowing the LDL receptors to take up and remove LDL-C. Some trials, including Treating to New Targets and the ongoing ILLUMINATE trial, are now measuring PCSK9 levels in the population with familial hypercholesterolemia, Dr Kastelein noted; they also investigate the suitability of PCSK9 inhibitors in patients with acute coronary syndromes because of the rapid reduction of LDL-C levels with these agents.

Continued from page 1

New Approaches to HDL

CETP Inhibitors Anacetrapib (Merck) and evacetrapib (Eli Lilly) are 2 cholesterol ester transfer protein (CETP) inhibitors under development. These potent CETP inhibitors modify nearly all lipoproteins in the right direction, reducing LDL (by approximately 40%), non-HDL, apoB, lipoprotein(a), and particle numbers, and raising HDL (by approximately 138%).

No increase in cardiovascular events was seen with anacetrapib in the longterm Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) safety trial.

The Randomized Evaluation of the Effects of Anacetrapib Through LipidModification (REVEAL) Heart Protection Study (HPS)-3 Thrombolysis In Myocardial Infarction (TIMI)-55 trial, which includes approximately 30,000 patients in the United States, Europe, and Asia with occlusive arterial disease, is comparing anacetrapib 100 mg versus placebo, in addition to atorvastatin, to determine its effect on the primary outcome of coronary death, myocardial infarction, or coronary revascularization. Results are expected to be reported in late 2016 or early 2017.

With evacetrapib, similar LDL reductions were seen (approximately 36% with the 500-mg dose and approximately 22% with the 100-mg dose), as well as increases in HDL (129% with the 500-mg dose and 95% with the 100-mg dose).

ApoA1-Based Strategies A number of apoA1-based therapies are currently being developed.

APL-180 (Novartis) is an apoA1 mimetic, which is an artificially constructed part of apoA1.

A full-length ApoA1 (Cerenis Ther-

apeutics) is another drug in this class currently under development.

A delipidation approach to create pre-beta HDL (HDL Therapeutics) is generated by removing lipids from mature HDL to create immature HDL to be infused back into the patient with familial hypercholesterolemia. A small proof-of-concept study showed that this approach reduced total atheroma volume as assessed by intravascular ultrasound imaging. “Selective delipidation removes the cholesterol and restores it to pre-beta HDL,” said Dr Kastelein; he anticipates this approach will be tested in larger trials.

“In the next 5 years, we will prove or disprove that additional LDL-lowering with agents other than statins is effective, and whether or not the HDL hypothesis is true.”

—John J.P. Kastelein, MD, PhD

The SUSTAIN trial is a phase 2b clinical study of RVX-208, an apoA1inducer (Resverlogix). Results from this trial of 176 patients were announced by the company just after the ESC Congress. At 24 weeks, RVX-208 increased HDL-C levels, the study primary end point, and increased apoA1 and large HDL particles, the secondary end points.

“In the next 5 years, we will prove or disprove that additional LDL-lowering with agents other than statins is effective, and whether or not the HDL hypothesis [with the infusion of HDL] is true,” said Dr Kastelein, referring to trials including IMPROVE IT with ezetimibe; HPS-2, with nicotinic acid; and REVEAL, with CETP inhibitors. ■

RELAX-AHF: Serelaxin Reduces Dyspnea in Acute Heart Failure

By Mary Mosley Los Angeles, CA—Reductions in dyspnea and cardiovascular (CV) death, and improvement in the signs and symptoms of congestion and worsening heart failure (HF), in the RELAXAHF study were attributed to serelaxin, a novel investigational agent for the treatment of acute HF, which was compared with placebo plus conventional therapy.

“All of the benefits were achieved with less use of intravenous diuretics and less use of other vasoactive therapies,” by approximately 25%, said co-

primary investigator John R. Teerlink, MD, FACC, FAHA, Professor of Clinical Medicine, University of California, San Francisco, and San Francisco VA Medical Center, at the 2012 meeting of the American Heart Association. In addition, “serelaxin was well tolerated and safe,” Dr Teerlink said.

Serelaxin is the recombinant form of human relaxin, which is present in men and women and is elevated throughout pregnancy, where it mediates “marked improvements in cardiac, arterial, and renal function—the

changes desired in acute heart failure,” said Dr Teerlink. Relaxin also has antiischemic, anti-inflammatory effects.

A total of 1161 patients (mean age, 72 years) were hospitalized for HF and were randomized within an average of 8 hours of presenting for a 48-hour infusion of intravenous serelaxin (30 mcg/kg daily) or to placebo plus usual therapy for HF. All patients had dyspnea, objective signs of congestion, normal-to-elevated systolic blood pressure, and mild-to-moderate renal dysfunction.

Mixed Results Dyspnea relief, the first coprimary end point, was significantly improved with serelaxin, with a 19.4% increase in the area under the curve (AUC) from baseline through day 5 compared with placebo (P = .075). The mean difference between the 2 arms was 448 mm per hour from baseline as assessed with the visual analog scale.

The second coprimary end point of dyspnea relief as measured by the Likert scale showed improvement at hours 6, 12, and 24, but did not reach signifiContinued on page 12

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DECEMBER 2012

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

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Emerging Therapies

First-in-Class Angiotensin Receptor Neprilysin Inhibitor

Promising in Heart Failure with Preserved Ejection Fraction

By Mary Mosley Munich, Germany—The first-in-class agent LCZ696, an angiotensin receptor neprilysin inhibitor, was associated with greater reductions of several measures that are associated with worse outcomes in patients who have heart failure with preserved ejection fraction (HFpEF) compared with the angiotensin receptor blocker (ARB) valsartan.

These results from the phase 2 PARAMOUNT study were presented

by Scott D. Solomon, MD, Director of Noninvasive Cardiology at the Brigham and Women’s Hospital, Boston, and Professor of Medicine at Harvard Medical School, at the 2012 European Society of Cardiology Congress.

“LCZ696 in the PARAMOUNT study is the first compound to show both reductions in NT-proBNP and left-atrial size in HFpEF patients, each a powerful predictor of outcomes in heart failure,” said Dr Solomon. “The favorable effects of LCZ696 seen in patients with HFpEF in PARAMOUNT are encouraging, and further testing of this agent in this patient population is warranted.” LCZ696 is

“LCZ696 in the PARAMOUNT study is the first compound to show reductions in both NT-proBNP and left-atrial size in HFpEF patients, each a powerful predictor of outcomes in heart failure. The favorable effects of LCZ696 seen in…PARAMOUNT are encouraging.”

—Scott D. Solomon, MD

also being studied as an antihypertensive agent.

Approximately 50% of patients with heart failure have preserved ejection fraction compared with reduced ejection fraction, but no treatment has been shown to reduce morbidity and mortality in this population with HFpEF. The PARAMOUNT study, which was conducted in 13 countries, randomized 308 patients (mean age, 70 years) to LCZ696 (50 mg twice daily for week 1, doubled to 100 mg twice daily) or to the ARB valsartan (40 mg twice daily for week 1, then doubled to 80 mg twice daily) to determine the effect on the natriuretic peptide NTproBNP, a marker of cardiac wall stress that increases in patients with heart failure. Therapy with an angiotensinconverting enzyme inhibitor or an ARB was discontinued 1 day before randomization.

A 23% reduction in NT-proBNP, the primary end point, was found with LCZ696 compared with valsartan at 12 weeks (P = .005). This reduction was evident at week 4 and was sustained to week 36, but at 15% it was not a signif-

icant difference. The treatment effect was similar across all predefined subgroups and favored LCZ696, except in patients with diabetes, in whom there was a significantly greater effect with the novel agent.

LCZ696 reduced the left-atrial size, which indicates improvement in leftatrial remodeling. There were significant improvements in left-atrial width, left-atrial volume, and left-atrial volume index at 36 weeks.

After 36 weeks, the extended followup period, there was improvement in the New York Heart Association class in the patients taking LCZ696 compared with those taking valsartan.

The change in blood pressure at 12 weeks and at 36 weeks correlated poorly with the change in NT-proBNP, and the reduction in this marker remained significant between groups after adjustment for blood pressure.

“The favorable effects of LCZ696 seen in patients with HFpEF in PARAMOUNT are encouraging, and further testing of this agent in this patient population is warranted,” said Dr Solomon. ■

RELAX-AHF: Serelaxin Reduces Dyspnea... Continued from page 11 cance, because it did not show moderate or marked improvement at each of the 3 time periods as prespecified.

CV death or rehospitalization resulting from HF or renal failure through day 60, the first secondary end point, was not different between groups; the improvement in CV death was offset by a slight increase in rehospitalization rates. The number of days alive and out of hospital showed an overall increase of 0.6 days with serelaxin, but did not reach significance (P = .37).

“We were able to show a 37% reduction in cardiovascular death up through day 180,” said Dr Teerlink, “with a number needed to treat of 29 patients to prevent 1 cardiovascular death,” with serelaxin (P = .028). Allcause mortality through day 180 was reduced by 37%, with a number needed to treat of 25 patients (P = .020).

Marked reductions in congestions were seen through day 2, and “early and persistent reductions in worsening of heart failure,” said Dr Teerlink; by day 14, there was a significant 30% reduction in the risk of worsening HF in

12

the patients treated with serelaxin.

There were reductions in the length of care in the intensive care unit by approximately 0.33 days, and in the length of the initial hospitalization by approximately 0.9 days (P = .039).

“While we did not see a reduction in rehospitalization in this trial, the significant reductions in worsening of heart failure and death are encouraging signals that we can change the course of this devastating disease.”

—Marco Metra, MD

“While we did not see a reduction in rehospitalization in this trial, the significant reductions in worsening of heart failure and death are encouraging signals that we can change the course of this devastating disease,”

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DECEMBER 2012

said coprincipal investigator Marco Metra, MD, Associate Professor of Cardiology, Section on Cardiovascular Diseases, University of Brescia, Italy.

Clinical Implications “There is little doubt that this agent was beneficial, and the totality of the evidence (the breathlessness measurement, signs and symptoms, the use of other therapies) quite clearly indicates that this drug is doing something good in terms of relief of symptoms and congestion,” commented John J. McMurray, MD, Professor of Cardiology, University of Glasgow, Scotland, the designated discussant of the trial.

Dr McMurray said that there will be discussions about the meaning of the change in the AUC and whether a single trial is sufficient for regulators to approve a therapy. “This trial is paradigm-shifting at least in making us think about what is going on in acute heart failure, and what we are trying to do for this condition,” he noted.

The lack of benefit for rehospitalization for HF or for renal failure is a concern, Dr McMurray added, because it

is unusual to see a treatment for HF that improves survival but not hospitalization. Another concern is the robustness of the mortality improvement,

“The totality of the evidence…quite clearly indicates that this drug is doing something good in terms of relief of symptoms and congestion.”

—John J. McMurray, MD

noting that with such small numbers, the benefit may not be reliable, and that if only 2 deaths moved from the serelaxin arm to the placebo arm, the finding would no longer be significant.

If the findings in this study are replicated, “it would be an extraordinary advance in the management of acute heart failure, for which we have no disease-modifying or life-saving therapies,” Dr McMurray concluded. ■

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Obesity/Overweight

Belly Fat Triples CV and All-Cause Mortality... had normal-weight central obesity, as defined by a high WHR. The risk for CV death was 2.75 times higher and the risk for all-cause death was 2 times higher (hazard ratio, 2.08) in persons with normalweight central obesity than in those with a normal weight and normal WHR. Persons with normal-weight central obesity had the highest risk of CV and all-cause deaths of the 6 subgroups studied. “From a public health point of view, this is very important,” Dr Sahakyan noted.

In obese persons with a normal WHR, the risk of CV mortality was 1.41 times higher compared with 2.34 times higher in obese persons with a high WHR, both compared with people with normal weight and normal WHR. Previous studies have shown that central obesity is bad, Dr Sahakyan pointed out, but “this is the first study to show that even if a person has normal weight but with central adiposity, that person is at a higher risk of death.”

What to Look for Dr Sahakyan and colleagues used National Health and Nutrition Examination Survey III data from 12,785 adults and matched baseline data to the National Death Index to obtain mortal-

“This is the first study to show that even if a person has normal weight but with central adiposity, that person is at a higher risk of death.”

—Karine Sahakyan, MD, PhD, MPH

ity status. People with cancer, chronic obstructive pulmonary disease, or those who were underweight were excluded.

Over the long follow-up (median, 14.3 years), 2562 deaths were reported; of these, 1138 were CV related.

Participants were categorized by

normal, overweight, and obese BMI and were further categorized by WHR using the World Health Organization criteria (normal, <0.85 in women and <0.90 in men; high, ≥0.85 in women and ≥0.90 in men).

Current guidelines do not include patients with normal BMI, so there is no requirement for lifestyle modification or measurement of WHR in these patients, Dr Sahakyan said. “Thus, these patients can be overlooked.”

Clinicians should pay greater attention to patients with normal-weight central obesity, including risk stratification and lifestyle interventions.

The WHR should be measured in all persons, even those with normal weight, she said, and she cautioned against relying on a visual assessment of fat distribution, which is very subjective.

Although the reasons that belly fat increases the risk of death are unknown and are being studied, Dr Sahakyan suggested 3 possible explanations. Visceral fat accumulation is a risk factor for

Continued from page 1

diabetes and other CV risk factors, and inflammation is common among all of these. The amount of fat on the hips and legs and the muscle mass on the legs, which are known to be protective, are reduced in people with normal-weight central obesity compared with overweight and obese people. ■

Behavioral Interventions Can Result in Weight Loss

By Wayne Kuznar Boston, MA—Intensive behavioral interventions can be successful in helping overweight patients achieve modest weight loss, said Lawrence J. Appel, MD, MPH, Director, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, MD, at the 2012 Cardiometabolic Health Congress.

Even small amounts of weight loss have beneficial effects on cardiovascular (CV) risk, including reducing the risk of developing diabetes or hypertension and improving the lipid profile of patients with dyslipidemia.

Components of Behavioral Intervention The patient’s readiness to participate in behaviorial intervention to effect weight loss should be assessed.

Candidates for weight-loss intervention are those who are in the contemplation, preparation, and action stages of behaviorial change. For these patients, a weight-loss goal of 5% through behavioral intervention is achievable, said Dr Appel. The intervention should incorporate: • Reduced caloric intake: consumption of a health dietary pattern based on the DASH (Dietary Approaches to Stop Hypertension) diet • Exercise for at least 180 minutes weekly • Counseling patients to monitor their

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weight, caloric intake, and duration of exercise regularly.

For the intervention to have the highest chance of success, realistic goals for target weight must be set.

“Aim for a healthier weight, not ideal weight,” advised Dr Appel. “Promote slow, incremental progress to the goal.” The initial 6-month weight-loss goal should be 1 to 2 lb weekly until a weight loss of 5% to 10% is achieved; the subsequent goal should be maintenance of the weight loss.

“Aim for a healthier weight, not ideal weight. Promote slow, incremental progress to the goal.”

—Lawrence J. Appel, MD, MPH

A loss of 1 to 2 lb weekly is achievable and corresponds to a caloric deficit of approximately 500 to 1000 kcal daily. This rate of weight loss is safe and does not require close monitoring, with the exception of patients with diabetes. In contrast, rapid weight loss can have complications, Dr Appel pointed out.

Weight Loss in Clinical Studies In studies of behavioral weight-loss

intervention, patients who undertake lifestyle intervention typically experience a “check mark” pattern of weight loss, which is weight loss followed by regain, although occasionally the initial weight loss is sustained. Patients in control groups in such studies have a variable pattern of weight change: some will gain weight, others will lose weight, or some will have no change in body weight.

“Mean weight loss [in active intervention groups] of 3% to 7% of initial body weight is typical, but interindividual variability is high,” said Dr Appel.

A trial called POWER-UP, which was carried out at the University of Pennsylvania, demonstrated that primary care physicians working in their own practices can induce clinically significant weight loss in their obese patients, and that medical assistants could contribute to weight management efforts. The 2-year trial compared 3 interventions in 390 obese people: usual care (quarterly visits to a primary care physician), brief lifestyle counseling, or enhanced lifestyle counseling.

The patients in the brief lifestyle counseling group had quarterly visits to their primary care physician and brief visits with a medical assistant approximately every month. The enhanced lifestyle counseling group had the same brief lifestyle counseling with

DECEMBER 2012

the addition of the use of meal replacements or weight-loss medications.

At 2 years, the usual-care group lost a mean of 1.7 kg, the brief lifestyle counseling group lost a mean of 2.9 kg, and the enhanced lifestyle counseling group lost a mean of 4.6 kg (significantly more than the usual-care group; P = .003). At month 12, twice as many patients in the enhanced lifestyle counseling group lost at least 5% of their body weight than patients in the usual-care group (47.3% vs 24.6%, respectively; P <.001), an advantage that was lessened but still significant at month 24 (34.9% vs 21.5%, respectively; P = .027). The percentage that lost at least 5% of body weight was also significantly greater at months 12 and 24 in the enhanced lifestyle counseling group versus the brief lifestyle counseling group.

The Centers for Medicare & Medicaid Services now covers intensive behavioral weight-loss counseling, noted Dr Appel.

