AHDB ADA 2013 Highlights by Dalia Buffery

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

august 2013 I Vol 6 I SPECIAL ISSUE

Payers’ Perspectives in diabetes Including ADA 2013 Highlights

Highlights from the ADA President’s Research Sessions By Mary Mosley

Look AHEAD: Lifestyle Intervention Cost-Effective in Overweight Patients with Type 2 Diabetes But it fails to reduce the number of CV events By Wayne Kuznar

Chicago, IL—At the 2013 American Diabetes Association (ADA) annual meeting, John E. Anderson, MD, President of Medicine & Science of the ADA, hosted the President’s Oral Research Sessions I and II, one session focused on basic science and the other on clinical and behavioral science. A subcommittee for the ADA’s Program Committee selected the abstracts of the 2 sessions. Commenting on these ses sions, Dr Anderson said, “The Presidential Oral Research Sessions highlight the best and most promising research of all the abstracts submitted to the Continued on page 8

SGLT-2 Inhibitors Show Durability in Glycemic Control, Weight-Loss Maintenance Empagliflozin reduces HbA1c, Invokana first in class By Wayne Kuznar Chicago, IL—The new drug class of so dium glucose cotransporter (SGLT)-2

inhibitors was the subject of several poster presentations at the 2013 Continued on page 12

Chicago, IL—An intensive lifestyle intervention designed for weight loss had no significant effect on the risk of cardiovascular (CV) events after a dec ade compared with diabetes support and education, but it did lead to re duced use of antidiabetes and cardiac medications, fewer hospitalizations, and lower cost, reported researchers at the 2013 American Diabetes Associa tion annual meeting. The study, called Look AHEAD,

Reduced Healthcare Utilization, Costs The rates of hospitalizations were Continued on page 15

Pooled Analysis Confirms CV Benefits of DPP-4 Inhibition By Mary Mosley Chicago, IL—Diabetes is known to confer approximately a 2-fold in creased risk for vascular disease, independent of other cardiovascular (CV) risk factors. The topic was dis cussed in a session at the 2013 Ameri can Diabetes Association (ADA) an nual meeting. The presence of diabetes is equivalent in risk to a history of

coronary heart disease. Key characteristics of the CV biopathology in patients with type 2 diabetes include: • Younger age • Asymptomatic disease or atypical symptoms • More advanced disease at the time of diagnosis

Continued on page 6

in th is is s u e

DIABETES MANAGEMENT. . . . . . . . 6 Adding linagliptin to basal insulin reduces hypoglycemia, improves A1c in older patients New predictors of outcomes in diabetes Lifestyle intervention beneficial in diabetes, but not for CV parameters

was conducted at 16 centers in the United States. It enrolled 5145 over weight or obese patients with type 2 diabetes who were randomly assigned to intensive lifestyle intervention that was intended to promote weight loss or to diabetes support and education (see article, page 9).

EMERGING THERAPIES. . . . . . . 12 First SGLT-2 inhibitor approved by the FDA GLP-1 agonists may protect patients with diabetes from heart failure Albiglutide effective in various scenarios in type 2 diabetes

HEALTH ECONOMICS . . . . . . . . 15 Financial incentives can promote weight-loss maintenance Canagliflozin monotherapy can reduce costs of diabetes complications Comparing resource utilization and costs: saxagliptin versus sitagliptin Substantial costs for diabetes consumed by the diabetic foot and arthritis DRUG UPDATE . . . . . . . . . . . . . . 19 Nesina, Kazano, and Oseni: 3 alogliptinbased agents approved for treatment of patients with type 2 diabetes

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FOR ADULT PATIENTS WITH TYPE 2 DIABETES TRADJENTA® (LINAGLIPTIN) TABLETS: THE ONLY SINGLE-STRENGTH DPP-4 INHIBITOR

TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

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Indication and Important Limitations of Use

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Use with Medications Known to Cause Hypoglycemia Insulin secretagogues and insulin 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

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ADVERSE REACTIONS

WARNINGS AND PRECAUTIONS

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Adverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis. 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 TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. In patients receiving

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

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

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in a clinical trial. Therefore, a lower dose of the insulin secretagogue or insulin 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.

CONTRAINDICATIONS

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TRADJENTA delivers proven glycemic control Placebo-adjusted difference in A1C with oral monoand dual therapy at 24 weeks (%) TRADJENTA monotherapy1,2* Baseline A1C 8.0%

*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. Full analysis population using last observation on study.

TRADJENTA add-on to metformin2,3† Baseline A1C 8.1%

–0.7%

‡

(n=333) P<0.0001

†

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. 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.

‡

0.3% adjusted mean increase from baseline A1C 8.0% with placebo (n=163).2

0.15% adjusted mean increase from baseline A1C 8.0% with placebo plus metformin (n=175).2

–0.6%§ (n=513) P<0.0001

TRADJENTA: A single-strength DPP-4 inhibitor No dose adjustment required regardless of declining renal function or hepatic impairment TRADJENTA is primarily nonrenally excreted with 80% eliminated via the bile and gut and 5% eliminated via the kidney within 4 days of dosing

TRADJENTA as add-on therapy to a stable dose of insulin, severe hypoglycemic events were reported in 11 (1.7%) patients compared with 7 (1.1%) for placebo. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient-years of exposure while being treated with comparator (placebo and active comparator, sulfonylurea). 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

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TRADJENTA has a demonstrated safety profile evaluated in more than 6000 patients

ENTA TRADJ 30 5 MG # O QD Sig: i P ILLS x2 REF

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 Sept 28 2012

References: 1. Del Prato S, Barnett AH, Huisman H, et al. 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.

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

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 milk, caution

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Tradjenta® (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information. INDICATIONS AND USAGE Monotherapy and Combination Therapy: 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. CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity. WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues and insulin 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. The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with a higher rate of hypoglycemia. Therefore, a lower dose of the insulin secretagogue or insulin 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.

Nasopharyngitis Diarrhea Cough

Number (%) of Patients TRADJENTA 5 mg Placebo n = 3625 n = 2176 254 (7.0) 132 (6.1) 119 (3.3) 65 (3.0) 76 (2.1) 30 (1.4)

Rates for other adverse reactions for TRADJENTA 5 mg versus placebo when TRADJENTA was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. Following 104 weeks’ treatment in a controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥5% of patients treated with TRADJENTA (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%). Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin. Hypoglycemia: In the placebo-controlled studies, 199 (6.6%) of the total 2994 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to 56 patients (3.6%) of 1546 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when TRADJENTA was administered as monotherapy or in combination with metformin, or with pioglitazone. When TRADJENTA was administered in combination with metformin and a sulfonylurea, 181 of 792 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea. Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflect true hypoglycemia. In the study of patients receiving TRADJENTA as add-on therapy to a stable dose of insulin for up to 52 weeks (n=1261), no significant difference in

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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 strong 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: There were 4040 type 2 diabetes patients treated with linagliptin 5 mg from 15 clinical trials of TRADJENTA; 1085 (27%) were 65 years and over, while 131 (3%) were 75 years and over. Of these patients, 2566 were enrolled in 12 doubleblind placebo-controlled studies; 591 (23%) were 65 years and over, while 82 (3%) 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. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

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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 evaluation of TRADJENTA 5 mg once daily in patients with type 2 diabetes is based on 14 placebo-controlled trials, 1 activecontrolled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, a total of 3625 patients were randomized and treated with TRADJENTA 5 mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks. TRADJENTA 5 mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks’ duration and in five additional placebocontrolled studies lasting ≤18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: 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); one with pioglitazone (24 weeks’ treatment duration); and one with insulin (primary endpoint at 24 weeks). In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in ≥2% of patients receiving TRADJENTA (n = 3625) and more commonly than in patients given placebo (n = 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo. Table 1 Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy

the incidence of investigator reported hypoglycemia, defined as all symptomatic or asymptomatic episodes with a self measured blood glucose ≤70 mg/dL, was noted between the TRADJENTA (31.4%) and placebo (32.9%) treated groups. During the same time period, severe hypoglycemic events, defined as requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 11 (1.7%) of TRADJENTA treated patients and 7 (1.1%) of placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 3 (0.5%) patients on TRADJENTA and 1 (0.2%) on placebo. Use in Renal Impairment: TRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose ≤54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in 3 (4.4%) TRADJENTA treated patients and 3 (4.6%) placebo treated patients. Events that were considered life-threatening or required hospitalization were reported in 2 (2.9%) patients on TRADJENTA and 1 (1.5%) on placebo. Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks treatment compared to placebo. 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.

OVERDOSAGE In the event of an overdose with TRADJENTA, contact the Poison Control Center. 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. 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. Copyright © 2012 Boehringer Ingelheim International GmbH Revised: September 2012

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Payers’ Perspectives in Diabetes

The Peer-Reviewed Forum For Real-world Evidence in Benefit Design™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Directors, Client Services Joseph Beck Ron Gordon Projects Manager John Welz Senior Production Manager Lynn Hamilton The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonato Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications 1249 South River Road, Suite 202A Cranbury, NJ 08512 Phone: 732-992-1880

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks 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 American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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DIABETES MANAGEMENT Pooled analysis confirms CV benefits of DPP-4 inhibition Linagliptin added to basal insulin reduces hypoglycemia in older patients New predictors of outcomes in diabetes Intensive treatment early in type 1 diabetes produces substantial long-term benefits EMERGING THERAPIES SGLT-2 inhibitors show durability in glycemic control, weight loss GLP-1 agonists may protect patients with diabetes from heart failure Albiglutide effective in various treatment scenarios

HEALTH ECONOMICS Financial incentives can promote weight-loss maintenance Canagliflozin monotherapy can reduce costs of diabetes complications Comparing resource utilization and costs: saxagliptin versus sitagliptin Substantial costs for diabetes consumed by the diabetic foot and arthritis Future of healthcare reform: expect new payment and delivery models DRUG UPDATE Nesina, Kazano, and Oseni: 3 alogliptin-based agents approved for type 2 diabetes

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

Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine

Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville

Deputy Editors

HEALTH OUTCOMES RESEARCH

Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Senior Director, North America Medical Affairs, Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc. Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

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

Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes Personalized Health Care Program, University of Utah Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Aging and Wellness Eric G. Tangalos, MD, FACP, AGSF Steven Miff, PhD Professor of Medicine Senior Vice President Mayo Clinic, Rochester, MN VHA, Inc., Irving, TX CANCER RESEARCH Christopher (Chris) P. Molineaux Al B. Benson, III, MD, FACP, FASCO President, Pennsylvania BIO Professor of Medicine, Associate Director Malvern, PA for Clinical Investigations Terri S. Moore, PhD, RPh, MBA Robert H. Lurie Comprehensive Cancer Senior Manager, Product Development Center Northwestern University, IL URAC, Washington, DC Past Chair, NCCN Board of Directors Kavita V. Nair, PhD Samuel M. Silver, MD, PhD, FASCO Associate Professor, Director, Graduate Professor of Internal Medicine, Program Track in Pharmaceutical Hematology/Oncology Outcomes Research Assistant Dean for Research, Associate Univ. of Colorado, Aurora, CO Director, Faculty Group Practice, Gary M. Owens, MD University of Michigan Medical School President, Gary Owens Associates EMPLOYERS Ocean View, DE Arthur F. Shinn, PharmD, FASCP Andrew M. Peterson, PharmD, PhD President, Managed Pharmacy Dean, Mayes School of Healthcare Consultants, LLC, Lake Worth, FL Business and Policy, Associate Professor, F. Randy Vogenberg, RPh, PhD University of the Sciences, Philadelphia Principal, Institute for Integrated Sarah A. Priddy, PhD Healthcare, Greenville, SC Director, Competitive Health Analytics ENDOCRINOLOGY Humana, Louisville, KY James V. Felicetta, MD Timothy S. Regan, BPharm, RPh, CPh Chairman, Dept. of Medicine Executive Director, Strategic Accounts Carl T. Hayden Veterans Affairs Xcenda, Palm Harbor, FL Medical Center, Phoenix, AZ Vincent J. Willey, PharmD Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Associate Professor, School of Pharmacy, Adjunct Associate Professor Endocrinology University of the Sciences, Philadelphia Touro University Nevada Paul Wilson Senior VP, Health Consumer Insights and EPIDEMIOLOGY Research Analytics, Blue Bell, PA Joshua N. Liberman, PhD Executive Director, Research, Development David W. Wright, MPH & Dissemination, Sutter Health President, Institute for Interactive Patient Concord, CA Care, Bethesda, MD 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

