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Inside Risk of falls and major bleeds with oral anticoagulants page 139 Primary prevention of CVD using novel risk markers page 140
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Financial Disclosure:
Internal Medicine Alert’s editor, Stephen Brunton, MD, serves on the advisory board for Lilly, Boehringer Ingelheim, Novo Nordisk, Sunovion, and Teva; he serves on the speakers bureau of Boehringer Ingelheim, Lilly, Kowa, Novo Nordisk, and Teva. Peer reviewer Gerald Roberts, MD; executive editor Leslie Coplin; and managing editor Neill Kimball report no financial relationships relevant to this field of study.
Optimal Management for Obese Patients with Type 2 Diabetes: Surgery vs Medical Therapy Abstract & Commentary
Director, Metabolic Studies, Catalina Research Institute, Chino, CA Dr. Unger reports no financial relationships relevant to this field of study.
Synopsis: At 2 years, none of the patients maintained on medical therapy had entered into a state of diabetes remission, whereas 75% of the gastric bypass and 95% of the biliopancreatic diversion patients had become diabetes free. Source: Mingrone G, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med 2012;366:1577-1585.
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t baseline, the median a1c of the medically managed patients
was 8.51% (± 1.24), whereas the surgical cohort A1C averaged 8.72% (± 1.55). Initial body mass index (BMI) was 45.62 kg/m2 (± 6.24) vs 44.99 kg/m2 (± 6.47) for the medical vs the surgical cohort, respectively. All patients received periodic evaluations from a diabetologist, RD, and a nurse throughout the 2-year study period. Oral hypoglycemic agents and insulin doses were optimized among the intensive medically managed patients with the ultimate glycemic target being an A1C < 7%. Programs for diet and lifestyle modifications, including reduced fat intake and increased physical activity (≥ 30 minutes of brisk walking daily and intermittent moderate-intensity aerobic activity), were also encouraged. The Roux-en-Y gastric bypass procedure is named after the surgeon who first described the operation in 1993 and the “Y” shape produced by the redirected intestines as food is rerouted around the stomach. The surgeon creates a walnut-sized pouch (1-2 tablespoons) on the proximal area of the stomach and “bypasses” the remaining stomach by attaching a section of the small bowel to the pouch. Although the stomach does not receive any nutrients, gastric enzymes continue to be produced. The •
Number 18
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September 29, 2012
EDITOR Stephen A. Brunton, MD Adjunct Clinical Professor University of North Carolina, Chapel Hill ASSOCIATE EDITORS James Chan, PharmD, PhD Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA William T. Elliott, MD, FACP Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco
By Jeff Unger, MD
Volume 34
CME for Physicians—www.cmeweb.com
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Pages 137-144
Internal medicine Alert is available online www.internalmedicinealert.com
Ken Grauer, MD Professor Emeritus in Family Medicine, College of Medicine, University of Florida Rahul Gupta, MD, MPH, FACP Clinical Assistant Professor, West Virginia University School of Medicine Charleston, WV Harold L. Karpman, MD, FACC, FACP Clinical Professor of Medicine, UCLA School of Medicine Louis Kuritzky, MD Clinical Assistant Professor, University of Florida, Gainesville Barbara A. Phillips, MD, MSPH Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington Joseph E. Scherger, MD, MPH Vice President, Primary Care, Eisenhower Medical Center; Clinical Professor, Keck School of Medicine, University of Southern California Penny Tenzer, MD Associate Professor and Vice Chair, Department of Family Medicine and Community Health Chief of Service, Family Medicine, University of Miami Hospital University of Miami Miller School of Medicine Jeff Unger, MD Director, Metabolic Studies Catalina Research Institute Chino, CA Joseph Varon, MD, FACP, FCCP, FCCM Clinical Professor of Medicine and Professor of Acute and Continuing Care, University of Texas Health Science Center, Houston; Clinical Professor of Medicine, University Texas Medical Branch, Galveston Allan J. Wilke, MD, MA Professor and Chair Program Director Department of Family Medicine Western Michigan University School of Medicine, Kalamazoo PEER REVIEWER Gerald Roberts, MD Assistant Clinical Professor of Medicine, Albert Einstein College of Medicine, New York, NY