In Johns Hopkins’ POWER trial, weight loss at 24 months was nearly equal between a group assigned to remote support versus in-person delivery of weight-loss interventions. Approximately 40% of both groups lost at least 5% of body weight, and approximately 20% in each group lost at least 10% compared with 19% and 9%, respectively, of a control group. ■

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13

Hypertension

New Hypertension Guidelines Will Be Strictly Evidence-Based

By Wayne Kuznar Boston, MA—Expect new national guidelines for the management of hypertension (HTN) to back away from recommending a target blood pressure (BP) of <130/80 mm Hg in patients with diabetes and/or chronic kidney disease (CKD), according to George Bakris, MD, Professor of Medicine at the University of Chicago and Director of the Comprehensive Hypertension Center, Chicago, IL, who discussed the new guidelines at the 2012 Cardiometabolic Congress.

Although nearly all current HTN guidelines recommend <130/80 mm Hg as a target in patients with diabetes or CKD to reduce the risk for cardiovascular (CV) events and slow the progression of nephropathy, there is no evidence to support this recommendation, he said.

The update to JNC-7 (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) guidelines that were issued nearly a decade ago has been anticipated for some time. The initial recommendations will address 3 main questions: • Does initiating antihypertensive drug therapy at specific BP thresholds improve outcomes in adults with HTN? • Does treatment with antihypertensives to a specified BP goal lead to improved outcomes in adults?

• In adults with HTN, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes?

Of 16 current clinical practice guidelines for the prevention of CV disease

with level of evidence recommendations, only 9% had class I level A evidence to support statements made in the guidelines. “The rest of it was ‘professional opinion’ or ‘some evidence,’” said Dr Bakris.

“The new guidelines are going to be really different from what you’re used to seeing. There will be a statement, and then there will be references to defend the statement.”

—George Bakris, MD The methods used for the new guidelines meet many of the new Institute of Medicine standards for systematic reviews. The guidelines will be strictly evidence-based, focusing on randomized controlled clinical trials, and will grade evidence statements.

Meta-analyses will not be part of the evidence base.

Evidence quality will range from high (well-designed and conducted randomized controlled trials [RCTs]) to low (RCTs with limitations; observational studies with major limitations), and recommendation strength will be strong (A), moderate (B), weak (C), against (D), expert opinion (E), or no recommendation (N).

“The new guidelines are going to be truly different from what you’re used to seeing,” Dr Bakris noted. “There will be a statement, and then there will be

references to defend the statement.”

For initial therapy, “We can probably get by with a single agent for patients with blood pressure <160/100 mm Hg if they adhere to lifestyle recommendations. If they don’t, you’re going to need 2 or 3 agents,” said Dr Bakris.

“Even in the ALLHAT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack] study of patients with stage 1 hypertension, the average number of drugs required to achieve goal blood pressure was 2.1.”

He continued, “As initial therapy, don’t be afraid to start with combinations. If the patient is at >160/100 mm Hg, you need to start with combination therapy, and you have a panoply of combination therapies to pick from.”

In Diabetes, No Support for <130/80 mm Hg Another near-universal recommendation is the target of <130/80 mm Hg in patients with CKD and/or diabetes, “but the evidence does not support <130/80 mm Hg if you carefully look at it,” Dr Bakris said.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial failed to support a systolic BP (SBP) target of <120 mm Hg compared with <140 mm Hg with the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, and CV death.

CV outcomes from the diabetes subgroup in the International Verapamil SR-Trandolapril trial also failed to show better outcomes in patients randomized to a goal SBP of <130 mm Hg compared with a goal SBP of 130 to 140 mm Hg.

“Clearly, there’s no good evidence to support <130 mm Hg. There’s a trunkload of evidence to support <140 mm Hg,” Dr Bakris advised.

Lower Targets Not Beneficial in CKD Three RCTs of BP targets in patients with CKD, which included a total of 2272 participants, have been conducted.

“All failed to show a benefit of the lower level of blood pressure,” said Dr Bakris. None of these trials enrolled patients with diabetic nephropathy, so the optimal goal BP in this group is unknown, he added.

Finally, an examination of the Kidney Early Evaluation Program, a screening program of >16,000 persons at high risk of kidney disease started by the National Kidney Foundation, found no benefit to an SBP goal of <130 mm Hg in postponing dialysis for a mean follow-up of 2.8 years, and a diastolic BP of <60 mm Hg was associated with faster progression to endstage renal disease. <150/80 mm Hg Goal in the Elderly In the elderly, the goal BP in patients with uncomplicated HTN generally has been <140/90 mm Hg, but an SBP goal of 140 to 145 mm Hg is deemed acceptable. This target for elderly patients with HTN, however, is based on expert opinion rather than data from RCTs, which supports a goal of <150/80 mm Hg, concluded Dr Bakris. “It is unclear if target SBP should be the same in 65 to 79 year olds as in patients older than 80 years,” he said. ■

New Prognostic Markers in Hypertension Identified

By Mary Mosley Munich, Germany—New prognostic markers of hypertension were presented at the 2012 European Society of Cardiology Congress. Roland E. Schmieder, MD, Head of the Clinical Unit of Hypertension and Vascular Medicine, Erlangen University Hospital in Nürnberg, Germany, discussed the results of 3 studies that “identified prognostic markers in hypertensive patients.” These markers include blood pressure (BP) variability, low testosterone levels, and treatment-resistant hypertension.

BP Variability An analysis by a team from the University of California that involved 20,952 patients in the lipid-lowering TNT, IDEAL, and CARDS trials showed

14

that visit-to-visit BP variability (ie, control of BP over months and years) was a significant risk factor for stroke and coronary events. The statin treatment effect in each trial was not affected or mediated by the adjustment for systolic BP or diastolic BP variability or other BP parameters.

“These trials more accurately reflect daily real-life practice” of BP control, said Dr Schmieder, because the protocols did not dictate BP management.

“Epidemiologic studies show that total testosterone is a cardiovascular [CV] risk predictor,” said Dr Schmieder.

of testosterone was associated with a higher risk of major CV events. A 2.5times higher risk of CV events was found in the men with hypertension who were in the lowest tertile of testosterone (<4.0 ng/mL) compared with the highest tertile (>4.9 ng/mL).

“This was an independent determinant of risk,” said Dr Schmieder, independent of age, BP values, metabolic profile, antihypertensive therapy, and statins. A total of 29 events occurred in the 275 hypertensive men (mean age, 52 years) during the 43-month study.

Low Testosterone Levels In a prospective study by a team of researchers from the Medical School of Athens University, Greece, a low level

Treatment-Resistant Hypertension Treatment-resistant hypertension was an independent predictor of risk in a single-center study of 2345 patients

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

DECEMBER 2012

with uncomplicated hypertension (mean age, 58 years) that was conducted by another group of researchers from the Medical School of Athens University, Greece.

The 18.4% of patients who had treatment-resistant hypertension had a much higher rate of CV complications, such as coronary artery disease (4.7% vs 2.1%, respectively), stroke (1.9% vs 0.7%, respectively), and atrial fibrillation (6.1% vs 2.7%, respectively), and the composite of these (11.9% vs 5.5%, respectively) compared with patients with hypertension that was not treatment resistant.

On average, the treatment-resistant hypertension group was older by 5 years, had larger waist circumference and greater body mass index, and more patients had diabetes. ■

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Lipid Management

Lipid Therapy Update: HDL Therapies Falling Short, Promising LDL Agents, 2 Potential Treatments for Familial Hypercholesterolemia

By Wayne Kuznar Boston, MA—High-density lipoprotein (HDL) cholesterol as a target for treatment in patients with dyslipidemia remains an unfulfilled promise.

Christie Ballantyne, MD, Chief, Section of Cardiology Research, and Chief of Cardiology at Baylor College of Medicine, Houston, TX, presented an update on HDL-raising therapies and other developments in pharmacotherapy for dyslipidemia at the 2012 Cardiometabolic Health Congress.

CETP Inhibitors A large randomized controlled clinical outcomes trial with dalcetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, was terminated early because of a lack of clinically meaningful efficacy. The planned follow-up was 4 years, but the trial was stopped early when it became apparent that dalcetrapib would have no effect on the primary efficacy measure—a composite of various cardiovascular outcomes.

Unlike with a previous CETP inhibitor torcetrapib, there were no safety concerns with dalcetrapib.

Lancet. 2012;380:572-580) showed no association between gene variants that are related exclusively to HDL cholesterol and the reduction in the risk of coronary heart disease (CHD).

“The gene that had the greatest im-

pact on HDL, endothelial lipase, had no impact on CHD,” he said. “There are 6 genes related to HDL metabolism that are associated with CHD, but all 6 of them also have some impact on triglycerides or LDL. So, it

really calls into a little more complexity to target HDL.” In addition, 2 studies expected to be reported in 2013 should offer some answers about the HDL hypothesis, said Dr Ballantyne. One study is testing an Continued on page 16

For your patients with type 2 diabetes who need more than A1C control, choose Levemir ® (insulin detemir [rDNA origin] injection)

24/7 GLUCOSE CONTROL MORE

Karen’s doctor said taking Levemir ® (insulin detemir [rDNA origin] injection) once-daily may get her the control she needs & more Low rates of hypoglycemia In 1 study, approximately 45% of patients in each treatment arm achieved A1C <7% with no hypoglycemic events within the last 4 weeks of observation.1 t A single major hypoglycemic event was reported in the 70-90 mg/dL group; no major hypoglycemic events in the 80-110 mg/dL group t Minor hypoglycemia rates were 5.09 (70-90 mg/dL) and 3.16 (80-110 mg/dL) per patient-year*

“These agents profoundly reduce low-density lipoprotein cholesterol along with raising HDL, so they won’t give us a clear answer with regard to the HDL hypothesis.”

—Christie Ballantyne, MD

Two other CETP inhibitors are under active investigation, said Dr Ballantyne. Anacetrapib increases HDL cholesterol by 138% compared with placebo and is being studied in the clinical outcomes trial known as Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification (REVEAL). Evacetrapib increases HDL cholesterol by 54% to 129% (vs –3% with placebo) and is also being tested in the clinical outcomes trial A Study of Evacetrapib in High-Risk Vascular Disease (ACCELERATE), which is in progress.

“These agents profoundly reduce low-density lipoprotein [LDL] cholesterol along with raising HDL, so they won’t give us a clear answer with regard to the HDL hypothesis,” said Dr Ballantyne.

A recent analysis of genome-wide association studies (Voight BF, et al.

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From a 20-week, randomized, controlled, multicenter, open-label, parallel-group, treat-to-target trial using a self-titration algorithm in insulin-naïve patients with type 2 diabetes, A1C ≥7% and ≤9% on OAD therapy randomized to Levemir® and OAD (1:1) to 2 different fasting plasma glucose (FPG) titration targets (70-90 mg/dL [n=121] or 80-110 mg/dL [n=122]). At study end, in the 80-110 mg/dL group, 55% of patients achieved goal (A1C <7%) with A1C decrease of 0.9%. The mean A1C was 7%.1

Covered on more than 90% of managed care plans2† hypoglycemia usually reflects the time action profile of the administered insulin formulations. Glucose monitoring is essential for all patients receiving insulin therapy. Any changes to an insulin regimen should be made cautiously and only under medical supervision.

Needles and Levemir ® FlexPen® must not be shared.

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Levemir ®. Adverse reactions associated with Levemir ® include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, rash and pruritus. Careful glucose monitoring and dose adjustments of insulin, including Levemir ®, may be necessary in patients with renal or hepatic impairment.

Levemir ® has not been studied in children with type 2 diabetes, and in children with type 1 diabetes under the age of six.

Indications and Usage Levemir ® (insulin detemir [rDNA origin] injection) is indicated to improve glycemic control in adults and children with diabetes mellitus.

Important Limitations of Use: Levemir ®isnotrecommendedforthetreatmentof diabeticketoacidosis.Intravenousrapid-actingor short-acting insulin is the preferred treatment for this condition.

Important Safety Information Levemir ® is contraindicated in patients hypersensitive to insulin detemir or one of its excipients.

Do not dilute or mix Levemir® with any other insulin solution, or use in insulin infusion pumps. Do not administer Levemir® intravenously or intramuscularly because severe hypoglycemia can occur.

Hypoglycemia is the most common adverse reaction of insulin therapy, including Levemir®. The timing of

Please see brief summary of Prescribing Information on adjacent page.

Needles are sold separately and may require a prescription in some states. *Minor=SMPG <56 mg/dL and not requiring third-party assistance.

On your iPhone®

†

Scan the QR code to download the NovoDose™ app to know how to optimally dose Levemir®

Intended as a guide. Lower acquisition costs alone do not necessarily reflect a cost advantage in the outcome of the condition treated because other variables affect relative costs. Formulary status is subject to change.

References: 1. Blonde L, Merilainen M, Karwe V, Raskin P; TITRATE™ Study Group. Patient-directed titration for achieving glycaemic goals using a once-daily basal insulin analogue: an assessment of two different fasting plasma glucose targets - the TITRATE™ study. Diabetes Obes Metab. 2009;11(6):623-631. 2. Data on file. Novo Nordisk Inc, Princeton, NJ. iPhone ® is a registered trademark of Apple, Inc. FlexPen® and Levemir ® are registered trademarks and NovoDose™ is a trademark of Novo Nordisk A/S. © 2012 Novo Nordisk Printed in the U.S.A. 0911-00005042-1 April 2012

DECEMBER 2012

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

15

Lipid Management Lipid Therapy Update: HDL Therapies Falling Short... Continued from page 15 agent that increases apolipoprotein (apo) A1 transcription, and the other is using infusions of synthetic HDL. Neither study is looking at the effect of the therapies on outcome end points.

Interim Safety Results from HPS2-THRIVE An interim safety and tolerability analysis from the Treatment of HDL to

Reduce the Incidence of Vascular Events (HPS2-THRIVE) study shows that 24.0% of patients randomized to niacin plus laropiprant at a median follow-up of 3.4 years compared with 15.4% of those assigned to placebo.

Flushing was responsible for 0.8% of withdrawals from the laropiprant arm compared with 0.1% of the placebo arm. Other skin-related reasons (mainly

pruritus and rash) caused discontinuation in 5.1% of patients who were randomized to niacin/laropiprant and in 1.2% assigned to placebo. Gastrointestinal problems also caused more withdrawals in the niacin/laropiprant arm than in the placebo arm (3.6% vs 1.6%, respectively).

An emerging profile that is appearing in global studies of some lipid-

LEVEMIR® (insulin detemir [rDNA origin] injection) Rx ONLY BRIEF SUMMARY. Please consult package insert for full prescribing information.

INDICATIONS AND USAGE: LEVEMIR® is indicated to improve glycemic control in adults and children with diabetes mellitus. Important Limitations of Use: LEVEMIR® is not recommended for the treatment of diabetic ketoacidosis. Intravenous rapid-acting or short-acting insulin is the preferred treatment for this condition.

CONTRAINDICATIONS: LEVEMIR® is contraindicated in patients with hypersensitivity to LEVEMIR® or any of its excipients. Reactions have included anaphylaxis.

WARNINGS AND PRECAUTIONS: Dosage adjustment and monitoring: Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision.

Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment. As with all insulin preparations, the time course of action for LEVEMIR® may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity. Administration: LEVEMIR® should only be administered subcutaneously. Do not administer LEVEMIR® intravenously or intramuscularly. The intended duration of activity of LEVEMIR® is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia. Do not use LEVEMIR® in insulin infusion pumps. Do not dilute or mix LEVEMIR® with any other insulin or solution. If LEVEMIR® is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR® and the mixed insulin may be altered in an unpredictable manner. Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR®. The risk of hypoglycemia increases with intensive glycemic control. Patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR®. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia. The prolonged effect of subcutaneous LEVEMIR® may delay recovery from hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. Hypersensitivity and allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR®. Renal Impairment: No difference was observed in the pharmacokinetics of insulin detemir between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment.

Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with renal impairment. Hepatic Impairment: Nondiabetic individuals with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dose adjustments of insulin, including LEVEMIR®, may be necessary in patients with hepatic impairment. Drug interactions: Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia.

ADVERSE REACTIONS: The following adverse reactions are discussed elsewhere: Hypoglycemia; Hypersensitivity and allergic reactions. Clinical trial experience: Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of adverse reactions (excluding hypoglycemia) reported during LEVEMIR® clinical trials in patients with type 1 diabetes mellitus and

16

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

DECEMBER 2012

modifying therapies is a difference in pharmacokinetics and side effects in Asian populations versus the rest of the world, said Dr Ballantyne. In HPS2-THRIVE, although myopathy was rare, occurring in 0.54% of the niacin plus laropiprant arm, it occurred approximately twice as often (1.13%) in the study participants in China. Elevations in liver enzymes

type 2 diabetes mellitus are listed in Tables 1-4 below. See Tables 5 and 6 for the hypoglycemia findings.

Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Pharyngitis Influenza-like illness Abdominal Pain

LEVEMIR®, % (n = 767) 26.1 22.6 9.5 7.8 6.0

NPH, % (n = 388) 21.4 22.7 8.0 7.0 2.6

Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR® to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Back pain Influenza-like illness Gastroenteritis Bronchitis

LEVEMIR®, % (n = 161) 26.7 14.3 8.1 6.2 5.6 5.0

Glargine, % (n = 159) 32.1 19.5 6.3 8.2 4.4 1.9

Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache

LEVEMIR®, % (n = 432) 12.5 6.5

NPH, % (n = 437) 11.2 5.3

Table 4: Adverse reactions (excluding hypoglycemia) in a 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

Upper respiratory tract infection Headache Pharyngitis Gastroenteritis Influenza-like illness Abdominal pain Pyrexia Cough Viral infection Nausea Rhinitis Vomiting

LEVEMIR®, % (n = 232) 35.8 31.0 17.2 16.8 13.8 13.4 10.3 8.2 7.3 6.5 6.5 6.5

NPH, % (n = 115) 42.6 32.2 20.9 11.3 20.9 13.0 6.1 4.3 7.8 7.0 3.5 10.4

Hypoglycemia: Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR®. Tables 5 and 6 summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR® clinical trials. Severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a blood glucose below 50 mg/ dL or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. Non-severe hypoglycemia was defined as an asymptomatic or symptomatic plasma glucose < 56 mg/dL (<50 mg/dL in Study A and C) that was self-treated by the patient. The rates of hypoglycemia in the LEVEMIR® clinical trials (see Section 14 for a description of the study designs) were comparable between LEVEMIR®-treated patients and non-LEVEMIR®-treated patients (see Tables 5 and 6).

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Lipid Management were also more common in Chinese patients who were assigned to niacin plus laropiprant compared with those from other countries.

The outcomes from HPS2-THRIVE will be released in April 2013.

Omega-3 Fatty Acid Gains FDA Approval Icosapent ethyl (Vascepa), an ultrapure omega-3 fatty acid product, gained

approval from the US Food and Drug Administration (FDA) over the summer, as an adjunct to diet to reduce triglyceride levels in adult patients with severe hypertriglyceridemia (>500 mg/dL). An outcomes trial called the Reduction of Cardiovascular Events with EPA-Intervention Trial (REDUCE IT) has been initiated with icosapent in addition to statin therapy in patients with CHD and mixed dyslipidemia,

Table 5: Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 16 weeks In combination with insulin aspart Twice-Daily Twice-Daily NPH LEVEMIR® Severe hypo- Percent of patients 8.7 10.6 with at least 1 event glycemia (24/276) (14/132) (n/total N) Event/patient/year 0.52 0.43 89.4 88.0 Non-severe Percent of patients (118/132) (243/276) hypoglycemia (n/total N) Event/patient/year 26.4 37.5

Study B Type 1 Diabetes Adults 26 weeks In combination with insulin aspart Twice-Daily Once-Daily LEVEMIR® Glargine

with the goal of getting an additional indication for the treatment of patients with mixed dyslipidemia.

Potential Treatments for Familial Hypercholesterolemia Homozygous familial hypercholesterolemia (FH) is the most severe form of FH, and it has few options for treatment, Dr Ballantyne pointed out. Two investigational agents with potential in-

Study C Type 1 Diabetes Adults 24 weeks In combination with regular insulin Once-Daily Once-Daily NPH LEVEMIR®

Study D Type 1 Diabetes Pediatrics 26 weeks In combination with insulin aspart Once- or Twice Once- or Twice Daily LEVEMIR® Daily NPH

5.0 (8/161)

10.1 (16/159)

7.5 (37/491)

10.2 (26/256)

15.9 (37/232)

20.0 (23/115)

0.13 82.0 (132/161) 20.2

0.31 77.4 (123/159) 21.8

0.35 88.4 (434/491) 31.1

0.32 87.9 (225/256) 33.4

0.91 93.1 (216/232) 31.6

0.99 95.7 (110/115) 37.0

Table 6: Hypoglycemia in Patients with Type 2 Diabetes

Severe hypo- Percent of patients with at least 1 event (n/total N) glycemia Event/patient/year Non-severe Percent of patients hypoglycemia (n/total N) Event/patient/year

Study E Type 2 Diabetes Adults 24 weeks In combination with oral agents Twice-Daily NPH Twice-Daily LEVEMIR® 2.5 0.4 (6/238) (1/237) 0.01 0.08 40.5 64.3 (96/237) (153/238) 3.5 6.9

Insulin Initiation and Intensification of Glucose Control: Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy: Long-term use of insulin, including LEVEMIR®, can cause lipodystrophy at the site of repeated insulin injections.

Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin adsorption. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy. Weight Gain: Weight gain can occur with insulin therapy, including LEVEMIR®, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema: Insulin, including LEVEMIR®, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Allergic Reactions: Local Allergy: As with any insulin therapy, patients taking LEVEMIR® may experience injection site reactions, including localized erythema, pain, pruritis, urticaria, edema, and inflammation. In clinical studies in adults, three patients treated with LEVEMIR® reported injection site pain (0.25%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy. Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks. Systemic Allergy: Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LEVEMIR®, and may be life-threatening. Antibody Production: All insulin products can elicit the formation of insulin antibodies. These insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase 3 clinical trials of LEVEMIR®, antibody development has been observed with no apparent impact on glycemic control. Postmarketing experience: The following adverse reactions have been identified during post approval use of LEVEMIR®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Medication errors have been reported during post-approval use of LEVEMIR® in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR®. To avoid medication errors between LEVEMIR® and other insulins, patients should be instructed always to verify the insulin label before each injection.

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Study F Type 2 Diabetes Adults 22 weeks In combination with insulin aspart Once- or Twice Daily LEVEMIR® Once- or Twice Daily NPH 4.0 1.5 (8/199) (3/195) 0.04 0.13 32.3 32.2 (64/199) (63/195) 1.6 2.0

More detailed information is available upon request.

For information about LEVEMIR® contact: Novo Nordisk Inc., 100 College Road West Princeton, NJ 08540 1-800-727-6500 www.novonordisk-us.com Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark Revised: 1/2012 Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® are registered trademarks of Novo Nordisk A/S. LEVEMIR® is covered by US Patent Nos. 5,750,497, 5,866,538, 6,011,007, 6,869,930 and other patents pending.

FlexPen® is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,400 and other patents pending. © 2005-2012 Novo Nordisk 0212-00007333-1 2/2012

DECEMBER 2012

dications for the treatment of patients with homozygous FH are lomitapide capsules and mipomersen injection.

The manufacturers of each of these drugs were seeking indications for each agent as adjuncts to other maximally tolerated lipid-lowering agents, and both agents were the subject of FDA advisory committee meetings in October 2012. The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee endorsed that approval of lomitapide capsules by a vote of 13 to 2 and endorsed mipomersen by a vote of 9 to 6.

“There are 6 genes related to HDL metabolism that are associated with CHD, but all 6 of them also have some impact on triglycerides or LDL. So, it really calls into a little more complexity to target HDL.” —Christie Ballantyne, MD

Lomitapide is a microsomal triglyceride transfer protein inhibitor that lowers LDL cholesterol by approximately 40% while also reducing levels of total cholesterol, apo B, triglycerides, non-HDL cholesterol, very-low-density lipoprotein (VLDL), and lipoprotein(a) (Lp[a]). Elevations in alanine transaminase greater than 3 times the upper limit of normal occurred in 38% of lomitapide recipients in a pivotal trial.

Mipomersen is an apo B antisense drug that inhibits the release of apo B100, an important structural and functional component of lipoproteins, from the liver. Blocking apo B-100 release blocks the production of VLDL, LDL, and Lp(a). Concern has been raised with mipomersen over increases in serum transaminases and in hepatic fat in phase 3 trials.

Monoclonal Antibody Substantially Lowers LDL Proprotein convertase subtilisin/ kexin 9 (PCSK9) is a hepatic regulator of the LDL receptor. PCSK9 in the plasma binds to LDL receptors, reduces recycling, effectively downregulating LDL receptor activity, thus resulting in increased plasma LDL cholesterol.

Injectable human PCSK9 monoclonal antibodies bind to PCSK9 to block its effect and to prevent the degradation of LDL receptors.

In a phase 2 study of the PCSK9 monoclonal antibody SAR236553/ REGN727 released earlier in 2012, LDL cholesterol reductions as high as 72% were achieved in patients already being treated with atorvastatin. ■

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Drug Update

Belviq: A New Prescription Weight-Loss Treatment for Overweight or Obese Patients

By Loretta Fala, medical writer

O

verweight and obesity are major health concerns in the United States and worldwide, and they are associated with increased health risks.

The Impact and Burden of Obesity and Overweight Being overweight or obese is associated with specific health risks. Obesity increases the risk for type 2 diabetes, hypertension, adverse lipid concentrations, heart disease, stroke, and certain types of cancer—some of the leading causes of preventable deaths.1,2 Obesity is defined as a body mass index (BMI) of ≥30 kg/m2, and overweight is defined as a BMI of ≥25 kg/m2.3 Based on data from the 2009-2010 National Health and Nutrition Examination Survey, approximately 78.1 million (35%) men and women and 12.5 million (16.9%) children (aged ≤19 years) in the United States are obese; overall, older adults (aged ≥60 years) have a greater likelihood of being obese than younger adults (aged <60 years).2 Furthermore, more than 34% of American adults aged ≥20 years are overweight.4 A number of serious comorbidities are associated with obesity, including cardiovascular (CV) disease, type 2 diabetes, hypertension, sleep apnea, and some types of cancer. Obesity and overweight can also lead to cardiac complications, such as congestive heart disease, heart failure, and even sudden death.5 Even a weight loss of 5% to <10% of initial body weight is associated with significant reductions in CV risk factors, including improvements in glycemic control, blood pressure, high-density lipoprotein cholesterol, and triglycerides at 1 year in overweight and obese patients with type 2 diabetes.6 Moreover, a weight loss of 10% to 15% of initial body weight is associated with a greater improvement in these risk factors.6 Traditionally, achieving meaningful weight loss has been more challenging for patients with diabetes—particularly those taking insulin and other oral medications that treat type 2 diabetes—than for nondiabetic populations.7,8 In addition, according to the Centers for Disease Control and Prevention, obesity and overweight impose a substantial economic burden on the US healthcare system.1 The total annual medical costs associated with obesity are estimated at $147 billion.1 The perperson medical costs are $1429 higher for obese people than for normalweight individuals.1

18

Given the impact of obesity on overall health and outcomes—and its association with increased morbidity and mortality and a reduced life expectancy—approaches to meaningful weight loss may help improve outcomes in appropriate patients.

First Weight-Loss Prescription Therapy Approved in 13 Years In June 2012, the US Food and Drug Administration (FDA) approved lorcaserin hydrochloride (Belviq; Arena Pharmaceuticals) as an addition to a reduced-calorie diet and exercise for the treatment of chronic-weight management. This was the first FDA approval of a prescription weight-loss treatment in the past 13 years.9 Lorcaserin hydrochloride, a novel oral serotonin 2C receptor antagonist, is indicated as an adjunct to a reducedcalorie diet and to increased physical activity in adults with an initial BMI of ≥30 kg/m2 (ie, obese) or a BMI of ≥27 kg/m2 (ie, overweight) in the presence of at least 1 weight-related comorbid condition, including hypertension, dyslipidemia, or type 2 diabetes.10 Lorcaserin is scheduled to be launched after a US Drug Enforcement Administration review to determine the final scheduling designation based on the US Controlled Substances Act.9 A Risk Evaluation and Mitigation Strategy program for lorcaserin was not required by the FDA; however, as part of the FDA approval of lorcaserin, postmarketing studies are being conducted to evaluate the safety and efficacy of this medication for weight management in obese pediatric patients and for the long-term treatment effect of lorcaserin on the incidence of major CV adverse events (AEs) in overweight and obese persons with CV risk factors.9 Studies evaluating CV effects will include echocardiographic assessments.9

Table 1 BLOOM-DM: Weight-Loss Changes from Baseline to 1 Year Study populationa Lorcaserin 10 mg twice daily (N = 251)

Placebo (N = 248)

P value vs placebo

Patients with ≥5% weight loss, %

37.5

16.1

<.001

Patients with ≥10% weight loss, %

16.3

4.4

<.001

End point

a

All patients who received the study medication and had a postbaseline measurement. Of the total patients, 34% of those receiving lorcaserin and 38% of those receiving placebo dropped out before the 52-week end point.

Sources: References 7, 10.

BLOOM-DM: Mean Changes in Cardiometabolic Parameters and Waist Table 2 Circumference in Patients with Type 2 Diabetes Lorcaserin (N = 256)a

Baseline

Change from baseline (LS meanb)

Baseline

Change from baseline, (LS meanb)

8.1

–0.9

8.0

–0.4

Fasting glucose, mg/dL

163.3

–27.4

160.0

–11.9

Systolic BP, mm Hg

126.6

–0.8

126.5

–0.9

Diastolic BP, mm Hg

77.9

–1.1

78.7

–0.7

Heart rate, bpm

72.3

–2.0

72.7

–0.4

Baseline

Change from baseline (LS meanb)

Baseline

Change from baseline (LS meanb)

Total cholesterol, mg/dL

173.5

–0.7

172.0

–0.1

LDL cholesterol, mg/dL

95.0

4.2

94.6

5.0

HDL cholesterol, mg/dL

45.3

5.2

45.7

1.6

Triglycerides, mg/dL

172.1

–10.7

163.50

–4.8

Waist circumference, cm

115.8

–5.5

113.50

–3.3

HbA1c, %

a

Including intent-to-treat population using last observation carried forward method and all patients who received the study medication and had a postbaseline body weight measurement. b Least squares means adjusted for baseline value, baseline HbA1c stratum, and prior antihyperglycemic medication stratum.

BP indicates blood pressure; bpm, beats per minute; Hb, hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LS, least squares.

Sources: References 7, 10.

Mechanism of Action Lorcaserin is believed to decrease food consumption and promote satiety by selective activation of 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons that are located in the hypothalamus. At therapeutic concentrations, lorcaserin is selective for 5-HT2C receptors compared with 5-HT2B receptors. The exact mechanism of action is not known.10

and 40 mg once daily with corrected QT (QTc) interval was evaluated in a randomized, placebo- and active (moxifloxacin 400 mg)-controlled 4-treatment arm parallel in 244 healthy subjects. In a study designed to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baselinecorrected QTc interval based on individual correction method was below 10 ms (the regulatory threshold).10

Pharmacodynamics (cardiac electrophysiology) The effect of oral lorcaserin 15 mg

Pharmacokinetics Peak plasma concentration occurs 1.5 to 2 hours after oral dosing of lor-

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

DECEMBER 2012

Placebo (N = 252)a

caserin. The absolute bioavailability of lorcaserin has not been determined.

Lorcaserin has a plasma half-life of approximately 11 hours; steady state is reached within 3 days after twicedaily dosing, and accumulation is estimated to be approximately 70%.

Lorcaserin can be administered with or without food. Lorcaserin is extremely metabolized by the liver.10 Dosing Lorcaserin is available as a 10-mg, film-coated tablet; its recommended dose is 10 mg, administered orally twice daily.10 If a 5% weight loss is not

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Drug Update Table 3 BLOOM: Weight-Loss Changes from Baseline to 1 Year Intention-to-treat analysis of LOCF imputation

Coprimary end points

Lorcaserin 10 mg twice daily (N = 1538)

Mean Changes in Cardiometabolic Parameters and Waist Circumference Table 5 in the BLOOM and BLOSSOM Studies, Year 1 Lorcaserin (N = 3096)

Placebo (N = 1499)

P value vs placebo

Loss of ≥5% body weight Patients, % Weight change, kg

Baseline, mg/dL

Change from baseline, % (LS meana)

Baseline, mg/dL

Change from baseline, % (LS meana)

47.5

20.3

<.001

Total cholesterol

194.4

–0.9

194.8

0.4

−5.8 ± 0.2

−2.2 ± 0.1

<.001

LDL cholesterol

114.3

1.6

114.1

2.9

HDL cholesterol

53.2

1.8

1.8

0.6

22.6

7.7

<.001

Triglycerides

135.4

–5.3

137.0

–0.5

Baseline

Change from baseline (LS meana)

Baseline

Change from baseline (LS meana)

Systolic BP, mm Hg

121.4

–1.8

121.5

–0.1

Diastolic BP, mm Hg

77.4

–1.6

77.7

–0.1

Heart rate, bpm

69.5

–1.2

69.5

–0.4

Loss of ≥10% body weight Patients, %

LOCF indicates last observation carried forward.

Source: Reference 11.

Table 4 BLOSSOM: Weight-Loss Changes from Baseline to 1 Year

End point

Placebo (N = 3039)

Lorcaserin Placebo 10 mg twice daily (N = 1541) (N = 1561)

P value vs placeboa

Patients with ≥5% weight loss, %

25.0

47.2

<.001

Fasting glucose, mg/dL

92.1

–0.2

92.4

0.6

Patients with ≥10% weight loss, %

9.7

22.6

<.001

Fasting insulin,b µIU/mL

15.9

–3.3

15.8

–1.3

−2.8

−5.8

<.001

Waist circumference, cm

109.3

–6.6

109.6

–4.0

Least squares mean weight loss (change from baseline), kg

a

a

Analysis of difference in proportions or least squares means.

