Value-Based Care Cardiometabolic Health August 2012, Vol 1, No 2

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AMERICAN DIABETES ASSOCIATION 2012 HIGHLIGHTS

AUGUST 2012, VOL 1, NO 2

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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Cardiometabolic health highlighted at ADA 2012

UKPDS Follow-Up: Early HbA1c Reductions Linked to a Decrease in MI, All-Cause Mortality

By Wayne Kuznar

Major benefits of sustained control are seen 5-10 years later

The Diabetes Epidemic Is Like a Tsunami Hitting in Waves

By Mary Mosley

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educing hemoglobin (Hb) A1c levels as soon as possible after the diagnosis of type 2 diabetes results in a reduction in the diabetesrelated complications, including myocardial infarction (MI) and all-cause mortality. This early reduction in the HbA1c level explains the so-called legacy effect found in the UKPDS (United Kingdom Prospective Diabetes Study), stated Marcus Lind, MD, of the Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden, who presented an analysis in a late-breaking abstract

Philadelphia, PA—The epidemic of diabetes is like a tsunami that will strike in waves, said Geralyn R. Spollett, MSN, ANP-CS, CDE, President of Health Care & Education, American Diabetes Association (ADA), Alex-

andria, VA, and Associate Director of the Yale Diabetes Center, Yale School of Medicine, New Haven, CT, at the 2012 ADA annual meeting. The result will be 380 million people worldwide in 2025 with diagnosed diabetes,

session at the 2012 ADA meeting.

The legacy effect refers to the significantly lower risk for diabetes-related complications found in patients randomized to intensive glycemic control compared with patients randomized to conventional glucose control, although the HbA1c levels were virtually the same in both groups during the 10-year observational follow-up of the original UKPDS. The legacy effect, which is the continuing benefit of early improvements in glucose control, is similar to the “metabolic memory” described in type 1 diabetes, said Dr Lind.

Continued on page 7

Incretin Therapies Lower Cardiovascular Risk Score

By Wayne Kuznar

Continued on page 10

Medical Spending for Diabetes, 1987-2008: Where Does the Money Go?

By Mary Mosley

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edical expenditures for diabetes have increased over the past 2 decades, along with improvements in the management of the disease and the availability of new

drugs. But the major increase seen from 1987 to 1997 slowed thereafter through 2008, said Xiaohui Zhuo, PhD, Health Economist, Division of Diabetes Translation, Centers for Disease Control Continued on page 12

*This publication is not endorsed by nor associated with the American Diabetes Association.

©2012 Engage Healthcare Communications, LLC

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hree incretin-based therapies— exenatide, liraglutide, and sitagliptin—are associated with a reduction in cardiovascular (CV) risk scores, “an effect more clearly observed in patients using glucagon-like peptide-1 agonists,” said Christopher J. Smith, MD, Department of Diabetes and Endocrinology, Glasgow Royal Infirmary, Scotland, during the 2012 ADA annual meeting.

Incretin-based therapies are not simply “glucocentric” but also confer benefits with respect to weight control and possibly blood pressure (BP) reduction, Dr Smith said.

Dr Smith presented the results of a planned observational analysis of the relative CV risk and benefit of these agents in routine care in a university hospital–based diabetes center.

Dr Smith and his colleagues anaContinued on page 6

INSIDE CARDIOMETABOLIC IMPLICATIONS . . . . . . . . . . . . . . . . .6 Sustained glycemic control reduces cardiometabolic risk factors Pediatric diabetes rising with obesity epidemic

INSULIN UPDATE . . . . . . . . . . . .17 1 in 4 patients using insulin inappropriately Head-to-head comparisons of insulin therapies

HEALTH ECONOMICS . . . . . . . . . .10 Medical costs increase as CKD worsens Value-based benefit design reduces low-value therapies

DIABETES MANAGEMENT . . . .22 Novel risk factors for diabetes New data in young patients with diabetes Quality improvement programs enhance diabetes care

INCRETIN THERAPIES . . . . . . .14 Exenatide versus glimepiride Role of GLP-1 and DPP-4 in type 2 diabetes

EMERGING THERAPIES . . . . . .28 Diabetes pipeline is promising New long-acting insulin degludec Novel basal insulin reduces weight

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.

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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

Mission Statement 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 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.

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 © 2012 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.

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, Value-Based Care in Cardiometabolic Health, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Fax: 732992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

CARDIOMETABOLIC IMPLICATIONS Sustained glycemic control reduces cardiometabolic risk factors Diabetes rates surging in youth with rising obesity More…..

INSULIN UPDATE 1 in 4 diabetic patients not using insulin as prescribed Head-to-head comparison of insulin therapies Ninety years of insulin therapy More…..

HEALTH ECONOMICS Medical spending for diabetes, 1987-2008 Medical costs increase as CKD worsens Value-based benefit design maximizes return on investment Paying patients to change behavior is effective More…..

DIABETES MANAGEMENT Novel risk factors for type 2 diabetes New data in young patients with diabetes Quality improvement programs enhance diabetes care More…..

INCRETIN THERAPIES Incretin therapies reduce cardiovascular risk factors Exenatide versus glimepiride Role of GLP-1 and DPP-4 in type 2 diabetes More…..

EMERGING THERAPIES Diabetes pipeline is promising Empagliflozin safe, effective, reduces weight Long-acting insulin degludec shows promise Novel basal insulin reduces weight More…..

EDITORIAL BOARD EDITOR-IN-CHIEF

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

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia, PA Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia, PA AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University, IL Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine Hematology/Oncology Assistant Dean for Research Associate Director, Faculty Group Practice, University of Michigan Medical School, MI EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare and Bentteligence Sharon, MA ENDOCRINOLOGY RESEARCH

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX 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, MI HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes Personalized Health Care Program University of Utah Salt Lake City, UT Joseph Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steve Miff, PhD Senior Vice President VHA, Inc., Irving, TX Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver, CO Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor University of the Sciences Philadelphia, PA Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, Philadelphia School of Pharmacy, University of the Sciences Philadelphia, PA David W. Wright, MPH President, Institute for Interactive Patient Care, Bethesda, MD HEALTH & VALUE PROMOTION

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Waukesha, WI MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Medical Lead, Payer and Specialty Channel Strategy, Medical Affairs, Pfizer Specialty Care Business Unit, PA

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

William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane, WA Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC PERSONALIZED MEDICINE

Emma Kurnat-Thoma, PhD, MS, RN Director, Research Services URAC, Washington, DC PHARMACOECONOMICS

Josh Feldstein President & CEO CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Senior VP, PBM Leader Humana Solutions, Louisville, KY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate Menlo Park, CA Michael S. Jacobs, RPh Vice President, National Accounts Truveris, Inc., New York, NY Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Health Solutions, Chadds Ford, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA Scott R. Taylor, BSPharm, MBA Executive Director, Industry Relations Geisinger Health System, Danville, PA

AUGUST 2012

POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute, Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy Practice and Administration, School of Pharmacy University of Missouri Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA Executive Director Drug Information Association Horsham, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Senior Vice President Managed Markets/Clinical Services Diplomat Specialty Pharmacy Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics Collegeville, PA

AMERICAN HEALTH & DRUG BENEFITS

5

Cardiometabolic Implications

Incretin Therapies Lower Cardiovascular...

Continued from page 1

See also Incretin Therapies lyzed the effect of exenatide, liraglutide, and sitagliptin on hemoglobin (Hb) A1c level, weight, systolic BP, and lipid profile over 12 months. CV risk was calculated with the United Kingdom Prospective Diabetes Study (UKPDS) calculator, using a fixedeffects model that corrected for sex, age, diabetes duration, heart rhythm, and smoking status. The UKPDS risk engine is a validated CV risk assessment tool for patients with type 2 diabetes.

“The benefits of exenatide and liraglutide were slightly better than for sitagliptin,” said Dr Smith.

In 102 patients, exenatide lowered the mean HbA1c level from 9.41% to 9.08% and reduced weight from 110.35 kg to 105.82 kg. Systolic BP was unchanged (134.76 mm Hg at baseline vs 134.11 mm Hg) at 12 months. The UKPDS risk

score for coronary heart disease (CHD) was lowered from 18.5% to 16.3%.

“The benefits of exenatide and liraglutide were slightly better than for sitagliptin….

The reductions in the UKPDS risk scores are signals that perhaps we’re doing the right thing for our patients.”

—Christopher J. Smith, MD A total of 30 patients used a combination of insulin and exenatide. The mean daily insulin dosage in patients receiving exenatide declined from 83.1 U to 77.5 U.

In 97 patients, liraglutide lowered the mean HbA1c level from 9.94% to 9.42%, weight from 107.97 kg to 104.07 kg, and systolic BP from 138.36 mm Hg to 134.84 mm Hg. The UKPDS risk for CHD declined from 22.4% to 20.2%.

A total of 42 patients used an insulin and liraglutide combination. The mean daily insulin dosage was reduced from 101.0 U to 94.7 U. In 102 patients, sitagliptin lowered the HbA1c level from 9.22% to 8.95% at 12 months (a change that was not statistically significant) and had no effect on weight (93.30 kg to 92.72 kg) or systolic BP (137.03 mm Hg to 139.81 mm Hg). The UKPDS risk score decreased from 18.5% to 17.3%.

There were 12 patients who used a combination of insulin and sitagliptin.

In these patients, daily insulin dosage

increased significantly, from 62.8 U to 76.0 U. “The reductions in the UKPDS risk scores are signals that perhaps we’re doing the right thing for our patients,” said Dr Smith.

Because the data for this analysis came from a clinic database, “it’s not accounting for variables like compliance,” he said.

Key Findings • Liraglutide lowered HbA1c level, weight, systolic BP, CV risk score, and insulin dosage • Exenatide lowered HbA1c level, weight, and CV risk score • Sitagliptin lowered HbA1c level (nonsignificantly) and CV risk score, but the effect of this agent on weight was neutral. ■

Sustained Glycemic Control with Once-Weekly Exenatide Reduces Cardiometabolic Risk Factors

By Mary Mosley

A

2-year open-label study of exenatide once weekly showed that this medication was safe when combined with a thiazolidinedione (TZD) plus metformin, and that it significantly lowered hemoglobin (Hb) A1c in patients with type 2 diabetes. A second study of patients with type 2 diabetes, the open-label extension study of DURATION-1 (Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention with Exenatide Once Weekly) trial, showed that the reductions in HbA1c in the trial were sustained at 4 years, along with improvements in cardiometabolic measures.

Michael E. Trautmann, MD, Consultant, Diabetes Drug Development at Eli Lilly, presented the results of these studies at the 2012 ADA annual meeting.

Exenatide plus a TZD: 2-Year Results In the 2-year, single-arm, open-label study of the safety of exenatide in combination with a TZD, “there were no new safety findings and no negative interaction between the drugs,” said Dr Trautmann.

The known side effects for each drug were seen at the same level as was already known, he stated. For exenatide, these were the gastrointestinal (GI)related side effect of nausea (17.2%) and injection-site nodule (11.9%). For

the TZDs, side effects included mild peripheral edema in 3 patients and edema in 1 patient, but no reports of heart failure. No major hypoglycemic events were reported, and minor hypoglycemic events were rare.

“Body weight was reduced despite the continuous use of TZDs, which are known to increase body weight quite significantly. Body weight was well maintained over the course of the 2 years.”

—Michael E. Trautmann, MD

Of the 134 patients, 44 were exenatide-naive and 90 were switched from exenatide twice daily to the onceweekly 2-mg dose. The TZD pioglitazone (≥30 mg daily) was taken by 90% of patients and the TZD rosiglitazone (24 mg daily) was taken by 10% (physicians were free to select the TZD), and metformin by 90% of the patients. No impact was seen from the use of rosigli-

tazone, and its use was low, with many patients switching to pioglitazone during the trial, because of cardiovascular concerns, Dr Trautmann stated.

To be included in the study, patients had to have an HbA1c level between 7% and 10%. All patients had diabetes for 6 years, most of them were white males, and the average age was 55 years.

The HbA1c was significantly lowered in the overall intention-to-treat (ITT) analysis, from 7.2% at baseline to 6.7%; a similar reduction, from 7.0% to 6.6%, was seen in patients who switched from the twice-daily exenatide dose to the once-weekly dose.

The exenatide-naive patients had a slightly larger reduction in HbA1c— from 7.7% to 6.6% at study end.

“Body weight was reduced despite the continuous use of TZDs, which are known to increase body weight quite significantly. Body weight was well maintained over the course of the 2 years,” said Dr Trautmann.

Overall baseline body weight was 98.1 kg; body weight was reduced the most in the exenatide-naive patients, by 2.7 kg, compared with reductions of 0.6 kg and 0.5 kg in the ITT and the switched groups, respectively.

DURATION-1: 4-Year Sustained Benefits with Exenatide The 4-year open-label extension study of DURATION-1 that included 295 patients showed the durability of

exenatide once weekly, resulting in a sustained reduction of 1.7% in HbA1c and a 4-year maintenance of the 2.5-kg weight loss from baseline.

In the randomized DURATION-1 trial, a significantly greater reduction was seen in HbA1c level with exenatide once weekly than with the twiceweekly administration of the drug— a 1.9% reduction compared with 1.5% (P = .002), respectively, at 30 weeks.

Weight-loss level was similar in the 295 patients in both groups.

The patients had to have an HbA1c level between 7.1% and 11% to be included in this study. At baseline, patients (average age, 56 years) had an HbA1c of 8.2%, body weight of 100 kg, and diabetes duration of 7 years.

The management regimen included exenatide once weekly, diet and exercise, and a TZD, metformin, or a sulfonylurea.

In the 176 patients who completed the 4-year extension, 55% achieved an HbA1c of <7% and 36% achieved an HbA1c <6.5% (mean, 6.9%). Fasting plasma glucose was reduced by 37 mg/dL. Blood pressure (BP) and lipid levels were improved at 4 years. Reductions were seen in: • Systolic BP, by 1.6 mm Hg • Total cholesterol, by 10.9 mg/dL • Low-density lipoprotein cholesterol, by 8.0 mg/dL. In addition, the mean change in Continued on page 7

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Cardiometabolic Implications

UKPDS Follow-Up: Early HbA1c Reductions...

This persistence in effect was seen for MI and for all-cause mortality. MI was reduced by 16% with intensive HbA1c control versus conventional control at the end of the original study. At 10 years of follow-up, a 15% risk reduction was found with intensive control.

All-cause mortality was reduced by 6% with intensive versus conventional control at the end of the original study, and the rate increased to a 13% risk reduction with intensive control at 10 years (P = .006), with similar glycemic control in both groups.

Benefits of Legacy Effects Revealed In the present analysis, the investigators examined data from 3849 patients assigned to intensive or conventional glycemic control in the UKPDS, using statistical models to determine the degree to which “historical” HbA1c values contribute to later reductions in the risks for MI and for all-cause mortality, and to elucidate the time-dependent impact of an earlier re-

duction in HbA1c values on a year-byyear outcome.

Older age, male sex, and HbA1c values, but not the treatment group, were significantly related to MI and allcause mortality, according to the analysis by Dr Lind and his colleagues.

“Achieving and maintaining optimal glycemic control is essential to minimize the long-term risk of diabetic complications,” including MI and all-cause mortality.

—Marcus Lind, MD

As the researchers learned from a model to determine the year-by-year benefit of the legacy effect, the benefit of a 1% reduction in HbA1c will increase over time. For all-cause mortality, the hazard ratio was 1 for years 0 to

10, but the risk reduction increased to 21% at year 15 and to 24.7% at year 20.

Furthermore, the earlier the HbA1c level is lowered, the greater the benefit.

If the HbA1c level is lowered from the time of diagnosis of type 2 diabetes, there is a 15% risk reduction in allcause mortality at year 15. This is cut nearly in half (7.1%) if HbA1c is not lowered until 10 years after the disease is diagnosed. Therefore, there is a 3fold greater risk reduction in all-cause mortality because of the legacy effect of early HbA1c reduction.

An increased risk reduction in allcause mortality, to 24.7%, is seen after 20 years if HbA1c level is lowered from the time of diagnosis versus a 14.1% reduction if HbA1c level is not lowered until 10 years after the diagnosis.

A similar pattern is seen in patients with MI. At year 15, there is a 21.6% risk reduction in MI if HbA1c is lowered 1% starting from the time of diagnosis, but the risk reduction was only 13.5% if lowering HbA1c was delayed until 10 years after diagnosis. At year

Continued from page 1

20, the risk reductions for the earlier and the delayed HbA1c lowering were 27.8% and 23.9%, respectively.

Using a fitted model, the benefit of early reduction of HbA1c and the legacy effect were illustrated by the example of a 50-year-old man with an 8% HbA1c at the time his type 2 diabetes was diagnosed. An immediate 1% HbA1c reduction will give him a 19% risk reduction in all-cause mortality when he is aged 60 to 70 years, whereas a delayed 1% HbA1c reduction will give him only a 6.6% risk reduction. An early HbA1c reduction provides a 3-fold greater effect on mortality.

“Achieving and maintaining optimal glycemic control is essential to minimize the long-term risk of diabetic complications,” said Dr Lind. Waiting to reduce glycemia will not recapture the full benefits of immediate intervention. These models confirm that an earlier reduction in HbA1c levels continues to contribute to reducing the risk of diabetic complications. ■

Glycemic Control in Patients with Type 2 Diabetes Significantly Lowers Cardiovascular Disease Risk

By Wayne Kuznar

I

mproved glycemic control in patients with type 2 diabetes lowers the risk of adverse cardiovascular (CV) events, reported Katarina EegOlofsson, MD, from the University of Gothenburg in Sweden at the 2012 ADA annual meeting.

In this study by Dr Eeg-Olofsson and colleagues, patients who reduced their mean hemoglobin (Hb) A1c levels by almost 1%—from 7.8% to 7%—had a significant 45% reduction in their risk of CV death.

In this observational study, Dr Eeg-

Patients who reduced their mean hemoglobin A1c levels by almost 1%—from 7.8% to 7%—had a significant 45% reduction in their risk of CV death. Superior glycemic control was also associated with a significant 39% reduction in the risk for fatal or nonfatal CHD events, and a significant 37% reduction in the risk for fatal or nonfatal CVD events.

Olofsson and colleagues evaluated the association between improved glycemic control during follow-up and the risk for

Sustained Glycemic Control... triglycerides was 13%. Improvement in beta-cell function was observed at the end of the study, as shown by a 26% increase in the homeostasis model assessment-B score and a 13% increase in the homeostasis model assessment-S score (which are measures of beta-cell function).