MANAGED MARKETS

Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA 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 PATIENT ADVOCACY National Pharmaceutical Council Mike Pucci Washington, DC Sr VP, Commercial Operations and Jack E. Fincham, PhD, RPh Business Development, PhytoChem Professor of Pharmacy, School of Pharmacy Pharmaceuticals University of Missouri, Kansas City, MO Lake Gaston, NC Walid F. Gellad, MD, MPH Personalized medicine Assistant Professor of Medicine Amalia M. Issa, PhD, MPH University of Pittsburgh, Staff Physician Director, Program in Personalized Pittsburgh VA Medical Center, Adjunct Medicine & Targeted Therapeutics Scientist, RAND Health University of the Sciences, Philadelphia Paul Pomerantz, MBA PHARMACOECONOMICs CEO, American Society of Josh Feldstein Anesthesiologists President & CEO, CAVA, The Center for Park Ridge, IL Applied Value Analysis, Inc., Norwalk, CT J. Warren Salmon, PhD Jeff Jianfei Guo, BPharm, MS, PhD Professor of Health Policy & Professor of Pharmacoeconomics & Administration Pharmacoepidemiology, College of School of Public Health Pharmacy, Univ of Cincinnati Medical University of Illinois at Chicago Center, OH Raymond L. Singer, MD, MMM, CPE, Grant D. Lawless, RPh, MD, FACP FACS Assoc. Prof. and Director, Healthcare Chief, Division of Cardiothoracic Surgery Decision Analysis, Dept. of Clinical Vice Chair, Department of Surgery for Pharmacy, Univ. of Southern California Quality & Patient Safety and Outreach Los Angeles Lehigh Valley Health Network, PA PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services 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 health & value promotion MSJ Associates, Sandy Springs, GA Craig Deligdish, MD Matthew Mitchell, PharmD, MBA Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA

RESEARCH & DEVELOPMENT

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Diabetes Management

Pooled Analysis Confirms CV Benefits of DPP-4... • High mortality rate (70%-75% of all deaths in diabetes result from CV disease). New Evidence for CV Benefits of DPP-4 Inhibition The ability of glucose-lowering drugs to reduce CV risk in type 2 diabetes continues to be debated. Mechanistic studies have indicated that dipeptidyl peptidase (DPP)-4 in hibitors may have nonglycemic CV benefits, including lowering of blood pressure and triglycerides; improv ing endothelial and left-ventricular function; and the reduction of myo cardial infarct size, inflammation and oxidative stress, and atherosclerotic plaque volume. In one recent study, CV events and all-cause mortality were reduced with a DPP-4 inhibitor compared with an active comparator in an independent meta-analysis of 70 trials with nearly 42,000 patients and a mean 44-week follow-up (Monami M, et al. Diabetes Obes Metab. 2013;15:112-120). The reduction in myocardial infarc tion (MI) with the DPP-4 inhibitor was greater than would be predicted based on traditional risk factors, suggesting a role for other mechanisms, stated the investigators. The Mantel-Haenszel odds ratio was 0.71 for major adverse coronary events. The CV safety of the DPP-4 inhibi tor linagliptin was evaluated by com

paring the incidence of CV events and mortality in type 2 diabetes with other glucose-lowering drugs. At the ADA meeting, Odd Erik Johansen, MD, PhD, Senior Clinical Program Leader, Boehringer Ingelheim, Norway.

“CV events rank as the major cause of death in patients with diabetes, accounting for more than 50% of all diabetes fatalities. It is therefore important to identify treatments that do not increase the risk of CV events even further.” —Odd Erik Johansen, MD, PhD

“There is a well-established associ ation between cardiovascular events and Type 2 diabetes,” said Dr Johan sen. “In fact, CV events rank as the major cause of death in patients with diabetes, accounting for more than

50% of all diabetes fatalities. It is therefore important to identify treat ments that do not increase the risk of CV events even further.” Dr Johansen presented the updat ed pooled analysis of 9569 patients in 19 multicenter, double-blind, paral lel-group studies in which patients were randomized to linagliptin (N = 5847) or to a comparator (N = 3612). The comparator was placebo (N = 2675), glimepiride (N = 775), or vogli bose (N = 162). The length of the tri als ranged from 12 weeks to 2 years. CV Events Reduced by 22% with Linagliptin A 22% reduction in the primary end point of combined CV death, MI, stroke, and hospitalization for unsta ble angina was seen with linagliptin versus the combined comparator (hazard ratio [HR], 0.78; 95% confi dence interval, 0.55-1.12). The inci dence rate of the primary end point was 13.4 per 1000 patient-years in the linagliptin group and 18.9 in the comparator group. The secondary CV end point of CV death, stroke, or MI was reduced by 26% with linagliptin, and all adjudi cated CV events by 18% with lina gliptin versus the combined compar ators for both end points. The incidence rates per 1000 patient-years were 9.3 and 14.0 for the secondary CV end point, and 21.5 and 29.1 for

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all adjudicated CV events for the linagliptin and comparator groups, respectively. A blinded independent expert committee prospectively adju dicated the CV events. The HRs for the tertiary CV end points were 1.04 for CV death, 0.86 for nonfatal MI, 0.34 for nonfatal stroke, 0.09 for transient ischemic stroke, and 1.08 for hospitalization for unstable angina. The mean age of the patients was 59 years, 45% were women, and ap proximately 60% were white. Ap proximately 55% of the population had diabetes for >5 years, and the mean hemoglobin A1c was 8.1%. Nearly 11% of the patients receiving linagliptin and 12% of the patients receiving a comparator had moder ate-to-severe renal insufficiency. Ap proximately 73% of the linagliptin group and 76% of the comparator group received CV drugs for primary and secondary prevention. In a representative cohort of pa tients with type 2 diabetes and a di verse background of CV risk (from low to high) and concomitant treat ment (treatment naïve to insulin), linagliptin was not associated with an increased risk of CV events, said Dr Johansen. CARMELINA, a CV and renal out comes study, and CAROLINA, a CV outcomes study, will more fully inves tigate the CV safety of linagliptin. n

Adding Linagliptin to Basal Insulin Reduces Hypoglycemia in Older Patients with Type 2 Diabetes DPP-4 inhibition noninferior to glimepiride in HbA1c reduction, with less hypoglycemia By Mary Mosley Chicago, IL—Hypoglycemia is a seri ous concern in elderly patients with type 2 diabetes who often require in sulin therapy. Two new analyses pre sented as late-breaking posters at the 2013 American Diabetes Association annual meeting showed that adding linagliptin to basal insulin in elderly patients reduces the incidence of hy poglycemia in diabetic patients. Reduced Hypoglycemia in Elderly Patients The first study was presented by lead investigator Silvio E. Inzucchi, MD, Clinical Director of the Section of Endocrinology and Metabolism, Yale

University, New Haven, CT. This ex ploratory analysis of data from 2 phase 3 trials included 247 elderly patients (mean age, 74 years) with type 2 diabetes, showing a 37% lower incidence of overall hypoglycemia (as defined by investigator) and a 34% lower incidence of confirmed hypo glycemia (blood glucose ≤70 mg/dL) when the oral dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (Tradjen ta) 5 mg daily was added to their basal insulin compared with placebo. The reduced risk of hypoglycemia with linagliptin was observed in addi tion to a significant reduction at 24 weeks from baseline in hemoglobin

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(Hb) A1c levels. The baseline insulin dose was 36 U daily, with little change during the studies. HbA1c was re duced by –0.77% with linagliptin compared with placebo, from mean baseline levels of 8.2%. In patients with a baseline HbA1c <7.5%, a simi lar trend was seen, with a 23% reduc tion in the incidence of hypoglycemia. “These new data, while highly pre liminary, suggest that DPP-4 inhibi tion may somehow affect hypoglyce mia rates in elderly patients managed with insulin,” said Dr Inzucchi. “This is obviously of clinical importance, given the detrimental effects, especial ly in an older patient group, of hypo

glycemia. Possible explanations in clude improved glucagon secretory dynamics at the level of the pancreatic alpha-cell, but this is obviously con jecture at this point. This signal needs to be confirmed by others in larger studies,” Dr Inzucchi added. The investigators noted that the finding of a reduction in hypoglyce mic risk in concert with a reduction in HbA1c was “in stark contrast” to re sults seen with other oral agents in combination with insulin therapy. Comparing Glimepiride and Linagliptin Another late-breaking poster pre

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Diabetes Management

Novel Predictors of Outcomes in Diabetes Diabetes directly linked to many CV events By Mary Mosley San Francisco, CA—New insights into the predictors of outcomes in patients with diabetes were provided by sev eral studies and registries presented at the 2013 American College of Cardiol ogy annual meeting by investigators from around the world. Diabetes Linked to Angina Pre/Post-MI An unexpected finding from the TRIUMPH Prospective Cohort Study was that patients with diabetes had a significantly greater prevalence of angina before and after an acute myo cardial infarction (MI) than patients without diabetes—49% versus 42%, respectively (P <.001). After the acute MI, the association between angina and diabetes was stronger over time, as well as in pa tients without multi vessel disease, presumably because of the diffuse na ture of coronary artery disease in pa tients with diabetes. The Seattle Angina Questionnaire was used at admission, and at 1, 6, and 12 months after an acute MI in this analysis of 3612 patients, 30% of whom had diabetes, from 24 hospitals across the United States. The investigators stated that this finding is “contrary to conventional wisdom” regarding the prevalence of angina in patients with and without diabetes, and its prevalence had not been previously quantified. Further

more, they found that diabetic pa tients took more antianginal medica tions, thus the association may be underestimated in this analysis. Angina after an acute MI leads to re peat hospitalizations and higher costs.

Patients with diabetes had a significantly greater prevalence of angina before and after an acute myocardial infarction than patients without diabetes, a finding that is “contrary to conventional wisdom.”