Source: Reference 12.

achieved with this treatment by week 12, lorcaserin should be discontinued.10 Clinical Studies Data The FDA approval of lorcaserin was based on safety and efficacy data from 3 randomized, placebo-controlled trials, which included more than 7700 overweight and obese participants.7,11,12 These studies are described in the product prescribing information10 and in relevant published articles; the key data are highlighted below.

ments in cardiometabolic parameters with lorcaserin twice daily versus placebo, including reductions in HbA1c and fasting glucose levels, improved lipid profile, and lower diastolic blood pressure (Table 2).7,10 The most common AEs included headache, back pain, nasopharyngitis, and nausea. Symptomatic hypoglycemia occurred in 7.4% of patients of the lorcaserin twice-daily group, 10.5% of the lorcaserin once-daily group, and in 6.3% of the placebo group.7

The BLOOM-DM Trial The safety and efficacy of lorcaserin for weight loss in patients with type 2 diabetes were evaluated in the Behavioral Modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus (BLOOM-DM) study, a 1-year, placebo-controlled trial that followed 604 adult overweight patients (BMI ≥27 kg/m2) with inadequately controlled type 2 diabetes (hemoglobin [Hb] A1c range, 7%-10%).7 Patients were randomized in a 1:1:1 ratio to receive placebo, lorcaserin 10 mg once daily, or lorcaserin 10 mg twice daily. The majority of patients (91.7%) received metformin, and 50.2% received a sulfonylurea. All the patients received diet and exercise counseling.7 Lorcaserin was associated with significant weight loss compared with placebo (Table 1).7,10 The least squares mean weight change was –4.5% (± 0.35%) with lorcaserin twice daily compared with −1.5% (± 0.36%) with placebo (P <.001). Lorcaserin was also associated with significant improve-

The BLOOM Trial The Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial evaluated weight loss at 1 year and the maintenance of weight loss at 2 years.11 In this double-blind study, 3182 obese or overweight adults (mean BMI, 36.2 kg/m2) were randomly assigned to receive lorcaserin 10 mg, or placebo, twice daily for 52 weeks. All patients received diet and exercise counseling. At week 52, the placebo group continued to receive a placebo, but patients who were receiving lorcaserin were randomly reassigned to receive a placebo or lorcaserin.

At 1 year, 55.4% (883:1595) of patients in the lorcaserin group and 45.1% (716:1587) of patients in the placebo group remained in the study; of these, 1553 patients continued into year 2.11 Lorcaserin, in combination with behavioral modification, was associated with significant weight loss and improved maintenance of weight loss compared with placebo (Table 3).11 In the group of patients who received

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Least squares means adjusted for baseline value, treatment, study and treatment by study interaction.

Measured in the BLOOM study only (N = 1538).

BP indicates blood pressure; bpm, beats per minute; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LS, least squares.

Source: Reference 10. b

lorcaserin in year 1 and lost ≥5% of their baseline weight at 1 year, weight loss was maintained in 67.9% of patients who continued to receive lorcaserin in year 2 compared with 50.3% of patients who received placebo during year 2 (P <.001).11 During year 1, significant decreases in waist circumference and in BMI were seen in those receiving lorcaserin compared with patients receiving placebo.11 There was no increase in the rate of cardiac valvulopathy with lorcaserin in the 2472 patients evaluated at 1 year and in the 1127 patients evaluated at 2 years.11 The most common AEs were upper respiratory infections, headache, dizziness, nasopharyngitis, and nausea.

The rates of serious AEs were similar in the lorcaserin and the placebo groups.11

The BLOSSOM Trial The Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) trial, a double-blind, randomized, placebocontrolled study conducted at 97 US research centers, evaluated the effects of lorcaserin on body weight, CV risk factors, and safety in 4008 obese and overweight patients.12 Patients were randomized in a 2:1:2 ratio to receive lorcaserin 10 mg twice daily, lorcaserin 10 mg once daily, or placebo.

All patients received diet and exercise counseling.12 Lorcaserin, in conjunction with lifestyle modification, was associated with a significantly greater dose-depen-

DECEMBER 2012

dent weight loss compared with placebo (Table 4). The most frequent AEs were headache, nausea, and dizziness. At 1 year, lorcaserin did not increase the rate of echocardiographic valvulopathy (as defined by the FDA), which occurred in 2% of patients receiving placebo and in 2% of patients in the 10-mg twice-daily lorcaserin group.12 Table 5 compares the cardiometabolic changes see with lorcaserin and placebo in the BLOOM and BLOSSOM trials.

Safety Profile and Metabolic Properties The most common AEs associated with lorcaserin (>5%) in nondiabetic patients are headache, dizziness, fatigue, nausea, dry mouth, and constipation; in diabetic patients, the most common AEs are hypoglycemia, headache, back pain, cough, and fatigue.10 Response to lorcaserin should be evaluated at 12 weeks of treatment to determine if therapy should be discontinued. (There are no black box warnings associated with the use of lorcaserin.)

The safety and efficacy of lorcaserin coadministration with other products for weight loss, including prescription drugs (eg, phentermine), over-thecounter drugs, and herbal preparations, have not been established. The effects of lorcaserin on CV morbidity and mortality have not been established.

Contraindications Lorcaserin is contraindicated during pregnancy, because weight loss offers

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

19

Drug Update no potential benefit to pregnant women and may result in fetal harm. It should not be taken during pregnancy or by women who are planning to become pregnant.10

Drug Interactions Serotonin syndrome or neuroleptic malignant syndrome–like reactions.

Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, lorcaserin should be used with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, but not limited to, triptans, monoamine oxidase inhibitors (MAOIs; including linezolid, an antibiotic which is a reversible nonselective MAOI), selective serotonin reuptake inhibitors, selective serotonin norepinephrine reuptake inhibitors, dextromethorphan, tricyclic antidepressants, bupropion, lithium, tramadol, tryptophan, and St John’s wort.10 CY P450 (2D6) substrates. Caution should be used when administering lorcaserin together with drugs that are cytochrome (CY) P450 2D6 substrates, because lorcaserin can increase exposure of these drugs.

Important Safety Information Valvular heart disease. Lorcaserin should not be taken in combination with drugs that have been associated with valvular heart disease (eg, cabergoline). Patients who develop valvular heart disease while taking lorcaserin should be evaluated.10 Changes in attention or memory.

Problems with somnolence, confusion, and fatigue have been reported in patients taking lorcaserin. Patients should be cautioned not to drive a car or operate heavy machinery until they know how lorcaserin affects them.10 Psychiatric disorders. Higher-thanrecommended doses of lorcaserin may

cause hallucinations, feelings of euphoria, and dissociation; the recommended dose of 10 mg twice daily should not be exceeded. Patients should be monitored for the development or the worsening of depression, suicidal thoughts or behaviors, and/or any changes in mood.10 Hypoglycemia. Weight loss may cause low blood glucose in people with type 2 diabetes who are receiving medications to treat it, such as metformin, insulin, or sulfonylureas. Lorcaserin has not been studied in combination with insulin. Blood glucose levels should be monitored for patients who take lorcaserin.10 Priapism. Patients who experience an erection lasting more than 4 hours, even if it is not painful, should stop using lorcaserin and should call their doctor or go to the nearest emergency department immediately. Lorcaserin should be taken with caution by men who have conditions that may predispose them to priapism (eg, sickle-cell anemia, multiple myeloma, or leukemia) or in men with a deformed penis.10 Heart rate decrease. Lorcaserin may cause a slow heartbeat. It should be used with caution in patients with bradycardia or with a history of heart block greater than first degree.10 Hematologic changes. Lorcaserin may cause decreases in red or white blood–cell count. The period monitoring of complete blood count during treatment with lorcaserin should be considered.10 Prolactin elevation. Lorcaserin moderately elevates prolactin levels.

Prolactin should be measured when symptoms and signs of prolactin excess are suspected.

Pulmonary Hypertension. Certain weight-loss drugs have been associated with the rare but life-threatening side effect of increased pressure in the arteries of the lung. It is unknown if lorcaserin increases the risk for this condition.

Specific Populations Nursing mothers. It is not known whether lorcaserin is excreted in human milk. Lorcaserin should not be taken while breastfeeding.

Pediatric use. The safety and effectiveness of lorcaserin in pediatric patients aged <18 years have not been established, and the use of lorcaserin is not recommended in pediatric patients.

Geriatric use. Clinical studies of lorcaserin did not include sufficient numbers of patients aged ≥65 years to determine whether they respond differently from younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Renal impairment. No dose adjustment of lorcaserin is required in patients with mild renal impairment. Lorcaserin should be used with caution in patients with moderate renal impairment.

Hepatic impairment. Dose adjustment is not required for patients with mild-to-moderate hepatic impairment (Child-Pugh score of 5-9).

Potential for Abuse and Dependence In short-term studies with healthy individuals, euphoria after oral administration of lorcaserin was seen in 16% of patients after receiving 40 mg and in 19% patients after receiving 60 mg.

However, in clinical studies with obese patients with durations of 4 weeks to 2 years, the incidence of euphoria and hallucinations after oral doses of lorcaserin up to 40 mg was low (<1.0%).10 The ability of lorcaserin to produce hallucinations, euphoria, and positive subjective responses at supratherapeutic doses suggests that lorcaserin may produce psychic dependence.

There are no data on overdosing with lorcaserin.

Conclusion Evidence from randomized, placebocontrolled clinical trials indicate that

lorcaserin, in combination with diet and exercise, is more effective than diet and exercise alone at helping patients lose ≥5% of body weight after taking this medication for 1 year. In addition, the use of lorcaserin helps to maintain the weight loss for up to 2 years, based on current evidence. As part of the FDA approval of lorcaserin, additional postmarketing safety and efficacy studies are being conducted. Lorcaserin is a new treatment option that may help to address some of the unmet medical needs of the growing population overweight and obese persons in the United States. ■ References 1. Centers for Disease Control and Prevention. Adult obesity facts. www.cdc.gov/obesity/data/adult.html.

Accessed August 25, 2012.

2. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012;82:1-8.

3. Centers for Disease Control and Prevention. Causes and consequences. www.cdc.gov/obesity/adult/causes/ index.html. Accessed August 25, 2012.

4. Centers for Disease Control and Prevention. Obesity and overweight. www.cdc.gov/nchs/fastats/overwt. htm. Accessed August 25, 2012.

5. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physician Activity, and Metabolism. Circulation. 2006;113:898-918.

6. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481-1486.

7. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring). 2012;20:1426-1436.

8. Mavian AA, Miller S, Henry RR. Managing type 2 diabetes: balancing HbA1c and body weight. Postgrad Med. 2010;122:106-117.

9. US FDA approves antiobesity agent BELVIQ (lorcaserin HCl) for adults [press release]. Woodcliff Lake, NJ: Eisai; June 28, 2012. www.eisai.com/news/news 201238.html. Accessed December 10, 2012.

10. Belviq (lorcaserin hydrochloride) tablets [prescribing information]. Woodcliff Lake, NJ: Eisai; 2012.

11. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363:245-256.

12. Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab. 2011;96:3067-3077.

Health Economics

CABG Surgery Outcomes Superior to PCI and Cost-Effective in Patients with Diabetes and Multivessel CAD

By Wayne Kuznar Los Angeles, CA—The outcomes of coronary artery bypass graft (CABG) surgery are superior to those of percutaneous coronary intervention (PCI) in patients with diabetes and multivessel coronary artery disease (CAD). The better outcomes with CABG were achieved with a small increase in costs over 5 years compared with PCI, making CABG highly cost-effective in this population.

These were the findings from a National Heart, Lung, and Blood Institute–supported study in which 1900 patients with diabetes and multivessel CAD were randomized to CABG or to PCI with deployment of a drugeluting stent. Valentin Fuster, MD, PhD, Director of Mount Sinai Heart Institute, New York City, and lead investigator of the study, presented the

results at the 2012 American Heart Association meeting.

“The results are clear; I think they are going to change practice,” Dr Fuster said.

The study, which enrolled patients with multivessel disease, but not of the left main coronary artery, was conducted at 140 international centers. All study participants received standard

care to control blood glucose (target hemoglobin A1c, <7.0%), low-density lipoprotein cholesterol (target, <70 mg/dL), and blood pressure (target, <130/80 mm Hg).

After a mean follow-up of 4.37 years, the combined rate of death, myocardial infarction (MI), and stroke was 18.7% in the CABG group and 26.6% in the PCI group, a relative risk reduction of Continued on page 21

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Health Economics CABG Surgery Outcomes... Continued from page 20 29%. The rate of all-cause mortality over the 5 years was 10.9% in the CABG group versus 16.3% in the PCI group; the rate of MI was also lower in the CABG group versus the PCI group (6.0% vs 13.9%, respectively).

“The results are clear; I think they are going to change practice.”

—Valentin Fuster, MD, PhD

As with other trials comparing CABG and PCI, the rate of stroke was higher among CABG recipients at 5.2% compared with 2.4% in the stented group. Cardiovascular deaths were less frequent with CABG than with PCI (55 vs 74, respectively) as was the number of repeat vascularizations at 1 year (42 vs 117, respectively).

“CABG surgery is the preferred method of revascularization for patients with diabetes and multivessel CAD,” concluded Dr Fuster.

Approximately 40% of eligible patients who were screened for the study did not consent to randomization, he noted, because they opted for stenting.

The study was published simultaneously online (Farkouh ME, et al. N Engl J Med. 2012;367:2375-2384). In an accompanied editorial, Mark A. Hlatky, MD, Professor of Health Research and Policy and Professor of Cardiovascular Medicine at Stanford University wrote, “Mortality has been consistently reduced by CABG, as compared with PCI, in more than 4000 patients with diabetes who have been evaluated in 13 clinical trials.

The controversy should finally be settled.”

The results of the study do not necessarily apply to other patient populations, said some interventional cardiologists. One is Alice K. Jacobs, MD, Director of the Cardiac Catheterization Laboratory and Interventional Cardiology, Boston Medical Center, and Professor of Medicine, Boston University School of Medicine, who said that CABG may be more beneficial than PCI in patients with diabetes, because CAD tends to be more diffuse in this group, as opposed to focal.

sources,” said Elizabeth A. Magnuson, ScD, Director of Health Economics and Technology Assessment, University of Missouri-Kansas City at Saint Luke’s Mid America Heart Institute, Kansas City, MO. Initial costs were higher with CABG, at $34,467 for the index hospitalization

versus $25,845 for PCI. Cumulative costs narrowed between the 2 groups over the course of the follow-up. At 5 years, CABG increased the total cost per patient by $3641 compared with PCI. This additional cost resulted in a cost per quality-adjusted life-year (QALY) gained of $116,699 at 5 years,

making it an attractive use of societal healthcare resources.

However, over a lifetime, patients such as those in the trial who undergo CABG rather than PCI could expect to live an average of 1.266 years longer, lowering the QALY to just $8132, Ms Magnuson said. ■

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Cost-Effectiveness Analysis The cost-effectiveness analysis demonstrated that the benefits of CABG in this study “provides not only better long-term clinical outcomes than PCI, but these benefits are achieved at an overall cost that represents an attractive use of societal health care re-

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DECEMBER 2012

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

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Drug Update

Qsymia: Combination Oral Therapy a New Weight-Loss Option for Obese or Overweight Patients

By Loretta Fala, Medical Writer

O

besity has reached epidemic proportions in the United States.1 Obesity, which is defined as a body mass index (BMI) of ≥30 kg/m2, affects an estimated 78.1 million Americans—more than 35% of all men and women.2,3 Moreover, more than 34% of adults aged ≥20 years are overweight, which is defined as a BMI of ≥25 kg/m2.3

Clinical and Economic Implications of Obesity Obesity is associated with clinically serious and costly consequences, including an increased risk for developing type 2 diabetes, cardiovascular (CV) disease, hypertension, sleep apnea, stroke, dyslipidemia, osteoporosis, and some types of cancer (ie, breast, colon, and endometrial).1,3 Furthermore, obesity is associated with social stigma, discrimination, reduced life expectancy, and a reduced quality of life.1,3 The costs associated with obesity and overweight are staggering. The annual medical burden of obesity has climbed to nearly 10% of all medical spending in the United States, with an annual total of $147 billion.4,5 Moreover, medical costs per person are $1429 higher for obese individuals compared with normal-weight individuals, according to the Centers for Disease Control and Prevention.4 Weight loss achieved by medically recommended approaches is associated with reduced comorbidities in patients with obesity.6 A weight loss of 5% to <10% of an overweight or obese person’s initial body weight can lead to significant improvements in cardiometabolic health at 1 year, including improved glycemic control, reduced blood pressure (BP), and improved high-density lipoprotein cholesterol and triglyceride levels in those with type 2 diabetes.7 These benefits can be even greater with a weight loss of 10% to 15% of body weight.7 Lifestyle changes may be particularly challenging for patients with physical restrictions that limit their activity, or for those whom the benefit of a multidisciplinary healthcare team is not available.8 Effective, long-term pharmacologic therapies—in conjunction with lifestyle modifications—may provide appropriate patients with a viable option for weight management and improved outcomes.8 Qsymia Receives FDA Approval On July 17, 2012, the US Food and

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Drug Administration (FDA) approved the combination of phentermine/topiramate extended-release (ER; Qsymia; Vivus) as an adjunct to a reducedcalorie diet and physical activity for chronic weight management in adults with an initial BMI of ≥30 kg/m2 (ie, obese) or ≥27 kg/m2 (ie, overweight) in the presence of at least 1 weight-related comorbidity, such as hypertension, type 2 diabetes, or dyslipidemia.9 Phentermine and topiramate are each approved by the FDA as a monotherapy, with different indications.