Of note, mild nausea decreased over time with exenatide once weekly, from 85 events per 100-year patient exposure during weeks 1 to

Continued from page 6

30, to 15 events for the study duration. Mild nausea is the most common adverse event associated with this regimen. Among patients receiving exenatide once weekly, 6 discontinued the drug because of GI adverse events, and 21 patients withdrew overall.

Few minor hypoglycemia events were observed, most with a sulfonylurea, and no major hypoglycemia event was observed. ■

coronary heart disease (CHD), CV disease (CVD), or total mortality in 18,035 patients with type 2 diabetes from the Swedish National Diabetes Register.

At baseline, participants (aged 30-75 years) were free of CVD and had an HbA1c level of 7% to 8.9%. The mean duration of diabetes since diagnosis was 8 to 10 years; the patients were followed from 2004 to 2009 (mean, 5.7 years).

The patients were divided into 2 groups based on their median change in HbA1c levels during follow-up— one group included 8923 patients whose HbA1c level had decreased by ≥0.1% from baseline to follow-up, and the second group included 9112 patients whose HbA1c level remained stable or increased.

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HbA1c Levels and CVDAssociated Mortality Risk After adjusting for covariates, the absolute risk for a death event from a CV cause was 9.9 events per 1000 personyears in patients with decreasing HbA1c levels compared with 17.8 events per 1000 person-years in patients with stable or increasing HbA1c levels.

Superior glycemic control was also associated with a significant 39% reduction in the risk for fatal and nonfatal CHD events, and a significant 37% reduction in the risk for fatal or nonfatal CVD events.

The absolute risk of a first fatal or nonfatal CHD event was 10.3 per 1000 person-years for those patients whose HbA1c levels declined versus 17.9 per 1000 person-years for those whose levels remained stable or increased.

The rates for a first CV event were 15.1 per 1000 person-years and 26.1 events per 1000 person-years in the 2 groups, respectively.

The study demonstrates that targeting HbA1c level to 7% can help reduce the excess CVD risk seen in patients with diabetes, said Dr EegOlofsson. ■

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Cardiometabolic Implications

ORIGIN: Insulin Glargine and Omega-3 Do Not Improve Cardiovascular Outcomes in Patients with Type 2 Diabetes But omega-3 fatty acids significantly reduce triglyceride levels

By Mary Mosley

C

ardiovascular (CV) outcomes were not improved with either omega-3 fatty acids or with insulin glargine in a 6-year study of 12,537 patients with dysglycemia and other CV risk factors. The multinational Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial showed that insulin glargine had no effect on cancer, and that it reduced the progression from dysglycemia to diabetes.

Hertzel C. Gerstein, MD, MSc, FRCPC, Professor, Department of Clinical Epidemiology and Biostatistics, McMaster University, Ontario, Canada, presented the CV results of the ORIGIN trial at the 2012 ADA annual meeting.

The ORIGIN trial included patients (mean age, 63.5 years) with type 2 diabetes who had impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), as well as CV risk factors. Using a 2 × 2 factorial design, the patients were randomized to insulin glargine or to standard care (without insulin), and to omega-3 fatty acids or to placebo.

All the patients had CV risk factors, 82% had a previous diagnosis of diabetes (average duration, 5 years), and 6% had diabetes detected at the time they were randomized. IFG or IGT was found in 12% of patients.

At baseline, 40% of the patients were not taking any glucose-lowering drugs, 27% were taking metformin, and 30% were taking a sulfonylurea.

The median fasting plasma glucose was 125 mg/dL, and the median hemoglobin A1c was 6.4%.

The study questions were (1) does insulin replacement therapy targeting fasting normoglycemia (≤95 mg/dL) with insulin glargine produce a greater reduction of CV outcomes than standard approaches, and (2) does adding omega-3 fatty acids reduce CV death?

CV Outcomes with Insulin Glargine “Basal insulin glargine has a neutral effect on CV events and cancers, and reduces the progression of diabetes,” said Dr Gerstein.

No difference was seen between the insulin glargine and the standard-care groups in the composite end point of myocardial infarction (MI), stroke, or CV death (adjusted hazard ratio [HR], 1.02), or in the composite end point of MI, stroke, CV death, revascularization, or heart failure (adjusted HR, 1.04). In addition, no difference was seen for allcause death (adjusted HR, 0.98).

Among the 1456 people without

8

diabetes at baseline, the development of new-onset diabetes was reduced by 28%. This finding was durable at 3 months when these individuals had another oral glucose tolerance test.

The risk for severe hypoglycemia was 0.7% higher in the insulin group (1% vs 0.3% annually with standard care).

“Basal insulin glargine has a neutral effect on CV events and cancers, and reduces the progression of diabetes.”

—Hertzel C. Gerstein, MD, MSc, FRCPC Overall, the rates of hypoglycemia were low. With insulin glargine, 57% of patients had ≥1 episodes of any hypoglycemic event versus 25% of patients in the standard group. The rate for any hypoglycemia in the insulin group was 17 per 100 person-years versus 5 per 100 person-years.

Patients taking insulin glargine gained a mean of 1.6 kg of body weight compared with a 0.5-kg weight loss with standard care.

CV Outcomes with Omega-3 Fatty Acids No difference was found between the patients taking omega-3 fatty acids (1 tablet daily) and those taking a placebo in terms of the primary end point of CV death (HR, 0.98). For the secondary composite end point of MI, stroke, or CV death, the finding was also neutral (HR, 1.01).

However, triglycerides were significantly reduced with omega-3 fatty acids, by 23.5 mg/dL compared with 9 mg/dL with placebo (P <.001), from the baseline value of 142 mg/dL in both groups.

The baseline values and reductions in low-density lipoprotein cholesterol were similar in both groups, with reductions of approximately 12 mg/dL from baseline values of 112 mg/dL in each group. Baseline high-density lipoprotein cholesterol values were also similar—46 mg/dL in both groups— with nominal reductions occurring.

Omega-3 supplementation was well tolerated, and adherence was high (88%), said Jackie Bosch, MSc, Associate Professor, School of Rehabilitation Science, McMaster University, who presented the omega-3 results from ORIGIN.

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

“There was neither benefit nor harm in the participants who were studied,” Ms Bosch commented. “However, the effect of this treatment in other groups, and the effect of a diet rich in omega-3 fatty acids, were not studied.”

there are many people with coronary artery disease or CV disease who actually have disturbed glucose metabolism. “Some of them walk around with hidden diabetes. For a cardiolo-

Implications of the ORIGIN Trial “People have been debating the question of whether there are adverse consequences to long-term insulin use for years,” Dr Gerstein said. “This study provides the clearest answer yet to that question: no, there are not.”

He noted that insulin glargine is the best studied of all glucose-lowering drugs with respect to long-term CV outcomes.

Furthermore, “This is the longest and most extensively conducted study of the effect of insulin versus no insulin on cancers,” Dr Gerstein added, and it showed that insulin glargine had no effect on cancer (HR, 1.0). “There is no evidence whatsoever of an effect of the drug on cancer or cancer death.”

Coinvestigator Lars Rydén, MD, PhD, Professor Emeritus, Cardiology Unit, Department of Medicine, Karolinska Institutet, Sweden, said that

“There was neither benefit nor harm [with omega-3 fatty acids] in the participants who were studied. However, the effect of this treatment in other groups, and the effect of a diet rich in omega-3 fatty acids, were not studied.”

—Jackie Bosch, MSc

gist, it is much more difficult to use insulin than for an expert endocrinologist. So for me, it is reassuring that this type of insulin is safe to use, easy to use, does not cause my patient a lot of hypoglycemia, and does not carry any risk of treatment-related cancer.” ■

Primary Care Physicians Underdiagnose Chronic Kidney Disease in Diabetic Patients Early diagnosis can reduce cardiovascular events

By Wayne Kuznar

C

hronic kidney disease (CKD) is significantly underdiagnosed in the population of patients with type 2 diabetes, say investigators from a multisite, observational, cross-sectional study conducted by the National Kidney Foundation, which was presented by lead investigator Lynda Szczech, MD, President of the National Kidney Foundation, New York City, at the 2012 ADA annual meeting.

Dr Szczech and colleagues assessed the prevalence and the proportion of patients with CKD and type 2 diabetes who were treated within the primary care setting. The study,

which was conducted at 466 primary care provider sites and included 9307 patients, used a clinician survey, a patient physical examination and medical history, a single patient blood draw to measure estimated glomerular filtration rate (eGFR) and hemoglobin A1c, a urine dipstick to assess protein, an albumin-creatinine ratio, 2 patient quality-of-life questionnaires, and a 15-month patient medical record review.

Early Stages of CKD Not Recognized Of the 9307 patients, 5036 (54.1%) had stage 1 to stage 5 CKD, based on Continued on page 9

Cardiometabolic Implications

Diabetes Rates Surging Among American Youth Linked to the pediatric obesity epidemic

By Wayne Kuznar

T

he prevalence of both type 1 and type 2 diabetes has increased substantially among American youth over the past decade, and, with this rise, the rates of diabetes complications have increased. This topic was discussed in a session on pediatric obesity at the 2012 ADA annual meeting.

The SEARCH for Diabetes in Youth study is a project undertaken by the Centers for Disease Control and Prevention and the National Institutes of Health to explore the burden of this disease among young Americans. The study is documenting the number of children and youth under age 20 years who are diagnosed with diabetes in 5 geographically dispersed populations in the United States, reported Dana Dabelea, MD, PhD, Associate Professor, Department of Epidemiology, University of Colorado, Denver.

Preliminary findings were presented at the meeting. From 2001 to 2009, the prevalence of type 2 diabetes among the young (age <20 years) increased by 21%, from 2.9 per 10,000 persons to 3.6 per 10,000 persons; during the same period, the prevalence of type 1 diabetes increased by 23%, from 1.7 per

1000 persons to 2.1 per 1000 persons, reported Dr Dabelea.

In 2009, the estimated number of young Americans under age 20 years who had diabetes was approximately 189,000; of those, approximately 168,000 young patients had type 1 diabetes, and 19,373 young patients had type 2 diabetes.

Only 2% of the cases of type 2 diabetes occurred in youth aged <10 years; however, the prevalence is rising rapidly among young Americans, with increasing age.

Although blacks and American Indians still have the highest prevalence of type 2 diabetes in all age-groups, the increase in the prevalence of type 2 diabetes in American youth was largest among non-Hispanic whites and Hispanics.

The Pediatric Obesity Epidemic The surge in type 2 diabetes among young Americans is believed to be the result of the obesity epidemic in that age-group, as well as “fetal overnutrition,” in which the developing fetus is exposed to maternal obesity and gestational diabetes associated with pregnancy, said Dr Dabelea. The risk for

type 2 diabetes in early life strongly increases with being exposed to maternal diabetes or obesity while in the womb.

“The vicious cycle of obesity creates a transgenerational problem, as the offspring of women who are obese or who have type 2 diabetes during pregnancy are more likely to develop diabetes early in life….All of these data provide evidence that diabetes in youth is not benign.”

—Dana Dabelea, MD, PhD

“The vicious cycle of obesity creates a transgenerational problem,” Dr Dabelea said, “as the offspring of women who are obese or who have type 2 diabetes during pregnancy are

more likely to develop diabetes early in life.”

Long-Term Implication The consequences of the increase in diabetes prevalence among American youth include signs of early diabetes complications, even after a relatively short duration of the disease. These complications include: • Neuropathy, which may be related to complications of heart disease later in life; “almost 12% of youth with type 1 diabetes and 26% with type 2 show signs and symptoms of neuropathy,” said Dr Dabelea, and “glucose control correlates strongly with these symptoms” • In addition, albuminuria is present in 22% of the young patients with type 2 diabetes and 9% of those with type 1 diabetes • Furthermore, young patients with type 2 diabetes are likely to have proteinuria, which may predispose them to kidney disease later in life.

“All of these data provide evidence that diabetes in youth is not benign,” Dr Dabelea said, noting that more data are needed on this disease among young Americans. ■

Primary Care Physicians Underdiagnose... Continued from page 8 eGFR and albuminuria; however, only 607 (12.1%) of the patients with CKD had been identified by their physicians as having the disease. Clinicians were more successful in diagnosing more advanced CKD—stages 3 to 5—than stages 1 and 2.

“More than 26 million Americans already have chronic kidney disease, which represents about 10% to 15% of the US population.

Millions more are at risk due to diabetes.”

—Lynda Szczech, MD

Of the 445 clinicians who enrolled at least 10 patients, 14.3% had a 50% or better likelihood of identifying patients with CKD, and 48.8% had a likelihood of less than 50%. Almost half (47.0%) of the physicians did not

identify any of their patients as having CKD. No differences were noted in the clinicians’ likelihood of identifying CKD based on practice setting, number of years in practice, or number of patients seen weekly.

“More than 26 million Americans already have chronic kidney disease, which represents about 10% to 15% of the US population. Millions more are at risk due to diabetes,” said Dr Szczech, stating that diabetes is the leading cause of kidney disease. She noted, “Early detection and treatment of kidney disease in patients with diabetes can help slow progression, reduce cardiovascular events, and delay time to kidney failure.”

CKD management guidelines are relatively new compared with guidelines for the management of diabetes or hypertension, and unfamiliarity with the guidelines regarding CKD may be a barrier in physicians recognizing the disease, she added.

The data set from this study will be undergoing further analysis. The re-

search will lead to further longitudinal studies to demonstrate that early recognition and treatment of CKD in people with diabetes will improve long-term health outcomes, including cardiovascular outcomes, Dr Szczech pointed out.

“Early detection and treatment of kidney disease in patients with diabetes can help slow progression, reduce cardiovascular events, and delay time to kidney failure.”

—Lynda Szczech, MD

A Call to Action The hope is that the study will be a clarion call to improve recognition of early-stage CKD so that appropriate preventive measures can be adopted as routine clinical practice, said

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Chester Fox, MD, Professor of Family Medicine, State University of New York at Buffalo, and a member of the study’s steering committee.

These measures include using specific diabetes drugs in individuals with renal impairment, avoiding the use of nonsteroidal anti-inflammatory drugs, and using renoprotective medications such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. ■

Look for the third issue of Value-Based Care in Cardiometabolic Health, with coverage from the 2012 European Society of Cardiology, the American Heart Association, and the Cardiometabolic Health Congress.

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Health Economics

The Diabetes Epidemic Is Like a Tsunami... with 53.1 million of them from the United States.

Tsunamis generally consist of a series of waves that arrive in a so-called wave train, Ms Spollett said.

The Obesity Wave The first wave in the diabetes epidemic is an increasing incidence of obesity. Worldwide, 2.8 million people die annually as a result of being overweight or obese. Between 1980 and 2008, the worldwide prevalence of obesity nearly doubled, Ms Spollett noted.

As with a natural tsunami, expect significant financial distress and destruction with the surge in diabetes, Ms Spollett pointed out. The impact of diabetes will be felt at the state and federal levels in the form of higher healthcare costs, and, as the costs for insurance increase, it will be felt at the small business level as well.

Diabetes will also place an increased burden on the primary care health system and will diminish the availability of specialty services. The most dire of these predictions asserts that annual medical and societal costs will increase by 72%, to a total of $514 billion.

The Hyperglycemic Wave The second wave of the diabetes tsunami is the alarming increase in the rate of hyperglycemia.

A 3-Step Process to Survive a Tsunami Surviving a tsunami is a 3-step process. The first step is to warn the public by sounding an alarm. Diabetes educators must “heighten our nation’s sense of urgency for the growing diabetes epidemic,” Ms Spollett said, by convincing the public that it must take diabetes very seriously, because the disease is potentially deadly. Diabetes kills more Americans annually than breast cancer and AIDS combined, she said.

The second step in survival is for clinicians and educators to help reduce the impact of diabetes by promoting increased allocation of resources for research into the prevention, care, and cure of diabetes.

The third step in surviving a tsunami is “taking” to higher ground. “Major change is usually driven from the bottom up, by an informed and assertive public,” she explained.

“My dream is that in understanding and responding to the crisis of diabetes, a national diabetes prevention plan will be seen as important, with the help of all of our citizens, and that the work we have done becomes a beacon for the broader future of

10

healthcare,” said Ms Spollett.

A national diabetes prevention plan would include building community awareness of diabetes, improving nutrition from farm to table, and fostering

“My dream is that in understanding and responding to the crisis of diabetes, a national diabetes prevention plan will be seen as important, with the help of all of our citizens, and that the work we have done becomes a beacon for the broader future of healthcare.”

—Geralyn R. Spollett, MSN, ANP-CS, CDE

activities to prevent an increase in diabetes (ie, supporting physical education, bike paths/exercise courses, and public transportation), Ms Spollett said, and would offer financial reimbursement for counseling and education for those at risk.

ADA’s Response to Hurricane Katrina In a separate address, Vivian Fon-

AMERICAN HEALTH & DRUG BENEFITS

seca, MD, ADA’s President of Medicine & Science and Chief of the Section of Endocrinology at Tulane University School of Medicine, New Orleans, LA, noted that the ADA was unprepared for the devastation that Hurricane Katrina brought to New Orleans and to the surrounding Gulf Coast in 2005.

“There were no physicians, no nurses, and no pharmacists available after the hurricane,” said Dr Fonseca.

“This had an immediate effect on the lives of people with diabetes.”

Interruptions of care meant that hemoglobin (Hb) A1c levels went uncontrolled, and the interruptions affected those with private insurance as well as those with public coverage or no insurance. Some of the uninsured went without diabetes care for as long as 2 years.

Most healthcare facilities in New Orleans, including research facilities, were destroyed by Hurricane Katrina.

The ADA responded with emergency grants to locate patients who had to abandon the city after the storm, said Dr Fonseca.

The ADA also created a task force that developed first responders’ best practices, which include diabetes care.

Disaster preparedness is now part of the ADA’s standard of care.

A strategic plan by the ADA demands new research priorities and transformational approaches to treatment. A new series of grants shifts the focus away from specific compounds to individual investigators, in the hopes of encouraging more risk taking in research, he said.

Discovery of a Third Type of Adipose Tissue After Dr Fonseca’s address, Bruce Spiegelman, PhD, Professor of Cell Biology, Harvard Medical School, Boston,

Continued from page 1

chronicled the discovery of irisin, a key regulatory hormone in glucose metabolism, and beige fat cells, a third type of adipose tissue in addition to brown fat and white fat.

Beige fat, which can burn off calories unlike white fat, is genetically distinct from brown fat, which is found in small mammals and human infants, affording them protection from the cold. High levels of the adipose tissue regulator PRDM 16 (PR domain containing 16) can turn white fat into beige fat. Genetically manipulated mice that create more brown or beige fat have increased glucose tolerance and antiobesity actions, explained Dr Spiegelman.