Hyperglycemia Predictor of Acute Kidney Injury Hyperglycemia at hospital admis sion after an acute MI was found to be an independent predictor of acute kidney injury in a study conducted at the National Cerebral and Cardiovas cular Center in Japan. In addition, the incidence of kidney injury increased as admission glucose levels increased. Of the 760 patients in the study, 13% had an acute kidney injury, de fined as an absolute increase in serum creatinine ≥0.3 mg/dL or a ≥50% rela

tive increase within 48 hours of hospi talization; 53% of the patients with kidney injury had diabetes. In-hospi tal mortality was significantly higher (24%) in the patients with kidney in jury compared with only 3% in the patients without. Diabetes and Renal Failure The Acute Coronary Syndrome (ACS) Registry of the large-scale, mul tinational Euro Heart Survey revealed that renal failure is an independent predictor of in-hospital mortality, but diabetes was not, in patients who had a non–ST-elevation ACS. The ACS Registry comprises 121,582 patients. Of the 12,833 patients with non–STelevation ACS, 8% had renal failure and 4% of these patients also had diabetes. The in-hospital rate of death was 7.9% in patients with renal failure alone, 8.3% with renal failure plus di abetes, 3.2% with diabetes alone, and 2.7% in patients without renal failure or diabetes. The patients with renal failure were older (aged >75 years) and had a higher incidence of previ ous MI or revascularization. Also from the ACS Registry, the in vestigators found that for ST-eleva tion MI (STEMI), diabetes and renal failure were independent predictors of in-hospital mortality. Of the 8646 patients with STEMI in the registry, 96% had diabetes and 20% of them

also had renal failure. The odds ratio (OR) for in-hospital mortality on mul tivariate analysis was 1.78 for renal failure alone, 1.27 for renal failure plus diabetes, and 1.34 for diabetes alone. Of note, the OR for female patients was 1.34 and for age >75 years was 3.22. The patients with renal failure had the highest rate of death, at 18.4% with renal failure plus diabetes and 17.4% with renal failure alone com pared with 9.2% in patients with dia betes alone and 5.9% without renal failure or diabetes. Heart Failure and Impaired Glucose Intolerance An analysis from the Cardiovas cular Health Study, a populationbased cohort of women aged >65 years in the United States, showed that heart failure is a risk factor for diabetes. It has been known that the presence of diabetes increases the risk of heart failure. Heart failure significantly in creased the risk for impaired glu cose tolerance (OR, 2.18) and overt diabetes (OR, 4.78) developing with in 3 to 4 years. This association re mained after adjustment for a vari ety of factors. The same increased risk was seen in the patients with impaired glucose tolerance at base line, although it was not statistically significant. n

Adding Linagliptin to Basal Insulin Reduces Hypoglycemia in... sented an exploratory analysis of the 2-year data from a phase 3 study that compared the benefit of DPP-4 inhibi tion with linagliptin 5 mg daily (N = 764) and the sulfonylurea glimepiride 1 mg to 4 mg daily (N = 755) in pa tients with hypoglycemia who re ceived the sulfonylurea metformin. Hypoglycemia is common in patients with type 2 diabetes who are receiv ing a sulfonylurea. In this study, Baptist Gallwitz, MD, of the Department of Medicine IV, Eberhard Karls Universität Tübin gen, Germany, and colleagues, com pared the use of linagliptin with glimepiride in patients with uncon trolled hypoglycemia who received metformin therapy. The incidence of hypoglycemia (in vestigator-defined) was significantly VOL. 6

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“These new data, while highly preliminary, suggest that DPP-4 inhibition may somehow affect hypoglycemia rates in elderly patients managed with insulin. This is obviously of clinical importance, given the detrimental effects, especially in an older patient group, of hypoglycemia.” —Silvio E. Inzucchi, MD reduced with linagliptin compared with glimepiride (7.5% vs 36.1%, re spectively; P <.001). A significant dif

ference in hypoglycemia incidence re mained after excluding the events that occurred during dose escalation of

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glimepiride (25.8% compared with 5.9% with linagliptin). Linagliptin outperformed glimepir ide at reducing the risk of hypoglyce mia at all time intervals examined up to 2 years, at all doses, at any age, and at level of change in HbA1c from base line. The results of this study drive home the point that linagliptin pro vides noninferior reductions in HbA1c levels compared with glimepiride, but with the additional benefits of a lower risk for hypoglycemia and cardiovas cular events, and without weight gain. The investigators noted that this analysis “adds to the body of evidence that informs clinical decision-making for second-line treatment on top of metformin” in this new era of a more patient-focused approach to diabetes treatment. n

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Diabetes Management

Highlights from the ADA President’s Research... Scientific Sessions Planning Commit tee this year.” A selection of the studies presented at these sessions are highlighted here.

“The Presidential Oral Research Sessions highlight the best and most promising research of all the abstracts submitted to the Scientific Sessions Planning Committee this year.” —John E. Anderson, MD

Triple-Drug Combination as Initial Therapy Outperforms Sequential Therapy in Type 2 Diabetes Beginning treatment with triple therapy compared with usual sequen tial therapy produced a faster and more sustained reduction in hemoglo bin (Hb) A1c levels in patients with new-onset type 2 diabetes. The sin gle-center, randomized study was presented by Muhammad A. Abdul- Ghani, MD, PhD, Assistant Professor, University of Texas Health Science Center, San Antonio. Dr Abdul-Ghani presented the 2-year interim results from a 3-year study that seeks to determine the best way to attain the ADA/European As sociation for the Study of Diabetes– recommended goal of HbA1c <6.5% without hypoglycemic events, which has not been studied previously. The initial triple therapy (N = 71) comprised metformin 1000 mg daily, pioglitazone 15 mg daily, and exena tide 5 μg twice daily (uptitrated at the end of month 1 as needed to 2000 mg, 45 mg, and 10 μg, respectively). Con ventional therapy (N = 76) included metformin followed by glyburide in month 2 and insulin glargine in month 3. The initial starting daily doses of 1000 mg, 5 mg, and 10 units, respec tively, were uptitrated if fasting plas ma glucose (FPG) was >100 mg/dL or HbA1c >6.5%. The patients (average age, 46 years) had an average body mass index of 36 kg/m2 and a 5-month average dura tion of diabetes since diagnosis. With triple therapy, HbA1c was reduced to 6.0% at 6 months (from 8.6% at baseline) and remained at this level at 24 months. By contrast, although the HbA1c level was re duced to 6.1% with conventional therapy at 6 months, it rose to 6.6% at 24 months. Postprandial hypoglycemia was

markedly lower with triple combina tion therapy than with conventional sequential therapy and was the major contributor to achieving HbA1c goals. FPG was also significantly lower with triple therapy compared with conven tional therapy. Other key improvements with tri ple combination therapy versus con ventional therapy were: • More patients achieved HbA1c <6.5% (60% vs 27%, respectively) • More patients achieved HbA1c <7.0% (92% vs 72%, respectively) • A lower rate of hypoglycemia (15% vs 46%, respectively) • A better weight profile (–1.2 kg vs +4.1 kg, respectively). Treatment failure was only 17% at 2 years with the triple therapy com pared with 42% with conventional therapy.

“Treat the disease— diabetes—not its symptom of hyperglycemia. Treat the patient, not his blood sugar.” —Muhammad A. Abdul-Ghani, MD, PhD Dr Abdul-Ghani said that their approach of correcting the known pathophysiologic defects of insulin resistance (with metformin and pio glitazone) and beta-cell dysfunction (with exenatide) at the time of diagno sis is more effective, safer, and more durable than targeting lowering plas ma glucose concentration. “Treat the disease—diabetes—not its symptom of hyperglycemia. Treat the patient, not his blood sugar,” he said. New Analysis of ACCORD: Insulin Exposure Not Linked to CV Mortality The results of the ACCORD trial showed that intensive treatment of patients with type 2 diabetes who also had high cardiovascular (CV) risk resulted in increased CV and all-cause mortality. A new analysis of the ACCORD data was presented at the session by Elias S. Siraj, MD, Associate Professor of Medicine, Temple University School of Medi cine, Philadelphia, PA. He and col leagues analyzed insulin exposure data from the ACCORD study for 10,163 patients with follow-up data (mean, 5 years) for CV mortality and insulin dose.

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The unadjusted data showed an 83% higher risk of CV mortality for every 1-unit-per-kg increase in the in sulin dose. However, no association was found between exposure to insu lin and increased risk for CV mortali ty, after adjustment for baseline char acteristics. The investigators conclud ed that after adjusting for 14 baseline characteristics and other covariates, including HbA1c and hypoglycemia, there was no support for the notion that insulin dose is an independent risk factor for CV mortality in this patient population. Education, Not Technology, Reduces Hypoglycemia in Type 1 Diabetes A structured 2-hour education pro gram reduced the incidence of bio chemical hypoglycemia in high-risk patients with type 1 diabetes, whether they were receiving insulin by a con tinuous subcutaneous insulin pump or by multiple daily injection. The Hypo COMPaSS trial is the first to in vestigate the management of impaired awareness of hypoglycemia, which is characteristic of approximately 20% of patients with type 1 diabetes and causes a 6-fold increase in severe hy poglycemia. Stuart A. Little, MBBS, Diabetes and Endocrinology Special ist Trainee, Newcastle University, England, presented the study results. The patients were randomized to continuous subcutaneous insulin with insulin aspart (N = 46) or to multiple daily injection with insulin aspart plus insulin glargine (N = 50), and to con tinuous glucose monitoring or not. Mr Little noted that all the patients (mean age, 49 years) were provided equal support to reach the treatment goal of avoiding biochemical hypo glycemia, but without relaxing the HbA1c goals. The patients’ mean dia betes duration was 29 years and the mean baseline HbA1c was 8.2%.

The “benefit of education trumped the technology of insulin delivery” to avoid severe biochemical hypoglycemia. —Stuart A. Little, MBBS The primary end point of the change in the Gold score—an estab lished measure of awareness of the onset of hypoglycemia—improved significantly (P <.001) in all partici pants, from a score of 5 to 4 (a lower number indicates greater awareness).

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There was no significant difference between groups. By week 4, all patients achieved a significant reduction in biochemical hypoglycemia, from 53.3 minutes daily to 24.5 minutes daily, as was measured by continuous glucose monitoring; this reduction was sus tained through week 24. A reduction in the number of epi sodes of severe hypoglycemia was also achieved, from 9 at baseline to <1 at 24 weeks, and the proportion of patients affected was reduced to 19% compared with 92% at 1 year before the study. Mr Little stated that the “benefit of education trumped the technology of insulin delivery” to avoid severe bio chemical hypoglycemia. Cognitive Decline in Type 1 Diabetes Quantified, Related to Systolic BP and HbA1c The first study to assess changes over time in brain function and struc ture showed that there is an acceler ated decline in executive functions and brain volume in patients with type 1 diabetes and microangiopa thy. However, these cognitive chang es are not comparable with the mild cognitive impairment known to lead to dementia. Eelco van Duinkerken, MSc, of the Diabetes Psychology Department, VU University Medical Center, Amsterdam, the Netherlands, presented the 4-year data at the Pres ident’s Oral Session. In the 25 patients with type 1 diabe tes and 25 healthy matched controls, baseline systolic blood pressure (BP) was related to a decline in brain vol ume, and baseline elevated HbA1c was related to a decline in executive function (ie, information processing, attention, memory). No correlation was found with severe hypoglycemic events. The patients (mean age, 45 years) with diabetes had proliferative reti nopathy as a marker of angiopathy, and their mean diabetes duration was 35 years. The systolic BP was 133.9 mm Hg in the diabetes group com pared with 126.9 mm Hg in the con trol group (P = .045). The baseline HbA1c values were 7.9% and 5.4% (P <.001) in the diabetes and control groups, respectively. As measured by magnetic resonance imaging, brain volume decreased by 1.34% in the patients with type 1 dia betes and by 0.68% in the control pa tients (P = .036). The decrease was most notable in the frontal and cen tral areas of the right hemisphere, which are associated with executive function performance (P = .021). n

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Diabetes Management

Reductions in HbA1c Levels, Hypoglycemia, and Weight with Linagliptin in Patients with Type 2 Diabetes and Renal Impairment By Mary Mosley

Chicago, IL—It is estimated that ap proximately 66% of patients with type 2 diabetes are at risk for declin ing renal function. A new dou ble-blind, randomized trial of patients with type 2 diabetes and moder ate-to-severe renal impairment—esti mated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2— showed that the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (Tradjen ta) significantly reduced hemoglobin (Hb) A1c compared with placebo at 12 weeks (the primary end point); com pared with glimepiride in the 40week extension study, there was less hypoglycemia with linagliptin. The trial, conducted in the United States and Europe, was presented at the 2013 American Diabetes Associa tion annual meeting by lead investi gator Markku Laakso, MD, PhD, Academy Professor, Department of Medicine, University of Eastern Fin land, Kuopio. Of the patients (mean age, 67 years), 76% had diabetes du

ration of >10 years, 86% of them were taking insulin. The mean eGFR was 37 mL/min/1.73 m2. For the primary efficacy end point analysis, patients were randomized to linagliptin 5 mg daily (N = 113) or to placebo (N = 122) for 12 weeks. For the 40-week extension study, the pa tients receiving placebo were switched to glimepiride 1 mg to 4 mg daily, and treatment continued until week 52 in both groups. The mean HbA1c at base line was 8.08% in the linagliptin group and 8.03% in the placebo plus glimep iride group. At 12 weeks, there was a greater mean reduction in baseline HbA1c with linagliptin of –0.53% compared with –0.11% with placebo plus glimepir ide—a treatment difference of –0.42% (P <.001). HbA1c was also lower with linagliptin compared with placebo plus glimepiride during the 40-week extension. The incidence of hypoglycemia was lower at 52 weeks with linagliptin

compared with placebo plus glimepir ide (57.9% vs 69.3%, respectively).