gastric pouch is anastomosed to a Roux-en-Y proximal jejunal segment, bypassing the remaining stomach, duodenum, and a small portion of jejunum. The standard Roux (alimentary) limb length is about 50 to 100 cm, and the biliopancreatic limb is 15 to 50 cm. The Roux limb allows the gastric content to mix with nutrients entering from the gastric pouch and bypassing the stomach. Patients experience very rapid fullness with this procedure and significant weight loss. The gallbladder is typically removed during this procedure, as patients who experience rapid weight loss have a higher incidence of cholelithiasis. The procedure may be performed laparoscopically. The bilio-pancreatic diversion (BPD) amputates 60% of distal stomach with stapled closure of the duodenal stump. This leaves a residual volume of 300 mL. The small bowel is transected and its distal end anastomosed to the remaining stomach pouch. The proximal end of the ileum comprising the remaining small bowel carrying the bilio-pancreatic juice, yet excluding bowel involved in food transit, is anastomised in an end-to-side manner to the bowel 50 cm proximal to the ileo-caecal valve. With minimal gastric capacity, patients quickly develop satiety and weight loss ensues. BPD is an open procedure. Two years following randomization, diabetes remission had occurred in none of the patients receiving medical therapy as compared with 75% of those who underwent gastric bypass and 95% of patients who had BPD (P < 0.001 for both comparisons). The average time to normalization for fasting glucose and A1C among the surgical patients was 10 months for gastric bypass and 4 months for BPD. After Internal Medicine Alert, ISSN 0195-315X, is published monthly by AHC Media, a division of Thompson Media LLC, 3525 Piedmont Rd., NE, Bldg. 6, Suite 400, Atlanta, GA 30305.
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2 years, the average percent of weight loss from baseline in the medical cohort was 4.74 (± 6.37%). Gastric bypass patients lost on average 33.31 % from baseline (± 7.88%) vs BPD patients 33.82% (± 10.17%). Two patients receiving metformin in the medical cohort had persistent diarrhea during the study. A BPD patient developed an incisional hernia requiring repair 9 months after undergoing their initial procedure. One gastric bypass patient required surgical intervention for an intestinal obstruction 6 months post procedure. The authors conclude that surgical intervention is more effective than conventional medical therapy in controlling hyperglycemia in severely obese patients with type 2 diabetes. n Commentary
The fact that surgery overpowers metformin et al as a means to cure type 2 diabetes should come as no surprise to those of us who study the history of diabetes. After all, insulin was discovered in 1922 by of all people, a general surgeon (Fred Banting) and his medical student (Charles Best). Interestingly, Dr. Banting was not permitted to administer the first insulin injection to a human subject (Leonard Thompson) on December 2, 1922, at Toronto General Hospital. Instead, the honor went to Ed Jeffrey, an intern at the facility. The dose of insulin was calculated by Banting based on the estimated glucoselowering effect that a similar dose would have on the weight of a dog. Now 90 years later, those of us who manage patients with diabetes are still reaching out to our surgical associates for assistance in treating this chronic, progressive disease state. The primary risk factor for type 2 diabetes is obesity, and 90% of all patients with diabetes are overweight or obese. The relative risk of diabetes increases nearly 42-fold in men as the BMI increases from 23 to 35 kg/m2 and approximately 93-fold in women as BMI increases from 22 to 35 kg/m2. Long-term maintenance of weight loss is difficult for anyone, especially those with diabetes. Bariatric surgery improves endogenous insulin secretion and peripheral insulin sensitivity two-to-three fold before any substantial weight loss is observed. A study by Keidar has suggested that weight-loss surgery reduces diabetes-related mortality by 90% over conventional care.2 As many as 14,300 lives can be saved in the United States over 5 years through bariatric surgery, yet fewer than 1% of eligible patients are referred to bariatric surgeons for consultation. This study, as well as one published by Schauer et al,3 suggest that bariatric surgery should be considered sooner rather than later in obese patients with diabetes. Within 1-2 years following surgical intervention, more patients September 29, 2012