Obesity is associated with clinically serious and costly consequences, including an increased risk for developing type 2 diabetes, cardiovascular disease, hypertension, sleep apnea, stroke, dyslipidemia, osteoporosis, and some types of cancer.

The FDA has required a Risk Evaluation and Mitigation Strategy (REMS) program for phentermine/topiramate ER to manage the known or potential serious risks that are associated with this new combination therapy. The purpose of this REMS is to inform prescribers and females of reproductive potential about several factors, including the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to the drug during the first trimester of pregnancy; the importance of pregnancy prevention for women of reproductive potential who are receiving the drug; and the need to discontinue use if pregnancy occurs.10,11 Dosing Phentermine/topiramate ER is dosed orally once daily in the morning, with or without food. Evening dosing should be avoided, because of the possibility of insomnia. The recommended starting dose is phentermine/topiramate ER 3.75 mg/23 mg daily for 14 days; after 14 days, it is recommended that the dose be increased to phentermine/topiramate ER 7.5 mg/46 mg once daily.10 If a patient has not lost at least 3% of baseline body weight after 12 weeks of treatment with phentermine/topira-

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

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mate ER 7.5 mg/46 mg, this dose should be discontinued or escalated. If a patient has not lost at least 5% of baseline body weight after an additional 12 weeks of treatment at the escalated dose of phentermine/topiramate ER 15 mg/92 mg, the patient should discontinue use gradually by taking a dose every other day for at least 1 week before stopping treatment altogether to reduce the possibility of precipitating a seizure.10 Phentermine/topiramate ER capsules are available in 3.75-mg/23-mg, 7.5-mg/46-mg, 11.25-mg/69-mg, and 15-mg/92-mg dosage strengths. The 3.75-mg/23-mg and the 11.25-mg/69mg dosages are used for titration purposes only.10 Clinical Pharmacology

Mechanism of Action Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class that are used to treat obesity, amphetamines (dextroamphetamine and dextroamphetamine/levoamphetamine), which are known as “anorectics” or “anorexigenics.” Although the exact mechanism of action is not known, the effect of phentermine on chronic weight management is likely mediated by the release of catecholamines in the hypothalamus, resulting in reduced appetite and decreased food consumption; other metabolic effects may also be involved.10 The precise mechanism of action of topiramate on chronic weight management is not known. The effect of topiramate on chronic weight management may be a result of its effects on both appetite suppression and on satiety enhancement, which are induced by a combination of pharmacologic effects, including the augmentation of the activity of the neurotransmitter gammaaminobutyrate, the modulation of voltage-gated ion channels, the inhibition of AMPA/kainite excitatory glutamate receptors, or the inhibition of carbonic anhydrase.10 Pharmacodynamics Typical actions of amphetamines include central nervous system stimulation and the elevation of BP. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been assessed.10 Cardiac electrophysiology. The effect of phentermine/topiramate ER on the corrected QT (QTc) interval was evalu-

ated in a randomized, double-blind, placebo- and active (400 mg moxifloxacin)-controlled, parallel-group, crossover study. A total of 54 healthy subjects were administered phentermine/topiramate ER 7.5 mg/46 mg at steady state and then titrated to phentermine/topiramate ER 22.5 mg/138 mg at steady state. Phentermine/topiramate ER 22.5 mg/138 mg—a supratherapeutic dose resulting in phentermine/ topiramate ER maximum concentrations (Cmax) of 4 times and 3 times higher than those at the phentermine/ topiramate ER 7.5-mg/46-mg dose, respectively—did not affect cardiac repolarization, as measured by the change from baseline in QTc.10

Pharmacokinetics Phentermine. On oral administration of a single phentermine/topiramate ER 15 mg/92 mg, the resulting mean plasma phentermine Cmax, time to Cmax (Tmax), area under the concentration curve (AUC) from time zero to the last time with measurable concentration (AUC0-t), and AUC from time zero to infinity (AUC0-∞) are 49.1 ng/mL, 6 hr, 1990 ng.hr/mL, and 2000 ng.hr/mL, respectively. A high-fat meal does not affect phentermine’s pharmacokinetics for phentermine/ topiramate ER 15 mg/92 mg.10 Topiramate. On oral administration of a single phentermine/topiramate ER 15 mg/92 mg, the resulting mean plasma topiramate Cmax, Tmax, AUC0-t, and AUC0-∞ are 1020 ng/mL, 9 hr, 61,600 ng.hr/mL, and 68,000 ng.hr/mL, respectively. A high-fat meal does not affect topiramate’s pharmacokinetics for phentermine/topiramate ER 15 mg/92 mg.10 Clinical Trials The FDA approval of phentermine/ topiramate ER was based on 2 randomized, double-blind, placebo-controlled studies—EQUIP and CONQUER— that evaluated its effect on weight loss in conjunction with reduced caloric intake and increased physical activity in obese patients (the EQUIP trial) and in obese and overweight patients with ≥2 significant comorbidities (the CONQUER trial).6,10,12 Both studies had a 4week titration period, followed by 52 weeks of treatment. In addition, both studies measured 2 coprimary efficacy outcomes after 1 year of treatment (week 56), including the percent weight loss from baseline and treatment response, which was defined as achieving at least 5% weight loss from baseline.10

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Drug Update Table 1 EQUIP Trial: Weight Loss at 1 Year in Obese Patients (ITT-LOCF Population)

Analysis method, weight (kg)

Placebo (N = 498)

Phentermine/ topiramate ER 3.75 mg/23 mg (N = 234)

LS mean change from baseline, % (SE)a

−1.6 (0.4)

−5.1 (0.5)b

−10.9 (0.4)c

3.5 (2.4-4.7)

9.4 (8.4-10.3)

45b

67c

Difference from placebo (95% CI) Patients losing ≥5% body weight, %

17

27.6 (20.4-34.8)

Risk difference vs placebo (95% CI) Patients losing ≥10% body weight, %

7

Risk difference vs placebo (95% CI)

Phentermine/ topiramate ER 15 mg/92 mg (N = 498)

49.4 (44.1-54.7)

19b

47c

11.4 (5.9-16.9)

39.8 (34.8-44.7)

a

Adjusted for baseline body weight.

P <.001 versus placebo based on LS mean from an analysis of covariance. c P <.01 versus 3.75-mg/23-mg dose.

Type 1 error was controlled across all pairwise treatment comparisons.

CI indicates confidence interval; ER, extended release; ITT-LOCF, intent-to-treat/last-observationcarried-forward; LS, least squares; SE, standard error.

Sources: References 6, 10. b

CONQUER Trial: Weight Loss at 1 Year in Overweight and Obese Patients Table 2 with Comorbidities (ITT-LOCF Population)

Analysis method, weight (kg)

Placebo (N = 979)

Phentermine/ topiramate ER 7.5 mg/46 mg (N = 488)

LS mean change from baseline, % (SE)a

−1.2 (0.3)

−7.8 (0.4)b

−9.8 (0.3)c

6.6 (5.8-7.4)

8.6 (8.0-9.3)

Difference from placebo (95% CI) Patients losing ≥5% body weight, %

21

62b

Phentermine/ topiramate ER 15 mg/92 mg (N = 981)

70c

CONQUER Trial: Mean Changea from Baseline in Cardiometabolic Table 3 Comorbidities in Overweight and Obese Patients with Phentermine/ Topiramate ER versus Placebo, at 1 Year

Cardiometabolic comorbiditiesb

Placebo (N = 979)

Phentermine/ topiramate ER, 7.5 mg/46 mg (N = 488)

Phentermine/ topiramate ER, 15 mg/92 mg (N = 981)

Heart rate, bpm Baseline mean (SD) LS mean change (SE)

72.1 (9.9) -0.3 (0.3)

72.2 (10.1) +0.3 (0.4)

72.6 (10.1) +1.4 (0.3)

Systolic BP, mm Hg Baseline mean (SD) LS mean change (SE)

128.9 (13.5) -2.4 (0.48)

128.5 (13.6) -4.7 (0.63)

127.9 (13.4) -5.6 (0.5)

Diastolic BP, mm Hg Baseline mean (SD) LS mean change (SE)

81.1 (9.2) -2.7 (0.3)

80.6 (8.7) -3.4 (0.4)

80.2 (9.1) -3.8 (0.3)

Total cholesterol, % Baseline mean (SD) LS mean change (SE)

205.8 (41.7) -3.3 (0.5)

201.0 (37.9) -4.9 (0.7)

205.4 (40.4) -6.3 (0.5)

LDL-C, % Baseline mean (SD) LS mean change (SE)

124.2 (36.2) -4.1 (0.9)

120.3 (33.7) -3.7 (1.1)

123.9 (35.6) -6.9 (0.9)

HDL-C, % Baseline mean (SD) LS mean change (SE)

48.9 (13.8) +1.2 (0.7)

48.5 (12.8) +5.2 (0.9)

49.1 (13.8) +6.8 (0.7)

Triglycerides, % Baseline mean (SD) LS mean change (SE)

163.5 (76.3) +4.7 (1.7)

161.1 (72.2) -8.6 (2.2)

161.9 (73.4) -10.6 (1.7)

Fasting insulin, µIU/mL Baseline mean (SD) LS mean change (SE)

17.8 (13.2) +0.7 (0.8)

18.0 (12.9) -3.5 (1.1)

18.4 (17.5) -4.0 (0.8)

Fasting glucose, mg/dL Baseline mean (SD) LS mean change (SE)

106.6 (23.7) +2.3 (0.6)

106.2 (21.0) -0.1 (0.8)

105.7 (21.4) -1.3 (0.6)

Waist circumference, cm Baseline mean (SD) LS mean change (SE)

113.4 (12.2) -2.4 (0.3)

112.7 (12.4) -7.6 (0.4)

113.2 (12.2) -9.2 (0.3)

a

Adjusted for baseline body weight and diabetic status.

Among the 388 patients with diabetes in this trial, HbA1c reductions from 6.8% baseline were 0.1% with placebo versus 0.4% with phentermine/topiramate ER, in both dosage strengths.

BP indicates blood pressure; bpm, beats per minute; ER, extended release: HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LS, least squares; SD, standard deviation; SE, standard error.

Source: Reference 10. b

Risk difference vs placebo (95% CI) Patients losing ≥10% body weight, %

7

Risk difference vs placebo (95% CI)

41.3 (36.3-46.3)

49.2 (45.4-53.0)

37b

48c

29.9 (25.3-34.5)

40.3 (36.7-43.8)

a

Adjusted for baseline body weight and diabetic status.

P <.001 versus placebo based on LS mean from an analysis of covariance. c P <.01 versus 7.5-mg/46-mg dose.

Type 1 error was controlled across all pairwise treatment comparisons.

CI indicates confidence interval; ER, extended release; ITT-LOCF, intent-to-treat/last-observationcarried-forward; LS, least squares; SE, standard error.

Sources: References 10, 12. b

EQUIP In the EQUIP trial, obese patients (BMI ≥35 kg/m2) were randomized to receive 1 year of treatment with placebo, phentermine/topiramate ER 3.75 mg/23 mg, or phentermine/topiramate ER 15 mg/92 mg, in a 2:1:2 ratio.6 Patients with type 2 diabetes were excluded from this study. A wellbalanced, reduced-calorie diet (approximate 500-kcal daily decrease in caloric intake) was recommended to all patients, and they were offered nutritional and lifestyle modification counseling.6,10 After 1 year of treatment with phen-

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termine/topiramate ER, all dose levels resulted in a significant weight loss compared with placebo (Table 1).6,10 Before week 56, 40% of randomized patients withdrew from the study. The most common adverse events (AEs) were paresthesia, dry mouth, constipation, dysgeusia, and insomnia.6,10

CONQUER In the CONQUER trial, overweight and obese patients were randomized to receive 1 year of treatment with placebo, phentermine/topiramate ER 7.5 mg/46 mg, or phentermine/topira-

mate 15 mg/92 mg, in a 2:1:2 ratio.12 Eligible patients had to have a BMI ≥27 kg/m2 and ≤45 kg/m2 (no lower limit on BMI for patients with type 2 diabetes) and ≥2 obesity-related comorbidities, including elevated BP (≥140/90 mm Hg, or ≥130/85 mm Hg for diabetic patients) or a requirement for ≥2 antihypertensive medications; triglycerides ≥200-400 mg/dL or receiving treatment with ≥2 lipid-lowering agents; elevated fasting blood glucose (>100 mg/dL) or diabetes; and/or a waist circumference of ≥102 cm for men and ≥88 cm for women.10,12 At the start of the study, 53% of the patients had hypertension and 16% had type 2 diabetes. Patients were advised to maintain a well-balanced, reduced-calorie diet (500-kcal daily decrease in caloric intake), and all were offered nutritional and lifestyle modification counseling.10,12

DECEMBER 2012

Treatment with all doses of phentermine/topiramate ER after 1 year showed significant weight loss compared with placebo (Table 2).10,12 Moreover, 1 year of therapy with phentermine/topiramate ER resulted in relative improvements compared with placebo in obesity-related cardiometabolic risk factors, with the exception of heart rate (Table 3).10 The most common AEs were dry mouth, paresthesia, constipation, insomnia, dizziness, and dysgeusia.12

A Recent Trial: SEQUEL Results of a third trial were published in 2012.8 The SEQUEL trial was a double-blind, placebo-controlled extension of the CONQUER trial that assessed the longer-term safety and efficacy of 2 doses of phentermine/ topiramate ER, in conjunction with lifestyle modification, for an additional

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Drug Update 52 weeks (total of 108 weeks’ treatment duration).8 At 108 weeks, phentermine/topiramate ER showed significant, sustained weight loss in the intent-to-treat/lastobservation-carried-forward population compared with placebo (P <.001); and significantly more patients achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared with placebo (P <.001).8 Phentermine/topiramate ER was also associated with sustained improvements in the clinical manifestations of weight-related cardiometabolic comorbidities, including hyperglycemia, dyslipidemia, and elevated BP.8 The most common AEs were upper respiratory tract infection, constipation, paresthesia, sinusitis, and dry mouth.8 Safety Profile and Metabolic Properties The effect of phentermine/topiramate ER on CV morbidity and mortality has not been established. The safety and effectiveness of phentermine/topiramate ER in combination with other products that are intended for weight loss, including prescription and overthe-counter drugs and herbal preparations, have not been established.10 The most common AEs associated with phentermine/topiramate ER (incidence ≥5% and at a rate of at least 1.5 times placebo) include paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth.10 There are no black box warnings associated with the use of phentermine/topiramate ER.

Contraindications Phentermine/topiramate ER is contraindicated in pregnant women; in patients with glaucoma; in patients with hyperthyroidism; in those receiving treatment or within 14 days after treatment with monoamine oxidase inhibitors; and in patients with hypersensitivity to sympathomimetic amines, topiramate, or any of the inactive ingredients in phentermine/topiramate ER.10 Important Safety Information Phentermine/topiramate ER can cause fetal harm. Women of reproductive potential should have a negative pregnancy test before treatment and monthly thereafter, and they should use effective contraception consistently during therapy with phentermine/ topiramate ER. Phentermine/topiramate ER can cause an increase in resting heart rate.

Regular measurement of resting heart rate is recommended for all patients taking phentermine/topiramate ER, particularly patients with cardiac or cerebrovascular disease or when initiating or increasing the dose.

Topiramate, a component of phentermine/topiramate ER, increases the risk of suicidal thoughts or behavior in pa-

24

tients taking these drugs for any indication. Patients should be monitored for the emergence or the worsening of depression, suicidal thoughts or behavior, and/or for any unusual changes in mood or behavior. Phentermine/topiramate ER should be discontinued in patients who experience suicidal thoughts or behaviors; it is not recommended in patients with a history of suicidal attempts or active suicidal ideation.

At 108 weeks, phentermine/ topiramate ER showed significant, sustained weight loss compared with placebo; and significantly more patients achieved ≥5%, ≥10%, ≥15%, and ≥20% weight loss compared with placebo.

Acute angle closure glaucoma has been reported in patients who are treated with topiramate, a component of phentermine/topiramate ER. Symptoms include acute onset of decreased visual acuity and/or eye pain. Symptoms typically occur within 1 month of the initiation of topiramate, but they may occur at any time during therapy.

The primary treatment to reverse symptoms is immediate discontinuation of phentermine/topiramate ER. Mood disorders, including depression and anxiety, as well as insomnia, can occur with phentermine/topiramate ER. In addition, phentermine/ topiramate ER has the potential to impair cognitive function, including impairment of concentration/attention, difficulty with memory, and speech or language problems. Patients should be cautioned about operating hazardous machinery, including automobiles.