These results suggest that linagliptin may be a convenient, effective, and safe treatment for patients with declining renal function, “a highly prevalent, complex, and vulnerable population in which other glucoselowering treatments have important restrictions.” —Markku Laakso, MD, PhD

Drug-related adverse events were similar at 12 weeks (23.9%, linagliptin; 24.6%, placebo plus glimepiride) but were lower with linagliptin at 52 weeks (38.3% and 46.5%, respective

ly). Weight gain was also less with linagliptin at 52 weeks (0.06 kg vs 1.74 kg with placebo plus glimepiride). There were no adverse changes in renal function or pancreatitis with linagliptin, and there were fewer renal and cardiovascular events with lina gliptin than with placebo plus glimepiride. Dr Laakso and his colleagues stated that these study results suggest that linagliptin may be a convenient, effec tive, and safe treatment for this pa tient population, noting that declining renal function comprises “a highly prevalent, complex, and vulnerable population in which other glu cose-lowering treatments have im portant restrictions,” because they are primarily excreted by the kidneys and thus are contraindicated or require dose adjustment. Linagliptin is nearly exclusively excreted by nonrenal pathways, and thus does not require dose adjustment, which is in contrast to most DPP-4 drugs. n

Lifestyle Intervention Beneficial in Patients with Diabetes, but Not for CV Parameters Best weight-loss rates reported in this trial compared with any current approaches Chicago, IL—The final results of the Look AHEAD study showed that an intensive lifestyle intervention pro gram provides a range of benefits in patients with type 2 diabetes who were overweight and obese. Howev er, it had no impact on the primary outcome of reducing cardiovascular (CV) morbidity and mortality. The results were presented in a spe cial session at the 2013 American Dia betes Association annual meeting to showcase the full range of beneficial outcomes. (A cost analysis of this study is presented on page 1 of this issue.) Look AHEAD was terminated in early October 2012 after a mean 9.6 years, because of futility. The inten sive lifestyle intervention that includ ed weight loss and moderate physical activity was compared with diabetes support and education. “Look AHEAD showed that partic ipants with diabetes can lose weight VOL. 6

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and maintain it,” said Rena R. Wing, PhD, Professor of Psychiatry and Human Behavior, the Warren Alpert Medical School of Brown University, Providence, RI. “This weight loss has many beneficial effects on glycemic control and on cardiovascular disease risk factors. However, it did not affect the risk of cardiovascular disease.” The primary outcome of the first CV event—CV death, nonfatal myo cardial infarction, nonfatal stroke, or hospitalization for angina—was re ported in 403 patients in the lifestyle intervention group and in 418 patients in the education group (P = .505). No significant difference in CV event inci dence was seen at any time point. No significant difference was seen in the secondary composite outcome measures or their components. In ad dition, no difference was seen across the 3 prespecified subgroup compari sons of history of CV disease, sex, and race and ethnicity.

“Look AHEAD showed that participants with diabetes can lose weight and maintain it. This weight loss has many beneficial effects on glycemic control and on cardiovascular disease risk factors. However, it did not affect the risk of cardiovascular disease.” —Rena R. Wing, PhD Key Benefits with Intensive Intervention Key benefits with the intensive life style intervention were: • Significantly improved fitness • Improved systolic blood pressure • Improved hemoglobin A1c (a sig nificant between-group difference of 0.22 at end of trial)

• Significant weight-loss reduction • A 31% reduction in advanced chronic kidney disease. Weight loss was significantly great er with the lifestyle intervention at all time points, and was greatest at 1 year. At the end of the study, the weight-loss rates were 6.0% with in tervention and 3.5% with education, and the difference across the entire study between the groups was 4%. Dr Wing stated that weight losses achieved during Look AHEAD repre sent the best possible achievement with current lifestyle approaches. However, “they may not be sufficient to reduce CV events.” Furthermore, more intensive medical management of CV disease risk factors, greater use of statins, and education may have reduced the differences between the groups. Also, earlier intervention during the course of diabetes or be fore diabetes develops may be needed to reduce CV risk.—MM n

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Diabetes Management

Intensive Treatment Early in Type 1 Diabetes Produces Substantial Long-Term Benefits By Mary Mosley

Chicago, IL—On the 30th anniversary of the landmark Diabetes Control and Complications Trial (DCCT), the re sults of its 20-year observational Epi demiology of Diabetes Interventions and Complications (EDIC) study showed substantial reductions in the risk of developing severe eye disease, impaired kidney function, heart dis ease, and stroke with long-term inten sive therapy in patients with type 1 diabetes. The results were presented at the 2013 American Diabetes Associ ation annual meeting. The 10-year results of this landmark government-funded trial showed that intensive therapy achieved near-nor mal glucose levels and reduced reti nopathy by 76%, kidney disease by 50%, and neuropathy by 60%. “On the basis of these results, DCCT intensive therapy has been adopted worldwide as the standard of therapy for type 1 diabetes,” said David M. Nathan, MD, Director of the Massachusetts General Hospital Diabetes Center in Boston. Dr Nathan cochairs the study. More than 95% of the surviving members of the original 1441 DCCT participants continue to be followed in the observational EDIC study. At the end of the DCCT, patients in the conventional therapy group were switched to intensive therapy. Greater benefits were seen in the patients who were initially random

ized to intensive therapy, according to the EDIC results. Judith E. Fradkin, MD, Director of the Division of Diabetes, Endocrinolo

“On the basis of these results, DCCT intensive therapy has been adopted worldwide as the standard of therapy for type 1 diabetes.” —David M. Nathan, MD

gy, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, said, “The long-term results of the DCCT/EDIC further reinforce the im portance of early intensive therapy over the lifetime of people with type 1 diabetes. Our challenge now is to en sure that all patients with type 1 dia betes are able to take advantage of these remarkable findings and to make intensive therapy as convenient and safe as possible.” During the DCCT, the target hemo globin (Hb) A1c was <6.5%, and more than 50% of patients reached that goal at least once, said Dr Nathan. The aver age HbA1c was 7% with intensive ther apy and 9% with conventional therapy.

In addition, the EDIC showed that impaired kidney function was re duced by 50% with intensive therapy, according to Ian H. de Boer, MD, MS, Associate Professor of Medicine, Uni versity of Washington, Seattle. “The reduction in impaired kidney func tion represents a major finding since kidney failure increases the risk of subsequent heart disease and death more than any other complications,” Dr de Boer said.

“Our challenge now is to ensure that all patients with type 1 diabetes are able to take advantage of these remarkable findings.” —Judith E. Fradkin, MD At 8 years after the DCCT, a contin ued benefit in terms of reduced risk of microalbuminuria and macroalbu minuria was seen in the intensive therapy group, and this benefit was

sustained through 20 years with con tinued separation of the curves be tween the groups. Hypertension incidence was ap proximately 50%, which was reduced by approximately 20% during the first 14 years of EDIC with intensive thera py. The risk of impaired glomerular filtration was also reduced by 50% over the long-term, as first reported in 2011 in the New England Journal of Medicine. Cardiovascular disease was reduced by approximately 50% at 21 years, as first reported in 2005 by Na than and colleagues (N Engl J Med. 2005;353:2643-2653). “The risk reduction in the former intensive therapy group has persist ed through 2012,” said John M. Lachin, ScD, Professor of Biostatis tics and Epidemiology, and of Statis tics, George Washington University, Rockville, MD, with the lower HbA1c during the DCCT trial explaining the reduction. Approximately a 50% reduction was found with intensive therapy for the risk of eye surgery and retinal detachment. An underappreciated condition in diabetes—progressive stiffening around the hands and shoulders—affected 66% of DCCT participants after 30 years of diabetes; however, lower glucose levels were associated with reduced risk of these complications. n

New Data Show Ranolazine Most Effective Antianginal Agent for Patients with Type 2 Diabetes and HbA1c >7% By Wayne Kuznar

San Francisco, CA—Ranolazine ex tended release (Ranexa) reduces the frequency of anginal episodes in pa tients with type 2 diabetes, and its ef fects are more pronounced in patients with poorer glycemic control, accord ing to new data released at the 2013 American College of Cardiology an nual meeting. Ranolazine is approved for the treatment of chronic angina, but it had not been studied specifical ly in patients with type 2 diabetes. In the international Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina trial, 927 patients with type 2 diabetes, chronic stable angina, and coronary artery dis ease were randomized to ranolazine 1000 mg twice daily or to placebo for 8 weeks. Nearly all (96%) patients had hypertension, and 74% had a history

“If the glucose-lowering action of ranolazine is confirmed in future studies, patients with diabetes and angina may derive a dual benefit from this drug.” —Mikhail N. Kosiborod, MD of myocardial infarction. More than 80% were taking statins and angioten sin-converting enzyme inhibitors. At baseline, patients in the ranolazine group had a mean of 6.6 anginal epi sodes weekly, and those in the placebo group had a mean of 6.8 episodes. Ranolazine had a modest effect in

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reducing angina frequency. From weeks 2 to 8, self-reported angina epi sodes were 4.3 weekly in the placebo group compared with 3.8 weekly in the ranolazine group (P = .008), re ported Mikhail N. Kosiborod, MD, a cardiologist at Saint Luke’s Mid Amer ica Heart Institute, Kansas City, MO. The need for sublingual nitroglyc erin was also lower in patients ran domized to ranolazine (1.7 doses weekly) than in those receiving place bo (2.1 doses weekly). The benefits of ranolazine were greater in patients with higher base line hemoglobin (Hb) A1c levels. Pre viously, ranolazine was found to have glucose-lowering effects. The superior effect of ranolazine was especially pronounced in patients with HbA1c >7%. “If the glucose-lowering

action of ranolazine is confirmed in fu ture studies, patients with diabetes and angina may derive a dual benefit from this drug,” said Dr Kosiborod. A subgroup analysis by geographic region revealed that the frequency of angina was not different between the ranolazine and placebo arms among patients enrolled in Russia, Ukraine, and Belarus. Among the patients en rolled in other countries, ranolazine recipients experienced a significant reduction in the frequency of angina versus placebo (3.1 vs 4.1 episodes weekly; P = .002). “The reasons for this geographic difference are not clear,” Dr Kosi borod said. “It wasn’t explained by differences in baseline characteristics but was driven by several sites located in Russia.” n

I august 2013 VOL. 6 I

Special Issue

Emerging Therapies

SGLT-2 Inhibitors Show Durability in Glycemic Control, Weight-Loss... Continued from cover

American Diabetes Association annu al meeting. In addition to lowering blood glucose levels in a series of phase 3 clinical trials, these agents show weight-loss benefits as well. The long-term effect of SGLT-2 in hibitors on the urinary tract is un known; over the short-term, the rate of genital infection has been increased with this class of agents. Below are some of the key studies that were pre sented at the meeting. Empagliflozin In a pooled analysis of 4 random ized, placebo-controlled phase 3 clini cal trials, the effects of 24 weeks of therapy with empagliflozin were eval uated in 2477 patients with type 2 diabetes. At a poster presented by Thomas Hach, MD, Senior Medical Director at Boehringer Ingelheim Pharma, Ingelheim, Germany, and colleagues, treatment with empagliflozin result ed in significant reductions in hemo globin (Hb) A1c and weight versus placebo. Those randomized to empaglifloz in versus to placebo experienced an increased frequency of genital infec tions but not urinary tract infections (UTIs). Compared with placebo, HbA1c levels declined by 0.62% in patients assigned to 10 mg daily of empagli flozin (P <.001), and by 0.68% in patients assigned to 25 mg daily (P <.001). Among patients with a baseline HbA1c level ≥7.0%, signifi cantly more who were assigned to empagliflozin at either dosage achieved an HbA1c <7.0% at week 24 compared with placebo (37.2%, 25 mg empagliflozin; 31.3%, 10 mg empagli flozin; 10.5%, placebo; P <.001 for both vs placebo). Compared with placebo, body weight declined by 1.81 kg in patients randomized to 10 mg of empagliflo zin and by 2.01 kg in those random ized to 25 mg of empagliflozin (P <.001 for both). Reductions in systolic or diastolic blood pressure, as well as uric acid levels also were reported in patients receiving empagliflozin. A safety analysis of the same 4 pooled studies revealed that the inci dence of UTI with empagliflozin was comparable with placebo (9.3% and 7.5% for 10 mg and 25 mg, respective ly vs 8.2% with placebo). The safety data were presented by Gabriel Kim, MD, Clinical Project Lead at Boeh ringer Ingelheim, Ingelheim, Germa ny, and colleagues. Of the reported

UTI episodes, most were mild in in tensity, Dr Kim indicated. There were more genital infec tions with empagliflozin compared with placebo—4.2% with empagli flozin 10 mg and 3.6% with empagli flozin 25 mg compared with 0.7% with placebo.