“Beige fat can improve the metabolic health of an animal,” he said. “In human beings, this same browning is linked with exercise.”

Exercise induces an improvement in glucose metabolism. Recent studies show that peroxisome proliferatoractivated receptor γ coactivator-1α (PGC-1α), a regulator of mitochondrial biogenesis that is upregulated by vigorous exercise, plays an important role in converting white fat into brown fat. In tissue culture, PGC-1α stimulates glucose uptake and angiogenesis, thus mimicking the beneficial effects of exercise.

Exercise is thought to produce the secretion of irisin, a molecule that increases the amount of beige fat. In obese humans, the expression of circulating levels of irisin increases by 40% to 60% after 4 weeks of exercise training.

“Irisin causes a browning reaction to protect against metabolic disease,” said Dr Spiegelman. Although irisin is a molecule at the proof-of-concept stage that is not appropriate for use in human beings, the hope is that an understanding of its actions can lead to the development of a new generation of therapeutics, he noted. ■

Medical Costs Increase as Chronic Kidney Disease Worsens Managed care analysis highlights disease burden on US healthcare

By Mary Mosley

C

urtailing the progression of established chronic kidney disease (CKD) could contribute to controlling its costs. New data show a 2-fold increase in medical costs in patients whose CKD progresses to a higher stage. An estimated 12% of patients with type 2

AUGUST 2012

diabetes progress to CKD, and approximately 40% have some form of diabetic nephropathy.

These new data, which were presented by Suma Vupputuri, PhD, Kaiser Permanente Center for Health Research, GA, at the 2012 ADA meeting, come from patients with type 2

diabetes and CKD in a real-world managed care setting, and reveal considerable worsening of CKD over time.

In this retrospective, observational, cohort study of patients in the Kaiser Permanente Northwest and Georgia health systems, 12% of 21,018 patients Continued on page 11

Health Economics

Medical Costs Increase as Chronic Kidney Disease... in stages 0 to 2 CKD progressed to a higher stage, with 327 patients reaching stage 4 and 76 reaching end-stage renal disease (ESRD). Approximately 27% of the 3885 patients in stage 3 CKD progressed, with 930 patients reaching stage 4 CKD and 217 reaching ESRD. Progression to ESRD was found in 30% of the 683 patients in stage 4 CKD.

Approximately 26% of the Medicare expenditure for diabetes is for patients who have CKD and diabetes, according to the US Renal Data System.

The incidence of CKD progression from one stage to a higher stage, per 1000 person-years, was 26 in stages 0 to 2, 74 in stage 3, and 78 in stage 4. The rates were adjusted for age, sex, and duration of diabetes.

The costs for CKD and diabetes are increasing rapidly. The current annual expenditure for CKD and diabetes is approximately $18 billion, which is approximately 11 times higher than in 1993. Approximately 26% of the Medicare expenditure for diabetes is for patients (aged ≥65 years) who have CKD and diabetes, according to the US Renal Data System.

The baseline pharmacy, outpatient, and inpatient costs, by CKD stage, were $6551 for stages 0 to 1, $8206 for stage 2, $12,529 for stage 3, and $23,229 for stage 4. In each CKD stage, the outpatient nonpharmacy cost was predominant, at approximately 60% in stages 0 to 1 and 40% to 43% in the other stages. Pharmacy costs accounted for approximately 21% to 24% of the total costs, except in stage 4 CKD, for which it was 15%.

A nearly 2-fold increase for inpatient costs occurred when CKD progressed from stage 3 to stage 4. Costs were annualized and standardized to 2010 dollars.

Even when adjusted for demographics and clinical characteristics, disease progression was associated with significantly greater costs in each stage, stated Dr Vupputuri. Medical costs were 2 times higher in the patients with stage 2 CKD who progressed to a higher stage, 3 times higher for stage 3 CKD, and 4 times higher in patients who had ESRD at baseline. Compared with the patients who did not progress to CKD, the costs

were $16,642 for stages 0 to 2 CKD, $34,698 for stage 3, and $57,509 for stage 4.

The study population of 25,586 patients, with a mean age of 60 years, had a 5.1-year duration of diabetes, and

51% were men. Men and blacks were less likely to be in the more severe stages of CKD, noted Dr Vupputuri.

Age progressively increased across the CKD stages, from 53 years in stage 1 to 71 years in stage 4. Comorbidities also

Continued from page 10

increased with higher CKD stages.

The medical costs of only the patients whose CKD worsened showed that their costs doubled, from $12,937 before progression to $23,233 after CKD progression. ■

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AUGUST 2012

AMERICAN HEALTH & DRUG BENEFITS

11

Health Economics

Medical Spending for Diabetes, 1987-2008... and Prevention, Atlanta, GA, who presented results of the first study documenting the US cost trend for diabetes at the 2012 ADA annual meeting.

Dr Zhuo noted the changing face of diabetes in his presentation—more cases of diabetes are being diagnosed at younger ages, and in more minority patients, and patients are living longer with diabetes. There has also been progress in diabetes management, including new medications and improved glucose measurement and self-management.

Dr Zhuo and colleagues analyzed medical expenditures and healthcare utilization for diabetes for 3 periods— 1987, 1997-1998, and 2007-2008—using cost data from the National Medical Expenditure Survey and Medical Expenditure Panel Survey.

Dr Zhuo and colleagues adjusted the data for sex, race, ethnicity, age, education, income, marital status, and geographic region, as well as for health insurance coverage and major health conditions other than diabetes.

Overall, the analysis showed an excess annual expenditure and healthcare utilization for patients with diabetes compared with those without the disease. All expenditures were adjusted to 2008 dollars.

An average of $3050 more was spent on medical care by a typical patient with diabetes than a patient without

diabetes in 1987 (Table). This gap in cost increased to $4560 during 19971998 and to $4670 during 2007-2008, noted Dr Zhuo.

—Xiaohui Zhuo, PhD

Among patients with diabetes, annual medical cost increased by 13% for patients with macrovascular complications compared with a 29% decrease in patients without macrovascular complications.

Although inpatient costs increased in absolute terms from 1987 to 2007-2008, the proportion of the total inpatient costs

Continued from page 1

Table Medical Costs for Patients with and without Diabetes Cost

1987, $

1997-1998, $

2007-2008, $

Patients with diabetes

8864

10,726

11,091

Patients without diabetes

5814

6166

6421

decreased from 52% in 1987 to 30% in 2007-2008. A modest decline was seen in the proportion of outpatient costs, from 24% in 1987 to 16% in 2007-2008.

Of note, there was a substantial increase in the costs for prescription medications, stated Dr Zhuo, resulting in a greater proportion of costs for prescription drugs, from 15% in 1987 to 31% in 1997-1998 and to 46% in 20072008. (The average cost for prescription drugs was approximately $2100 in 2007-2008 compared with approximately $474 in 1987.)

Annual Healthcare Utilization Patients with diabetes had 3 more physician office visits in 1987 and 3.9 more than patients without diabetes.

Despite a slight dip to a 3.4-visit gap in 2007-2008, this number was still increased compared with in 1987.

In line with the increase in spending for prescription medications, the numbers of additional prescription medications purchased also significantly increased, from 7.5 per person in 1987 to 16.5 per person in 1997-1998 and to

20.2 in 2007-2008.

There were significantly fewer hospital admissions for diabetes in 20072008 compared with in 1987.

CVD Adds Significant Cost to Diabetes The combination of cardiovascular disease (CVD) and diabetes progressively increased costs compared with costs for patients without diabetes.

The excess medical expenditure for CVD plus diabetes was $6000 in 1987, $8000 in 1997-1998, and $9000 in 20072008. By contrast, the cost increase for patients with CVD only was much smaller—from $2000 in 1987 to $3000 in 2007-2008.

Among patients with diabetes, the annual medical cost increased by 13% for patients with macrovascular complications compared with a 29% decrease in patients without macrovascular complications, according to Dr Zhuo.

Dr Zhuo noted that the expenditures do not represent actual resource costs, and that nursing home and long-term care were not included. ■

Value-Based Benefit Design: Reducing Copayment for High-Value Services Maximizes Return on Investment Therapies with proven benefit should have low or no cost-sharing

By Wayne Kuznar

V

alue-based insurance design (VBID) that reduces patient copayments to encourage the use of high-value therapies is cost-effective, because the cost of the additional use of high-value drugs encouraged by such a design may be offset by a reduction in the use of nondrug health services, said Allison B. Rosen, MD, MPH, ScD, Associate Professor, Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, at the 2012 ADA annual meeting.

Provide Incentives to Encourage Use of High-Value Therapies The silo-based approach to cost versus quality trade-offs defies common sense, said Dr Rosen. Increasing out-

12

of-pocket costs to consumers creates incentives for them to curb healthcare use, and at the same time the pay-forperformance approach creates incentives for providers to improve quality of care. These incentives can be conflicting in cases in which consumers are asked to pay an increasing share of the cost of a therapy with proven benefits, such as beta-blockers for some patients with heart disease.

If patients were discerning users of healthcare, they would curb the use only of low-value therapies. Unfortunately, Dr Rosen argues, cost-sharing reduces excess use as well as essential medication use alike. As such, increased cost-sharing may lead to adverse health outcomes.

“For some chronic diseases, copay-

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

related underuse actually results in higher cost of care,” said Dr Rosen.

“For some chronic diseases, copay-related underuse actually results in higher cost of care. Value-based insurance design has been proposed to realign incentives for value.”

—Allison B. Rosen, MD, MPH, ScD

“Value-based insurance design has been proposed to realign incentives for value,” she added.

When applying a value-based benefit design strategy, drugs associated with greater benefit would have a lower copay rather than a copay that is based on acquisition cost.

Value is the amount of health gained per dollar spent on healthcare services, Dr Rosen suggested. VBID reduces the copay for specific services or specific patients, “or some combination of the 2,” she said.

In the case of beta-blockers, for example, the clinical benefit is highest for patients with diabetes who have had 4-vessel coronary artery bypass graft surgery.

Socioeconomic Status Affects VBID One of the earliest controlled studies of VBID was conducted at a large nonContinued on page 13

Health Economics

Paying Patients to Change Their Health Behavior Is Effective Long-term change requires carefully planned immediate incentives

By Wayne Kuznar

F

inancial incentives to patients are increasingly being used, and they can be effective in driving better health behaviors, but their design is crucial to their success in motivating change, said Kevin G.M. Volpp, MD, PhD, Director of the Center for Health Incentives at the University of Pennsylvania, Philadelphia, during the 2012 ADA annual meeting.

The use of incentives by large employers to improve health has increased from slightly more than 30% of large employers in 2009 to approximately 70% in 2012. But the design of the reward programs is important, said Dr Volpp.

“Rewards once a year ignore myopia,” he said, citing one employer’s offer to rebate $150 to employees who join and regularly use a fitness center.

Such one-time incentives, especially if they occur at the end of a calendar year, may not prompt long-term change, because people tend to focus on the present. In addition, an incentive in the form of a discounted employee insurance premium will not be as effective in changing behavior as a direct payment.

These lessons are gleaned from studies of behavioral economics, in which immediacy is important. The impact tends to be greater with immediate rewards, he said. The use of frequent, small rewards tends to work better than single awards to promote positive behavior. The amount of the reward is not as critical as immediacy either.

As an example, he used his own randomized, controlled study in which “long-term smoking-cessation rates tripled in the incentive group.”

The study followed 878 General Electric employees from 85 worksites.

Half of the employees were offered $100 to complete a community-based smoking-cessation program, another $250 if they refrained from smoking

In this study, 3 types of incentives were compared. The first was a $25 cash award to an employee for completing an HRA, the second was a $25

The use of incentives by large employers to improve health has increased from slightly more than 30% of large employers in 2009 to approximately 70% in 2012; but the reward program design is important: “Rewards once a year ignore myopia.” —Kevin G.M. Volpp, MD, PhD

for 6 months after finishing the program, and $400 more if they remained smoke-free for an additional 6 months. The other half was asked to enroll in a smoking-cessation program without incentives.

Enrollment in the smoking-cessation program was more than double in the group that was offered incentives. Furthermore, smoking cessation rates at 12 months were 14.7% in the incentive group and 5% in the controls. At the last follow-up (at 15-18 months), 9.4% in the incentive group remained smoke-free compared with 3.6% of the controls.

Playing the Lottery Other types of incentive programs have been examined for their effectiveness in promoting behavior change, and lottery systems appear to be a winner, said Dr Volpp. A study that he coauthored showed that a Dutch lottery system added to a wellness program motivated individuals to complete health risk assessment (HRA) questionnaires.

cash award combined with a $25 grocery gift card, and the third was assignment to workforce groups of 4 to 8 members with a chance to win prizes (a Dutch lottery). Among those in the Dutch lottery, 1 group was chosen randomly each week. Each member of the chosen group who had completed an HRA received $100. The groups in which at least 80% of the members had completed HRAs had their cash prizes increased to $125.

The study was conducted among 1299 employees from 14 offices of a healthcare management company. Some 64% of the employees in the lottery groups completed HRAs compared with 42% in the $50 cash or grocery gift card group and 40% in the $25 cash–only group.

Similar success was achieved with enhancing compliance to warfarin, using a lottery in which patients could win money daily if they had taken their warfarin the previous day.

Because humans discount the future, they are not as motivated by far-off rewards, said Dr Volpp. This concept was

illustrated in a study of weight-loss programs. The patients who were randomly assigned to a deposit contract in which they had to put up their own money, which was matched by researchers monthly if they met their weight-loss goal, lost an average of 14.0 lb during the study. Those who were assigned to a lottery lost 13.1 lb, and those assigned to a control group lost only 3.9 lb.

Loss aversion was a powerful incentive for those in the deposit group, because they stood to lose money, Dr Volpp pointed out.

Peer Mentoring Works Well Peer mentorship worked well to improve glucose control, more so than financial incentive or usual care. Over 6 months, patients assigned to speak with a peer mentor at least weekly had a mean hemoglobin A1c level decline of >1% from baseline to 6 months compared with a 0.46% decline in the financial-incentive group and 0.01% in the usual-care group.

Because Americans spend only 1 to 2 hours annually with their physicians, monitoring their behaviors beyond the examination room may be key to their engagement in healthy behaviors.

Automated hovering is the principle of using wireless or electronic technologies to engage patients while they are away from a healthcare setting, offering constant reinforcement. In the study of warfarin mentioned above, electronic pill boxes were used to automatically enter patients into a lottery each time they took their warfarin. The use of the electronic pill dispenser increased the time spent in the therapeutic range and decreased the number of incorrect doses. ■

Value-Based Benefit Design: Reducing Copayment for... Continued from page 12 profit employer with more than 60,000 employees and dependents. In that program, patients with diabetes had copays reduced for angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), other antihypertensive agents, glucosecontrol agents, statins, and other lipidlowering agents.

The largest reduction in copay was for the use of tier 1 (ie, generic) drugs, when possible, for which the entire copay was waived. Copays were reduced by 50% for tier 2 (preferred brand-name) drugs, and by 25% for tier 3 (nonpreferred brand-name) drugs.

The institution of VBID increased the uptake of medications in all classes compared with the control group. The uptake of metformin increased by >4%, ACE inhibitors and ARBs by >8%, and statins by approximately 9%.

During 18 months, pharmacy spending increased by $28 per member per quarter in the intervention group compared with the controls, but nonpharmacy spending decreased by $14 per member per quarter in the intervention group versus the controls. Overall, the intervention was only slightly more costly over the 18-month period, said Dr Rosen.

There was a differential impact of the VBID by income, Dr Rosen pointed out. The uptake of glycemic agents and antihypertensive drugs in the intervention group was greater in those patients with a socioeconomic status lower than the median compared with those with a socioeconomic status above the median, she said.

Those in the intervention group with incomes below the mean had significantly greater uptake of metformin, ACE inhibitors or ARBs, and selective serotonin reuptake inhibitors compared with patients in the intervention group with incomes above the mean.

AUGUST 2012

Value-based interventions “may be a useful adjunct to efforts aimed at increasing patient initiation of and adherence to high-value medications and possibly an avenue for addressing disparities,” Dr Rosen noted.

The data show that the incremental costs of increased use of high-value services can be subsidized by medical cost offsets and higher cost-sharing for services of lower value. In addition, the financial impact of standalone VBIDs—those that focus on removing barriers to evidence-based care services for chronic conditions— are cost-neutral. ■

AMERICAN HEALTH & DRUG BENEFITS

13

Health Economics

Real-Time Continuous Glucose Monitoring Cost-Effective in Patients with Type 2 Diabetes

By Mary Mosley

R

eal-time continuous glucose monitoring improved glycemic control compared with selfmonitoring of blood glucose at 1 year in a recent clinical trial; real-time continuous glucose monitoring was cost-effective for providing modest increases in life expectancy and improved quality of life based on 2 statistical models.

Coinvestigator Stephanie J. Fonda, PhD, Walter Reed National Military Medical Center, Bethesda, MD, presented the data at the 2012 ADA annual meeting.

“We used the data from a study we completed that showed a sustained reduction of 1.1% in hemoglobin A1c with real-time continuous glucose monitoring at 1 year compared to a smaller (ie, 0.5%) reduction with self-monitoring of blood glucose to develop 2 different models to project cost-effectiveness, cost of complications, and quality of life,” explained Dr Fonda.

In the recently published study (Vigersky RA, et al. Diabetes Care. 2012; 35:32-38) of patients with type 2 diabetes, 50 patients wore a continuous loop monitor for the real-time continuous glucose monitoring and 50 patients performed self-monitoring of blood glucose during the 3-month intervention period. All patients were then followed until week 52.

The volunteer participants are representative of the motivated population of patients with type 2 diabetes. The

—Stephanie J. Fonda, PhD

The 2 Analyses The base-case analysis determined the costs at 5 years for using the intervention exactly as it was used in the clinical trial. The scenario analysis looked at the 5-year costs for adding a second “dose” of real-time continuous glucose monitoring in year 2 as a refresher for the participant. Assumptions included the convergence of HbA1c within 21 months of the intervention and that patients would be taking insulin by year 5. The validated IMS CORE Diabetes model was used to predict economic outcomes and estimated health outcomes in terms of quality-adjusted life-years (QALYs).

The researchers used a US payer perspective to calculate costs and included only direct costs obtained from published sources that were inflated to 2011 US dollars.

In the base-case analysis, an incremental increased cost of $250 versus self-monitoring of blood glucose was associated with a 1.03-month increase in life expectancy and a 0.8-month improvement of QALY with real-time continuous glucose monitoring.

of participants were black, reflecting the population in the military medical center. Most of the patients were taking an oral antidiabetic drug, insulin, or both, and the duration of their diabetes was approximately 9 years.