Hyperchloremic, nonanion gap, metabolic acidosis has been reported in patients being treated with phentermine/topiramate ER. If metabolic acidosis develops and persists, consideration should be given to reducing the dose or discontinuing the use of the drug.

Phentermine/topiramate ER can cause an increase in serum creatinine.

If persistent elevations in creatinine occur while taking phentermine/topiramate ER, the dose should be reduced or the drug should be discontinued.

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus who are being treated with insulin and/or insulin secretagogues (eg, sulfonylureas).

Phentermine/topiramate has not been studied in combination with insulin.

A reduction in the dose of antidiabetes medications that are non–glu-

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

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cose dependent should be considered to mitigate the risk of hypoglycemia.10

Specific Populations Nursing mothers. Phentermine/topiramate ER may be present in human milk, because topiramate and amphetamines (phentermine has pharmacologic activity and a chemical structure similar to amphetamines) are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother.10 Pediatric use. The safety and effectiveness of phentermine/topiramate ER in pediatric patients aged <18 years have not been established, and the use of phentermine/topiramate ER is not recommended in pediatric patients.10 Geriatric use. Clinical studies of phentermine/topiramate ER did not include sufficient numbers of subjects aged ≥65 years to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or of other drug therapies.10 Renal impairment. No dose adjustments are necessary in patients with mild renal impairment. In patients with moderate (creatinine clearance [CrCl] ≥30-<50 mL/min) and severe (CrCl <30 mL/min) renal impairments, the dose should not exceed phentermine/topiramate ER 7.5 mg/ 46 mg once daily.10 Hepatic impairment. No dose adjustments are necessary in patients with mild hepatic impairment. In patients with moderate hepatic impairment, the dose should not exceed phentermine/topiramate ER 7.5 mg/46 mg once daily. Phentermine/topiramate ER has not been studied in patients with severe hepatic impairment (Child-Pugh score 10-15). Use in this patient population should be avoided.10 Potential for Abuse and Dependence Phentermine/topiramate ER is a Schedule IV controlled substance because it contains phentermine, a Schedule IV drug. Topiramate is not a controlled substance. Phentermine, a component of phentermine/topiramate ER, is related chemically and pharmacologically to amphetamines, and it has a known potential for abuse.

The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including phentermine/topiramate ER as part of a weight-reduction program.10 Phentermine/topiramate ER has not

been systematically studied for its potential to produce physical dependence. Limited information on the potential for physical dependence for the individual components of phentermine/topiramate ER is available.

Abrupt discontinuation of topiramate has been associated with seizures in patients without a history of seizures or epilepsy. The abrupt cessation of phentermine after prolonged highdosage administration may result in extreme fatigue, mental depression, and changes on a sleep electroencephalogram. In situations where rapid withdrawal of phentermine/ topiramate ER is required, appropriate medical monitoring is recommended.10 Conclusion Clinical evidence has established the significant effect of phentermine/topiramate ER on weight loss, in conjunction with lifestyle modification, in obese patients and overweight patients with significant cardiometabolic comorbidities, such as diabetes type 2, dyslipidemia, and hypertension. Reducing weight in this patient population has been shown to improve overall health, specifically cardiometabolic health. This new combination therapy is another option to help patients reduce and maintain weight loss, in combination with diet and exercise, as a way to improve overall health. ■ References 1. National Institutes of Health, Department of Health and Human Services. About NIH obesity research.

Background. http://obesityresearch.nih.gov/about/.

Accessed December 4, 2012.

2. Centers for Disease Control and Prevention. Obesity and overweight for professionals. Causes and consequences. www.cdc.gov/obesity/adult/causes/index. html. Accessed December 4, 2012.

3. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009-2010. NCHS Data Brief. 2012;82:1-8.

4. Centers for Disease Control and Prevention. Overweight and obesity. Adult obesity facts. www.cdc.gov/ obesity/data/adult.html. Accessed December 4, 2012.

5. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable to obesity: Payerand service-specific estimates. Health Aff (Millwood).

2009;28:w822-w831.

6. Allison DB, Gadde KM, Garvey WT, et al. Controlledrelease phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.

7. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011;34:1481-1486.

8. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebocontrolled, phase 3 extension study. Am J Clin Nutr.

2012;95:297-308.

9. Fitzgerald K. Qsymia for weight management approved by FDA [press release]. July 22, 2012. Med News Today. MediLexicon, Intl. www.medicalnewstoday. com/ articles/248134.php. Accessed November 29, 2012.

10. Qsymia (phentermine and topiramate extended-release) capsules [prescribing information]. Mountain View, CA: VIVUS; 2012.

11. Qsymia (phentermine and topiramate extended-release) capsules. Risk Evaluation and Mitigation Strategy (REMS). www.qsymiarems.com/. Accessed November 29, 2012.

12. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial. Lancet.

2011;377:1341-1352; correction, Lancet. 2011;377:1494.

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Continuing Education

Value-Based Treatment Paradigms in Cardiovascular and Metabolic Disorders

E

ach year, more than 2 million Americans suffer a myocardial infarction (MI) or stroke, and more than 800,000 of them die.1,2 Moreover, annual direct and overall costs resulting from cardiovascular disease (CVD) are estimated at $273 billion and $444 billion, respectively, with inflation-adjusted direct medical costs for CVD projected to triple to $818 billion over the next 20 years if present trends continue (Figure).2-4 Indeed, the cost of treating and preventing CVD has been growing at an average annual rate of 6% and today represents 17% of overall national healthcare expenditures.3 Accompanying this growth in costs, however, has been greater life expectancy, which would seem to indi-

cate that the expense has been worthwhile. Nevertheless, there are many opportunities to further improve cardiometabolic health while controlling costs, both in the form of disease management and prevention.

CVD is largely preventable—in fact, several pivotal studies have shown that individuals with major atherosclerotic risk factors at favorable levels experience a significantly reduced incidence of CVD and heart failure.3,5,6 Moreover, epidemiologic data from observational studies have shown an association between lower blood glucose levels, blood pressure (BP), and lipid parameters and a lower incidence of microand macrovascular complications, especially in people with diabetes.7 This

Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by an educational grant from Amgen, Inc. Target Audience The activity was developed for physicians and pharmacists involved in the management of patients with cardiovascular and metabolic disorders.

Purpose Statement The purpose of this activity is to enhance competence of physicians and pharmacists concerning the management of cardiovascular and metabolic disorders.

Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-12-029-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Incorporate the existing and emerging clinical data and evolving evidence-based guidelines for the personalized management of (including hypertension, acute coronary syndromes, congestive heart failure, and atrial fibrillation) and stroke • Apply the latest prevention paradigms for and stroke that incorporate optimal lipid management and modification of lifestyle-associated risk factors Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted

by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

article will focus on improving valuebased care for hypertension and stroke (especially in patients with diabetes or chronic renal disease [CRD]), and on primary prevention of cardiometabolic disease as suggested by the Million Hearts™ initiative of the American Heart Association (AHA).

Management of CVD Risk Factors Hypertension is an independent risk factor for CVD-related events such as congestive heart disease, stroke, and heart failure.8,9 However, current control rates, ie, systolic blood pressure (SBP) <140 mm Hg and diastolic BP <90 mm Hg, are still far below the Healthy People goal of 50% of the population, despite the fact that results

from clinical trials such as ALLHAT, CONVINCE, HOPE, HOT, LIFE, PROGRESS, and Syst-EUR have firmly established that reducing BP in patients with hypertension significantly reduces the risk of CV events.10-16 Although effective BP control can be achieved in most patients with hypertension, the majority will need ongoing therapy with 2 or more antihypertensive drugs, in addition to lifestyle modifications.10,11 The improvements in clinical outcomes associated with virtually any reduction in BP can be quite substantial. For example, a recent meta-analysis of 61 studies involving more than 1 million patients showed that prolonged reduction of as little as 2 mm Hg can reduce the

Planners’ and Managers’ Disclosures Sy Schlager, MD, PhD, Medical Writer, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use of any product/device.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Kenneth L. Schaecher, MD, FACP, CPC, Medical Director, SelectHealth, Murray, UT, has nothing to disclose. He does not intend to discuss any non–FDA-approved or investigational use of any product/device.

Peter P. Toth, MD, PhD, Director of Preventative Cardiology, CGH Medical Center, Sterling, IL, and Professor of Clinical Family and Community Medicine, University of Illinois College of Medicine, Peoria, IL, is on the speakers’ bureau for Abbott, Amylin, AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Kowa, and Merck, and is a consultant for Amgen, AstraZeneca, Atherotech, Boehringer-Ingelheim, Kowa, and Merck. He does not intend to discuss any non–FDA-approved or investigational use of any product/device.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE activity for any amount during the past 12 months.

Disclaimer The information provided in this CME/CPE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12040.html.

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Supported by an educational grant from Amgen, Inc. This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

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Continuing Education risk of death due to stroke by 10% and the risk of death due to ischemic heart disease or other vascular causes by 7%; a reduction in SBP of 10 mm Hg can reduce the long-term risk of these events by 40% and 30%, respectively.14 Another study has shown that effective antihypertensive therapy reduces the risk of stroke by 35% to 40%, the risk of MI by 20% to 25%, and the risk of congestive heart failure (CHF) by >50%.15 Moreover, in patients with CVD, antihypertensive therapy has been associated with a decreased risk of stroke, CHF, composite CVD events, and all-cause mortality, even in those without overt hypertension.17 Thus, optimal use of antihypertensive agents is critical in reducing CV morbidity and mortality.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the 2007 AHA guidelines have set consensus goals for BP in patients with hypertension with or without overt CVD or comorbidities (eg, diabetes mellitus or CRD)10,11,18: <140/90 mm Hg for those without overt CVD or comorbid conditions and <130/80 mm Hg for individuals with diabetes mellitus or CRD. Moreover, it appears from the results of the TROPHY study that treatment of prehypertension (120-139/80-89 mm Hg) reduces the incidence of subsequent hypertension.19 More than two-thirds of hypertensive individuals cannot be controlled on 1 drug and will require 2 or more antihypertensive agents selected from different drug classes,10,11 thus posing complex management issues for clinicians. Although it has been suggested that certain classes of antihypertensive drugs, through mechanisms not related to their BP-lowering effect, may have greater antiatherosclerotic properties than others, studies have not convincingly demonstrated this fact.18 Toward Personalized, EvidenceBased Antihypertensive Therapy The choice of drug class for initial antihypertensive therapy and of agent(s) to add to the initial choice to obtain additional BP-lowering effects is still open to interpretation and is continuously evolving as emerging data from clinical trials become available. JNC 7 and AHA guidelines suggest thiazide-type diuretics as the preferred initial agent, largely on the basis of ALLHAT,20 either alone or in combination with one of the other classes of agents (angiotensinconverting enzyme inhibitors [ACEIs], angiotensin-receptor blockers [ARBs], β-blockers, or calcium channel blockers).10,11 Initiating therapy with 2 drugs should be considered when BP is >20 mm Hg above systolic goal or 10 mm

26

Hg above diastolic goal, either as separate prescriptions or in fixed-dose combinations. Moreover, JNC 7 and AHA guidelines allow for personalized, evidence-based antihypertensive therapy, allowing drug choices to be based on individual patient characteristics, including the severity of the hypertension and the presence of compelling indications (eg, heart failure, post-MI management, high coronary disease risk, diabetes, CRD, African American race, or recurrent stroke prevention).

As a result, the JNC 7, AHA, and American College of Cardiology guidelines provide a complex, outcome studies– based algorithm for hypertension management in which certain classes of drugs are especially recommended for specific patients with unique clinical conditions.10,11,18 In addition, the results from a number of epidemiologic and landmark studies have been incorporated into several recent evidencebased guidelines for hypertension management.18,21,22 In general, these guidelines recommend that the management of hypertension be individualized based on its severity and the presence of comorbidities, such as dia-

A substantial body of evidence indicates that direct renin inhibitors provide the most comprehensive inhibition of the reninangiotensin-aldosterone system compared with other inhibitors of the pathway.

betes, obesity, the metabolic syndrome, and renal disease or dysfunction, as well as the patient’s history and future risk of abnormalities in cardiac structure or function, stroke, atherosclerosis, and end-organ damage. In all cases, however, the guidelines stress that BP should be decreased to <140/90 mm Hg in patients with uncomplicated hypertension and to <130/80 mm Hg in those patients with diabetes or CRD. To further complicate the optimal management of patients with hypertension, a number of new agents, some with novel mechanisms of action, have been evaluated in recent clinical studies and approved for use by the US Food and Drug Administration (FDA).

These new agents are a welcome addition to the antihypertensive armamentarium. The 2007 European Society of Hypertension and European Society of Cardiology guidelines on combination therapy are clearly based on evidence that optimal BP control often requires

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DECEMBER 2012 2012 DECEMBER

Figure Estimated Direct and Indirect Costs of Major Cardiovascuar Diseases, United States, 2010 $108.9

Coronary Heart Disease $93.5

Hypertensive Disease

$53.9

Stroke

$34.4

Heart Failure 0

100

200

Cost in Billions Sources: References 2,3

combinations of agents with different and complementary mechanisms of action, additive or synergistic effects on BP lowering, and an enhanced safety profile due to complementary, counterregulatory mechanisms.22 In this regard, direct inhibitors of the renin-angiotensin-aldosterone system (RAAS) are important new agents in BP control. For example, a substantial body of evidence indicates that direct renin inhibitors (DRIs) provide the most comprehensive inhibition of RAAS compared with other inhibitors of the pathway.23 Several studies have demonstrated the antihypertensive efficacy of monotherapy with aliskiren (a first-in-class DRI) when compared with ACEIs/ARBs; this efficacy was further augmented when aliskiren was used concomitantly with these agents.24-29 Similarly, newer agents and fixeddose combinations have been developed with better efficacy, safety, tolerability, and/or patient adherence profiles in already established classes of drugs, such as the new-generation ARB azilsartan30 and single-pill combinations of amlodipine/valsartan31 and irbesartan/hydrochlorothiazide.32 It is critical that healthcare providers who manage patients with hypertension, especially those with important comorbid conditions such as diabetes and CRD, remain up-to-date on evolving guidelines, emerging new agents, and novel drug-combination strategies, so that they can provide their patients with optimal, value-based care.

New Strategies for the Prevention of Stroke Atherosclerotic intracranial arterial stenosis is one of the most common causes of stroke worldwide and is associated with a high risk of recurrent stroke.33-36 Patients with transient ischemic attack (TIA) or stroke and severe stenosis (70%-99% of the diameter of a major intracranial artery) are at particularly high risk for recurrent stroke (~23% at 1 year) in the territory of the

stenotic artery, despite treatment with aspirin and standard management of vascular risk factors.36,37 Therefore, alternative management approaches are needed for these patients.

One important approach involves the primary prevention of stroke. In this regard, the AHA and American Stroke Association (ASA) recently updated their guidelines for healthcare professionals to adopt.38 These new guidelines include novel schemes for assessing an individual’s risk for a first stroke and the potential to modify these risk factors, which include hypertension, smoking, diabetes, atrial fibrillation and other CV conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity/ body fat distribution. Less well-documented or potentially modifiable risk factors include the metabolic syndrome, excessive alcohol consumption, drug abuse, use of oral contraceptives, sleep-disordered breathing, migraine, hyperhomocysteinemia, elevated lipoprotein(a), hypercoagulability, inflammation, and infection. It is critical that clinicians be familiar with these authoritative, evidence-based guidelines for managing their patients who are at risk for stroke.

In addition, 2 important strategies have emerged for the treatment of highrisk patients who have had a stroke and are at high risk for recurrence: aggressive medical therapy and percutaneous transluminal angioplasty and stenting (PTAS), which has been available in the United States since 2005.39 In the recently reported SAMMPRIS trial, 451 patients who had had a recent TIA or stroke attributed to severe stenosis of a major intracranial artery were randomized to aggressive medical management, either alone or with PTAS utilizing the Wingspan stent system (Boston Scientific). Aggressive medical management was defined as the use of aspirin 325 mg/day and clopidogrel 75 mg/day plus aggressive management

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Continuing Education of primary (elevated SBP and low-density lipoprotein [LDL]-cholesterol levels) and secondary (diabetes, elevated non–high-density lipoprotein [HDL]cholesterol levels, smoking, excess weight, and insufficient exercise) risk factors. Target SBP was <140 mm Hg (<130 mm Hg in those with diabetes) and target LDL cholesterol was <70 mg/dL. The primary end point for the study was stroke or death within 30 days of enrollment or after a revascularization procedure. The trial was stopped early because an interim analysis revealed that the 30-day rate of stroke or death was 14.7% in the PTAS group and 5.8% in the medical management group (P = .002).39 This study was instructive in showing that in patients with severe intracranial arterial stenosis, aggressive medical management is superior to PTAS in reducing the risk of fatal and nonfatal stroke. Despite some issues with study design and technical aspects of the endovascular treatment protocol, the results of this study are expected to affect the practice of endovascular therapy for intracranial atherosclerotic disease.40 Clinicians should therefore be aware of these data to understand the optimal medical management of patients with intracranial stenosis who are at risk for recurrent stroke.