are able to attain remission of their diabetes and normalize their A1Cs than if prescribed intensive medical therapies. Surgeons are no doubt proud of their contributions to the field of diabetes management, knowing that use of their scalpel or laparoscope can normalize hyperglycemia in highly insulin-resistant patients within hours of their discharge from the recovery room. This week, a newly diagnosed patient with diabetes and a BMI presented to my office. Weighing in at 425 pounds and carrying a BMI of 67 kg/m2, do you really think that a trial of metformin and jumping rope for 30 minutes per day would result in remission of his diabetes? His baseline A1C was 10.6%. After explaining the pathogenesis of diabetes to this patient, he was immediately referred to our local bariatric surgeon for consultation. I told the patient that within the next 4 months his weight should be down by 40 pounds and his diabetes should be in remission. Have you ever had a patient thank you for placing him on insulin? In summary, bariatric surgery appears to be the most effective long-term intervention for inducing remission as well as minimizing morbidity and mortality associated with severe clinical obesity and type 2 diabetes. n References 1. Mechanick JI, et al. Endocr Pract 2008;14(Suppl 1):1-83. 2. Keidar A. Diabetes Care 2011;34(Suppl 2):S361-S366. 3. Schauer PR, et al. N Engl J Med 2012;366:1567-1576. 4. Bult MJ, et al. Eur J Endocrinol 2008;158:135-145.
Risk of Falls and Major Bleeds when on Oral Anticoagulants Abstract & Commentary
By Rahul Gupta, MD, MPH, FACP Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV Dr. Gupta reports no financial relationships relevant to this field of study.
Synopsis: Patients on oral anticoagulants at high risk of falls did not have significantly increased risk of major bleeds. Source: Donze J, et al. Risk of falls and major bleeds in patients on oral anticoagulation therapy. Am J Med 2012;125: 773-778.
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n Commentary
he effectiveness of oral anticoagulation thera-
py has been clearly established in prevention and
Internal Medicine Alert
treatment of a variety of cardiovascular and cerebrovascular conditions. As commonly as they are prescribed, a careful consideration of the risks and benefits of therapy always precedes the decision to initiate an oral anticoagulant, often regardless of the age. However, the prevalence of the two most common indications for such treatment with oral anticoagulants, atrial fibrillation (AF) and venous thromboembolism (VTE), actually rises with age. The most common reason cited for not providing oral anticoagulants to the elderly is a risk of falls.1 For example, studies have documented that elderly individuals with AF are often either undertreated or not treated at all with oral anticoagulant therapy, thus denying one of the most effective stroke prevention therapies to this population group.2 However, some studies have suggested that older individuals are at greater risk of bleeding than their younger counterparts with similar diagnoses.3 Because patients at high risk for falls are often excluded from prospective, clinical anticoagulation therapy trials, only limited retrospective data are available on the issue. In their research, Donze et al utilized data sets from a prospective cohort study conducted at a Swiss university hospital from January 2008 to March 2009. All consecutive adult inpatients and outpatients discharged on oral vitamin K antagonists (VKA) were eligible to be included in the study. The outcome measured was the time to a first major bleed within 12 months of follow-up. Out of the 650 eligible patients, 515 were enrolled in the study and 35 suffered a first major bleed during the follow-up period (7.5 per 100 patient-years). The median age was 71.2 years and 63.9% were men. A total of 308 patients (59.8%) were identified to be at high risk of falls based on screening questions. Patients at high risk of falls had a non-significantly higher crude incidence rate of major bleeds than patients at low risk of falls (8.0 vs 6.8 per 100 patient-years, P = 0.64). In multivariate analysis, a high falls risk was not statistically significantly associated with the risk of a major bleed. Overall, the main bleeding location was gastrointestinal tract and only three major bleeds occurred directly after a fall (incidence rate: 0.6 per 100 patient-years). The researchers concluded that being at risk of falls is not a valid reason to avoid oral anticoagulation in elderly medical patients. However, as expected, polypharmacy was found to be independently associated with a high risk of major bleeds in the study. A possible explanation could include a higher risk of drug interactions in patients on oral anticoagulants.