Incremental Cost Reductions in Treating Complications The incremental cost-effectiveness ratio (ICER) was $2903 for each lifeyear gained and $3735 for each QALY gained. The following reductions were seen with real-time continuous glucose

volunteers were typically middle-aged (mean age, 57.8 years), overweight or obese (mean body mass index, 32 kg/m2), and mostly men (60%), and they had poorly controlled type 2 diabetes (mean baseline hemoglobin [Hb] A1c , 8.3%). Approximately 35% to 40%

“We used the data from a study we completed that showed a sustained reduction of 1.1% in hemoglobin A1c with realtime continuous glucose monitoring at 1 year compared to a smaller, 0.5% reduction with selfmonitoring of blood glucose to develop 2 different models to project cost-effectiveness, cost of complications, and quality of life.”

monitoring in the cost of treating diabetes complications: • –$177 for cardiovascular diseases • –$141 for renal disease • –$212 for diabetic foot complications.

In the scenario analysis, a greater increase was found in life expectancy— 2 additional quality-adjusted lifemonths—than in the base-case analysis. The incremental cost was $1217 for 2 episodes of real-time continuous glucose monitoring (1 each in year 1 and year 2) more than self-monitoring of blood glucose, and the ICER was $10,071 per QALY. Dr Fonda noted that the cost of the interventions is low, which contributes to the cost-efficacy, and that behavioral interventions are known to have a modest impact when used without feedback from the clinician. A big improvement in glycemic control over the intervention period is being seen, she pointed out.

But the refresher dose of real-time continuous glucose monitoring is needed, because patients begin to regress after approximately a year. Furthermore, feedback from the clinician to enable patients to see the relationships between their eating and exercise habits and their HbA1c levels would likely give greater benefits, she said.

The real-time continuous glucose monitoring could be used for only 2 weeks, because the response is seen in this time frame. ■

Incretin Therapies See also Cardiometabolic Implications

Head-to-Head Comparison: Exenatide Outperforms Glimepiride in Controlling Glycemic Levels after Failing Metformin Therapy

By Mark Knight

I

n a recent head-to-head comparison, glycemic control was better with the glucagon-like peptide-1 (GLP-1) exenatide twice daily than with the sulfonylurea glimepiride once daily in patients with type 2 diabetes who are inadequately controlled with metformin, said Guntram Schernthaner, MD, Head of the Department of Medicine, Rudolfstiftung Hospital, Vienna, Austria, at the 2012 ADA annual meeting. Dr Schernthaner reported the results of the

European Exenatide trial known as EUREXA, which was simultaneously published in the Lancet (Gallwitz B, et al. Lancet. 2012;379:2270-2278).

Comparing Sulfonylurea and GLP-1 A sulfonylurea is a common choice as second-line therapy after metformin failure in many countries in patients with type 2 diabetes, because sulfonylureas are inexpensive and have a rapid effect, Dr Schernthaner noted.

Glycemic control subsequently deteri-

orates with a sulfonylurea, however, because its effect is not glucose-dependent, and the risk for hypoglycemia may limit the dosage of the sulfonylurea used in clinical practice, he said.

The EUREXA trial was conducted at 128 centers in 14 European countries and included 1029 adults with type 2 diabetes who were overweight or obese and whose hemoglobin (Hb) A1c level was between 6.5% and 9.0%, despite stable and maximally tolerated doses of metformin.

The study tested the following 2 hypotheses: (1) that exenatide is noninferior to glimepiride on time to treatment failure, and (2) if noninferiority is demonstrated, exenatide would prove superior to glimepiride.

Treatment failure was defined as treatment with the maximally tolerated dose of antidiabetic agents and 1 of 2 situations—the HbA1c level remains above 7% at 2 consecutive office visits 3 months apart, or the HbA1c level is more than 9% at any Continued on page 15

14

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

Incretin Therapies

DPP-4 Inhibitors Improve Glycemic Control in Elderly Patients with Diabetes Sitagliptin and saxagliptin investigated in 2 post hoc analyses

By Wayne Kuznar

R

esearchers analyzing trial data for 2 oral dipeptidyl peptidase (DPP)-4 inhibitors—sitagliptin and saxagliptin—have found them both to provide effective glycemic control in elderly patients with type 2 diabetes.

Controlling hypoglycemia is of great concern in this population, because of potential accidents or falls. In addition, elderly patients are at increased risk for adverse events associated with drug therapy; therefore, treatment must be chosen carefully, pointed out Barry Goldstein, MD, PhD, Vice President of Diabetes and Endocrinology Clinical Development, Merck & Co, who presented the results at the 2012 ADA annual meeting.

Similar Glucose Reductions with Sitagliptin and a Sulfonylurea A post hoc pooled analysis of 3 double-blind clinical trials in which older patients (aged ≥65 years) were treated with 100 mg of oral sitagliptin, a once-daily DPP-4 inhibitor, showed that these patients achieved blood glucose reductions similar to the reductions seen in patients managed with a sulfonylurea (glipizide or glimepiride). The investigators compared the changes from baseline in the level of hemoglobin (Hb) A1c, fasting plasma glucose, body weight, and

the proportion of patients who experienced ≥1 episodes of symptomatic hypoglycemia.

Patients aged ≥65 years who were receiving 100 mg of sitagliptin achieved blood glucose reductions similar to the reductions seen in patients managed with a sulfonylurea.

In 2 of the studies, patients with diabetes whose disease had been managed with diet alone or with metformin were randomized to receive sitagliptin or glipizide (each as monotherapy or in combination with metformin) for 104 weeks. In the third study, patients were randomized to receive sitagliptin or glimepiride for 30 weeks.

The pooled analysis focused on results at or close to 30 weeks in each of the 3 trials and included 373 patients who completed the trials through this time point.

Among this older patient population, 178 patients who were taking

sitagliptin had a 0.73% mean reduction in HbA1c from baseline, which was similar to the 195 patients who took a sulfonylurea (0.78% mean HbA1c reduction). In the patients receiving a sulfonylurea, 28.2% experienced ≥1 episodes of symptomatic hypoglycemia compared with 6.2% of patients receiving sitagliptin, a significant difference.

Comparing Saxagliptin Use in Older and Younger Patients The second post hoc analysis of saxagliptin was led by Bernard Charbonnel, MD, Professor of Endocrinology and Metabolic Diseases, Centre Hospitalier Universitaire de Nantes, France. In this analysis, the researchers conducted a subanalysis of outcomes from a 24-week, placebocontrolled trial of treatment with saxagliptin in 104 older patients (aged ≥65 years) and in 351 younger patients (aged <65 years).

All the patients had type 2 diabetes and an inadequate response to insulin alone or to insulin in combination with metformin. This trial showed that adding saxagliptin at a 5-mg daily dose improved glycemic control, regardless of metformin use, and the drug was generally well tolerated.

This subanalysis showed that improvement in glycemic control from

baseline to week 24 with saxagliptin add-on therapy was similar in the elderly and nonelderly groups (interaction of treatment by age, P = .942 for HbA1c; P = .184 for fasting plasma glucose; and P = .291 for 120-minute postprandial glucose), demonstrating

Saxagliptin 5-mg daily dose added to insulin, with or without metformin, was just as effective in older patients as it was in younger populations.

that saxagliptin added to insulin, with or without metformin, was just as effective in older patients as it was in younger populations.

At week 24, the overall incidence rates of adverse events with saxagliptin and placebo were 54.9% and 57.6%, respectively, in the older patients. No older patients discontinued the study because of adverse events, whereas 1.7% and 2.5% of the younger patients discontinued the study in the saxagliptin and placebo groups, respectively. ■

Head-to-Head Comparison: Exenatide Outperforms Glimepiride... Continued from page 14 visit after 3 months of treatment.

In this open-label study, participants were assigned to receive exenatide injected subcutaneously within 60 minutes before breakfast and evening meals—starting at 5 mcg twice daily for 5 weeks and followed by 10 mcg twice daily for the remaining study period—or to glimepiride 1 mg daily immediately before breakfast.

“Exenatide twice daily was associated with lower A1c levels over time compared with glimepiride,” said Dr Schernthaner.

Treatment failure occurred in 41% of patients in the exenatide group versus 54% of those in the glimepiride group, a risk difference of 12.4%, which corresponded to a 25% reduction in the risk of treatment failure with exenatide.

Exenatide met the criterion for noninferiority and separately showed superiority over glimepiride as an add-on treatment to metformin.

versus glimepiride at these time points.

“Exenatide-treated patients experi-

Reduced HbA1c Levels and Weight The median time to inadequate glycemic control was 180 weeks in the exenatide group versus 142 weeks in the glimepiride group. Overall, 45% of the patients assigned to exenatide achieved an HbA1c concentration <7% compared with 31% of the patients assigned to glimepiride.

Fasting plasma glucose concentration was significantly lower in the exenatide group at years 1, 2, and 3 compared with the glimepiride group. Glucose levels during oral glucose tolerance tests were also significantly lower with exenatide

“Exenatide twice daily was associated with lower A1c levels over time compared with glimepiride….Exenatidetreated patients experienced significantly greater weight loss over time.”

—Guntram Schernthaner, MD

enced significantly greater weight loss over time,” said Dr Schernthaner. Pa-

AUGUST 2012

tients in the exenatide group lost 3.32 kg of body weight from baseline through the last visit compared with a gain of 1.15 kg in those randomized to glimepiride.

The incidence of hypoglycemia was lower in patients receiving exenatide twice daily than in those receiving glimepiride, he said. Hypoglycemia of any type was reported by 36% of patients in the exenatide group and by 67% in the glimepiride group; documented symptomatic hypoglycemia occurred in 7% of the exenatide group versus 12% of the glimepiride group.

Gastrointestinal and injection-site reactions were more common in patients receiving exenatide twice daily than in patients receiving glimepiride once daily. ■

AMERICAN HEALTH & DRUG BENEFITS

15

Incretin Therapies

Incretin Impairment: The Role of GLP-1 and DPP-4 in Type 2 Diabetes Management

By Mary Mosley

T

he contribution of incretin impairment to type 2 diabetes is the focus of ongoing research, and many questions remain to be answered. Preliminary data from several ongoing studies have provided insights into the role of glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase (DPP)-4 in relation to the role of the incretin system in type 2 diabetes. These data were reviewed by Richard Pratley, MD, Medical Director of the Florida Hospital Diabetes Institute and Professor at the SanfordBurnham Medical Research Institute, Orlando, at the 2012 American Diabetes Association (ADA) annual meeting.

A number of metabolic defects contribute to the complexity of type 2 diabetes and its management. Some of these defects are insulin resistance in adipose tissue and skeletal muscle, decreased insulin secretion from pancreatic beta-cells, overproduction of glucagon (which drives hepatic glucose production), abnormalities in glucose absorption in the kidneys, and effects in the stomach and brain.

Impact of Incretin Impairment in Type 2 Diabetes GLP-1 is a natural hormone that is secreted in the gut during meals. Food triggers the release of the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) from the intestines into the blood. GLP-1 has effects on the pancreas to decrease glucagon and increase insulin secretion.

DPP-4 is an enzyme that inactivates GLP-1. The levels of GLP-1 can be enhanced for their beneficial effects by inhibiting the action of DPP-4 through a DPP-4 inhibitor, resulting in enhanced levels of endogenous secretion of GLP-1 and GIP. The use of a GLP receptor agonist bypasses incretin secretion but results in pharmacologic levels of GLP, which works through its receptor in the pancreas to decrease glucagon, increase insulin, and lower blood glucose.

Native GLP-1 increases insulin secretion from the beta-cell in a glucosedependent fashion. It decreases glucagon secretion from the alphacell, and, at pharmacologic levels, it decreases gastric emptying. In contrast, the DPP-4 enzyme inactivates native GLP-1, and this contributes to the regulation of glucose homeostasis by inactivating the incretin hormones GLP-1 and GIP. The incretin effect is the enhanced glucose-stimulated insulin secretion

16

from the beta-cells in response to an oral glucose challenge compared with an intravenous challenge in patients with type 2 diabetes.

A number of metabolic defects contribute to the complexity Richard Pratley, MD of type 2 diabetes and its management.

Impaired incretin effect is a key component of dysregulation of glucose in patients with type 2 diabetes.

It is not yet known whether an incretin defect in patients with type 2 diabetes is related to impaired incretin secretion or to impaired incretin action.

Abnormalities in the incretin system have been shown to contribute to progressive beta-cell failure.

One strategy to overcome an impaired incretin effect is to give higher levels of GLP-1.

The mechanisms of the incretin defect are not completely understood, and various investigations have shown multiple defects that contribute to this.

There are slight decreases in the secretion of GLP-1, a possible reduced insulinogenic response to GLP-1, impaired activity of GLP-1, and beta-cell resistance to GIP. Strategies to Overcome the Incretin Defect

Increase GLP-1 Levels One strategy to overcome an impaired incretin effect is to give higher levels of GLP-1. A physiologic infusion of GLP-1 over 2 hours under hyperglycemic conditions resulted in a very robust insulin secretory response in healthy controls, although it was markedly blunted in patients with type 2 diabetes.

In contrast, a higher dose of GLP-1 (double that of the infusion) restored

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

the insulin secretory response in patients with type 2 diabetes to nearly the same level as in the healthy controls who had normal glucose tolerance. Thus, pharmacologic levels of GLP-1 can restore the insulin secretory effect of GLP-1 in patients with type 2 diabetes, as shown in the study discussed by Dr Pratley.

Another study has shown that native GLP-1 stimulates insulin secretion and inhibits glucagon secretion in a glucose-dependent manner. In patients with poorly controlled type 2 diabetes (fasting plasma glucose, 220 mg/dL), the infusion of native GLP-1 markedly decreased the glucose response to a normal fasting glucose level at approximately 4 hours compared with placebo.

The prompt increase in the secretion of insulin and the prompt suppression of glucagon with the GLP-1 infusion were the mechanisms contributing to the improved glucose response. The long-term effect of GLP-1 to improve glucose control and improve beta-cell function was shown in another study.

DPP-4 inhibition relies on an endogenous secretion of GLP-1 and GIP, which enhances insulin secretion and decreases glucagon secretion. But this tends to be with levels in the high physiologic range, which gives clear improvements over baseline in patients with type 2 diabetes, but does not achieve pharmacologic levels.

To obtain the full pharmacologic effect, exogenous GLP-1 must be given through an infusion of a GLP-1 agonist. This provides some additional effects (eg, decreased gastric emptying, increased satiety, decreased energy intake, decreased body weight, and increased nausea and vomiting).

A proof-of-concept study in patients with type 2 diabetes showed that subcutaneous infusion of GLP-1 in 10 patients compared with saline infusion in 9 patients over 6 weeks resulted in an approximate 4-lb reduction of body weight with GLP-1 versus an approximate 1.5-lb loss with saline.

DPP-4 Inhibition Impaired incretin effect is a key component of dysregulation of glucose in patients with type 2 diabetes, said Dr Pratley. DPP-4, an enzyme found throughout the body, rapidly inactivates GLP-1 and GIP, and modulates endogenous, physiologic GLP-1 activity levels. The effects of GLP-1 when given at pharmacologic levels include

restoration of the insulin response and reduced body weight.

GLP-1 and DPP-4 interact with the GLP-1 receptor by slightly different mechanisms. These actions are: ➤ GLP-1 activation: • Directly stimulates GLP-1 receptor • Markedly increases GLP-1 activity • Markedly decreases glucagon secretion • Increases insulin response • Delays gastric emptying • Decreases appetite and energy intake ➤ DPP-4 inhibition: • Indirectly stimulates GLP-1 receptor • Modestly increases endogenous GLP-1 and GIP levels • Modestly decreases glucagon secretion • Increases insulin response • No effect on gastric emptying • No effect on appetite and energy intake.

The recent ADA and the European Association for the Study of Diabetes Position Statement for managing hyperglycemia in patients with type 2 diabetes calls for initiating treatment

To avoid weight gain, we want to avoid sulfonylureas, TZDs, and insulin; incretin therapies have the advantages of low rates of hypoglycemia and low or no weight gain.

with lifestyle changes and metformin, said Dr Pratley. In patients who are not achieving goals within 3 months, the second-line options include sulfonylureas, thiazolidinediones (TZDs), DPP-4 inhibitors, GLP-1 receptor agonists, and insulin.

The next steps in treatment would be the use of 3-drug combinations and more complex insulin strategies.

The clinical question is how to select from these different options. To maintain glycemic control without promoting hypoglycemia, we are limited to TZDs, DPP-4 inhibitors, or GLP-1 receptor agonists, said Dr Pratley.

To avoid weight gain, we want to avoid sulfonylureas, TZDs, and insulin; incretin therapies have the advantages of low rates of hypoglycemia and low or no weight gain. ■

Insulin Update

1 in 4 Patients with Type 2 Diabetes Does Not Take Basal Insulin as Prescribed In addition to skipping doses, many patients self-treat a hypoglycemic event

By Wayne Kuznar

A

mong patients with type 2 diabetes, 1 in 4 patients did not take the prescribed doses of basal insulin correctly in the past 30 days, and more than 33% of the patients treated themselves for hypoglycemia, according to the results of the Global Attitudes of Patients and Physicians (GAPP2) survey.

“Despite clinical awareness of hypoglycemia and dosing irregularities, type 2 diabetes patients using insulin analogs still need further support to improve medication-taking behavior and reduce rates of self-treated hypoglycemia,” said Meryl Brod, PhD, President of the Brod Group, a health outcomes and phase 4 strategic planning consultancy in Mill Valley, CA, who reported the study results at the 2012 ADA annual meeting.

“Despite clinical awareness of hypoglycemia and dosing irregularities, type 2 diabetes patients using insulin analogs still need further support to improve medication-taking behavior and reduce rates of selftreated hypoglycemia.”

—Meryl Brod, PhD The study included data on the frequency and effect of basal insulin–taking behavior and hypoglycemia from 3042 patients with type 2 diabetes who use insulin analogs and 1653 healthcare professionals (primary care physicians, diabetes specialists, and diabetes nurses and educators).

The GAPP2 was an online survey conducted in 6 countries (United States, Canada, Japan, Germany, United Kingdom, and Denmark) between January 2012 and March 2012.

The results showed that dosing irregularities were common.

As many as 22% of the surveyed patients reported missing taking a basal insulin dose (mean, 3 times) in the past 30 days, 24% took their prescribed basal insulin more than 2 hours before or after the scheduled time (mean, 4 times), and 14% reduced the prescribed dose (mean, 4.2 times). Of these patients, 39% worried when they missed an insulin dose and 37% felt guilty about missing a dose.