Primary Prevention of Cardiometabolic Disease On September 13, 2011, a consortium of federal and local government agencies, including the US Department of Health and Human Services, along with the AHA and a broad range of private-sector partners, launched the Million Hearts initiative to prevent 1 million MIs and strokes over the next 5 years by implementing evidencebased, cost-effective interventions.1,2,41 In addition to community initiatives, the Million Hearts program provides specific approaches for clinicians to adopt in preventing CVD and stroke in their patients who are at risk (Table).41 The so-called ABCS approach consists of a multidimensional program to institute aspirin use, achieve and maintain BP control, manage cholesterol and other dyslipidemias, and encourage smoking cessation. The clinical approaches specified by ABCS include communication, clinical measurement, and reporting by physicians, healthcare facilities, and healthcare systems; optimal use of health information technology, such as registries and electronic health record functions at the point of care, to help target interventions to patients in need of intensified care; and clinical innovations such as team-based care, interventions to support patient adherence to lifestyle changes and medication, and effective

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Table ABCS Goals of the American Heart Association’s Million Hearts™ Initiative41 Indicator

Baseline

2017 Goal

Aspirin use for high-risk patients

47%

65%

Blood pressure control

46%

65%

Effective treatment of elevated LDL cholesterol

33%

65%

Smoking prevalence

19%

17%

3.5 g/d

20% reduction

1% of calories/d

50% reduction

Average sodium intake Average artificial trans fat consumption

dissemination of patient information.1,2 Specific clinical recommendations for lifestyle modification and management of dyslipidemias have been extensively communicated to the healthcare community, including in JNC 7 and the Third Report of the National Choles-

Two critical lifestyle changes that have been found to be beneficial in preventing MI and stroke are weight reduction and smoking cessation.

terol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III), which was recently updated.10,11,42,43 Two critical lifestyle changes that have been found to be beneficial in preventing MI and stroke are weight reduction in overweight and obese patients and smoking cessation.44 Lifestyle changes beneficial in reducing weight include: • Decreasing time in sedentary behaviors such as watching television, playing video games, or spending time online • Increasing physical activity such as walking, biking, aerobic dancing, tennis, soccer, basketball, etc • Decreasing portion sizes for meals and snacks • Reducing portion sizes or frequency of consumption of calorie-containing beverages • Adopting healthy eating habits in which dietary fat and carbohydrates are carefully controlled In addition, there are a number of smoking cessation programs, including counseling and pharmacotherapy, that can be applied in the healthcare setting.45 These evidence-based strategies include identifying smokers in the healthcare setting, motivating the unwilling patient through interviewing, providing information about smoking cessation support groups, and providing counseling about FDA-approved

medications such as sustained-release bupropion; nicotine gum, inhaler, lozenges, nasal spray, or patch; varenicline; and combination therapies such as nicotine patch + bupropion or nicotine patch + gum, inhalers, or lozenges.

An evidence-based intervention algorithm has been developed for patients who are willing to initiate an attempt to quit smoking during a clinic visit45 and which healthcare providers should become familiar with and implement in their practice.

A comprehensive review of JNC 7 and ATP III guidelines for managing dyslipidemias, especially elevated cholesterol, is outside the scope of this article. However, it has been well documented that statins are significantly beneficial in lowering total LDL cholesterol and triglycerides while raising HDL cholesterol, conferring statistically significant, clinically important reductions in the risk for MI, stroke, and CV death.10,11,42,43 The updated ATP III guidelines recommend statin therapy to reach goals of LDL <70 mg/dL for high-risk patients, <100 mg/dL for moderate-risk patients, and <160 mg/dL for low-risk patients.43 Data from recent statin trials (HPS, PROSPER, ALLHAT-LLT, ASCOT-LLT, REVERSAL, PROVE-IT, CARDS, TNT) demonstrated that greater LDL reductions produce larger CVD benefits in high- and moderate-risk patients, including primary prevention in patients with the metabolic syndrome, as well as patients with diabetes, who should be treated as aggressively as those who have survived an MI or stroke.43 Conclusion The guidelines for primary prevention of CVD and stroke are continuously being updated, and it is imperative that healthcare providers remain up-to-date on these evolving recommendations, both in terms of lifestyle modification and pharmacologic intervention, to help empower their patients to make healthy lifestyle choices and lower their risk for cardiometabolic disease.

By the same token, payers must also improve their knowledge of the full range of risk factors for cardiometa-

DECEMBER 2012

bolic disease so as to make informed decisions regarding support for primary prevention of and value-based therapeutic approaches to CVD. In this regard, a recent survey of leading authorities from 240 health plans elucidated the following46: • A significant percentage of the payers were only marginally versed in the complexities of dyslipidemia management in preventing CVD (especially in diabetic patients) • The respondents’ payer organizations typically await definitive guidelines from AHA or the National Committee for Quality Assurance before including guidelines for best practice standards for providers to follow • Payers in general are not open to reimbursement for “exciting but unverified” types of clinical research in fighting cardiometabolic risk These results suggest that education of all stakeholders in the prevention and management of cardiometabolic disease—the provider, the patient, and the payer—is necessary to truly achieve value-based care. ■

References 1. Frieden TR, Berwick DM. The “Million Hearts” initiative—preventing heart attacks and strokes. N Engl J Med. 2011;365:e27.

2. Centers for Disease Control and Prevention (CDC).

Million hearts: strategies to reduce the prevalence of leading cardiovascular disease risk factors—United States, 2011. MMWR Morb Mortal Wkly Rep. 2011;60: 1248-1251.

3. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933-944.

4. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125: e20-e220.

5. Folsom AR, Yamagishi K, Hozawa A, Chambless LE; for the Atherosclerosis Risk in Communities Study Investigators. Absolute and attributable risks of heart failure incidence in relation to optimal risk factors. Circ Heart Fail. 2009;2:11-17.

6. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012-2018.

7. Tandon N, Ali MK, Narayan M. Pharmacologic prevention of microvascular and macrovascular complications in diabetes mellitus: implications of the results of recent clinical trials in type 2 diabetes. Am J Cardiovasc Drugs. 2012;12:7-22.

8. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension. 2007;49:69-75.

9. Wong ND, Lopez VA, L’Italien G, Chen R, Kline SE, Franklin SS. Inadequate control of hypertension in US adults with cardiovascular disease comorbidities in 2003-2004. Arch Intern Med. 2007;167:2431-2436.

10. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 2003;289:2560-2571.

11. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.

12. Turnbull F; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressurelowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362:1527-1535.

13. Duprez DA. Role of the renin-angiotensin-aldosterone system in vascular remodeling and inflammation: a clinical review. J Hypertens. 2006;24:983-991.

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Continuing Education 14. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-1913.

15. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other bloodpressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet. 2000; 356:1955-1964.

16. Ogden LG, He J, Lydick E, Whelton PK. Long-term absolute benefit of lowering blood pressure in hypertensive patients according to the JNC VI risk stratification. Hypertension. 2000;35:539-543.

17. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA. Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis.

JAMA. 2011;305:913-922.

18. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the councils on clinical cardiology and epidemiology and prevention. Circulation.

2007;115:2761-2788.

19. Julius S, Nesbitt SD, Egan BM, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354:1685-1697.

20. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium chan-

nel blocker vs diuretic: the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997.

21. Khan NA, Hemmelgarn B, Herman RJ, et al. The 2009 Canadian Hypertension Education Program recommendations for the management of hypertension: part 2—therapy. Can J Cardiol. 2009;25:287-298.

22. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-1187.

23. Sarafidis PA, Bakris GL. Renin-angiotensin blockade and kidney disease. Lancet. 2008;372:511-512.

24. O’Brien E, Barton J, Nussberger J, et al. Aliskiren reduces blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin-converting enzyme inhibitor, or an angiotensin receptor blocker. Hypertension. 2007;49:276-284.

25. Uresin Y, Taylor AA, Kilo C, et al. Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension. J Renin Angiotensin Aldosterone Syst. 2007;8:190-198.

26. Cherney DZ, Scholey JW, Jiang S, et al. The effect of direct renin inhibition alone and in combination with ACE inhibition on endothelial function, arterial stiffness, and renal function in type 1 diabetes. Diabetes Care. 2012;35:2324-2330. Epub 2012 Jul 26. doi: 10.2337 /dc12-0773.

27. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, double-blind trial. Lancet. 2007;370:221-229.

28. Chrysant SG, Murray AV, Hoppe UC, et al. Long-term safety, tolerability and efficacy of aliskiren in combination with valsartan in patients with hypertension: a 6-month interim analysis. Curr Med Res Opin. 2008;24:1039-1047.

29. Rizos EC, Agouridis AP, Elisaf MS, et al. Aliskiren in patients with diabetes: a systematic review. Curr Vasc Pharmacol. 2012;10:140-146.

30. Lam S. Azilsartan: a newly approved angiotensin II receptor blocker. Cardiol Rev. 2011;19:300-304.

31. Lins R, Aerts A, Coen N, et al. Effectiveness of amlodipine-valsartan single-pill combinations: hierarchical modeling of blood pressure and total cardiovascular disease risk outcomes (the EXCELLENT study). Ann Pharmacother. 2011;45:727-739.

32. Asmar R, Oparil S. Comparison of the antihypertensive efficacy of irbesartan/HCTZ and valsartan/HCTZ combination therapy: impact of age and gender. Clin Exp Hypertens. 2010;32:499-503.

33. Arenillas JF. Intracranial atherosclerosis: current concepts. Stroke. 2011;42(suppl 1):S20-S23.

34. Kim JS, Kang DW, Kwon SU. Intracranial atherosclerosis: incidence, diagnosis, and treatment. J Clin Neurol.

2005;1:1-7.

35. Meseguer E, Lavallée PC, Mazighi M, et al. Yield of systematic transcranial Doppler in patients with transient ischemic attack. Ann Neurol. 2010;68:9-17.

36. Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation. 2006;113:555-563.

37. Zaidat OO, Klucznik R, Alexander MJ, et al. The NIH registry on use of the Wingspan stent for symptomatic 70-99% intracranial arterial stenosis. Neurology.

2008;70:1518-1524.

38. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline

for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011; 42:517-584.

39. Chimowitz MI, Lynn MJ, Derdeyn CP, et al; SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med. 2011;365:993-1003.

40. Qureshi AI. Interpretation and implications of the prematurely terminated Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in the Intracranial Stenosis (SAMMPRIS) trial. Neurosurgery.

2012;70:E264-E268.

41. New public-private sector initiative aims to prevent 1 million heart attacks and strokes in 5 years [press release]. Washington, DC: US Department of Health and Human Services; September 13, 2011. http://www.hhs.gov/news/press/2011pres/09/201 10913a.html. Accessed September 12, 2012.

42. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation. 2002;106:31433421.

43. Hennekens CH, Hollar D, Eidelman RS, Agatston AS. Update for primary healthcare providers: recent statin trials and revised National Cholesterol Education Program III guidelines. MedGenMed. 2006;8:54.

44. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med. 2011;364:23922404.

45. Fiore MC, Baker TB. Treating smokers in the health care setting. N Engl J Med. 2011;365:1222-1231.

46. Henry RE. Residual cardiovascular risk. A research report. Value-Based Care Cardiometabol Health. April 2012.

population management and valuebased initiatives, due to regulations surrounding these markets.

Current approaches common to most health plans related to CV and metabolic health include disease management programs, patient education initiatives, and provider financial incentives around prespecified health targets such as low-density lipoprotein levels in diabetic patients or blood pressure control. The targets are often focused on Healthcare Effectiveness Data and Information Set (HEDIS®) and Star ratings, which form the basis of how plans are compared with each other and may impact their reimbursement levels. It is controversial as to whether this approach has helped improve the population’s health,1,2 and increasingly, health plans are looking at alternative, more cost-effective strategies geared toward improving both population health and the overall cost of care in the United States.

The biggest factor impacting the success of population health management efforts is individual patient engage-

ment. Payers are becoming more aware of the limits of their current measures and are seeking programs that engage patients in the management of their own health. The most common vehicles being explored are health and wellness programs and value-based benefit designs. Payers and employers have begun to recognize that a healthier population results in reduced cost expenditures, while those who are the least healthy generate a disproportionately greater share of healthcare expenses.3 Health and wellness programs center around members and employees being rewarded or penalized, depending on their involvement. These programs focus on primary prevention of healthcare problems and address root causes such as obesity, tobacco dependence, and other factors that trigger increased metabolic and CV risk. Value-based benefit designs, which can be used to complement health and wellness programs, strive to use evidence-based medicine to reduce the financial barriers for patients. These designs have com-

Payer Commentary Kenneth L. Schaecher, MD, FACP, CPC Medical Director, SelectHealth, Murray, UT

A

s discussed in the main article of this supplement, there is clearly a strong base of evidence for more effective management and improvement in health outcomes for patients with or at risk for cardiovascular (CV) and metabolic diseases.

It is equally clear that there are many effective tools available to providers to assist their patients. The challenge is translating this evidence into action.

Health plans, whether they are preferred provider organizations, health maintenance organizations involved as part of an integrated delivery system (IDS), accountable care organizations (ACOs), patient-centered medical home (PCMH), or any of the other alphabet soup of organizations out there, are the only part of the healthcare system triad (payers, providers, and facilities) whose main focus is the health of the general population. This primarily stems from the costs associated with population health and the mandate for health plans to hold the fiduciary responsibility for the healthcare system. As such, much of the need to translate the evi-

528

dence on CV health management in actuality falls on health plans.

It is my belief that most, if not all, health plans have embraced this challenge in some form. Several factors impact the manner in which they approach translating this evidence into

Payers are becoming more aware of the limits of their current measures and are seeking programs that engage patients in the management of their own health.

practice. These include whether a health plan is part of an IDS or has embarked on ACO or PCMH pilot projects. Whether a plan is focused on Medicaid or managed Medicare, large group, small group, or the individual market also affects the approach to

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Continuing Education monly been employed around CV and metabolic conditions such as diabetes, particularly as it applies to reduced copayment for drugs. Many health plans offer “zero dollar” copay options for drugs needed to treat diabetes and hypertension as a means of encouraging patients to treat these conditions. Reduced premium costs are also more frequently being implemented for those who demonstrate adherence to their medications. The success of this approach is undecided, with some studies suggesting little benefit and increased

costs, and others demonstrating improved health outcomes and significant healthcare dollar savings.4-6 Whether the program is disease management, provider performance incentives targeting patient outcomes, health and wellness, or value-based benefit designs, the focus of health plans’ efforts remains evidence-based.

Furthermore, payers continually strive to find solutions to the most critical factor that has the greatest impact on health outcomes and healthcare expenditures patient engagement in their

disease state. There remains no single tool that is uniformly effective for an entire population. With application of emerging evidence and the support of providers, we will continue to “move the needle” and achieve better health and lower costs for everyone. ■ References 1. Scanlon DP, Swaminathan S, Chernew M, et al. Competition and health plan performance: evidence from health maintenance organization insurance markets.

Med Care. 2005;43:338-346.

2. Maeng DD, Scanlon DP, Chernew ME, et al. The relationship between health plan performance measures

and physician network overlap: implications for measuring plan quality. Health Serv Res. 2010;45:1005-1023.

Epub 2010 Apr 9.

3. Soni A. Top 10 Most Costly Conditions among Men and Women, 2008: Estimates for the U.S. Civilian Noninstitutionalized Adult Population, Age 18 and Older.

Statistical Brief #331. July 2011. Agency for Healthcare Research and Quality, Rockville, MD. http://www. meps.ahrq.gov/mepsweb/data_files/publications/st3 31/stat331.shtml.

4. Choudhry NK, Rosenthal MB, Milstein A. Assessing the evidence for value-based insurance design. Health Aff. 2010;29:1988-1994.

5. Choudhry NK, Fischer MA, Avorn J, et al. At Pitney Bowes, value-based insurance design cut copayments and increased drug adherence. Health Aff. 2010;29:1995-2001.

6. Maciejewski ML, Farley JF, Parker J, et al. Copayment reductions generate greater medication adherence in targeted patients. Health Aff. 2010;29:2002-2008.

Physician Commentary Peter P. Toth, MD, PhD Director of Preventative Cardiology, CGH Medical Center, Sterling, IL Professor of Clinical Family and Community Medicine, University of Illinois School of Medicine, Peoria, IL

T

he Million Hearts initiative was launched by the US Department of Health and Human Services in 2011, with a stated goal of reducing 1 million strokes and myocardial infarctions (MIs) over 5 years.1 With currently available screening procedures and therapies, is this an achievable goal? Absolutely. It is also an objective to which every healthcare provider can contribute significantly. The approach is simple: stick to the ABCS. Specifically, this means instituting aspirin therapy in patients of appropriate risk, lowering blood pressure (BP), managing cholesterol, and promoting smoking cessation. The program also emphasizes the importance of eating a healthy diet, exercising, and removing barriers to the achievement of cardiovascular (CV) health. In an era of readily available generic medications, the combination of aspirin, BP-lowering medication, and a statin can be prescribed for generally less than a dollar a day. Does this make for a sound investment in health? Given the results of numerous large-scale, randomized, prospective clinical trials, there is no question that it does.