Studies have documented that oral anticoagulation therapy is withheld more frequently in elderly patients than in younger patients with identical elective indica
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tions. Perhaps due to the perceived age-related increase in bleeding complications, physicians remain reluctant to treat elderly patients as enthusiastically with oral anticoagulants. The study by Donze et al adds to the evidence that being at risk for falls should not be a valid reason to avoid oral anticoagulation in the elderly population. In this study, not only was the incidence of major bleeds found to be significantly lower than expected, but also only three major bleeds occurred directly after a fall. The Fang et al3 study of a large Kaiser Permanente database showed that, regardless of whether individuals were on oral anticoagulants, progressive age increased the risk of major bleeding. It raises the question whether age is simply a marker for an increased risk of bleeding. This would mean that other concomitants of aging, such as comorbid conditions and polypharmacy, may be to blame. Therefore, it would be fair to assume that the process of aging, regardless of being on anticoagulant therapy, appears to be a marker for a greater risk of bleeding, under which circumstances age would certainly represent a higher risk for those on oral anticoagulants. It remains unclear, however, whether age itself is an independent risk factor for increased risk of bleeding. Although this study will not resolve the debate, it certainly assists in expanding our understanding of the complex relationship of age to the use of oral anticoagulant therapy. As a result of this research, physicians should feel more comfortable in treating the elderly while attempting to minimize the modifiable risk factors. Although the research conducted by Donze et al studied patients on VKA, it may be worthwhile mentioning another issue â&#x20AC;&#x201D; the use of new, targeted oral thrombin and factor Xa inhibitors in the elderly. Although specific analysis of age as a risk for major bleeding has not been done, the limited data have found the overall incidence of major bleeding to be similar to or lower than warfarin. Additionally, a consistent lower incidence rate of intracranial hemorrhage has been found with these newer agents compared to warfarin, which should be good news in the elderly. In essence, oral anticoagulation therapy should not be withheld from the elderly simply because of age. Wellmanaged oral anticoagulation therapy when optimally used in clinical practice can achieve substantial benefit. I would stay tuned to the data on the effect of age and outcomes with the newer oral anticoagulants. n References 1. Garwood CL, Corbett TL. Ann Pharmacother 2008;42: 523-532. 2. Brophy MT, et al. J Am Geriatr Soc 2004;52:1151-1156. 3. Fang MC, et al. J Am Geriatr Soc 2006;54:1231-1236.
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Improvement in Primary Prevention of Cardiovascular Disease Using Novel Risk Markers Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP Clinical Professor of Medicine, UCLA School of Medicine Dr. Karpman reports no financial relationships relevant to this field of study.
Synopsis: Coronary artery calcium, ankle-brachial index, high-sensitivity CRP, and family history are all independent predictors of incident coronary heart disease/cardiovascular disease in intermediate-risk individuals. Coronary artery calcium scoring provided superior discrimination and risk reclassification compared with the other risk markers. Source: Yeboah J, et al. Comparison of novel risk markers for improvement in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788-795.
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urrent trends and guidelines for the primary prevention of cardiovascular disease (CVD) have emphasized the need to treat individuals based on their global cardiovascular risk.1 There are few clinical questions about how to treat low-risk and/or high-risk subjects. However, the most major current concerns are about how to treat the intermediate-risk subjects, especially since many of these patients will fall either into low-risk or high-risk categories if appropriate risk markers are determined and utilized. The risk markers under consideration include the coronary artery calcium score (CAC), carotid intima-media thickness, ankle-brachial index, brachial flow-mediated dilatation, high-sensitivity C-reactive protein (CRP), and family history of coronary heart disease (CHD). Yeboah and his colleagues observed that the clinical significance of these six risk markers had never been compared for CVD risk prediction in a single cohort. Therefore, they conducted a study2 to compare improvement in prediction of incident CHD/CVD utilizing these six risk markers within the intermediate-risk group among the participants of the Multi-Ethnic Study of Atherosclerosis (MESA). They determined that the CAC score, ankle-brachial index, high-sensitivity CRP, and family history were all independent predictors of incident CHD/CVD among the intermediate-risk subjects and the CAC score provided superior discrimination and risk reclassification when compared to the other risk markers.