By contrast, 48% of the patients said that they never missed a dose, 51% took a dose more than 2 hours later than prescribed, 38% reduced a dose,

and 80% self-treated for a hypoglycemic event; within the past year, these percentages were 10%, 10%, 9%, and 16%, respectively.

A correlation was seen between hypoglycemia and dosing irregularities.

Significantly more patients who missed a basal insulin injection in the previous Continued on page 18

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*

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-actinginsulinisthepreferredtreatmentfor thiscondition.

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

AUGUST 2012

AMERICAN HEALTH & DRUG BENEFITS

17

Insulin Update 1 in 4 Patients with Type 2 Diabetes Does Not Take... Continued from page 17 30 days reported a hypoglycemic event (41%) compared with those who did not (34%). Overall, 36% of the patients reported a hypoglycemic event in the past 30 days. Hypoglycemic events were nocturnal in 26% of the patients; 42% of patients worried about nocturnal events compared with 23% of

patients who worried about daytime hypoglycemic events.

Although 74% of the healthcare professionals surveyed said that they routinely discuss basal insulin dosing irregularities with their patients, including hypoglycemic events, only approximately 33% of the healthcare

professionals reported always discussing these events with their patients who were taking basal insulin only (27%) or basal-bolus (37%).

The researchers concluded that injection nonadherence and selftreated hypoglycemia are continued management challenges in insulin-

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

18

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

treated patients with type 2 diabetes.

Patient support should focus on interventions that address both the reasons for poor regular insulin-taking and the risk entailed by self-management of hypoglycemia “given the link between these 2 issues,” according to Dr Brod. ■

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).

Insulin Update

More Patients Reach Target HbA1c with an Approach Combining Insulin Glargine and Glulisine

By Mary Mosley

O

f 713 patients in a pooled analysis, approximately 45% were at target hemoglobin (Hb) A1c levels (ie, <7%) after 6 months of basal-plus treatment compared with

20% at baseline when taking oral antidiabetic drugs and insulin glargine (P <.001). Stefano Del Prato, MD, Professor of Endocrinology and Metabolism (School of Medicine) and Chief of

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 10.6 8.7 glycemia with at least 1 event (14/132) (24/276) (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

the Section of Diabetes, University of Pisa, Italy, presented the data at the 2012 ADA annual meeting.

The patients had poorly controlled type 2 diabetes (HbA1c >7%) when tak-

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.

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

AUGUST 2012

Patients with type 2 diabetes who were previously uncontrolled with an Stefano Del Prato, MD antidiabetic drug and insulin glargine would have improved glycemic control by the addition of once-daily insulin glulisine. ing oral antidiabetic drugs and insulin glargine. The mean baseline HbA1c was 7.6%, and the overall prevalence of severe hypoglycemia was 1.7%.

For the basal-plus regimen, insulin glulisine once daily at mealtime was added to insulin glargine for up to 6 months. The investigators pooled data from 4 previously reported clinical trials using this basal-plus regimen.

Dr Del Prato said the basal-plus regimen is becoming an increasingly common step when it is necessary to intensify insulin therapy, and that a single mealtime injection of a rapid-acting insulin analog, such as insulin glulisine, is added to antidiabetic drugs and once-daily basal insulin. This is thought to more closely mimic physiologic insulin levels and achieve good glycemic control with fewer daily injections.

Treatment guidelines recommend adding a prandial insulin, when needed, to reduce peaks of postprandial glucose (PPG).

In this analysis, the basal-plus regimen was associated with significant reductions in HbA1c and PPG (P <.001).

Over 6 months, mean HbA1c levels were reduced by nearly 0.5% (from 7.6% at baseline to 7.1%), and mean PPG levels were reduced by almost 55 mg/dL. Although the doses of insulin glargine and glulisine increased significantly from baseline, no significant increases in body weight or body mass index were observed.

The insulin glargine dose increased from 36.8 to 41.9 U daily, and the insulin glulisine dose increased from 4.9 to 13.2 U daily.

These results suggest that patients with type 2 diabetes who were previously uncontrolled with an antidiabetic drug and insulin glargine would have improved glycemic control by the addition of once-daily insulin glulisine, said Dr Del Prato. ■

AMERICAN HEALTH & DRUG BENEFITS

19

Insulin Update

rHuPH20 Added to Rapid-Acting Insulin Noninferior to Lispro in Type 1 Diabetes Similar safety and tolerability, improved postprandial glycemic control

By Mary Mosley

A

n insulin analog formulated with recombinant human hyaluronidase (rHuPH20) was noninferior to lispro in a comparator crossover study and had a similar safety and tolerability profile, said Irl B. Hirsch, MD, University of Washington, Seattle. He presented the study results at the 2012 ADA meeting. rHuPH20 is a genetically engineered soluble version of the naturally occurring human hyaluronidase enzyme, and there are more than 60 years of clinical use to support the safety of hyaluronidase, Dr Hirsch said. rHuPH20 is the first and only US Food and Drug Administration– approved recombinant human hyaluronidase enzyme.

“Current rapid-acting analog insulin products are too slow to mimic the physiologic insulin mean response,” said Dr Hirsch. Postprandial glucose control is improved with rHuPH20, because it accelerates the absorption and action of insulin.

Dr Hirsch and colleagues compared a rapid-acting insulin plus rHuPH20 with insulin lispro alone to determine the effects on glycemic control parameters, safety, and tolerability in an intensive basal-bolus insulin therapy regimen in patients with type 1 diabetes.

In this randomized, double-blind trial, after a 4- to 6-week run-in period when all patients received insulin glulisine for their prandial insulin and

twice-daily insulin glargine, patients were randomized to 1 of 2 cohorts. In one cohort, patients were randomized to initiate a regimen of insulin aspart (100 U/mL) plus rHuPH20 (5 mcg) or insulin lispro alone (100 U/mL). In the other cohort, the patients were randomized to start insulin lispro (100 U/mL) plus rHuPH20 (5 mcg) or insulin lispro alone (100 U/mL).

The study involved two 12-week intensive management periods; the patients were crossed over to the other regimen in their cohort for the second management period. Prandial doses were taken immediately before meals.

Dr Hirsch noted that only patients who met the aggressive fasting blood glucose targets of 80 to 120 mg/dL were included in the trial. Of the 117 randomized patients, 113 completed the trial. They were aged 42 years on average, 61 were women, and most were white. The mean body mass index was 27.3 kg/m2.

“The prespecified noninferiority margin of 0.4% was met, with a difference in the change of A1c from baseline of 0.05% with rHuPH20,” said Dr Hirsch.

In both the lispro and analog-rHuPH20 groups, the 7.43% hemoglobin A1c at screening was reduced to 7.02% at randomization, and was reduced further to 6.83% with lispro and 6.88% with analog-rHuPH20.

Prandial control was better with analog-rHuPH20 compared with

lispro throughout the study. The glycemic excursion was reduced by 73% at breakfast, 34% at lunch, and by 219% at dinner. The overall reduction in the glycemic excursion was a significant 82%.

“The glucose profile was flatter in the analog-rHuPH20 group,” compared with lispro, as measured by a 10-point glucose profile at the end of the study, said Dr Hirsch.

“Current rapid-acting analog insulin products are too slow to mimic the physiologic insulin mean response.”

Postprandial glucose control is improved with rHuPH20, because it accelerates the absorption and action of insulin.

—Irl B. Hirsch, MD

Overall hypoglycemia rates were significantly reduced with analogrHuPH20 compared with lispro. The prespecified hypoglycemia criterion for overall hypoglycemic events, ≤70 mg/dL, was reduced by 5%, and the criterion of <56 mg/dL by 7% with analog-rHuPH20.

One severe hypoglycemic episode

occurred in 1 patient in the analogrHuPH20 group, and 5 episodes occurred in 5 patients in the lispro group.

Two favorable trends were seen with analog-rHuPH20. Compared with lispro, there was a small reduction of 2.5 U/mL in the total daily insulin dose and a small difference in weight (a slight reduction of 0.25 lb with analog-rHuPH20 and a gain of 0.10 lb with lispro alone).

Adverse events were similar between the groups for all system-organ classes. Treatment-phase severe adverse events were limited to severe hypoglycemia, which occurred in 2 patients treated with lispro alone. No difference was seen for injection-site pain between groups, with approximately 70% of patients reporting none and 30% minimal injection-site pain.

Immunogenicity profiles were not changed, regardless of the sequence in which the patient received analogrHuPH20 or lispro. The anti-insulin antibodies were at 86% at baseline and at 81% at the end of the second treatment period for patients receiving analog-rHuPH20 first and then lispro, and were 76% at baseline and 71% at the end of the second treatment period in the patients receiving lispro and then analog-rHuPH20.

Positive anti-rHuPH20 antibodies were found in 13 patients at baseline and in 12 patients at the end of the second treatment period. ■

Head-to-Head Comparison: Early Insulin Glargine Can Help Achieve Glycemic Target in Type 2 Diabetes DPP-4 inhibitor versus basal insulin as add-on therapy to metformin

By Wayne Kuznar

I

nsulin glargine as a second-line treatment after metformin in patients with type 2 diabetes is superior to adding the dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin to achieve glycemic control, according to a first randomized head-to-head comparison of a DPP-4 and basal insulin presented at the 2012 ADA annual meeting.

The study showed that the reduction in hemoglobin (Hb) A1c was greater with insulin glargine than with the DPP-4 sitagliptin, reported principal investigator Pablo J. Aschner, MD, MSc, Professor, Department of Endocrinology, Javeriana Pontificia University, Colombia. The results of this study

“The results of this study support the option of introducing basal insulin (glargine) in patients with type 2 diabetes inadequately controlled by metformin, with the potential for long-term benefits arising from the achievement of optimum glycemic control early in the course of the disease.”

—Pablo J. Aschner, MD, MSc were simultaneously published in the Lancet (Aschner PJ, et al. Lancet. 2012; 379:2262-2269).

Long-Term Benefits with Early Basal Insulin “The results of this study support the option of introducing basal insulin

(glargine) in patients with type 2 diabetes who are inadequately controlled by metformin, with the potential for long-term benefits arising from the achievement of optimum glycemic control early in the course of the disease,” Dr Aschner said.

This open-label study demonstrated

that patients assigned to insulin glargine were 60% more likely to achieve an HbA1c level <7% than those assigned to sitagliptin, “with concurrently lower fasting and postprandial blood glucose.”

The trial included 515 metformintreated patients with type 2 diabetes whose HbA1c level was between 7% and 11% while receiving metformin.

The patients were randomized to insulin glargine, starting at 0.2 U/kg injected at dinner or bedtime, or to sitagliptin 100 mg daily. The dosage of insulin glargine was adjusted according to patients’ self-monitored fasting plasma glucose (FPG) concentration to maintain FPG between 4.0 mmol/L and 5.5 mmol/L. Continued on page 22

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Insulin Update

Ninety Years of Insulin: What’s Needed? What’s New?

By Mary Mosley

T

he introduction of insulin glargine in 2000 and of insulin detemir in 2004 responded to some of the problems associated with neutral protamine Hagedorn (NPH) insulin, introduced 90 years ago. Continuous subcutaneous insulin infusion (CSII) delivered through an insulin pump became the gold standard replacement of insulin for type 1 diabetes in 1978. Yet, improved basal insulins are needed, said Geremia B. Bolli, MD, University of Perugia, Italy, in a session providing an update on insulin therapy at the 2012 ADA annual meeting.

Dr Bolli said that NPH is not appropriate when beta-cell function is lost, as in the case of patients with type 1 diabetes, or worsens, as in patients with type 2 diabetes. Also, as body mass index decreases, NPH is less indicated because of the increased risk for hypoglycemia.

Insulin Glargine versus Detemir The merits of insulin glargine, the first long-acting insulin analog, include its relatively peakless pharmacodynamic profile, solubility that makes its absorption more reproducible, and a steady-state duration of action beyond 24 hours. In patients with type 1 diabetes, glargine is noninferior to CSII, is superior to NPH because of less hypoglycemia, particularly nocturnal, and results in the achievement of a lower or similar hemoglobin (Hb) A1c. These improvements with insulin glargine “make intensive treatment in type 1 diabetes much safer,” said Dr Bolli.

Insulin detemir, by contrast, is soluble, and therefore its absorption is less variable than that of glargine, it is nearly as peakless as glargine, and it is protective against hypoglycemia; however, detemir’s duration of action is shorter than glargine’s, and detemir has a weaker efficacy in obesity.

Dr Bolli reviewed several studies that showed the benefits of these drugs; however, he noted that glargine and detemir have limitations.

For glargine, the duration of action is not sufficient, and the day-to-day variability is too great in approximately 20% of patients with type 1 diabetes.

For detemir, the duration of action needs to be longer in the majority of patients with type 1 diabetes, and greater potency is needed in obese patients (primarily those with type 2 diabetes).

Novel Basal Insulins on the Horizon Dr Bolli also reviewed 2 investigational basal insulins—insulin degludec and PEGylated insulin lispro (LY2605541).

Table Advantages and Benefits of Rapid-Acting Insulin Analogs vs Regular Insulin Insulin degludec. Insulin degludec, a second-generation agent, has a sustained release, with an approximate 25-hour duration of action in patients with type 1 diabetes. Its pharmacokinetic profile predicts that degludec will have a sustained effect for more than 24 hours, low variability in subcutaneous absorption, and a low rate of hypoglycemia.

An interesting possibility with a long-acting insulin such as degludec is the ability to vary the timing of the dosing, without excessive disruption of glucose control or differences in HbA1c levels.

—Geremia B. Bolli, MD

In one study, degludec had a 4-fold lower day-to-day variability in its glucose-lowering effect compared with insulin glargine; however, a crossover study is needed to confirm this observation, said Dr Bolli.

A noninferiority trial in patients with type 1 diabetes showed that degludec was noninferior to glargine at a similar dose, showing a 25% risk reduction in nocturnal hypoglycemia with degludec, translating to 1.5 fewer events per patient-year.

In a noninferiority trial in patients with type 2 diabetes, degludec, at a similar dose as glargine, produced a similar reduction in HbA1c at 1 year, with an 18% risk reduction in hypoglycemia and a 25% reduction in nocturnal hypoglycemia.

An interesting possibility with a long-acting insulin such as degludec, noted Dr Bolli, is the ability to vary the timing of the dosing, without excessive disruption of glucose control or differences in HbA1c or nocturnal hypoglycemia, as shown in 2 studies.

PEGylated insulin lispro. PEGylated insulin lispro (LY2605541) has a prolonged duration of action because it delays insulin absorption and reduces clearance. In vitro studies have shown that this agent is safe.

In patients with type 1 diabetes, a short phase 2 study showed that LY2605541 was noninferior to glargine on daily mean blood glucose, HbA1c, and fasting plasma glucose (FPG) variability. Dr Bolli said that these results were obtained with a prandial dose of LY2605541 that was 24% lower than the glargine dose, which could be in-

Advantages

Benefits

Earlier onset and peak of biologic activity

Lower prandial glucose

Shorter duration of action

Less late prandial hypoglycemia

Less biologic activity

Fewer hypoglycemic fluctuations

terpreted as a “better provision of basal insulin” with LY2605541.

In this study, patients lost weight with LY2605541 but gained weight with glargine. Although there was more hypoglycemia overall with the new insulin, the nocturnal hypoglycemia was reduced.

Other findings included an elevation in hepatic enzymes and triglycerides, an increase in low-density lipoprotein cholesterol (LDL-C), and a decrease in high-density lipoprotein cholesterol (HDL-C), although this value remained in the normal range.

Another study of patients with type 2 diabetes demonstrated that LY2605541 was noninferior to glargine on FPG and HbA1c after 12 weeks. The weight loss was consistent with that in the study in patients with type 1 diabetes. Hypoglycemia (including nocturnal) was reduced with LY2605541.

Continuous glucose monitoring revealed that there was less time spent in hypoglycemia (24-hour, nocturnal) and lower blood glucose variability.

The increase in hepatic enzymes with LY2605541 was within the normal range, triglycerides were higher, and LDL-C and HDL-C did not change.

Further work is needed to answer remaining questions about degludec and LY2605541, including questions on the day-to-day variability at doses relevant to clinical practice, titration, and protection against hypoglycemia.

Bolus Insulin Analogs The bolus (prandial) insulin analogs lispro, aspart, and glulisine address the limitations seen with regular human insulin. These analogs are more physiologically active in terms of their appearance and disappearance from the circulation than regular insulin, said Luigi F. Meneghini, MD, MBA, University of Miami, FL. Key advantages of rapidacting insulins are listed in the Table.

Bolus Insulin in the Pipeline An insulin formulated with a synthetic hyaluronidase, analog-rHuPH20, is under development. Combining a rapid-acting insulin with rHuPH20 results in higher insulin concentrations at 1 hour after injection and lower insulin concentrations at 2 hours after injection compared with rapid-acting insulin

AUGUST 2012

alone. The biologic activity of the rapid-acting insulin or the rapid-acting insulin analog is enhanced by rHuPH20, making it more physiologic, stated Dr Meneghini.

Inhaled insulin is currently under development. Technosphere-inhaled insulin is in phase 3 clinical trials. Compared with subcutaneous insulin, technosphere-inhaled insulin produced a slightly better clinically relevant improvement in HbA1c in patients with type 1 diabetes, according to a metaanalysis published in 2006.

A greater reduction in fasting FPG was found with inhaled insulin, and no difference was seen in hypoglycemia or weight; however, one study of patients with type 2 diabetes showed less weight gain with inhaled insulin. Patient satisfaction was higher with inhaled insulin, and quality of life was improved in 2 studies.

However, pulmonary issues with inhaled insulin were found in the metaanalysis. Nonproductive cough is 3- to 4-fold higher with inhaled insulin but is not associated with changes in pulmonary function. The cough begins immediately after inhalation and tends to improve after the first month. First expiratory volume in 1 second (FEV1) progressively decreases for the first 6 months and then stabilizes, which is seen more in patients with type 1 diabetes. Diffusion capacity is slightly decreased, mostly in patients with type 1 diabetes, but this has been seen only in short-term studies.

A 52-week study in patients with uncontrolled type 2 diabetes showed a similar reduction in HbA1c with prandial inhaled insulin plus insulin glargine compared with twice-daily biaspart insulin. The inhaled insulin was associated with less weight gain, lower FPG, lower postprandial glucose excursions after a meal challenge, and less hypoglycemia.