Dyslipidemia and hypertension are highly prevalent throughout the world. The use of statin therapy to reduce the incidence of CV events in both primary and secondary prevention settings is well established.2-6 In general, when it comes to atherogenic lipoprotein burden in serum, greater reductions are more beneficial than lesser ones.7 Reducing BP with a wide variety of medications (eg, thiazide diuretics, calcium channel blockers, β-blockers, angiotensin-converting en™

zyme inhibitors) is also associated with significant reductions in CV morbidity and mortality.8 An increasing epidemic of insulin resistance, the metabolic syndrome, and diabetes mellitus (DM) is occurring throughout the world. According to the Centers for Disease Control and Prevention, in 2010, 79 million adults in the United States had prediabetes and more than 25 million had type 2 DM.9 Factors that potentiate systemic insulin resistance include obesity, sedentary lifestyle, and cigarette smoking.10,11 The Million Hearts’ focus on lifestyle modification will help to impact the prevalence of these conditions.

Ideally, risk factors for DM are identified and treated early to prevent the development and progression of CV disease.

Insulin resistance is the primary etiology for metabolic syndrome and DM, and induces a host of biochemical alterations that can result in impaired glucose metabolism, endothelial dysfunction, hypertension, dyslipidemia, increased inflammatory and oxidative tone, a prothrombotic state, and accelerated atherogenesis.12 Patients with metabolic syndrome and DM have at least a 2- to 4-fold increased risk for acute CV events, including stroke and MI.13,14 Ideally, risk factors for DM are iden-

tified and treated early to prevent the development and progression of CV disease. Weight loss, reductions in caloric intake, smoking cessation, and exercise are critical therapeutic approaches to reducing cardiometabolic risk and new-onset DM. If these measures prove inadequate, aspirin, BP-lowering drugs, statins, and antiglycemic medications are used to manage risk factor burden as appropriate. There is unequivocal evidence that reducing atherogenic lipoprotein burden, normalizing BP, and controlling blood glucose levels decrease risk for a variety of adverse outcomes.15 It will be critical for healthcare providers and managed care organizations to partner effectively in order to take on the challenge of the Million Hearts program. Critical steps to success for reducing the incidence of CV events and new-onset DM will involve instituting guideline-driven treatment of abnormalities in cholesterol and BP, making pharmacologic interventions more readily available for smoking cessation, and providing monitored exercise and dietary programs to patients. We know that these interventions are effective. It is important that we work together for optimal implementation. ■ References 1. New public-private sector initiative aims to prevent 1 million heart attacks and strokes in 5 years [press release]. Washington, DC: US Department of Health and Human Services; September 13, 2011. http://www. hhs.gov/news/press/2011pres/09/20110913a.html.

Accessed November 21, 2012.

2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.

Circulation. 2004;110:227-239.

3. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med. 1996;335:1001-1009.

4. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-thanaverage cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2004;64(suppl 2):43-60.

5. Colhoun HM, Betteridge DJ, Durrington PN, et al.

Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696.

6. Heart Protection Study Collaborative Group: MRC/ BHF Heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.

7. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.

8. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in highrisk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

JAMA. 2002;288:2981-2997.

9. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2011. http://www.cdc.gov/diabetes/pubs/ pdf/ndfs_2011.pdf. Accessed October 21, 2012.

10. Toft I, Bonaa KH, Jenssen, T. Insulin resistance in hypertension is associated with body fat rather than blood pressure. Hypertension. 1998;32:115-122.

11. Facchini FS, Hollenbeck CB, Jeppesen J, et al. Insulin resistance and cigarette smoking. Lancet. 1992;339: 1128-1130.

12. Toth PP. Effective management of the type 2 diabetes patient with cardiovascular and renal disease: secondary prevention strategies after a myocardial infarction.

Curr Diabetes Rev. 2012;8:219-228.

13. Cardiovascular disease and diabetes. American Heart Association Web site. http://www.heart.org/ HEARTORG/Conditions/Diabetes/WhyDiabetes Matters/Cardiovascular-Disease-Diabetes_UCM_ 313865_ Article.jsp. Accessed October 25, 2012.

14. Haffner SM, Lehto S, Rönnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-234.

15. Triplitt C, Alvarez CA. Best practices for lowering the risk of cardiovascular disease in diabetes. Diabetes Spectrum. 2008;21:177-189.

COE100

VOL 1

NO 3

DECEMBER 2012

VALUE-BASED CARE IN CARDIOMETABOLIC HEALTH

29

Jentadueto™ (linagliptin and metformin hydrochloride) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

INDICATIONS AND USAGE: Indication: JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

Important Limitations of Use: JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. JENTADUETO has not been studied in combination with insulin.

CONTRAINDICATIONS: JENTADUETO is contraindicated in patients with:

s Renal impairment (e.g., serum creatinine 1.5 mg/dL for men, 1.4 mg/dL for women, or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions] s Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions] s A history of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin [see Adverse Reactions]

WARNINGS AND PRECAUTIONS: Lactic Acidosis: Metformin: Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 µg/mL are generally found. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, a carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions]. The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointestinal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on a chronic, stable, dose of metformin.

Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease. To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling. Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a

patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery [see Boxed Warning].

Monitoring of Renal Function: Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impairment. Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present. Linagliptin may be continued as a single entity tablet at the same total daily dose of 5 mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment.

Use of concomitant medications that may affect renal function or metformin disposition: Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions]. Radiological studies and surgical procedures: Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin.

Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal. JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal. Impaired Hepatic Function: Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions]. Hypoglycemia: Linagliptin: Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. Metformin: Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking β-adrenergic blocking drugs. Vitamin B12 Levels: In controlled, 29-week clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful. Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions]. Hypoxic States: Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued [see Warnings and Precautions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug.

ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Linagliptin/ Metformin: The safety of concomitantly administered linagliptin (daily dose 5 mg) and metformin (mean daily dose of approximately 1800 mg) has been evaluated in 2816 patients with type 2 diabetes mellitus treated for 12 weeks in clinical trials. Three placebo-controlled studies with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 study was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse events which occurred in 5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo + metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design study, adverse events reported in 5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.

Table 1

Adverse Reactions Reported in 5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Study Placebo Linagliptin Metformin Combination of n=72 Monotherapy Monotherapy Linagliptin with n=142 n=291 Metformin n=286 n (%) n (%) n (%) n (%)

Nasopharyngitis

1 (1.4)

8 (5.6)

8 (2.7)

18 (6.3)

Diarrhea

2 (2.8)

5 (3.5)

11 (3.8)

18 (6.3)

Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.

Linagliptin Monotherapy: Nasopharyngitis was reported in 5% of patients treated with linagliptin and more commonly than in patients treated with placebo (5.8% vs 5.5%). In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient-years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient-years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperactivity) and myalgia. Metformin Monotherapy: The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia) [see Warnings and Precautions]. Hypoglycemia: In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea. Laboratory Tests: Changes in laboratory findings were similar in patients treated with linagliptin + metformin compared to patients treated with placebo + metformin. Changes in laboratory values that occurred more frequently in the linagliptin + metformin group and 1% more than in the placebo group were not detected. No clinically meaningful changes in vital signs were observed in patients treated with linagliptin.

DRUG INTERACTIONS: Drug Interactions with Metformin: Cationic Drugs: Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system [see Warnings and Precautions]. Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase [see Warnings and Precautions]. Drug Interactions With Linagliptin: Inducers of P-glycoprotein and CYP3A4 Enzymes: Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp inducer or CYP 3A4 inducer. As JENTADUETO is a fixed-dose combination of linagliptin and metformin, use of alternative treatments (not containing linagliptin) is strongly recommended when concomitant treatment with a strong P-gp or CYP 3A4 inducer is necessary. Drugs Affecting Glycemic Control: Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving JENTADUETO, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving JENTADUETO, the patient should be observed closely for hypoglycemia.

USE IN SPECIFIC POPULATIONS: Pregnancy: Pregnancy Category B: JENTADUETO: There are no adequate and well controlled studies in pregnant women with JENTADUETO or its individual components, and some clinical data is available for metformin which indicate that the risk for major malformations was not increased when metformin is taken during the first trimester in pregnancy. In addition, metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibility of harm, JENTADUETO should be used during pregnancy only if clearly needed. JENTADUETO was not teratogenic when administered to Wistar Han rats during the period of organogenesis at doses similar to clinical exposure. At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations.

Linagliptin: Linagliptin was not teratogenic when administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times the clinical dose in rats and 1943 times the clinical dose in rabbits, based on exposure. No functional, behavioral, or reproductive toxicity was observed in offspring of female Wistar Han rats when administered linagliptin from gestation day 6 to lactation day 21 at a dose 49 times the maximum recommended human dose,

based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits. Metformin Hydrochloride: Metformin has been studied for embryofetal effects in 2 rat strains and in rabbits. Metformin was not teratogenic in Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to 200 mg/kg (2-3 times the clinical dose based on body surface area or exposure, respectively). At higher maternally toxic doses (9 and 23 times the clinical dose based on exposure), an increased incidence of rib and scapula skeletal malformations was observed in the Wistar Han strain. Metformin was not teratogenic in rabbits at doses up to 140 mg/kg (similar to clinical dose based on body surface area). Metformin administered to female Sprague Dawley rats from gestation day 6 to lactation day 21 up to 600 mg/kg/day (2 times the maximum clinical dose based on body surface area) had no effect on prenatal or postnatal development of offspring. Metformin crosses the placenta into the fetus in rats and humans. Nursing Mothers: No studies in lactating animals have been conducted with the combined components of JENTADUETO. In studies performed with the individual components, both linagliptin and metformin were secreted in the milk of lactating rats. It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of JENTADUETO in pediatric patients have not been established.

Geriatric Use: Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney. Considering that aging can be associated with reduced renal function, JENTADUETO should be used with caution as age increases [see Warnings and Precautions]. Linagliptin: Of the total number of patients (n=4040) in clinical studies of linagliptin, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. Therefore, no dose adjustment is recommended in the elderly population. While clinical studies of linagliptin have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.

Metformin: Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and young patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function [see Contraindications and Warnings and Precautions].

OVERDOSAGE: In the event of an overdose with JENTADUETO, employ the usual supportive measures (e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as dictated by the patient’s clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely. However, metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful partly for removal of accumulated metformin from patients in whom JENTADUETO overdosage is suspected. Linagliptin: During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose), there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.

Metformin: Overdose of metformin has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Boxed Warning and Warnings and Precautions].

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USA Licensed from: Boehringer Ingelheim International GmbH Ingelheim, Germany Copyright 2012 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED January 2012

JD/BS/01-12

JD148400PROF

what matters Improving glycemic control for adult patients with type 2 diabetes *A randomized, double-blind, placebo-controlled, parallel-group study of drug-naïve or previously treated (4 weeks washout and 2 weeks placebo run-in) adult patients with type 2 diabetes and insufficient glycemic control (aged 18-80) who were randomized to placebo (n=72), linagliptin 5 mg once daily (n=142), metformin 500 mg twice daily (n=144), linagliptin 2.5 mg twice daily + metformin 500 mg twice daily (n=143), metformin 1000 mg twice daily (n=147), or linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily (n=143). Primary endpoint was change from baseline A1C at 24 weeks. Results adjusted for 0.1% mean A1C increase for placebo. 29.2% of patients in the placebo group required use of rescue therapy vs 11.1% of patients receiving linagliptin 5 mg once daily, 13.5% of patients receiving metformin 500 mg twice daily, 8.0% of patients receiving metformin 1000 mg twice daily, 7.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 500 mg twice daily, and 4.3% of patients receiving linagliptin 2.5 mg twice daily + metformin 1000 mg twice daily. Full analysis population using last observation on study. † Superiority of both free combination therapies, consisting of the twice daily administration of linagliptin 2.5 mg and metformin (500 mg or 1000 mg), was shown over the individual metformin components (500 mg and 1000 mg, both BID) and over linagliptin 5 mg QD for the change in A1C from baseline at Week 24. Linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to metformin 1000 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 1000 mg BID was superior to linagliptin 5 mg QD (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to metformin 500 mg BID (P<0.0001); linagliptin 2.5 mg BID + metformin 500 mg BID was superior to linagliptin 5 mg QD (P<0.0001). ‡ JENTADUETO studied as coadministered linagliptin and metformin tablets; total daily dose of linagliptin was equal to 5 mg.

Indication and Important Limitations of Use JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate.

JENTADUETO should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin.

Important Safety Information WARNING: RISK OF LACTIC ACIDOSIS Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.

The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately.

CONTRAINDICATIONS JENTADUETO is contraindicated in patients with: Renal impairment (e.g., serum creatinine ≥1.5 mg/dL for men or ≥1.4 mg/dL for women, or abnormal creatinine clearance).

Acute or chronic metabolic acidosis, including diabetic ketoacidosis.

History of hypersensitivity reaction to linagliptin (such as urticaria, angioedema, or bronchial hyperreactivity) or metformin.

WARNINGS AND PRECAUTIONS LACTIC ACIDOSIS Lactic acidosis is a serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases.

The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.

Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis.

The risk of lactic acidosis increases with the degree of renal impairment and the patient’s age.

The risk of lactic acidosis may be significantly decreased by regular monitoring of renal function in patients taking metformin. Treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patients unless measurement of creatinine clearance demonstrates that renal function is not reduced.

Metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.

MONITORING OF RENAL FUNCTION Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified as normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.

Radiological studies and surgical procedures: JENTADUETO should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.

IMPAIRED HEPATIC FUNCTION Impaired hepatic function has been associated with cases of lactic acidosis with metformin therapy. JENTADUETO tablets should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment.

HYPOGLYCEMIA Insulin secretagogues are known to cause hypoglycemia. The use of linagliptin in combination with

Significant A1C reductions (placebo-adjusted) at 24 weeks*†

Placebo-adjusted mean change in A1C at 24 weeks (%)

D LINAGLIPTIN AND METFORMIN IN A SINGLE TABLET W E FOR ADULT PATIENTS WITH TYPE 2 DIABETES NO ROV P Focusing on AP

0

Linagliptin 5 mg QD

Metformin 500 mg BID

8.7%

8.7%

JENTADUETO Linagliptin 2.5 mg/ Metformin 500 mg BID‡

Metformin 1000 mg BID

JENTADUETO Linagliptin 2.5 mg/ Metformin 1000 mg BID‡

Baseline A1C: 8.7%

8.5%

8.7%

-1.3%

(n=138)

-0.2 -0.4 -0.6 -0.8

-0.6% (n=135)

-0.8% (n=141)

-1.0 -1.2 -1.4

-1.2%

(n=137) -1.6

-1.7%

-1.8

(n=140)

JENTADUETO was approved based on clinical trials that evaluated linagliptin and metformin as separate tablets. Bioequivalence of JENTADUETO to linagliptin and metformin coadministered as individual tablets was demonstrated in healthy subjects. an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial. A lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO. VITAMIN B12 LEVELS Vitamin B12 deficiency: Metformin may lower Vitamin B12 levels. Monitor hematologic parameters annually.

ALCOHOL INTAKE Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients should be warned against excessive alcohol intake while receiving JENTADUETO. HYPOXIC STATES Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued.

MACROVASCULAR OUTCOMES There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug.

ADVERSE REACTIONS In a 24-week factorial design study, adverse reactions reported in ≥5% of patients treated with JENTADUETO and more commonly than in patients treated with placebo were nasopharyngitis and diarrhea.

In a 24-week factorial design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin + metformin, 6 (2.1%) of 291 subjects treated with metformin and 1 (1.4%) of 72 subjects treated with placebo. In the placebo-controlled studies, hypoglycemia was more commonly reported in patients treated with the combination of linagliptin and metformin with SU (22.9%) compared with those treated with the combination of placebo and metformin with SU (14.8%).

Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus 0 in 433 person-years for comparator).

DRUG INTERACTIONS Because cationic drugs eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems, careful patient monitoring and dose adjustment of JENTADUETO and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

The efficacy of JENTADUETO may be reduced when administered in combination with a strong P-glycoprotein inducer and CYP3A4 inducer (e.g., rifampin). Use of alternative treatments is strongly recommended.

The concomitant use of carbonic anhydrase inhibitors (e.g., topiramate) and metformin may induce metabolic acidosis. Use these drugs with caution in patients treated with JENTADUETO, as the risk of lactic acidosis may increase.

USE IN SPECIFIC POPULATIONS As there are no adequate and well-controlled studies in pregnant women, the safety of JENTADUETO in pregnant women is not known. JENTADUETO should be used during pregnancy only if clearly needed.

It is not known whether linagliptin is excreted in human milk. Metformin is excreted in human milk in low concentrations. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The safety and effectiveness of JENTADUETO in patients below the age of 18 have not been established.

JENTADUETO should be used with caution as age increases, as aging can be associated with reduced renal function.

JD PROF ISI FEB272012

Please see adjacent pages for brief summary of full Prescribing Information and Boxed Warning regarding the risk of lactic acidosis.

Find out more about JENTADUETO and the Savings Card program at www.jentadueto.com Copyright © 2012, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(03/12)

JD184306PROFB