September 29, 2012
n Commentary
3. Collins, GS. BMJ 2009;339:b2584.
Current standard practice guidelines recommend classifying individuals as high, intermediate, or low CVD risk using the Framingham Risk Score (FRS) or other similar CVD risk prediction models.3,4 However, there has been an increasing recognition of the imprecision of these classifications based solely on the FRS because the intermediaterisk group includes both a composite of higher-risk individuals for whom more aggressive drug therapy should be utilized and lower-risk individuals whose CVD risk should be managed only with lifestyle measures and not with drugs. Therefore, it makes the most sense to have additional proven risk markers to help reclassify and guide more specific therapy for these intermediate-risk individuals. The Yeboah study2 suggests that compared to other risk markers, the CAC score provides the highest improvement in discrimination over the FRS in subjects who have been classified as intermediate risk. These findings have also been confirmed in multiple other studies.5 Of course, it must be recognized that the CAC scoring procedure is burdened with a small but nontrivial amount of ionizing radiation (approximately 0.9-1.1 mSv). However, this dose will almost certainly be reduced in the future because major efforts have been made to standardize equipment and imaging protocols in order to reduce radiation exposure during CAC imaging. Some authors remain concerned about the magnitude of long-term cancer risks, since even the lowest possible radiation dose during CAC imaging could possibly translate into a large number of avoidable cancers if CAC scoring were to be uniformly applied to the estimated 23 million adults in the United States currently classified in the intermediate- risk category by the FRS.6 It should be recognized that the CAC score changes very slowly; therefore, obtaining a baseline score that rarely is repeated in less than 5 to 7 years will provide invaluable information in the primary prevention of CVD. A zero CAC score is an extremely important negative-predictive value risk marker and an elevated CAC score adds important information in determining when to institute statin therapy, especially in patients who have elevated total cholesterol/LDL cholesterol levels, known CAD, and/or diabetes mellitus. In summary, the results of the Yeboah study2 confirm many previous studies suggesting that a CAC score is one of the most valuable risk markers that can be used in the primary prevention of CAD, especially in intermediaterisk subjects. Recognizing the small radiation risk and the economic cost of the study, it should be used as frequently as possible in intermediate-risk patients unless there are specific contraindications to its use from a medical and/or economic point of view. n
4. Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. JAMA 2001;285: 2486-2497.
References 1. Hayward RA, et al. Ann Intern Med 2010;152:69-77. 2. Yeboah J, et al. JAMA 2012;308:788-795.
Internal Medicine Alert
5. Kavousi M, et al. Ann Intern Med 2012;156:438-444. 6. Ford ES, et al. J Am Coll Cardiol 2004;43:1791-1796.
Herpes Zoster Vaccine and the Incidence of Recurrent Herpes Zoster in the Elderly Abstract & Commentary
By Richard R. Watkins, MD, MS, FACP Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH Dr. Watkins reports no financial relationships relevant to this field of study. This article originally appeared in the September issue of Infectious Disease Alert.
Synopsis: In a matched cohort study involving immunocompetent individuals â&#x2030;Ľ 60 years of age, the incidence of herpes zoster recurrence following a recent initial episode was low in both herpes zoster vaccine recipients and the unvaccinated. This low-risk questions the need for vaccinating immunocompetent adults with recent herpes zoster infections. Source: Tseng HF, et al. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population. J Infect Dis 2012;206:190-196.