In patients with type 1 diabetes, inhaled technosphere insulin plus glargine produced a similar HbA1c reduction at 1 year as aspart plus glargine. FPG was lower with technosphere-inhaled insulin. But fewer than 20% of patients reached an HbA1c level <7.0% with the inhaled insulin, which is a criticism of inhaled insulins, said Dr Meneghini. ■

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Diabetes Management

Novel Risk Factors for Type 2 Diabetes Sleep apnea, second-hand smoking exposure, and fetuin-A

See also Insulin Update

By Mary Mosley

S

everal presentations at the 2012 ADA annual meeting focused on new risk factors for diabetes, independent of obesity, that were found in recent studies; these risk factors are obstructive sleep apnea (OSA), exposure to second-hand smoking, and the hepatokines fetuin-A.

Obstructive Sleep Apnea and Diabetes OSA and type 2 diabetes are major obesity-associated diseases that coexist in the same individuals with insulin resistance. A recent meta-analysis showed a positive relationship between OSA and the risk for diabetes, independent of obesity. Furthermore, OSA was shown to cause diabetes, said Kazuya Fujihara, MD, Department of Internal Medicine, University of Tsukuba Institute of Clinical Medicine, Japan.

Because of the strength of the association between OSA and type 2 diabetes, Dr Fujihara and colleagues conducted a systematic review of cross-sectional and longitudinal studies to investigate whether this association is dependent on obesity. In addition, the causal nature of this relationship was not clear from the available cohort studies.

A total of 41,813 patients were included in the 17 cross-sectional studies

identified for this systematic review; of these, 2513 patients had type 2 diabetes and 6524 had OSA. Compared with mild OSA, the patients with severe OSA had a 91% increased risk of type 2 diabetes.

Even after adjusting for obesity, the risk for diabetes in people with OSA remained high (odds ratio [OR], 2.03).

When instrumentation rather than questionnaires was used to ascertain OSA, the risk for diabetes was even higher (OR, 2.59 vs 1.56, respectively).

To determine the causal relationship between diabetes and OSA, Dr Fujihara and colleagues examined the data from 11 studies with nearly 38,500 patients. Results showed that severe OSA significantly predicted the risk of developing type 2 diabetes (OR, 1.99).

However, having diabetes did not significantly predict the risk of future OSA (OR, 1.03).

Based on these data, said Dr Fujihara, incident diabetes is caused by severe OSA. Conversely, diabetes did not cause OSA. The proposed mechanisms for OSA as causing diabetes include intermittent hypoxia, unhealthy lifestyles, or a change in endocrine hormones that contribute to increased insulin resistance, decreased insulin sensitivity, and, ultimately, to a worsening of glycemic control.

Head-to-Head Comparison... Continued from page 20 At 24 weeks, the adjusted mean reduction in HbA1c level in the modified intent-to-treat patient population was 1.72% in the patients assigned to insulin glargine and 1.13% in those assigned to sitagliptin, with a final mean HbA1c concentration of 6.8% in the insulin glargine group versus 7.4% in the sitagliptin group.

At the last available visit during study treatment in which HbA1c level was measured, 68% of insulin glargine users versus 42% of sitagliptin users achieved a target of <7% HbA1c.

The adjusted mean difference in selfmonitored FPG between the 2 groups was 2.3 mmol/L (41 mg/dL) in favor of insulin glargine.

Advantages of DPP-4 Inhibitors “As expected, the estimated rate of hypoglycemia per patient-year was 8 times higher with glargine, but the risk of severe events, although also 3 times higher, was not significantly different from that with sitagliptin,” said Dr Aschner.

22

The rates of hypoglycemia were 46% with insulin glargine compared with 13% for sitagliptin. Symptomatic hypoglycemia occurred more often in the insulin glargine recipients, and severe symptomatic hypoglycemia was rare in either group—1% of the insulin glargine group and <1% in the sitagliptin group. The risk for severe nocturnal hypoglycemia was <1% in each group.

Body weight declined by a mean of 1.08 kg from baseline in the sitagliptin group but increased by a mean of 0.44 kg in the insulin glargine group, for an adjusted mean difference of 1.51 kg (P <.001).

There were no new safety signals observed with insulin glargine in the study.

“Results show that if people learn to titrate basal insulin and do not have episodes of severe hypoglycemia, more of them might continue over time to reach their glycemic goal with the combination of insulin glargine plus metformin,” concluded Dr Aschner. ■

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AUGUST 2012

All patients with OSA should therefore be screened for diabetes, suggested Dr Fujihara, to facilitate early detection of the disease and initiation of appropriate management.

Severe OSA, independent of obesity, significantly predicts the risk of developing type 2 diabetes, but having diabetes does not significantly predict the risk of future OSA. Exposure to second-hand smoking and fetuin-A are 2 additional novel, independent risk factors for type 2 diabetes.

Second-Hand Smoking and Diabetes A second study presented at the meeting showed that exposure to second-hand smoking, as measured by serum cotinine levels in never-smokers, is associated with type 2 diabetes in adults in the general population, said Omayma O. Alshaarawy, MBBS, West Virginia University, Morgantown.

Several studies have reported an association between active smoking and diabetes among smokers, but only a few studies have investigated the relationship between environmental tobacco smoking and diabetes in never-smokers. The present study used an objective measure of exposure rather than a self-report as was used in previous studies.

Using data from the National Health and Nutrition Examination Survey (NHANES), Alshaarawy and colleagues studied 8407 participants; of these, 57% were women and 68% were non-Hispanic whites. Their weight was equally distributed across all parts of the spectrum.

Diabetes was identified in 6.5% of the participants, and the geometric mean serum cotinine was 0.07 ng/mL. NHANES is a nationally representative sample of US adults aged >20 years. The data were adjusted for age, sex, race, and physical activity. The data represented 5 time periods between 1999 and 2008. Persons who were pregnant, had cardiovascular disease, were former or current smokers, or who had missing data on serum cotinine were excluded from the study.

Serum cotinine levels were significantly associated with glycohemoglobin, and the mean change in

glycohemoglobin increased with elevations in the cotinine levels.

A significant relationship was found between serum cotinine levels and the development of diabetes; the risk for diabetes increased with elevations in the cotinine levels in the blood.

Cotinine levels in the middle range were associated with a 28% increased risk for diabetes, whereas the highest range of cotinine was associated with a 56% increased risk for diabetes.

The association between secondhand smoke exposure and diabetes risk was stronger in women, non-Hispanic whites, and nonobese persons. Whether this association represents a preventable risk factor requires prospective study.

Fetuin-A, a Hepatokine, and Diabetes Fetuin-A was identified as a risk factor for diabetes in data from the Nurses’ Health Study in an analysis presented

by Qi Sun, MD, SCD, Research Associate, Department of Nutrition, Harvard School of Public Health, Boston.

The liver plays a pivotal role in glucose metabolism. Accumulating evidence shows that the liver produces a group of molecules called hepatokines, including fetuin-A, selenoprotein P, and angiopoietin-like protein 4, which directly regulate glucose sensitivity.

Fetuin-A, also called alpha-2HSglycoprotein, inhibits insulin receptor activity. A total of 3 previous studies have shown an association between fetuin-A levels and an increased risk of type 2 diabetes, said Dr Sun. The present study was a prospective, nested, case-control study within the Nurses’ Health Study. The average patient age was 65 years. In 470 women with diabetes, the body mass index was higher at baseline (30 kg/m2), and physical activity was lower than in 470 women without diabetes. The levels of fetuin-A and the liver enzymes alanine aminotransferase (ALT) and gammaglutamyl peptidase were also elevated in the women with diabetes.

Dr Sun and colleagues found that high plasma fetuin-A levels were significantly associated with an increased risk for developing type 2 diabetes.

This association was independent of the established risk factors for diabetes and from the levels of ALT and gamma-glutamyl peptidase.

Overall, the existing data from prospective studies, including the present study, consistently support the hypothesis that fetuin-A is a novel independent risk factor for type 2 diabetes, according to Dr Sun. ■

Diabetes Management

Achieving Normoglycemia, Even Once, Significantly Reduces Diabetes Risk in Patients with Prediabetes Restoring normal glucose regulation provides long-term benefits

By Wayne Kuznar

R

eversing prediabetes and returning to a normal state of glucose regulation, even transiently, significantly reduces future risk of developing diabetes, reported investigators from the Diabetes Prevention Program Research Group at the 2012 ADA annual meeting.

Data were analyzed from participants in the 1990 Diabetes Prevention Program who were randomized to intensive lifestyle intervention (N = 736), to metformin (N = 647), or to placebo (N = 607) and who then continued follow-up in the observational, postintervention Diabetes Prevention Program Outcomes Study (DPPOS). The primary outcome was the proportion of patients who progressed to diabetes during the DPPOS.

achieved it 3 times had a 66.9% reduction in risk.

Prediabetes, defined as an FPG concentration of 5.6 mmol/L to 6.9 mmol/L

or 2-hour plasma glucose of 7.8 mmol/L to 11.0 mmol/L, is itself a very high risk factor for development of type 2 diabetes and carries with it the risk of diabetes complications, Dr Perreault pointed out.

Several clinical trials have shown that the incidence of diabetes can be prevented or delayed in people with prediabetes through diet, physical activity, and drugs. Together, studies have shown incidence reductions beContinued on page 24

“The treatment arm did not affect the reduction in diabetes onset in DPPOS in those who reached normal glucose regulation in the Diabetes Prevention Program.” —Leigh Perreault, MD Patients who had at least 1 annual oral glucose tolerance test during the Diabetes Prevention Program and had normal glucose regulation (fasting plasma glucose [FPG] <100 mg/dL or a 2-hour glucose <140 mg/dL) lowered their risk for developing diabetes by 56% compared with those who continued to have prediabetes, independent of how the reduction was achieved, said principal investigator Leigh Perreault, MD, a physician in the department of endocrinology and metabolism, and a clinical researcher at the University of Colorado Denver School of Medicine, Aurora.

“The treatment arm did not affect the reduction in diabetes onset in DPPOS in those who reached normal glucose regulation in the Diabetes Prevention Program,” Dr Perreault noted.

Diabetes Prevention Risk reduction was strongly associated with the number of times normal glucose regulation was achieved.

Those who achieved normal glucose regulation once had a 47% reduction in the risk of progression to diabetes, those who achieved it twice had a 60.7% reduction in risk, and those who

AUGUST 2012

AMERICAN HEALTH & DRUG BENEFITS

23

Diabetes Management

TODAY Study: New Data, Implications for Young Patients with Diabetes

See also Insulin Update

By Mary Mosley

T

he rise of diabetes in American youth was the focus of a session at the 2012 ADA annual meeting that was devoted to the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

Philip S. Zeitler, MD, PhD, Section Head, Endocrinology, University of Colorado, Denver, presented updated data from new analyses released after the publication of the key results in April 2012.

The TODAY trial, which was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, followed 699 young individuals who were between the ages of 10 and 17 years at study entry (mean age, 14 years).

The average duration of diabetes among study participants was 7.8 months; the average body mass index (BMI) was 34.9 kg/m2; and the average hemoglobin (Hb) A1c was 6.0% at baseline. Nearly 90% of the participants had a family history of diabetes; 65% of the participants were female, 41% Hispanic, 32% black, 20% white, and 6% were American Indian.

The 3 treatment groups were (1) metformin-alone, (2) metformin-pluslifestyle, and (3) metformin-plusrosiglitazone; participants were followed for 2 to 6 years. (Rosiglitazone is not approved by the US Food and Drug Administration for the treatment of type 2 diabetes in young patients.)

Nearly 46% met the primary end

point of failure to maintain HbA1c <8% for 6 months.

Treatment of type 2 diabetes in youth may need to be individualized.

There were “very intriguing race and gender differences that need further analysis, including adherence, socioeconomic status, and other predictors” of treatment failure.

—Philip S. Zeitler, MD, PhD Outcomes and Implications Metformin monotherapy is inadequate in 50% of young patients with type 2 diabetes, said Dr Zeitler, based on the TODAY study. This percentage is greater than has been shown in studies of metformin in adults. The addition of rosiglitazone did not change the median time to failure. Lifestyle intervention increased weight reduction at 6 months but did not improve sustained glycemic control.

Early addition of a second agent to metformin may be required in this patient population, but additional studies

Achieving Normoglycemia... Continued from page 23 tween 25% and 72%, but most participants remain with prediabetes.

Some trial results mention the 20% to 50% of participants who did not progress to diabetes and in fact regressed to normoglycemia; however, these studies offer little in the way of explaining predictive factors.

Restoring Normal Glucose Regulation This analysis outlined 3 factors that had significant associations with the achievement of normal glucose regulation during the DPPOS: • Previous normal glucose regulation during the Diabetes Prevention Program • Increased beta-cell function • Insulin sensitivity.

One surprise finding was that patients from the Diabetes Prevention

24

Program who were randomized to intensive lifestyle intervention but remained persistently prediabetic had a 31% greater risk of progressing to diabetes and a 41% lower risk of achieving normal glucose regulation during the DPPOS than did participants randomized to placebo.

This finding emphasizes a particular susceptibility for this group, who may benefit from additional interventions. These results suggest that the management strategy is unimportant, as long as the lifestyle intervention occurs early and can restore normal glucose regulation.

The analysis supports aggressive glucose-lowering treatments to achieve normal glucose levels in people with prediabetes to maximize long-term slowing or preventing the progression to diabetes. ■

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

are needed to determine the best agent for this purpose.

The role of intensive lifestyle intervention in young patients with type 2 diabetes is uncertain. Despite increased weight loss at 6 months in the metformin-plus-lifestyle group, glycemic control was not improved.

Dr Zeitler noted that treatment assignment did not affect long-term control of HbA1c, which was nearly the same in each arm in the almost 50% of young patients who maintained glycemic control over the course of the study. Furthermore, the onset of elevated HbA1c is quick and therefore cannot be predicted before HbA1c levels are first elevated.

Treatment of type 2 diabetes in youth may need to be individualized.

There were “very intriguing race and gender differences that need further analysis, including adherence, socioeconomic status, and other predictors” of treatment failure, said Dr Zeitler.

Slightly more males (48%) than females (44%) failed to maintain HbA1c control. In addition, failure rates were 53% in non-Hispanic blacks, 45% in Hispanics, 37% in non-Hispanic whites, and 40% in American Indians.

“Overall, these findings show that these young people with type 2 diabetes have large hearts, suggestive of risk for cardiovascular disease.”

—Neil H. White, MD, CDE Furthermore, the response to treatment differed: the metformin-plusrosiglitazone combination was more effective in controlling HbA1c in females, and greater improvement was seen in males with metformin plus a lifestyle intervention.

In non-Hispanic blacks, there was a “strikingly poor response to metformin,” said Dr Zeitler, with 50% losing glycemic control by 6 months. No treatment difference was found among Hispanics.

TODAY’s Comorbidities A snapshot of the comorbidities in the TODAY study raises concerns. Co-

morbidities were apparent early in the course of type 2 diabetes, within 2 to 6 years of the initial diagnosis, said Neil H. White, MD, CDE, Professor of Pediatrics, Washington University School of Medicine in St. Louis, MO. Between 10% and 30% of participants had dyslipidemia (low-density lipoprotein cholesterol ≥130 mg/dL and triglycerides ≥150 mg/dL), and 34% had hypertension, which was defined as a blood pressure (BP) of ≥95th percentile, systolic BP ≥130 mm Hg, or diastolic BP ≥80 mm Hg. In addition, 17% had microalbuminuria (defined as an albumin-creatinine ratio ≥30 mg/g creatinine), a risk factor for nephropathy along with hypertension.

The predictive factors for hypertension were sex, age at baseline, and an increase in BMI over time, and for microalbuminuria, a predictive factor was an increase in HbA1c over time.

The only difference in adverse events between the treatment groups was hepatotoxicity, which was lower in the metformin-plus-rosiglitazone group (3.1 events per person-year) than in the metformin-only (8.1 events) and the metformin-plus-lifestyle (5.9 events) groups.

Fundus photography revealed a 14% rate of nonproliferative diabetic retinopathy, Dr White noted, after an average of 4 to 5 years of diabetes.

Increased levels of echocardiography measures were found as well: 85% to 90% for left ventricular (LV) mass and 75% for left atrial (LA) diameter.

LV mass and LA diameter did not differ between the treatment arms.

“Overall, these findings show that these young people with type 2 diabetes have large hearts, suggestive of risk for cardiovascular disease,” said Dr White. “Glycemic control appears to matter in the development of leftventricular hypertrophy.”

Factors Predicting Poor Glycemic Control Increased obesity and HbA1c levels, as well as lower insulinogenic index (IGI) levels at baseline, were associated with failing to maintain glucose control for 6 months, according to an analysis of 2 subsets of patients, said Kenneth C. Copeland, MD, Associate Director, University of Oklahoma Diabetes Center. (IGI is an indicator of insulin secretion.)

The HbA1c rate increase (even within the normal range) was the only longitudinal factor associated with the primary end point.

Continued on page 25

Diabetes Management

Quality Improvement Programs Enhance Diabetes Care, Especially When Baseline Measures Are Poor These interventions can improve cardiometabolic health

By Wayne Kuznar

R

esults of a meta-analysis that looked at the effectiveness of quality improvement (QI) strategies beyond controlling hemoglobin (Hb)A1c levels indicate that many trials of such strategies show improvements in patient care for diabetes.

“QI strategies significantly improved intermediate disease outcomes, including HbA1c, low-density lipoprotein cholesterol, systolic blood pressure, and diastolic blood pressure,” said the study’s principal investigator, Andrea C. Tricco, PhD, MSc, Instructor, Systematic Reviews and Meta-Analysis, King Saud University Medical Research at the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Ontario, Canada.

“These effects are important on a population level, and the effects were larger with poor baseline control,” said Dr Tricco, who presented the results of this meta-analysis at the 2012 ADA annual meeting; the study was simultaneously published in the Lancet (Tricco AC, et al. Lancet. 2012;379:2252-2261).

Through a systematic review of published trial data, the investigators assessed the effects of QI strategies on HbA1c levels, vascular risk management, microvascular complication monitoring, and smoking cessation in patients with diabetes.

A total of 142 clinical trials were re-

viewed, which included 38,664 patients from patient-randomized trials and 84,865 patients from cluster-randomized trials. In addition, predefined QI strategies or financial incentives targeting health systems, providers, and patients were also assessed.

The QI strategies targeting health systems were case management, team changes, electronic patient registries, facilitated relay of information to clinicians, and continuous QI. Strategies assessing providers were audit and feedback, clinician education, clinician reminders, and financial incentives. For patients, the strategies were education, promotion of selfmanagement, and reminder systems.