Empagliflozin treatment resulted in significant reductions in HbA1c and weight versus placebo. Dapagliflozin Results of a late-breaking abstract were reported for the selective SGLT-2 inhibitor dapagliflozin, showing that dapagliflozin reduced hyperglycemia in an insulin-independent way by rais ing the urinary glucose excretion in patients with type 2 diabetes, according to 4-year data presented by Stefano Del Prato, MD, Professor of Endocrinology at the University of Pisa, Italy. Among patients whose disease was inadequately controlled with metformin, those who received da pagliflozin had greater durability of HbA1c reduction over 4 years com pared with the patients receiving glipizide. Dapagliflozin was com pared with glipizide in a randomized, double-blind trial as add-on therapy in 801 patients who had inadequate glycemic control with metformin.

From week 52 to week 208, the rise in HbA1c was significantly lower with dapagliflozin compared with glipizide. At 52 weeks, the change in HbA1c with dapagliflozin was inferior to that with glipizide, but from week 52 to week 208, the rise in HbA1c was sig nificantly lower with dapagliflozin compared with glipizide; the differ ence in HbA1c levels between the 2 treatment arms was significant at 208 weeks—a 0.30% difference in favor of dapagliflozin. Weight loss was sustained and sta ble with dapagliflozin, reaching a 3.65-kg loss at study’s end, whereas patients receiving glipizide showed a gain of 0.73 kg.

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Approximately 13.5% of the pa tients in the dapagliflozin group had evidence of a UTI, and 14.3% had ev idence of a genital infection. Canagliflozin First SGLT-2 Inhibitor Approved by FDA In 2013, canagliflozin (Invokana) became the first SGLT-2 inhibitor to receive US Food and Drug Adminis tration (FDA) approval for the treat ment of patients with type 2 diabetes. In patients with impaired renal func tion, canagliflozin reduced levels of HbA1c, an effect that was more pro nounced with higher levels of estimat ed glomerular filtration rate (eGFR), said Gary Meininger, MD, Franchise Medical Leader, Janssen Research and Development, Raritan, NJ. According to Mary H. Parks, MD, Director, Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Re search, “Invokana is the first diabetes treatment approved in a new class of drugs known as sodium-glucose cotransporter 2 inhibitors….We con tinue to advance innovation with the approval of new drug classes that provide additional treatment options for chronic conditions. Dr Meininger presented a pooled analysis of canagliflozin compared with placebo in patients with inade quately controlled type 2 diabetes and stage 3 chronic kidney disease (CKD) who were enrolled in 4 ran domized, double-blind, placebo-con trolled phase 3 clinical trials. The op tions for glycemic control in patients with advanced CKD are limited, said Dr Meininger. Canagliflozin received FDA approv al as an adjunct treatment to diet and exercise to improve glycemic control in adult patients with type 2 diabetes. The FDA-approved dosage is limited to 100 mg once daily in patients with moder ate renal impairment with eGFR from 45 mL/min/1.73 m2 to <60 mL/min/ 1.73 m2, and the drug is not indicated for the treatment of patients with eGFR <45 mL/min/1.73 m2. The pooled analysis included 1085 patients with type 2 diabetes and stage 3 CKD (eGFRs between ≥30 mL/min/1.73 m2 and <60 mL/min/ 1.73 m2) who were randomized to canagliflozin 100 mg or 300 mg, or to placebo, for 18 to 26 weeks. In the overall study population, the mean change from baseline to efficacy assessment in HbA1c was –0.14% in the placebo group, –0.52% in the group assigned to canagliflozin 100

mg (P <.001 vs placebo), and –0.62% in the group assigned to canagliflozin 300 mg (P <.001 vs placebo). When assessed by baseline eGFR, a greater reduction in HbA1c with canagliflozin was observed in patients with eGFR ≥45 mL/min/1.73 m2 than in those with eGFR <45 mL/min/1.73 m2.

In patients with impaired renal function, canagliflozin reduced levels of HbA1c, an effect that was more pronounced with higher levels of estimated glomerular filtration rate.

Weight loss in the canagliflozin groups was also greater than in the placebo groups (–2.0% with 100 mg, –2.4% with 300 mg, –0.5% with place bo). The weight-loss effect was great er in patients with eGFR ≥45 mL/ min/1.73 m2 than in those with eGFR <45 mL/min/1.73 m2.

Adverse Events with Canagliflozin Adverse events related to reduced intravascular volume were more common in the canagliflozin groups (5.0% and 8.5% in the 100-mg and 300-mg groups, respectively) com pared with placebo (2.6%), said Dr Meininger. The percentage of these events was greater in patients with eGFR <45 mL/min/1.73 m2 relative to placebo than in those with eGFR ≥45 mL/min/1.73 m2. Also, renal-re lated adverse events occurred more frequently with canagliflozin com pared with placebo, and the rates were higher in all 3 groups with eGFR <45 mL/min/1.73 m2. Low Rates of Hypoglycemia with All SGLT-2 Inhibitors All of the SGLT-2 inhibitors are associated with low rates of hypogly cemia. The rate of hypoglycemic events was 10-fold less with dapagli flozin versus placebo. The rates of confirmed hypoglyce mic adverse events were between 4.0% and 5.2% with empagliflozin. In the study of patients with stage 3 CKD, the rate of documented hypo glycemic events was between 2.4% and 8.1% with canagliflozin in pa tients not receiving insulin or a sulfonylurea. n

I august 2013 VOL. 6 I

Special Issue

Emerging Therapies

GLP-1 Agonists May Protect Patients with Diabetes from Heart Failure By Wayne Kuznar San Francisco, CA—Medications that act on the glucagon-like peptide (GLP)-1 pathway may protect patients with type 2 diabetes from developing heart failure, according to a singlecenter retrospective study. The study showed a reduced risk of heart failure–related hospitalization and all-cause mortality in patients with type 2 diabetes who had no his tory of heart failure and were pre scribed GLP-1 agonists or dipeptidyl peptidase (DPP)-4 inhibitors, said David E. Lanfear, MD, Senior Staff Cardiologist, Henry Ford Hospital, Detroit, MI, at the 2013 American Col lege of Cardiology annual meeting.

“It looks like these medicines [GLP-1 agonists] are protective or may have favorable cardiac effects, particularly in terms of heart failure. It definitely makes further investigation a higher priority.”

ization was reduced by 41% among patients who used GLP-1 agonists compared with other classes of antidi abetes medications. The group of pa tients taking a GLP-1 agonist also had a 44% reduction in the risk of all-cause hospitalization and an 80% reduction in the risk of all-cause death. The use of antihypertensive medi

cations did not influence the effect of the GLP-1 drugs on heart failure risk. “This study doesn’t tell us anything definitively, but it looks like these medicines are protective or may have favorable cardiac effects, particularly in terms of heart failure,” said Dr Lan fear. “It definitely makes further in vestigation a higher priority.”

The study offers some reassurance about the safety of GLP-1 drugs “but real safety data are coming and will take a couple of years,” he said. Fur ther study will also explore the poten tial mechanisms behind the cardio vascular effects of these agents and the effects of GLP-1 agonists versus DPP-4 inhibitors. n

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—David E. Lanfear, MD “Studies in animal models showed that GLP-1 drugs may have a benefi cial impact on heart failure, such as in creasing cardiac output,” Dr Lanfear said. “Two small human studies have also been consistent with this, so we decided to look at it in a larger popula tion that did not have heart failure, but we know that diabetics are at higher risk of developing heart failure.” The 4227 patients included in this analysis received care through the Henry Ford Health System and its af filiated HMO. The patients had an oral antidiabetic medication filled between January 1, 2000, and July 1, 2012, and were free of heart failure at baseline. Electronic databases were used to track medication use and outcomes. Patients receiving thiazolidinediones were ex cluded from the analysis. Patients who started treatment with a GLP-1 agonist were matched in a 1 to 2 ratio to controls, using propensity score matching for age, sex, history of coronary artery disease or heart fail ure, duration of diabetes, and number of antidiabetic medications. Over an observation period of 663 days, 281 hospitalizations occurred, including 184 hospitalizations for heart failure and 158 total deaths. The risk of a heart failure–related hospital VOL. 6

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Emerging Therapies

Albiglutide, a GLP-1 Receptor Agonist, Effective in Various Treatment Scenarios in Patients with Type 2 Diabetes By Mary Mosley Chicago, IL—A series of 8 phase 3 clin ical trials that compared albiglutide, an investigational glucagon-like pep tide (GLP)-1 receptor agonist, with 5 currently used treatment scenarios showed the drug effectively lowered hemoglobin (Hb) A1c, the primary out come of the studies, in patients with uncontrolled type 2 diabetes. Albiglu tide is administered once weekly, via an easy-to-use injection pen. Philip D. Home, DPhil, DM, Profes sor of Diabetes Medicine, Newcastle University, England, and lead investi gator of the HARMONY 5 study, said, “Albiglutide can be used throughout the stepped algorithm of therapy, from immunotherapy to combina tion,” based on the results of the HARMONY 1 to 5 studies, which were presented as late-breaking ab stracts at the 2013 American Diabetes Association annual meeting. “Albi glutide compared to placebo is as ef fective as other glucose-lowering agents, and does not cause weight gain,” he said. Dr Home noted that in the series of studies, the incidence of nausea and vomiting were relatively low, and that this was an improvement against other GLP-1 drugs. Although there were some injection-site reactions in the 5 trials, he thinks that this is re lated more to the volume of the once-weekly injection, and that these “are not allergic reactions, [and] this particular preparation is very nonimmunogenic.” “There were no specific consistent side effects which caused withdraw al,” Dr Home noted, from the drug in these studies. Weight loss was less with albiglutide compared with the other GLP-1 drugs (ie, eventide, lira

glutide [Victoza]). In the HARMONY 1 study, when added to pioglitazone, with or with out metformin, albiglutide 30 mg once weekly significantly reduced HbA1c in patients with diabetes from base line to week 52 compared with place bo. The mean difference in the HbA1c reduction was –0.75% between the 2 groups (mean age, 55 years), a base line HbA1c of 8.1%, a body mass index of 34 kg/m2, and an 8-year diabetes duration.