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common question in clinical practice about the
shingles vaccine is whether it is effective in preventing recurrent episodes in patients who have had herpes zoster (HZ). Currently, the Advisory Committee on Immunization Practices (ACIP) recommends it for patients â&#x2030;Ľ 60 years of age, including those with prior HZ.1 The actual risk of recurrence has not been elucidated, although it is thought to be higher in patients with more severe disease.2 Since it was first licensed in 2006, the shingles vaccine has been hampered by production difficulties and shortfalls in availability. Although the FDA approved the shingles vaccine for adults aged 50 through 59 years in March 2011, the ACIP declined to follow suit, citing available evidence and the supply issues.3 Health care policy makers and providers therefore need guidance in determining shingles vaccination priorities. To clarify these issues, Tseng and colleagues conducted a matched cohort study in the Kaiser Permanente system
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in Southern California. Members aged ≥ 60 years who received the shingles vaccine between 1/1/07 and 12/31/10 served as the vaccinated cohort. The unvaccinated cohort included randomly selected members who were matched 5:1 to the vaccinated group based on birth date (± 1 year) and were assigned an index date that corresponded with the vaccination date of the matched vaccinated member. Both groups had the same selection criteria: 1) no diagnosis of HZ during 180 days prior to the date of vaccination; 2) they had a visit for a diagnosis of HZ that included a prescription of antiviral medication on the same day 180 to 730 days prior to vaccination; 3) they had not received a diagnosis of HZ ≤ 1 year prior to the index HZ case, defined as the first HZ case diagnosed in the reference period. Immunocompromised patients were excluded from both cohorts, including those with HIV, leukemia, lymphoma, or those who had been prescribed immunosuppressive agents during the period from ≤ 1 year before the index date until the end of follow-up. A propensity score was used to account for potential confounders and was created using a logistic regression model that predicted the probability of receiving the zoster vaccine. The study included 1036 vaccinated and 5180 unvaccinated subjects. Compared with the unvaccinated cohort, the vaccinated cohort had more female, white, and Asian members and a lower prevalence of chronic diseases. The incidence of recurrent HZ per 1000 person-years in those aged < 70 years was similar in the vaccinated and unvaccinated cohorts, 0.99 (95% confidence interval [CI] 0.02-5.5) and 2.20 (95% CI 1.10-3.93), respectively. The unadjusted incidence rate ratio was 0.45 (95% CI 0.06-3.51; P = 0.45). There was a trend toward the incidence being lower in the vaccinated group, but the scarcity of events precluded the ability to detect a meaningful difference between the two cohorts. There were a few limitations to the study. The authors did not confirm the initial HZ episode or the recurrence by laboratory testing. The cases were detected using electronic medical records, which could introduce bias from misclassification. Moreover, the incidence rate was calculated from the period from the index date (the first day of follow-up set by the vaccinated cohort) instead of the period starting from the previous episode. Thus, comparing the incident rate from this study to other studies is difficult and may be open to different interpretations.
and the shingles vaccine both generate a comparable VZV cell-mediated immunity that is protective against further episodes.4 This study is important because it suggests that the risk of recurrent HZ following a recent initial episode is low among immunocompetent adults. Therefore, vaccination immediately following a recent HZ episode may not be necessary. But before this becomes routine clinical practice, larger studies with longer follow-up and laboratory confirmation of cases need to be completed. Also, whether certain immunocompromised patients should be vaccinated following an episode of HZ remains an open question. Given the high cost of the vaccine and its frequent shortages, this study and future ones will hopefully aid policy makers and payers in prioritizing which patients should undergo vaccination. n References 1. Harpaz R, et al. MMWR 2008;57:1-30. 2. Yawn BP, et al. Mayo Clin Proc 2011;86:88-93. 3. Harpaz R, et al. MMWR 2011;60:1528. 4. Weinberg A, et al. J Infect Dis 2009;200:1068-1077.
Pharmacology Update Linaclotide Capsules (Linzess®) By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
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he first in the class of guanylate cyclase c-receptor agonists has been approved by the FDA for constipation associated with irritable bowel syndrome and chronic idiopathic constipation. Linaclotide is a synthetic peptide that is chemically related to the endogenous guanylin peptide family. It is marketed by Forest and Inwood Pharmaceuticals as Linzess.