Cardiometabolic Implications Overall, compared with usual care, implementing QI strategies was associated with reductions in: • HbA1c levels (mean reduction, 0.37%) • Low-density lipoprotein cholesterol (LDL-C; 0.10 mmol/L) • Systolic blood pressure (BP; 3.13 mm Hg) • Diastolic BP (1.55 mm Hg).

Implementing QI strategies increased the likelihood that patients received aspirin by 33%, antihypertensive drugs by 17%, screenings for retinopathy by 22%, screenings for renal function by

28%, and screenings for foot abnormalities by 27%.

The results for some cardiovascular outcomes were not as robust, because statin use, hypertension control, and smoking cessation were not increased significantly with QI strategies versus usual care. Few studies reported harmful outcomes, said Dr Tricco.

“QI strategies significantly improved intermediate disease outcomes, including HbA1c, low-density lipoprotein cholesterol, systolic blood pressure, and diastolic blood pressure.”

—Andrea C. Tricco, PhD, MSc

Larger effects on outcomes were noted when baseline concentrations were >8% for HbA1c , 2.59 mmol/L for LDL-C, and 80 mm Hg and 140 mm Hg for diastolic BP and systolic BP, respectively. For lowering HbA1c levels, the most effective QI strategies were promotion of self-management, team changes, case management, and patient education, which accounted for a reduction of approximately 0.60%.

The effectiveness of QI intervention strategies targeting providers and patients varied, depending on baseline HbA1c control. According to the researchers, the results show that the strategies involving interventions targeting the entire system of chronic disease management were associated with the best results, regardless of baseline HbA1c levels.

Interventions aimed only at patients may be beneficial regardless of baseline HbA1c , whereas interventions solely targeting providers are beneficial only if baseline HbA1c control was poor (>8%). Therefore, optimization of all of the systems of care should be included in programs to improve diabetes management, said Dr Tricco.

If these quality indicators are widely adopted, the population benefits would be potentially important.

Data from the United Kingdom Prospective Diabetes Study showed that a 1% reduction in mean HbA1c results in 21% fewer deaths, 14% fewer myocardial infarctions (MIs), and a 37% decrease in microvascular complications at the population level.

Using these data, the reduction in mean HbA1c shown in this metaanalysis could translate into 7% fewer deaths, 5% fewer MIs, and 12% fewer microvascular complications at the population level. ■

TODAY Study: New Data, Implications for Young... Continued from page 24 The changes from baseline values over time were evaluated to determine their relationship to durable glycemic control in 172 participants who maintained glycemic control for at least 48 months and in 305 participants who lost glycemic control before that time point.

Treatment assignment was not significantly associated with maintaining or losing glycemic control. Race/ethnicity predicted durable glycemic control, said Dr Copeland. A lower failure rate was found in non-Hispanic whites (16%), and a higher failure rate was seen in non-Hispanic blacks (38%).

Failure rates for glycemic control decreased with increases in income and education. Only 20% of participants failed to maintain glycemic control in the >$50,000 category compared with 45% in the <$25,000 category and 35% in the $25,000 to $49,999 category.

A significantly higher HbA1c at base-

line predicted failure. Participants with a 6.4% HbA1c at baseline failed compared with participants with an HbA1c of 5.7%, who maintained glycemic control. In addition, a significantly lower IGI (1.12 vs 2.04) predicted failure.

Factors that were associated with failure over time were a rise in HbA1c, a lower IGI at baseline, and a higher BMI. Baseline HbA1c, even within the nondiabetic range, was the best predictor of failure to maintain glycemic control for 6 months, regardless of the treatment arm. During treatment, a rapidly rising HbA1c, even within the normal range, is associated with failure and may suggest the need to intensify treatment early.

Professor of Pediatrics (Endocrinology), Yale School of Medicine, New Haven, CT.

Combination Therapy Combination treatment may be required for young patients with type 2 diabetes “to address the profound degree of insulin resistance observed in the study,” said Sonia Caprio, MD,

Beginning aggressive therapy very early may slow the decline in beta-cell adaptation and may achieve more durable glycemic control.

Dr Caprio presented results from an analysis of 674 participants in the

Combination treatment may be required for young patients with type 2 diabetes “to address the profound degree of insulin resistance observed in the study.” —Sonia Caprio, MD

AUGUST 2012

TODAY study who had a slower rate of decline in beta-cell function in the metformin-plus-rosiglitazone group, which was relatively stable from 6 months to 24 months compared with the metformin-alone or the metforminplus-lifestyle cohorts. This favorable change accounts for the lower rate of glycemic control loss observed in the metformin-plus-rosiglitazone group, she said.

Treatment with metformin plus rosiglitazone resulted in a 20% significant increase in insulin sensitivity in the first 6 months, but no change was found in the other 2 groups. However, insulin sensitivity decreased thereafter to approximately 10%, and no difference was seen between the groups at the end of the study.

The metformin-alone and metforminplus-lifestyle groups had no significant effect on insulin sensitivity or beta-cell adaptation, both of which decreased progressively across 48 months. ■

AMERICAN HEALTH & DRUG BENEFITS

25

Diabetes Complications

Diabetic Retinopathy: Beneficial Effects Shown in Experimental Model with Linagliptin

By Mary Mosley

T

he dipeptidyl peptidase (DPP)-4 inhibitor linagliptin was shown to have a protective effect on the microvasculature of the diabetic retina, most likely as a result of a combined effect on the neurovascular unit, according to data presented at the 2012 ADA annual meeting by Hans-Peter Hammes, MD, PhD, of the University of Heidelberg, Germany.

The effect of DPP-4 inhibitors on the diabetic vasculature is still being studied. DPP-4 inhibition could have effects on oxidation, apoptosis, and vasoprotection, but it has also been shown to be proangiogenic, which could be an untoward effect in the diabetic eye.

Glucose and hemoglobin (Hb) A1c levels were reduced by 10% to 15% with linagliptin in the diabetic rats.

Diabetes was induced in the rats with streptozotocin. One group of diabetic rats was fed food containing linagliptin

(0.083 g/kg) for 26 weeks, and another diabetic group and the control group were fed regular food.

DPP-4 inhibition could have effects on oxidation, apoptosis, and vasoprotection, but it has also been shown to be proangiogenic, which could be an untoward effect in the diabetic eye.

DPP-4 activity was reduced by 75% with linagliptin. Surprisingly, active glucagon-like peptide (GLP)-1 was increased by more than 12-fold with linagliptin; Dr Hammes said that this may contribute to the benefits seen in this study.

Methylglyoxal, a major factor in the

reduction of vascular damage, was significantly reduced by 50% in the diabetic rats receiving linagliptin compared with a 4-fold increase in the diabetic rats who did not (P = .01).

Regarding the retinal morphology, for the first time, the researchers discriminated between the superficial layer of the retina and the layer proximal to the large vessels. Notably, they found a >80% reduction of acellular capillaries with linagliptin, primarily in the deep capillary layer proximal to the photoreceptors. In neurodegenerative models, this layer is the site where capillary degeneration starts. Diabetic retinopathy is thought to be a neurodegenerative disease.

Dr Hammes and colleagues established 4 years ago that pericyte loss occurs in the diabetic retina of most models of hyperglycemia, and that pericyte migration is an important contributing mechanism to this loss. In the

present study, the usual 25% rate of pericyte loss was found in the diabetic rats, but this was normalized with linagliptin. Pericyte migration, which occurs when endothelial cells are damaged, was normalized.

No proangiogenic effect of linagliptin was found in the diabetic retina.

Stromal-derived factor concentrations were not changed, indicating that there was no signal to recruit more stem cells to the diabetic retina for repair.

The major effect of DPP-4 inhibition on the vasculature was seen in the ganglion-cell layer, the location of the large neurons, of the diabetic retina.

Linagliptin increased active GLP-1 and phospho-Akt and reduced capillary damage. The reduction in reactive oxygen species and methylglyoxal found in the present study has since been confirmed by the investigators in another experimental model that contained only neurons. ■

Diabetes Management

Early Intensive Therapy in Type 2 Diabetes Preserves Beta-Cell Function

By Wayne Kuznar

I

ntensive therapy initiated in newly diagnosed patients with type 2 diabetes can preserve beta-cell function, according to data released by Ildiko Lingvay, MD, Assistant Professor of Internal Medicine at the University of Texas Southwestern Medical Center, Dallas, at the 2012 ADA annual meeting.

Progression of type 2 diabetes hinges on a progressive decline in betacell function over time, and Dr Lingvay recommended that “we try to achieve glycemic normalization as quickly as possible after diagnosis. In addition, I recommend we maintain glycemic control long-term.”

Dr Lingvay and colleagues sought to study the effects of a treatment strategy they devised, with the intent of preserving beta-cell function. The study started with a run-in period of 3 months in which 63 newly diagnosed, treatment-naive patients aged 21 to 70 years were treated with insulin (70/30 aspart premix) and metformin (500 mg daily, which was titrated weekly to 1000 mg twice daily). The run-in period was designed to remove any preexisting glucotoxicity and associated

26

“Treatment intensification should be done while the patient’s glycemic control is still within the target range. I would not recommend waiting until HbA1c goes above target before intensifying treatment.” —Ildiko Lingvay, MD temporary beta-cell stunning.

Patients were then randomized to either continuation of insulin and metformin or to triple oral therapy— glyburide 1.25 mg twice daily, which was titrated throughout the study; metformin 1000 mg twice daily; and pioglitazone 15 mg daily, titrated monthly to a final dosage of 45 mg daily). A total of 58 patients finished the 3-month run-in and were randomized.

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

A mixed-meal challenge test was used to assess beta-cell function at randomization and at 6, 12, 18, 30, and 42 months.

Treatment failure was predefined as a hemoglobin (Hb) A1c level >8%. If patients in the triple oral arm achieved this target, they were transitioned to insulin and metformin. Those assigned to the insulin group who achieved this target remained on insulin, with the option to change the frequency or type of treatment.

Treatment failure occurred in 3 patients in the insulin group and 5 patients in the triple oral therapy group.

At the time of diagnosis, the average HbA1c was 10.6%. After the 3-month run-in period, the HbA1c was reduced to 5.9% and all participants achieved an HbA1c level <7%.

After 3.5 years, 83% of patients receiving insulin plus metformin and 72% of those receiving triple oral therapy had completed the study.

Beta-cell function was preserved in both groups, with no significant change over time in beta-cell function between or within groups, as calculated by Cpeptide area under the curve (AUC) or glucose AUC, said Dr Lingvay.

There was an increase in body weight in both groups, with no signif-

icant difference between groups.

Mild hypoglycemia, defined as home glucose measurement of <70 mg/dL associated with any symptoms suggestive of hypoglycemia, occurred at a rate of 1 monthly during the first 4 months.

The rate decreased significantly over time, to <0.5 events monthly by the end of the study, and did not differ significantly between groups.

“This is a very important finding, in light of a very low HbA1c achieved and maintained throughout the study,” noted Dr Lingvay.

Because diabetes is a multifactorial disease, monotherapy may not be adequate to change the course of the disease, she pointed out. “I recommend combination treatment with complementary mechanisms of action….Treatment intensification should be done while the patient’s glycemic control is still within the target range. I would not recommend waiting until HbA1c goes above target before intensifying treatment.”

Because of the design of the study, it is not known whether the beta-cell preservation effect could be attributed to the initial insulin-based therapy during the run-in phase or to the ongoing therapy received after randomization, Dr Lingvay noted. ■

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Emerging Therapies

Diabetes Drug Pipeline: Promising Agents in Late Stages of Development

By Wayne Kuznar

A

number of promising oral and injectable agents for diabetes are currently in late-stage development and were featured in posters, oral abstract presentations, and symposia during the 2012 ADA annual meeting. The following is a sampling of new medications with potentially important implications for the treatment of patients with diabetes.

Lixisenatide is an injectable glucagonlike peptide-1 (GLP-1) receptor agonist currently in phase 3 clinical trials; in the multinational GetGoal-P study, lixisenatide was able to lower hemoglobin (Hb) A1c levels further in patients with type 2 diabetes who were already being treated with pioglitazone, with or without metformin, but who had failed to achieve glycemic control with pioglitazone, with or without metformin (see article on page 31).

The news was mixed regarding albiglutide, because this GLP-1 receptor agonist, currently in phase 3 clinical trials, was noninferior to insulin lispro in achieving glycemic control in pa-

tients with type 2 diabetes who were not adequately controlled with insulin; however, albiglutide was not able to demonstrate noninferiority on this end point in a comparative trial versus liraglutide.

Several sodium glucose cotransporter (SGLT)-2 inhibitors are in latestage development. Canagliflozin is an SGLT-2 inhibitor that was superior to glimepiride and to sitagliptin in lowering HbA1c levels in 2 separate phase 3 clinical studies of patients with type 2 diabetes in whom metformin, with or without a sulfonylurea, failed to achieve glycemic control.

Another investigational SGLT-2 inhibitor, empagliflozin, which is currently in phase 2b clinical trials, showed sustained reductions in average HbA1c levels for up to 90 weeks in patients with type 2 diabetes when used as monotherapy or as an add-on to metformin. Furthermore, empagliflozin was associated with significant reductions in fasting plasma glucose (FPG) and excess body weight (see article below).

A third SGLT-2 inhibitor, dapagliflozin, improved glycemic control in 2 clinical trials in patients with type 2 diabetes, cardiovascular (CV) disease, and hypertension. Dapagliflozin had no effect on CV safety. Another study showed no renal toxicity with dapagliflozin. In addition, dapagliflozin demonstrated a long-term (up to 104 weeks) reduction in HbA1c levels in patients with type 2 diabetes and poor glycemic control despite previously receiving high doses of insulin.

Ipragliflozin is yet another SGLT-2 inhibitor in phase 3 clinical trials. In a 24-week, placebo-controlled, randomized study of 168 patients with type 2 diabetes who were receiving a constant metformin dose for at least 12 weeks before being randomized, ipragliflozin therapy lowered HbA1c levels by 1.3% compared with placebo.

Significant reductions in FPG and blood pressure levels were also seen with ipragliflozin.

Imeglimin is the first in a new, tetrahydrotriazine-containing class of

oral antidiabetes agents—the glimins.

In a 12-week, multicenter, phase 2 clinical trial, imeglimin was shown to be effective as add-on therapy to metformin in reducing HbA1c levels and FPG in patients with type 2 diabetes.

The ultra–long-acting insulin degludec was as effective as insulin glargine in terms of glycemic control in patients with type 2 diabetes. Furthermore, insulin degludec resulted in lower rates of severe hypoglycemia and nocturnal hypoglycemia than insulin glargine.

The pharmacokinetic profile of insulin degludec suggests an effect in excess of 24 hours and low variability in subcutaneous absorption (see article on page 32).

The long-acting basal insulin LY2605541 performed well compared with insulin glargine in studies of patients with type 1 or type 2 diabetes, with mean reductions in HbA1c of 0.6% with LY2605541 versus 0.4% with insulin glargine. Of note, LY2605541 also was associated with weight reduction (see article on page 33). ■

Empagliflozin Safe and Effective with or without Metformin, Reduces Weight Also safe in patients with liver impairment

By Mary Mosley

D

ata presented from a phase 2b study with empagliflozin, a sodium glucose cotransporter-2, which increases renal glucose excretion, showed reductions in hemoglobin (Hb) A1c, fasting plasma glucose (FPG), and body weight in patients with type 2 diabetes at 90 weeks. Hans-Juergen Woerle, MD, Vice President, Boehringer Ingelheim, Germany, presented this randomized, multinational, open-label extension study in a late-breaking abstract session at the 2012 ADA annual meeting.

A total of 659 adults with type 2 diabetes who had participated in 1 of two 12-week, blinded, dose-finding trials of empagliflozin were treated for an additional 78 weeks with openlabel empagliflozin (10 mg or 25 mg) alone or added to metformin, with metformin alone, or with metformin plus sitagliptin.

Empagliflozin showed sustained efficacy over 90 weeks, with a clearly significant and meaningful efficacy with both doses, said Dr Woerle.

28

Average HbA1c was approximately 8% at baseline. At 90 weeks, HbA1c levels were reduced with the 10-mg and 25-mg doses of empagliflozin monotherapy (–0.34% and –0.47%, respectively), metformin monotherapy (–0.56%), both doses of empagliflozin in

Empagliflozin showed sustained efficacy and safety over 90 weeks, with reduced HbA1c levels, and greater weight loss with either dose compared with metformin or with sitagliptin. combination with metformin (–0.34% and –0.63%, respectively), and sitagliptin plus metformin (–0.40%).

FPG was reduced with empagliflozin 10 mg (–30.4 mg/dL) and 25 mg (–27.8 mg/dL) compared with metformin (–26 mg/dL). FPG reductions were greater with both doses of

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

empagliflozin in combination with metformin compared with sitagliptin plus metformin.

Body weight ranged from 82 kg to 87 kg at baseline. Weight loss was greater in all empagliflozin groups compared with the metformin alone or the sitagliptin plus metformin groups; reductions were –2.24 kg with the 10mg dose and –2.61 kg with the 25-mg dose of empagliflozin alone compared with –1.28 kg with metformin. Reductions with sitagliptin plus metformin were small compared with the 2 empagliflozin doses in combination with metformin.

Empagliflozin was generally well tolerated. Adverse events (AEs) were mostly mild or moderate and reported in 63.2% to 74.1% of patients taking empagliflozin, and in 69.6% of patients taking metformin or sitagliptin plus metformin.

Hypoglycemic events were more frequent with metformin or with sitagliptin plus metformin than with empagliflozin.

Patients with Liver Impairment In a phase 1, open-label, parallelgroup study presented by Sreeraj Macha, PhD, Boehringer Ingelheim, Ridgefield, CT, the drug was found to be safe and well tolerated in patients with varying degrees of liver impairment.

The increased exposure to empagliflozin in patients with hepatic impairment was less than 2-fold.

Therefore, the investigators concluded that dose adjustment of empagliflozin is not required in this patient population.

The 36 patients in this study—8 each with mild, moderate, or severe hepatic impairment and 12 controls—were given a single dose of empagliflozin 50 mg and were monitored for 5 days in the study center. AEs were reported in 5 subjects with hepatic impairment and in 6 healthy persons.

A phase 3 clinical trial with empagliflozin is currently in development, with planned enrollment of more than 14,500 patients. ■

Emerging Therapies

The Ancient Anti-Inflammatory Drug Salsalate Lowers Blood Glucose Levels

By Wayne Kuznar

T

he anti-inflammatory agent salsalate, used for decades as a treatment for rheumatoid arthritis, also has glucose-lowering properties, said Steven Shoelson, MD, PhD, Associate Director of Research at the Joslin Diabetes Center, Boston, and principal investigator of a placebocontrolled study of salsalate in patients with type 2 diabetes.