“Albiglutide compared to placebo is as effective as other glucose-lowering agents, and does not cause weight gain….GLP-1 drugs are particularly useful for people who have glucose control problems…or problems managing their body weight.” —Philip D. Home, DPhil, DM

In the HARMONY 2 study, albiglu tide monotherapy significantly re duced HbA1c levels in patients whose diabetes was uncontrolled with diet and exercise and who had not re ceived antihyperglycemic drug treat ment. At week 52, the mean difference in HbA1c reduction was –0.84% with albiglutide 30 mg versus placebo, and –1.04 with albiglutide 50 mg. The pa tient profile was similar to HARMO NY 1, but the diabetes duration was 4 years. The significant reductions in

Table H ARMONY 3: Mean Treatment Difference with Albiglutide versus Comparators HbA1c, %

Fasting plasma glucose, mg/dL

Placebo + metformin

–0.91

–27.7

Sitagliptin + metformin

–0.35

–15.5

Sulfonylurea + metformin

–0.27

–10.1

Albiglutide 30 mg + metformin vs

fasting plasma glucose (FPG) at week 52 mirrored the reductions in HbA1c (–34 mg/dL for albiglutide 30 mg and –43 mg/dL for albiglutide 50 mg). The patients’ weight was reduced in each group (–0.7 kg with placebo, –0.4 kg with albiglutide 30 mg, and –0.9 kg with albiglutide 50 mg). The rates of injection-site reaction were 10% with placebo, 18% with albiglutide 30 mg, and 22% with albiglutide 50 mg. In patients with uncontrolled type 2 diabetes who were receiving met formin, HARMONY 3 compared the effect of adding albiglutide 30 mg, sitagliptin, sulfonylurea, or placebo on the reduction of HbA1c at 104 weeks. The mean differences in HbA1c and FPG levels with albiglutide ver sus the comparators are shown in the Table. Weight loss was significantly greater with albiglutide compared with sulfonylurea, and the rates of ad verse events were similar across the groups. The HARMONY 4 trial showed that albiglutide was noninferior to insulin glargine for the primary outcome of change in HbA1c at week 52 in pa tients with uncontrolled diabetes who were using metformin with and with out sulfonylurea. Albiglutide and glargine were uptitrated as needed according to a predefined schema. In jection-site reaction was 13.9% with once-weekly albiglutide and 8.7%

with once-daily glargine. The patients were similar to those in HARMONY 1, but 82% of patients were taking metformin plus a sulfonylurea. Albi glutide significantly reduced weight and the rates of hypoglycemia; nausea was higher, and 1 patient had pancre atitis. The change in FPG was greater with glargine than with albiglutide. Triple therapy with albiglutide was tested in HARMONY 5. In patients taking metformin and glimepiride, the reduction in HbA1c at week 52 was –0.55% with albiglutide, –0.80% with pioglitazone, and –0.33% with placebo. The FPG changes were –12.4 mg/dL, –31.4 mg/dL, and +11.5 mg/dL, re spectively. Patients taking albiglutide or placebo lost 0.4 kg, whereas those taking pioglitazone gained 4.4 kg. Dr Home said that the use of GLP-1 drugs will increase, particularly in combination with insulin therapy, be cause there is more evidence of their benefit. The success with liraglutide has offset the lesser success with exen atide, because of its high rate of nau sea and vomiting. Yet, he noted that the issue of whether GLP-1 agents cause pancreatitis and pancreatic can cer remains to be resolved. “I think GLP-1 drugs are particularly useful for people who have glucose control problems, obesity-related problems, or problems managing their body weight,” he said. n

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I august 2013 VOL. 6 I

Special Issue

Health Economics

Look AHEAD: Lifestyle Intervention Cost-Effective... 11.9% lower in the intensive lifestyle intervention group compared with the diabetes education group (0.193 vs 0.17 hospitalizations annually, respec tively; P = .003), which translated into an annual reduction in cost of $294 (P = .03; Table), said Henry A. Glick, PhD, Professor of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. The proportion of patients receiv ing home care was reduced by 16.2% —from 7.4% in the education group to 6.2% in the lifestyle intervention group (P = .003). The number of medications per participant was reduced by 6.3% with the lifestyle intervention, from 4.92 to approximately 4.61 annually (P <.001), leading to a 10-year cost offset of $2455 annually and an annual savings

of $278. The present discounted value of 10 years of costs for diabetes educa tion was $77,124 versus $71,746 for lifestyle intervention—a savings of $5378 (P <.001).

The number of medications per participant was reduced by 6.3% with the lifestyle intervention, from 4.92 to approximately 4.61 annually, leading to a 10-year cost offset of $2455 annually and an annual savings of $278. The largest relative reductions in medication use in the lifestyle inter vention group were for diabetes drugs

Continued from cover

Table Look AHEAD: Average Annual Healthcare Costs and Medications Diabetes support and education

Intensive lifestyle intervention

P value

Hospitalization

2749

2455

.03

Home care

122

108

.28

1.43

1.24

<.001

Cost, $

Medication used, N Antidiabetes Lipid-lowering

0.65

0.61

.003

Antihypertensive

1.23

1.17

.02

Source: Wing R, et al. Results of the Look AHEAD Trial. Presented at the 2013 American Diabetes Association Annual Meeting; June 24, 2013; Chicago, IL.

(13.3%; P <.001), lipid-lowering drugs (6.1%; P = .003), and antihypertensive drugs (4.9%; P = .02). The average overall annual costs were $8807 for the education group and $8205 for the

lifestyle intervention group (P = .001). The data do not include the cost of interventions, making it unclear wheth er intensive lifestyle intervention re duced the total costs, said Dr Glick. n

Financial Incentives Can Promote Maintenance of Weight Loss, a Major Factor in Diabetes By Wayne Kuznar San Francisco, CA—The impact of obesity on patients with diabetes is well-established. Weight loss can sig nificantly impact diabetes. In a recent study, obese patients who were of fered modest financial incentives over an extended period of time as part of a weight-loss program were signifi cantly more likely to maintain their weight loss than patients in an identi cal program without the financial in centives, according to Steven L. Driv er, MD, MPH, Internal Medicine Resident, Department of Internal Medicine, Mayo Clinic, Rochester, MN, at the 2013 American College of Cardiology annual meeting. Many employers and insurers have already instituted workplace wellness programs that include financial incen tives aimed at improving engagement and outcomes, Dr Driver said. How ever, when the financial incentives are ultimately removed, the participants tend to regain the lost weight. In an attempt to achieve sustained weight loss, Dr Driver and colleagues de signed a novel, long-term, continuous financial incentive scheme based on research in behavioral economics. The effectiveness of the program was studied in 100 healthy adult em ployees and their dependents who had a body mass index (BMI) between 30 kg/m2 and 39.9 kg/m2, which is classified as obese BMI. Each partici pant was randomly assigned to 1 of 4 VOL. 6

Special Issue

Effective incentive programs “have to have appropriate magnitude, so there has to be enough money to matter; there has to be a proximity to the desired behavior change…and they have to have salience. The most powerful of the 3 was probably the negative incentive.” —Steven L. Driver, MD, MPH weight-loss groups: 12 once-weekly education sessions with and without financial incentives, or the education sessions combined with a structured behavior modification plan with and without financial incentives. All par ticipants were given a weight-loss goal of 4 lb monthly, with the goal adjusted based on the monthly weight. Weigh-ins occurred monthly for 1 year.

“Participants in the incentive groups who showed up for their weigh-ins earned $10 and those who met their 4-lb weight-loss goal re ceived $20 per month,” said Dr Driv er. However, if they failed to meet their weight-loss goals, they paid a $20 penalty into a bonus pool. The bonus pool was later awarded via lottery among participants who com pleted the study. The financial incentive groups maintained greater participation rates and lost more weight than the control groups. Completion rates were 62% and 26%, respectively, in the incen tive groups and nonincentive groups. Even participants who were subject to financial penalties were more like ly to continue to participate than those in the groups without financial incentives, possibly because taking this risk also made them eligible to earn rewards. On an intent-to-treat analysis, mean weight loss was 9.08 lb for the combined incentive groups versus 2.34 lb for the combined nonincentive groups. The estimated effect of the incentives was 6.5 lb. Effective Incentive Components Effective incentive programs have 3 components, said Dr Driver. “They have to have appropriate magnitude, so there has to be enough money to matter; there has to be a proximity to

the desired behavior change, which is why we had people pay out the $20 they owed while they were still stand ing on the scale; and they have to have salience,” he said. “The most power ful of the 3 was probably the negative incentive. People tend to be motivated about 2.5 times more by losing money as they would by the prospect of gain ing the same amount of money.”

“We need to understand better what drives people and what works long-term.” —Vera A. Bittner, MD, MSPH Previous studies have shown that financial incentives are effective in empowering people to exercise and to lose weight over the short-term. This is the first study to examine the effects of a long-term incentive plan to help employees achieve sustained weight loss for 1 full year. “We need to understand better what drives people and what works long-term,” said Vera A. Bittner, MD, MSPH, Section Head of Preventive Cardiology, University of Alabama at Birmingham School of Medicine, who was not involved in the study. “The investigators should be commended for trying to get at the science…in stead of doing real-life experiments in the community.” n

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Health Economics

Costs of Diabetes-Related Complications Reduced with Canagliflozin Monotherapy By Mary Mosley Chicago, IL—Microvascular and mac rovascular complications in type 2 di abetes were shown to be reduced with canagliflozin (Invokana) 100 mg and 300 mg compared with lifestyle mea sures alone, according to Cheryl A. Neslusan, PhD, Global Strategic Mar keting and Market Access, Janssen Global Services, Raritan, NJ, and col leagues. They presented the results of their long-term economic model at the 2013 American Diabetes Association annual meeting. Dr Neslusan and colleagues noted that this is the first economic model to analyze the cost benefits for pa tients with type 2 diabetes with the use of canagliflozin that reflect the 2012 treatment patterns of microvas cular and macrovascular events in this setting, showing “sizable gains in life-years and QALYs [quality-ad justed life-years] and substantial cost offsets.” The data came from the phase 3 DIA3005 study of canagliflozin, the first-in-class sodium glucose cotrans porter (SGLT)-2 inhibitor that had re cently received US Food and Drug Administration approval for the treat ment of patients with type 2 diabetes in addition to diet and exercise.

In the DIA3005 study, the 100-mg dose of the SGLT-2 inhibitor reduced hemoglobin (Hb) A1c by 0.91% and by 1.16% with the 300-mg dose com pared with placebo. The 584 patients (aged 55 years) in that study had a baseline HbA1c of 8.01%.

treatment effects of canagliflozin in the DIA3005 study.

verage Costs of Diabetes Complications per Patient over 30 Years: Table A Canagliflozin vs Lifestyle Measures Canagliflozin Lifestyle Canagliflozin Lifestyle Complication 100 mg, $ measures only, $ 300 mg, $ measures only, $ Nephropathy

The cost offset per patient over 30 years was $3948 with canagliflozin 100 mg and $5428 with canagliflozin 300 mg. Economic Model Results In the economic model, the investi gators simulated the effect of the change in HbA1c, body weight, sys tolic blood pressure, and cholesterol on future clinical outcomes and costs. The well-validated Economic and Health Outcomes (ECHO)-T2DM model was used to compare treat ment with lifestyle measures alone versus canagliflozin 100 mg or cana gliflozin 300 mg in various scenarios over 30 years, including treatment intensification, and reflecting the

The costs for the known adverse events of urinary tract infections and

5306

6417

4818

6637

11,924

13,121

12,029

13,422

Stroke

5716

6449

5502

6522

Hypoglycemia

587

903

509

911

38,144

42,092

37,305

42,733

Myocardial infarction

Total costs

QALYs were increased by 0.17 with canagliflozin 100 mg and by 0.21 with canagliflozin 300 mg compared with lifestyle measures only. The investiga tors noted that this gain in QALYs is related in part to the improvement in weight with canagliflozin. The in crease in life-years was 0.12 for both doses of canagliflozin. The cost offset per patient over 30 years was $3948 with canagliflozin 100 mg and $5428 with canagliflozin 300 mg. The reductions in myocardial infarction (MI) and nephropathy were the biggest drivers of the cost offsets (Table).

female genital mycotic infections were $31 and $10 for canagliflozin 100 mg and canagliflozin 300 mg, respectively. The relative risk reductions for macrovascular complications—car diovascular disease composite, MI, heart disease, heart failure, stroke— ranged from 6.3% to 11.3% with cana gliflozin 100 mg, and from 4.9% to 15.4% with canagliflozin 300 mg. Retinopathy and nephropathy had relative risk reductions from 6.2% and 23.5% with canagliflozin 100 mg and 8.0% to 36.5% with canagliflozin 300 mg. n

Resource Utilization and Costs: Comparing Saxagliptin and Sitagliptin A lower trend seen with saxagliptin, with a few exceptions Chicago, IL—The first US-based study to compare healthcare resource utili zation and costs during the first 6 months after starting treatment with the dipeptidyl peptidase (DPP)-4 agent saxagliptin (Onglyza) or sita gliptin (Januvia) in patients with type 2 diabetes was reported at the 2013 American Diabetes Association annu al meeting by Jasmina I. Ivanova, Vice President, Analysis Group, New York. Results of the analysis showed lower costs for overall and diabe tes-related inpatient care, as well as emergency department visits with saxagliptin. These 2 DPP-4 agents are relatively new to the market. Patients taking saxagliptin were sig nificantly less likely to have an inpatient hospitalization compared with patients taking sitagliptin, overall (odds ratio [OR], 0.80) or related to diabetes (OR, 0.74; P <.001 for both, risk adjusted).