n Commentary
As the authors describe, the occurrence of HZ is believed to result from a decline in a threshold level of varicella zoster virus (VZV) specific cell-mediated immunity. Ongoing exposures to VZV, both through endogenous and exogenous sources, may propagate effective VZV memory immunity. The shingles vaccine likely restores VZV-specific T cells to a level above the threshold. HZ 142
Indications Linaclotide is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults.1 Dosage The recommended initial dose is 290 mg once daily for September 29, 2012
IBS-C and 145 mg for CIC.1 The capsules should be taken on an empty stomach at least 30 minutes before the first meal of the day. Linaclotide is available as 145 mg and 290 mg capsules. Potential Advantages Linaclotide offers a drug with a different mechanism of action for this difficult indication. Potential Disadvantages Diarrhea is the most frequent side effect. The discontinuation rate due to diarrhea was 7%-8% compared to 4% for placebo.1,3 Linaclotide should not be used in patients younger than 18 years of age.1 Comments Linaclotide is a minimally absorbed peptide that is an agonist for guanylate cyclase C receptors. This results in stimulation leading to the secretion of water and electrolytes, which enhances the frequency and ease of bowel movements.1,3 Safety and efficacy of linaclotide for the management of IBS-C were evaluated in two randomized, placebo-controlled, double-blind, 12-week studies in patients who met the Rome II criteria of IBS. This included a mean abdominal pain score of at least 3 on a 0- to 10-point scale, fewer than three complete spontaneous bowel movements (CSBMs) per week, and five or fewer spontaneous bowel movements (SBM) per week. Subjects were randomized to 290 mcg (n = 405, 401) or placebo (n = 395, 403) once daily. Subjects were allowed to continue stable doses of bulk laxatives or stool softeners. Treatment response was combined endpoints of at least a 30% reduction from baseline in mean abdominal pain, at least three CSBMs, and an increase of at least one CSBM from baseline all in the same week for at least 9 out of the first 12 weeks of treatment. Two studies evaluated the efficacy and safety of linaclotide in CIC in subjects who met the Rome II criteria for functional constipation. These included fewer than three SBMs per week and one of the following symptoms for at least 12 weeks, straining, lumpy or hard stool, and sensation of incomplete evacuation during 25% of bowel movements. Subjects were randomized to 145 mcg (n = 217, 213) daily or placebo (n = 213, 215). The primary endpoint was three or more CSBMs per week and an increase of one or more CSBMs from baseline during at least 9 of 12 weeks. Efficacy responder rates for IBS-C for the combined endpoint (at least 9 out of 12 weeks) were 12.1% and 12.7% for linaclotide and 5.1% and 3% for placebo. These represent a treatment difference (95% confidence interval) of 7% (3.2, 10.9) and 9.7 (6.1, 13.4). For CIC, the response rates were 20.3% and 15.5% compared to 3.3% and 5.6% for placebo. In both Internal Medicine Alert
IBS-C and CIC, bowel frequency and abdominal pain returned to baseline after drug discontinuation. Clinical Implications Constipation is a common gastrointestinal disorder that affects 12% to 19% of the U.S. population.3 Linaclotide is the first of a new class of drugs for the treatment of constipation associated with IBS and CIC. There are currently no comparative studies for currently available agents. n References 1. Linzess Prescribing Information. St. Louis, MO: Forest Pharmaceuticals, Inc.; August 2012. 2. Lembo AJ, et al. N Engl J Med 2011;365:527-536. 3. Lee N, Wald A. Core Evid 2012;7:39-47.
CME Objectives Upon completion of this educational activity, participants should be able to: • describe new findings in the differential diagnosis and treatment of various diseases; • describe the advantages, disadvantages and controversies surrounding the latest advances in the diagnosis and treatment of disease; • identify cost-effective treatment regimens; • explain the advantages and disadvantages of new disease screening procedures.
CME Questions 1. A male subject whose BMI increases from 23 to 35 kg/m2 will also note a rise in his risk of developing type 2 diabetes by: a. 2-fold. b. 42-fold. c. 16-fold. d. 4-fold. 2. In the study by Donze et al, which of the following is true regarding patients on oral anticoagulants and risk of bleeds? a. Patients on oral anticoagulants at high risk of falls did not have a significantly increased risk of major bleeds. b. Patients on oral anticoagulants at high risk of falls did have a significantly increased risk of major bleeds. c. Patients on oral anticoagulants at low risk of falls did not have a significantly increased risk of major bleeds. d. Patients on oral anticoagulants at low risk of falls did have a significantly increased risk of major bleeds. 3. For CVD risk determination in intermediate-risk patients, coronary artery calcium scoring: a. was similar to other risk markers. b. proved to be of little value. c. should rarely be utilized because of radiation risk. d. provided superior discrimination and risk reclassification compared with other risk markers.