Salsalate lacks many of the side effects of aspirin; however, in the current study, this drug was associated with weight gain and an increase in lowdensity lipoprotein cholesterol (LDLC), said Dr Shoelson.

In 2012, a 12-week study demonstrated that salsalate reduced levels of hemoglobin (Hb) A1c by approximately 0.5% at the highest dose (4 g/day).

“We now have to determine whether the degree to which this drug

lowers blood glucose levels is large enough to warrant using it as an addition to the diabetes drug armamentarium,” Dr Shoelson said.

The data he presented came from a year-long trial sponsored by the National Institutes of Health. The researchers compared 3.5-g daily salsalate with placebo in 286 patients with type 2 diabetes who had a baseline HbA1c of 7.5% despite antidiabetic treatment.

Compared with placebo, salsalate reduced HbA1c levels by 0.24% and fasting blood glucose levels by 11 mg/dL over 48 weeks. These modest improvements occurred while patients required lower doses of other diabetes medications compared with the control group.

Salsalate did reduce inflammation— white blood cell, neutrophil, and lymphocyte counts decreased from high levels to lower levels within the normal

range. Although the anti- inflammatory effects of salsalate have long been known, these particular effects have not been previously documented in clinical

“We now have to determine whether the degree to which this drug lowers blood glucose levels is large enough to warrant using it as an addition to the diabetes drug armamentarium.”

—Steven Shoelson, MD, PhD

trials. In addition, those who took salsalate saw an increase in levels of adiponectin by 21% and a decrease in

uric acid levels by 11%, which suggest some cardiovascular protective qualities and a potential reduction in the risk for gout.

However, patients randomized to salsalate gained a mean of 2.2 lb more of body weight than those who received placebo, and their LDL-C levels increased by 8 mg/dL; by contrast, triglyceride levels declined.

In addition, a small change in urinary albumin of 1.8 mcg/mg of creatinine was observed in the salsalate group, which was reversed on discontinuation of the drug. This suggests that it may have an impact on kidney function; however, there was no change in glomerular filtration rate with salsalate.

There were few gastrointestinal side effects with salsalate, Dr Shoelson noted, which caused no discontinuations. ■

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Emerging Therapies

Novel Basal Insulin LY2605541 Lowers Blood Glucose, Enhances Weight Loss

By Wayne Kuznar

T

he investigational long-acting basal insulin LY2605541 is associated with a lower rate of nocturnal hypoglycemia compared with insulin glargine, while also promoting weight loss. LY2605541 consists of insulin lispro modified with a 20-kDa polyethylene glycol moiety. The large hydrodynamic size of LY2605541 slows insulin absorption and reduces its clearance, resulting in a prolonged duration of action. Exposure is unaffected by renal impairment.

Studies comparing LY2605541 with insulin glargine in patients with type 2 diabetes were presented by Richard M. Bergenstal, MD, Executive Director of the International Diabetes Center at Park Nicollet, MN. LY2605541 and insulin glargine had similar effects on lowering hemoglobin (Hb) A1c and average daily self-monitored fasting glucose levels over 12 weeks.

In an open-label study, 289 adults with type 2 diabetes who were receiving neutral protamine Hagedorn or insulin glargine were randomized in

The mean body weight declined by 0.58 kg from baseline to week 12 in the LY2605541 group and increased by 0.31 kg in the glargine group.

a 2:1 ratio to morning administration of LY2605541 or to insulin glargine.

The primary end point was the reduction in fasting plasma glucose (FPG) measured by self-monitoring of

blood glucose. In the LY2605541 group, mean FPG at week 12 was 118 mg/dL, and in patients assigned to insulin glargine it was 117 mg/dL, a difference that was not significant. The mean HbA1c level declined from 7.8% to 7.2% with glargine, and from 7.7% to 7.0% with LY2605541, a nonsignificant difference, said Dr Bergenstal.

The mean body weight declined by 0.58 kg from baseline to week 12 in the LY2605541 group and increased by 0.31 kg in the glargine group, a 0.84-kg difference.

Patients assigned to LY2605541 had a 48% reduction in the rate of nocturnal hypoglycemic events compared with glargine (0.25 events vs 0.39 events per patient for 30 days).

LY2605541 was associated with mean increases in levels of alanine aminotransferase and aspartate amino-

transferase of 9 U/L and 4 U/L, respectively, compared with insulin glargine, but these levels remained within the normal range.

A substudy assessed hypoglycemia and glucose variability using continuous glucose monitoring of interstitial glucose in 76 of the 289 patients.

At 12 weeks, patients treated with LY2605541 spent less time with interstitial glucose <70 mg/dL than glargine-treated patients during the nocturnal period (11 minutes vs 38 minutes, respectively) and during the 24-hour period. Fewer LY2605541treated patients experienced hypoglycemia (50.0% vs 78.3%, respectively), including nocturnal hypoglycemia (20.5% vs 47.8%, respectively).

The 2 treatments resulted in similar mean glucose values during a 24hour period at 12 weeks. ■

Lixisenatide Continues to Show Good Results in GetGoal Program Studies Novel GLP-1 receptor agonist provides significant glycemic reductions

By Mary Mosley

S

everal studies related to the GetGoal Program involving the investigational glucagon-like peptide (GLP)-1 agonist lixisenatide were presented at the 2012 ADA annual meeting. Glycemic control was improved in patients with type 2 diabetes with once-daily lixisenatide added to various antidiabetes medications, including basal insulin in the GetGoal-L study, pioglitazone in the GetGoal-P study, and insulin glargine and oral agents in the GetGoal Duo 1 study.

More patients achieved hemoglobin (Hb) A1c target levels of <7.0% or ≤6.5% with lixisenatide compared with placebo in these studies. This novel GLP-1 agonist was safe and well tolerated in these 24-week, randomized, double-blind, parallel-group, placebocontrolled, multicenter studies.

GetGoal-L Study Ronnie Aronson, MD, of the LMC Diabetes & Endocrinology in Toronto, Canada, presented results of the GetGoal-L study. Patients insufficiently

controlled with basal insulin, with or without metformin, were randomized to lixisenatide (20 mcg) to placebo once daily after breakfast. The mean HbA1c was 8.4%, and the body mass index was 32.1 kg/m2. Previous in-

More patients achieved HbA1c target levels of <7.0% or ≤6.5% with lixisenatide compared with placebo. In one study, patients receiving lixisenatide lost 0.21 kg in body weight, but those using a placebo gained 0.21 kg.

sulin therapy (mean, 55 U/day) included glargine, neutral protamine Hagedorn, detemir, and premix. By protocol, the insulin dose was to be reduced by 20% for an HbA1c ≤7.5% to limit hypoglycemia.

At 24 weeks there was a significant reduction in HbA1c, the primary end point, to 7.8% with lixisenatide compared with 8.1% with placebo, from the mean baseline level of 8.4% in both groups. Of the patients receiving lixisenatide, 28% achieved an HbA1c <7.0% compared with 12% of the patients receiving placebo.

Greater reductions with lixisenatide were also found in postprandial glucose (PPG) and body weight. The PPG level 2 hours after breakfast was reduced by 5.54 mmol/L with lixisenatide and by 1.72 mmol/L with placebo, and weight was reduced by 1.80 kg from 87.4 kg and by 0.52 kg from 89.1 kg, respectively.

The frequency of adverse events (AEs) and serious AEs was similar in the 2 groups. Discontinuation because of an AE was 7.6% with lixisenatide, primarily because of gastrointestinal (GI) problems, and 4.8% with placebo.

GetGoal-P Study The patient population was similar in

the GetGoal-P study; patients taking pioglitazone, with or without metformin, were randomized to lixisenatide or to placebo. More than 80% of patients were taking metformin at baseline. The study was presented by Dr Aronson and Michel Pinget, MD, University Hospital of Strasbourg in France.

The HbA1c target <7.0% was achieved by 52.3% of the patients taking lixisenatide and by 26.4% taking placebo.

More patients taking lixisenatide (28.9%) also achieved an HbA1c target <6.5% compared with placebo (10.1%).

Other key findings with lixisenatide in GetGoal-P include a significantly larger reduction in fasting plasma glucose (FPG) by 1.16 mmol/L versus 0.32 mmol/L with placebo. Patients receiving lixisenatide lost 0.21 kg in body weight, but those using a placebo gained 0.21 kg.

There was less of a need for rescue therapy by patients receiving lixisenatide (3.8%) compared with 11.3% of patients receiving placebo.

AEs and drug discontinuation were Continued on page 32

AUGUST 2012

AMERICAN HEALTH & DRUG BENEFITS

31

Emerging Therapies

New Long-Acting Insulin Degludec Lowers Hypoglycemia Significantly versus Insulin Glargine Head-to-head comparison in insulin-naive patients with type 2 diabetes

By Wayne Kuznar

T

he investigational ultra–long-acting insulin degludec improves long-term glycemic control in patients with type 2 diabetes similar to insulin glargine but with a reduced rate of nocturnal and severe hypoglycemia, and greater weight loss, said Bernard Zinman, MD, Director of the Diabetes Center at Mount Sinai Hospital, Professor of Medicine, University of Toronto, and lead investigator of a randomized head-to-head comparison.

In this randomized, open-label, phase 3a, noninferiority, treat-to-target trial, 1030 adults with insulin-naive type 2 diabetes that was inadequately controlled with oral antidiabetic medications were randomized in a 3:1 ratio to insulin degludec or to insulin glargine. Both insulins were used once daily and were titrated to achieve selfmeasured blood glucose targets calibrated to plasma glucose values of 70 mg/dL to 89 mg/dL. The mean baseline hemoglobin (Hb) A1c level was 8.2%.

Completion rates were 79% with insulin degludec and 77% with insulin glargine by week 52 (ie, study end), at which time the mean HbA1c level declined by 1.06% with insulin degludec and by 1.19% with insulin glargine, meeting the study’s criterion for noninferiority. Reductions in fasting

plasma glucose levels were significantly greater with insulin degludec (–67.7 mg/dL) compared with insulin glargine (–59.5 mg/dL).

The rates of nocturnal hypoglycemia were 36% lower with insulin degludec than with insulin glargine (0.25 vs 0.39 episodes per patient annually). “The difference in hypoglycemia rate corresponds to less than 8 patients needed to treat for a year with insulin degludec in place of insulin glargine to avoid 1 nocturnal hypoglycemic episode,” said Dr Zinman.

poglycemia were 1.52 versus 1.85 episodes per patient annually for insulin degludec and insulin glargine, respectively. Overall severe hypoglycemia was infrequent in both groups, but it was significantly lower with insulin degludec.

Adverse events occurring in >5% of patients were bronchitis, gastroenteritis, nasopharyngitis, upper respiratory tract infection, headache, diarrhea, vomiting, back pain, and cough. The mean weight gain was similar between the 2 groups.

“The difference in hypoglycemia rate corresponds to less than 8 patients needed to treat for a year with insulin degludec in place of insulin glargine to avoid 1 nocturnal hypoglycemic episode.”

—Bernard Zinman, MD

“Treating 100 patients for 1 year with insulin degludec would result in 13 fewer nocturnal hypoglycemic events compared to treatment with insulin glargine,” he added.

The overall rates of confirmed hy-

In a separate meta-analysis comparing hypoglycemia between these 2 agents in more than 4300 patients, the rates of overall and nocturnal hypoglycemia were significantly lower with insulin degludec at similar levels

Lixisenatide Continues to Show Good Results... similar in the 2 groups. GI events were the primary cause of the 2.8% drug discontinuation in the patients taking lixisenatide compared with 0.6% in those taking placebo; 6.5% and 5.0% of patients in these groups, respectively, stopped taking their study drug.

GetGoal Duo 1 Study In the GetGoal Duo 1 study reported

by Julio Rosenstock, MD, Director, Dallas Diabetes and Endocrine Center, Texas, targeting PPG glucose with the GLP-1 agonist in patients with uncontrolled type 2 diabetes significantly improved HbA1c levels and reduced PPG level, without affecting weight.

In this randomized, double-blind, multicenter trial, lixisenatide was added to insulin glargine and to oral antidiabetic agents. During the 12-week run-

32

in phase, glargine was titrated to achieve a FPG of 80 to 100 mg/dL. A total of 446 patients with an HbA1c ≥7.5% were evenly randomized to lixisenatide or to placebo once daily in the morning and were followed for 24 weeks. All patients were taking metformin and 12% were receiving a thiazolidinedione. Sulfonylurea therapy was stopped at randomization.

During the randomized follow-up, HbA1c was reduced to 6.96% with lixisenatide and to 7.30% with placebo (P <.001). More patients taking lixisenatide achieved an HbA1c <7.0% (56%) than patients taking placebo (39%).

At study end, FPG values were 6.56 mmol/L and 6.69 mmol/L in the lixisenatide and placebo groups, respectively, and were reduced to 6.70 mmol/L and 6.86 mmol/L, respectively.

A robust reduction in the PPG was

AMERICAN HEALTH & DRUG BENEFITS

AUGUST 2012

seen with lixisenatide, stated Dr Rosenstock. PPG measured 2 hours after a standardized breakfast was reduced with lixisenatide from 13.02 mmol/L at baseline to 9.87 mmol/L at 24 weeks but increased from 12.85 mmol/L to 13.04 mmol/L with placebo.

There was a trend toward greater weight loss with lixisenatide. Only a small increase in the insulin dose was found in both arms, suggesting that the patients could not be titrated, or that there was more potential effect with more aggressive titration, Dr Rosenstock stated.

AEs occurred more frequently (80%) in the lixisenatide group versus placebo (68%) and were the usual GLP-1–related events of nausea and vomiting, which abated as the study progressed. Drug discontinuation because of AEs was higher in the lixisen-

of HbA1c, reported Robert E. Ratner, MD, Senior Research Scientist at MedStar Health Research Institute, Hyattsville, MD, and Professor of

“Treating 100 patients for 1 year with insulin degludec would result in 13 fewer nocturnal hypoglycemic events.” —Bernard Zinman, MD Medicine, Georgetown University, Washington, DC. For this meta-analysis, hypoglycemia was defined as rates of selfreported confirmed hypoglycemia (plasma glucose <56 mg/dL or severe hypoglycemia requiring assistance) and nocturnal confirmed hypoglycemia (00:01 through 05:59 hours).

Compared with insulin glargine, insulin degludec resulted in a 17% lower rate of overall hypoglycemia and a 32% lower rate of nocturnal hypoglycemia in patients with type 2 diabetes, both of which were statistically significant. In patients with type 1 diabetes, there were 25% fewer episodes of nocturnal hypoglycemia in patients treated with insulin degludec. ■

Continued from page 31

atide group. Hypoglycemia was more frequent with lixisenatide, but the overall numbers were low.

After treatment, a blood glucose level <60 mg/dL was measured in 26% of the placebo group and in 45% of the lixisenatide group. The number of events per patient annually was 0.44 in the placebo group and 0.80 in the lixisenatide group. Severe hypoglycemia was reported in only 1 patient (in the lixisenatide group).

Dr Rosenstock noted that the composite end points showed more benefit with the GLP-1 receptor. More patients in the lixisenatide than in the placebo group achieved an HbA1c of <7% without hypoglycemia (44% vs 34%, respectively), an HbA1c of <7% without weight gain (34% vs 20%), and an HbA1c of <7% without hypoglycemia or weight gain (28% vs 18%). ■

Emerging Therapies

Novel Basal Insulin LY2605541 Lowers Blood Glucose, Enhances Weight Loss ous glucose monitoring of interstitial glucose in 76 of the 289 patients.

At 12 weeks, patients treated with LY2605541 spent less time with interstitial glucose <70 mg/dL than glargine-treated patients during the nocturnal period (11 minutes vs 38 minutes, respectively) and during the

By Wayne Kuznar

T

he investigational long-acting basal insulin LY2605541 is associated with a lower rate of nocturnal hypoglycemia compared with insulin glargine, while also promoting weight loss. LY2605541 consists of insulin lispro modified with a 20-kDa polyethylene glycol moiety. The large hydrodynamic size of LY2605541 slows insulin absorption and reduces its clearance, resulting in a prolonged duration of action. Exposure is unaffected by renal impairment.

Studies comparing LY2605541 with insulin glargine in patients with type 2 diabetes were presented by Richard M. Bergenstal, MD, Executive Director of the International Diabetes Center at Park Nicollet, MN. LY2605541 and insulin glargine had similar effects on lowering hemoglobin (Hb) A1c and average daily self-monitored fasting glucose levels over 12 weeks.

The mean body weight declined by 0.58 kg from baseline to week 12 in the LY2605541 group and increased by 0.31 kg in the glargine group.

In an open-label study, 289 adults with type 2 diabetes who were receiving neutral protamine Hagedorn or insulin glargine were randomized in a 2:1 ratio to morning administration of LY2605541 or to insulin glargine.

The primary end point was the reduction in fasting plasma glucose (FPG) measured by self-monitoring of blood glucose. In the LY2605541 group, mean FPG at week 12 was 118 mg/dL, and in patients assigned to insulin glargine it was 117 mg/dL, a difference that was not significant. The mean HbA1c level declined from 7.8% to 7.2% with glargine, and from 7.7% to 7.0% with LY2605541, a nonsignificant difference, said Dr Bergenstal.

The mean body weight declined by 0.58 kg from baseline to week 12 in the LY2605541 group and increased by 0.31 kg in the glargine group, a 0.84-kg difference.

Patients assigned to LY2605541 had a 48% reduction in the rate of nocturnal hypoglycemic events compared with glargine (0.25 events vs 0.39 events per patient for 30 days).

LY2605541 was associated with mean increases in levels of alanine aminotransferase and aspartate aminotransferase of 9 U/L and 4 U/L, respec-

tively, compared with insulin glargine, but these levels remained within the normal range.

A substudy assessed hypoglycemia and glucose variability using continu-

24-hour period. Fewer LY2605541treated patients experienced hypoglycemia (50.0% vs 78.3%, respectively), including nocturnal hypoglycemia (20.5% vs 47.8%, respectively).

The 2 treatments resulted in similar mean glucose values during a 24hour period at 12 weeks. ■

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Rami H. Ben-Joseph, PhD; Kent H. Summers, PhD, BSPharm

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

INDUSTRY TRENDS Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape

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AUGUST 2012

AMERICAN HEALTH & DRUG BENEFITS

33

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

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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 (%)

LINAGLIPTIN AND METFORMIN IN A SINGLE TABLET D 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.

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