For this analysis, patients with a primary or secondary diagnosis of type 2 diabetes whose index treatment after 2009 was saxagliptin (N = 13,929) or sitagliptin (N = 36,813) were identi fied from the Truven MarketScan da tabase of privately insured members.

During the first 6 months of treatment with either of the 2 agents, overall medical costs per patient were $5073 with saxagliptin and $5535 with sitagliptin. Approximately 47% of the patients were women, and patients taking saxagliptin were slightly but signifi

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cantly younger (58 years vs 59 years with sitagliptin). The mean Charlson Comorbidity Index was lower in the patients receiving saxagliptin, but they had higher rates of dyslipidemia (44.8% vs 41.9% with sitagliptin) and hypertension (51.8% vs 49.8% with sitagliptin). Resource utilization was signifi cantly lower overall with saxagliptin, except for the lower rate of outpatient visits; it was also significantly lower for diabetes-related causes with sax agliptin, except for outpatient diabe tes-related visits. Although the use of other antidia betic drugs (as monotherapy or com binations) was higher with saxaglip tin, the use of sulfonylureas, insulin, and thiazolidinediones was lower. The patients receiving saxagliptin had higher rates of cardiometabolic risk factors, but they also had less evi

dence of acute comorbidities than the patients receiving sitagliptin; never theless, patients receiving saxagliptin were less likely to be hospitalized. Healthcare Costs Healthcare costs were based on third-party payer reimbursements and were adjusted to 2011 US dollars for the first 6 months of treatment with either of the 2 agents. All calcula tions were based on intention to treat. During the first 6 months of treat ment, the costs per patient were: • Overall total costs, $7802 with saxagliptin versus $8302 with sitagliptin • Overall medical costs, $5073 versus $5535, respectively • Diabetes-related medical costs, $1149 versus $1387, respectively • Total diabetes-related costs, $2510 versus $2772, respectively.—MM n

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Health Economics

Substantial Costs for Diabetes Are Consumed by the Diabetic Foot and Arthritis By Mary Mosley Chicago, IL—Diabetes foot infection comprised 2.5 million (3.8%) of the 66.1 million diabetes-related inpatient visits that occurred between 2001 and 2010 in the United States, according to data presented at the 2013 American Diabetes Association annual meeting. The Economic Burden of the Diabetic Foot The cost associated with the diabet ic foot was $113 billion (2012 US dol lars; mean, $11.3 billion annually). The data were compiled from dis charge records from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Proj ect, and were presented by Grant H. Skrepnek, PhD, RPh, Assistant Pro fessor, University of Arizona College of Pharmacy, Tucson, AZ. Of the 66.1 million diabetes-related inpatient visits between 2001 and 2010, 2.5 million involved patients with diabetic foot infections. The aver age cost for a patient with a diabetic foot was $46,107 per case. The prima ry payers included Medicare, for 63% of the patients; Medicaid, for 11% of the patients; and private insurance for 19%. Inpatient mortality occurred in 2.3% of the patients, sepsis in 8%, and surgical complications in 11%. Of note, from 2006 to 2010, diabetic foot was the cause of 1 million cases presenting to the emergency depart

ment in the United States, approxi mately 1.9% of the total diabetes cases, at a cost of $1.2 billion. When the cost of inpatient charges was included for the 81.2% of emergency department visits for patients who were subse quently admitted, the costs increased by $41.5 billion.

“The inpatient burden of diabetic foot disease is substantial in terms of morbidity, mortality, and costs. Increased outpatient prevention and management may ultimately lessen the clinical and economic impact of this condition.” —Grant H. Skrepnek, PhD, RPh, and colleagues

Loss of Preventive Services for Diabetic Foot Costs Money Inpatient medical costs for the care of the diabetic foot were increased by $44 for every $1 that was not spent on preventive services, according to this retrospective analysis by Dr Skrepnek and colleagues, who investigated the impact of the cancellation of reim

bursement coverage for podiatric physicians for Medicaid beneficia ries, as part of healthcare cost-con tainment legislation that took effect in 2010 in Arizona. During the index period from 2006 to 2010, the total cost for the 4663 in patient cases of diabetic foot was $234 million (2010 US dollars). The mean length of stay was 7.1 days, and the mean charges were $50,096 ± $56,888. The increased inpatient medical costs after 2010 resulted from a 37.5% increase in diabetic foot admissions, with a 45% increased cost in medical charges. The length of stay was in creased by 29%, and the severe aggre gated outcomes (ie, mortality, ampu tation, sepsis, surgical complications) increased from 30% before the 2010 change in reimbursement to 50% after. “The inpatient burden of diabetic foot disease is substantial in terms of morbidity, mortality, and costs. In creased outpatient prevention and management may ultimately lessen the clinical and economic impact of this condition,” the investigators concluded. Arthritis Adds Significant Economic Toll to Diabetes Care A second analysis of the economic burden of arthritis in patients with diabetes was presented at the meet ing by Rui Li, PhD, of the Division of

Diabetes Translation, Centers for Dis ease Control and Prevention, Atlanta, GA. Approximately 50% of adults with diabetes have arthritis, but the associated costs have not been well studied before. Using data from the 2009 and 2010 Medical Expenditure Panel Survey, Dr Li and his team found that the treat ment of arthritis accounted for 16% of the total medical costs in patients with diabetes. The mean costs were greater for patients who had diabetes and ar thritis than for patients who “only” had diabetes and no arthritis. The following costs reflected the annual increase in costs per patient with diabetes who also had arthritis compared with a patient with diabe tes alone: • The total medical costs were $2897 higher (ie, 23% more) • Inpatient care was $620 higher (17% more) • Outpatient care was $1025 higher (43% more) • Prescription drug costs were $849 higher (32% more). The investigators recommended that diabetes control programs in clude components to address arthri tis, including physical activity and chronic disease self-management edu cation courses, which are evidencebased strategies to improve arthritis and diabetes. n

Specialized Team Approach and Education Improve Care, Save Money in Diabetes Chicago, IL—A “team of 4” approach to achieve the “ABC goals”—hemo globin (Hb) A1c <7%, blood pressure <130/80 mm Hg, and low-density li poprotein cholesterol <100 mg/dL— and to reduce cardiovascular disease (CVD) risk provides significant costsavings in managed care, according to an outcomes evaluation presented by Swarna S. Varma, MD, of Pitts burgh Endocrine and Diabetes Asso ciates, Bridgeville, PA, at the 2013 American Diabetes Association annu al meeting. The team care approach entails the involvement and account ability of the physician, staff, patient, and family. The incremental cost per patient

“Early comprehensive diabetes education, early endocrine consultation, appropriate transition of care, and compliance can lead to the costs that you really want.” —Vivek Bansal, MD, MPH

was $180 to achieve the ABC goals and $480 to reduce CVD risk com pared with standard of care, based on

National Health and Nutrition Exam ination Survey population statistics for patients with diabetes. All costs are in 2012 US dollars. Over a 10-year period (2000-2009), this led to a cost avoidance of $9,044,500 for the ABC goal attainment and $24,043,500 for CVD risk reduction in a 50,000-person managed care system. At the practice level, the cost avoidanc es were $71,451 and $189,943, respec tively, for 395 patients. A total of 22% of patients in the team care approach in the communi ty-based practice attained the ABC goals compared with only 7% of pa tients receiving standard of care, whereas CVD was projected in only

18% of the patients under the team care and in 24% of the patients receiv ing standard of care. Specialized Diabetes Team Reduces Hospital Costs Hospital care accounts for 43% of the $176 billion spent annually on dia betes care in the United States, driving the need for improved in-hospital re source utilization. A double-blind, retrospective study conducted at a tertiary academic medical center showed that care pro vided by a specialized diabetes team reduced overall costs compared with a usual primary service team in non critical care units in patients with Continued on page 18

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Health Economics

Future of Healthcare Reform: Expect New Payment and Delivery Models By Wayne Kuznar San Francisco, CA—Reform to the healthcare system did not end with passage of the Affordable Care Act. The rise in healthcare costs may force capitated payments, integrated-care payment methods, and alternate forms of care delivery, according to presenters in a session on healthcare reform at the 2013 American College of Cardiology (ACC) meeting. Costs and Reimbursement Concerns Cost versus quality, progressive in tegration of medicine, and increased measurement of outcomes should be 3 areas of focus in the healthcare re form, suggested R. Scott Wright, MD, Professor of Medicine, Mayo Clinic College of Medicine, Rochester. “Medicare should stop paying for treatments that offer no benefit or offer harm, and it should only pay for things that work and are optimal,” Dr Wright said. Progressive integration of medicine can help eliminate duplication of ser vices to increase value, according to Dr Wright. Expect more providers in any area of medicine to be employed by hospitals in the coming years, as well as more integration of healthcare delivery through contracts with ac countable care organizations, he said. Value-Based Payment Models Inaccurate attribution is one of the

problems with using claims-only data to measure value, said Thomas J. Lewandowski, MD, president of the

care and reward value rather than vol ume, said Dr Lewandowski. The Quality and Resource Use Re

“Medicare should stop paying for treatments that offer no benefit or offer harm, and it should only pay for things that work and are optimal.” —R. Scott Wright, MD

Wisconsin chapter of the ACC and a cardiologist at Appleton Cardiology, ThedaCare, WI. The lack of informa tion in coding and billing prevents using these data sets to detect any dif ferences in clinical outcomes between providers. Medicare is taking quality metrics and outcomes into consideration in promoting a value-based purchasing model in which penalties or bonuses are awarded based on performance. In 9 states, the Centers for Medicare & Medicaid Services is disseminating Quality and Resource Use Reports to Medicare physicians paid on a fee-forservice basis in an effort to improve

ports provide information to provid ers on the clinical care and costs to Medicare beneficiaries of other phy sicians as a comparison. The reports show the various types of services (eg, inpatient hospital stays, outpa tient visits) used by Medicare benefi ciaries whose care the physician di rected. As part of these reports, risk-adjusted per-capita costs are cal culated. The value modifier will be applied to some physicians starting in 2015. Attribution remains a problem with the Quality and Resource Use Re ports, Dr Lewandowski said. “Fifty percent of the imaging studies in my

state are ordered by the primary care community. Those studies are at tributed to me, because I’m the one who billed for them. Rather than em powering me to make a change, it is more likely to make me walk away from the process.” Bundling payments involves a new payment model that could cover an entire episode of care or be broken into smaller bundles. The hope is that

“Fifty percent of the imaging studies in my state are ordered by the primary care community. Those studies are attributed to me, because I’m the one who billed for them. Rather than empowering me to make a change, it is more likely to make me walk away from the process.” —Thomas J. Lewandowski, MD this model could help eliminate un necessary procedures, reduce admin istrative burdens related to prior au thorization of individual services, and result in better coordinated care across the many clinical sources and sites. n

Specialized Team Approach and Education Improve Care... diabetes. The specialized team was comprised an of endocrinologist and a diabetes educator. Vivek Bansal, MD, MPH, Hospital ist, Beth Israel Deaconess Medical Center, Boston, MA, said that the re duction in 30-day hospital readmis sions translated to a postulated cost-savings of $3,570,480 for 15,094 admissions in 2011 and $2,975,400 for 12,514 admissions in 2012, using na tional average costs. The rates of 30day readmissions were 1.3 for the primary service team versus 1.1 for the specialized team (P = .107). The total hospital costs for these patients were $60,878,250 with the primary service team and $57,307,770 with the diabetes team in 2011, and $50,480,010 and $47,504,610, re

spectively, in 2012. “Early comprehensive diabetes ed ucation, early endocrine consultation, appropriate transition of care, and compliance can lead to the costs that you really want,” said Dr Bansal. Strikingly, Dr Bansal said, the spe cialist team took care of more complex patients (ie, more type 1 diabetes, higher baseline HbA1c, more insulin therapy), which led to cost-savings. The greatest cost-savings was in the medical patients, because of longer hospitalization and a higher rate of readmission for surgical patients. Informal Counseling by Endocrinologists Improves Reaching Goals One-on-one informal counseling