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Clinical Briefs By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville Dr. Kuritzky is an advisor for Endo, Kowa, Pricara, and Takeda.
Could Thinner be Worse for Newly Diagnosed Diabetics? Source: Carnethon MR, et al. JAMA 2012;308:581-590.
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sually, we anticipate a direct re-
lationship between overweight and cardiovascular adversity, attributed to increases in blood pressure, lipids, glucose, insulin resistance, and sympathetic tone that are associated with obesity. There appears to be some exception to this general rule in reference to diabetes. For instance, in the TRIAD study, diabetics who were normal weight at entry to the study had a higher mortality than overweight/obese study subjects; similarly, in the PROactive trial, normal weight subjects or those who lost weight had higher mortality than overweight subjects. Because these two studies included confounding issues such as diabetes of varying duration and preexisting cardiovascular disease, a more clear-cut relationship between body mass index (BMI) and outcome in diabetes could be discerned by selecting newly diagnosed diabetics. Carnethon et al performed a pooled analysis of five longitudinal cohort studies (n = 2625) to examine the relationship between mortality and BMI for persons with newly diagnosed diabetes. Overall, only 12% of study subjects had a BMI < 25 at the time of diagnosis, but the relative risk for total mortality during follow-up (up to 15 years) was essentially doubled in this population compared to overweight individuals. The mechanism(s) by which lower BMI increases mortality risk are unknown. Clinicians must not be falsely reassured that this lower-BMI phenotype, which is commonly seen in Asian-Americans, portends a favorable future. n
The Impact of Exercise on Depression in Heart Failure Source: Blumenthal JA, et al. JAMA 2012;308:465-474.
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5 million americans have chronic heart failure (CHF), and almost half of these patients fulfill diagnostic criteria for depression. Subsyndromal depression is present in as many as 75%. Notwithstanding the burden of depression on quality of life, a direct impact on mortality has been shown in post-myocardial infarction patients, and even in patients with hypertension in the Systolic Hypertension in the Elderly Program. Unfortunately, to date the information on the impact of treating depression is both limited and generally disappointing. For instance, a clinical trial of sertraline in depressed patients with CHF found no cardiovascular event outcomes benefit. Exercise is a treatment for depression, and exercise has been shown to provide event reduction in CHF patients. Whether it might improve depression and cardiovascular events in CHF patients was the object of the HF-ACTION trial (Heart Failure-A Controlled Trial Investigating Outcomes of Exercise Training). More than 2000 patients with stable CHF were randomized to an aerobic exercise program. The exercise subjects enjoyed a statistically significant 11% reduction in mortality over the next 30 months. Although the mean score on the Beck Depression Inventory was statistically significantly lower in the exercise group, the improvement was sufficiently modest to be of uncertain clinical impact. Exercise in CHF reduces mortality and may have a modest t is estimated that
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effect on depression. n
Reversible Dementia from Corticosteroid Therapy Source: Cipriani G, et al. Clin Geriatrics 2012;20:38-41.
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lthough there are many clinical
situations in which corticosteroids (CTS) are disease modifying and life saving, one aspect of CTS that has not received much attention is the potential for central nervous system (CNS) adverse effects. CTS may be largely subgrouped into mineralocorticoids exemplified by aldosterone, and glucocorticoids (GLC) like prednisone, the latter of which is the object of this case report. There are at least two types of CTS receptors in the brain: type I (mineralocorticoid receptors) and type II (glucocorticoid receptors). Type II receptors are found in the hippocampus as well as other diffuse sites throughout the brain. The hippocampus is required for voluntary recollection of learned information, such as recalling what you had for dinner last night. Even low doses of GLC have been shown to impair hippocampal function, despite being used for short time periods, doses of prednisone of 80 mg/ day have been shown to alter cognitive function within 4-5 days. The authors include discussion of a report detailing six cases of dementialike cognitive decline (distinct from steroid psychosis) in patients whose cognitive function was restored upon GLC discontinuation. Clinicians should be vigilant for decline in cognitive function in persons receiving GLC treatment, even over the short-term. n
Updating the Published Guidelines for Preventing Episodic Migraine: Is Anyone Listening?
September 29, 2012