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by an endocrinologist improved dia betes care provided by clinicians in affiliated Joslin Diabetes Centers. Using the newly devised Joslin Clini cal Analytical Tool as a quality mea sure for achieving goals that have been adjusted based on disease se verity, clinicians were provided their metrics and national benchmarks. The providers who also received the counseling had significantly higher rates (13%) of achieving the HbA1c targets set for 5 medication groups compared with 4% without counseling. Group 0 received no medications, Group 1 received 1 medication, Group 2 received 2 med ications; Group 3 received 3 oral medications or basal insulin or a glu cagon-like peptide-1 agonist, and

Continued from page 17

Group 4 included pumps or basal/ bolus combinations. In Group 4, the most complex pa tients, fewer patients with type 2 dia betes achieved an HbA1c <8.5% than patients with type 1 diabetes. It was “a surprise that the patients with type 2 DM [diabetes mellitus] do not do as well with their A1c. Most of the improvement came through the T2DM [type 2 diabetes mellitus] pa tients, through whatever means this was assessed,” said Richard A. Jack son, MD, Director, Hood Center for Prevention of Childhood Diabetes, Joslin Medical Center, Boston. This was also the group that had the greatest improvements in reaching targets, from 46% before counseling to 69% after counseling.—MM n

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Drug Update

Nesina, Kazano, and Oseni: Three Alogliptin-Based Agents Approved for the Treatment of Type 2 Diabetes By Loretta Fala, Medical Writer

iabetes affects an estimated 25.8 million people in the United States—a staggering 8.3% of the population.1 Type 2 diabe tes accounts for 90% to 95% of all adult cases of diabetes.1 In addition, an estimated 35% of US adults aged ≥20 years have prediabetes, and the prevalence of prediabetes jumps to 50% in adults aged ≥65 years.1 The number of people with diabe tes is projected to rise dramatically over the next few decades, from ap proximately 1 in 10 adults today to as many as 1 in 3 by 2050.2 This increased prevalence is attributed to the aging population, the increasing number of high-risk groups, and a longer life ex pectancy for patients with diabetes.2 In addition to being the 7th lead ing cause of mortality in the United States, diabetes is associated with serious morbidities, including cardio vascular disease, stroke, and nervous system damage.1 It is also the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness in adults.1 Economic Burden In 2012, diabetes accounted for an estimated $245 billion in total costs in the United States, including $176 bil lion in direct medical costs and $69 billion in indirect costs (ie, disability and lost or reduced productivity).3 Hospital inpatient care accounted for the largest portion (43%) of the total medical expenses. Patients with diag nosed diabetes incurred an average of $13,700 annually in medical expendi tures, of which $7900 was attributed directly to diabetes.3 Overall, medical expenditures for patients with diabetes are 2.3 times higher than expenditures for persons without diabetes, with more than 1 in 5 healthcare dollars in the United States attributed to diabetes.3 Health care costs are expected to increase as the prevalence of diabetes rises in subsequent years. By the year 2034, the annual costs attributed to diabetes are projected to reach $336 billion (in 2007 dollars).4 Glycemic Control Improvements in glycemic control have been shown to benefit patients with diabetes.5 In fact, every 1% re duction in hemoglobin (Hb) A1c is correlated with a 35% decrease in microvascular complications associ ated with diabetes.5 A 1% reduction in HbA1c is also linked to a 15% rela

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tive risk reduction in nonfatal myo cardial infarction, although this bene fit does not extend to stroke or to all-cause mortality.6 In a 2012 position statement, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) reinforced the importance of a pa tient-centered approach to managing hyperglycemia in type 2 diabetes.6 The ADA and EASD also emphasize the role of diet, exercise, and educa tion as the hallmarks of type 2 diabe tes treatment. Other recommenda tions include tailoring glycemic targets and glucose therapies to the individual patient and engaging pa tients in healthcare decisions—an ap proach that may improve adherence to treatment.6 For initial treatment of patients with type 2 diabetes, the ADA and EASD recommend lifestyle changes (ie, healthy eating, weight control, in creased physical activity) and met formin monotherapy.6 If the target A1c goal is not achieved within 3 months, a 2-drug combination therapy with metformin plus one of the following agents is recommended: a sulfonyl urea, a thiazolidinedione, a dipeptidyl peptidase (DPP)-4 inhibitor, a gluca gon-like peptide (GLP)-1 receptor ago nist, or insulin (usually basal).6 If an individualized A1c target is not achieved after 3 months, a 3-drug combination is recommended; and if the target A1c is not achieved after 3 to 6 months, a more complex insulin strategy is warranted, usually in com bination with 1 or 2 noninsulin agents.6 Three New Agents Approved for Patients with Type 2 Diabetes On January 25, 2013, the US Food and Drug Administration (FDA) ap proved 3 new oral agents for use with diet and exercise to improve glycemic control in adults with type 2 diabetes— Nesina (alogliptin), Kazano (alogliptin/ metformin hydrochloride), and Oseni (alogliptin/pioglitazone).7 (Metformin and pioglitazone have been previously approved by the FDA for the manage ment of type 2 diabetes.) These 3 new agents are distributed by Takeda Phar maceuticals. All 3 agents contain the new DPP-4 inhibitor alogliptin, and none of them is indicated for the treatment of patients with type 1 dia betes or with diabetic ketoacidosis.8-10 Nesina is the single alogliptin agent; Kazano is a fixed-dose combi nation of alogliptin and metformin, a

Table 1 Alogliptin versus Placebo: Glycemic Parameters at Week 26 Alogliptin 25-mg Glycemic parameters cohort Placebo cohort (N = 128) (N = 63) A1c, % Mean baseline A1c

7.9

Change from baseline (adjusted mean )

8.0

–0.6

Difference from placebo (adjusted mean with 95% confidence interval)

–0.6 (–0.8 to –0.3)

—

(N = 129)

(N = 64)

172

173

–16

–28 (–40 to –15)

—

% of patients who achieved A1c ≤7% Fasting plasma glucose, mg/dL Mean baseline Change from baseline (adjusted mean ) a

Difference from placebo (adjusted mean with 95% confidence interval)

Least squares means adjusted for treatment, baseline value, geographic region, and disease duration. b P <.01 versus placebo. Source: Nesina (alogliptin) tablets prescribing information; 2013. a

dverse Reactions in ≥4% of Patients Receiving Alogliptin 25 mg and Table 2 A More Often than in Patients Receiving Placebo Alogliptin Placebo, Active comparator, 25 mg, N (%) N (%) N (%) Adverse reactions (N = 5902) (N = 2926) (N = 2257) Nasopharyngitis

257 (4.4)

89 (3.0)

113 (5.0)

Headache

247 (4.2)

72 (2.5)

121 (5.4)

Upper respiratory tract infection

247 (4.2)

61 (2.1)

113 (5.0)

Source: Nesina (alogliptin) tablets prescribing information; 2013.

biguanide; and Oseni is a fixed-dose combination of alogliptin and pioglit azone, a thiazolidinedione.7 According to Mary Parks, MD, Di rector of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, “Controlling blood sugar levels is very important in the overall treatment and care of diabe tes. Alogliptin helps stimulate the re lease of insulin after a meal, which leads to better blood sugar control.”7 Nesina (alogliptin)

Dosing Alogliptin (Nesina) is an oral tablet available in 3 strengths—25 mg, 12.5 mg, and 6.25 mg. The recommended dose for patients with normal renal function or with mild renal impairment is 25 mg once daily. Alogliptin can be taken with or without food. If the pa tient has moderate or severe renal im pairment, the dose should be adjusted.9 Mechanism of Action Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones GLP-1 and glucose-depen

dent insulinotropic polypeptide, there by increasing their bloodstream con centrations in a glucose-dependent manner in patients with type 2 dia betes. Alogliptin selectively binds to and inhibits DPP-4 (but not DPP-8 or DPP-9) activity in vitro at concen trations approximating therapeutic exposures.9

Clinical Studies The FDA approval of alogliptin as monotherapy (Nesina) was based on safety and efficacy data from 14 clini cal studies with approximately 8500 patients with type 2 diabetes.7 With its approval, the FDA required 5 post marketing studies for alogliptin—1 a cardiovascular outcomes trial; 2 en hanced pharmacovigilance programs to monitor liver abnormalities, serious cases of pancreatitis, and severe hyper sensitivity reactions; and 2 pediatric safety and efficacy studies under the Pediatric Research Equity Act.7 The safety and efficacy of alogliptin as monotherapy were evaluated in a 26-week, double-blind, placebo-con trolled study in patients with type 2 diabetes inadequately controlled with

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Drug Update Nesina, Kazano, and Oseni: Three Alogliptin-Based Agents... diet and exercise. Treatment with alogliptin 25 mg demonstrated statis tically significant improvements from baseline in A1c and fasting plasma glucose compared with placebo at week 26 (Table 1).9

Adverse Events The most common adverse reac tions reported in ≥4% of patients re ceiving alogliptin 25 mg and were more frequent than in the placebo arm are nasopharyngitis, headache, and upper respiratory tract infection (Table 2).9 In clinical trials that compared alogliptin and placebo, adverse events included acute pancreatitis (0.2% vs <0.1%, respectively), hyper sensitivity (0.6% vs 0.8%, respective ly), and hypoglycemia (1.5% vs 1.6%, respectively). Table 3 outlines the warnings and precautions associated with the use of alogliptin based on clinical trials, as well as postmarketing studies. Contraindications Alogliptin is contraindicated in patients with a history of a serious hypersensitivity reaction to alogliptin- containing products, including ana phylaxis, angioedema, or severe cuta neous adverse reactions. Alogliptin is not associated with a boxed warning. Kazano (alogliptin/metformin) Dosing Alogliptin/metformin (Kazano) is an oral tablet available in 2 strengths— alogliptin 12.5 mg/metformin 500 mg, and alogliptin 12.5 mg/met formin 1000 mg. The starting dose of alogliptin/ metformin is individualized based on the patient’s current regimen. Alo gliptin/metformin is taken twice daily with food. Dosing may be adjusted based on effectiveness and tolerabili ty, without exceeding the maximum recommended daily dose of alogliptin 25 mg/metformin 2000 mg.8

Mechanism of Action The combination of alogliptin and metformin hydrochloride—2 antihy perglycemic agents with complemen tary and distinct mechanisms of ac tion—improves glycemic control in patients with type 2 diabetes.8 The alogliptin mechanism of ac tion was discussed earlier in this arti cle (see page 19). Metformin is a biguanide that im proves glucose tolerance in patients with type 2 diabetes, lowering basal and postprandial plasma glucose. Metformin decreases hepatic glucose

Continued from page 19

Table 3 Warnings and Precautions: Alogliptin Alone, Alogliptin/Metformin, and Alogliptin/Pioglitazone Alogliptin

Alogliptin/ metformin

Alogliptin/ pioglitazone

√

Serious hypersensitivity reactions have been reported postmarketing, including anaphylaxis, angioedema, and severe cutaneous adverse reactions: in such cases, promptly discontinue treatment with agents noted, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative antidiabetes therapies Hepatic effects Hepatic failure cases, sometimes fatal, have been reported postmarketing; causality cannot be excluded If liver injury is detected, promptly interrupt treatment with these agents and assess patient for probable cause, then treat the cause, if possible, to resolution or to stabilization Do not restart agents noted if liver injury is confirmed and no alternative etiology can be found Hypoglycemia

√

When used with an insulin secretagogue (eg, sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to mimimize the risk of hypoglycemia when used in combination with any of these 3 agents Macrovascular outcomes

√

No clinical studies have established conclusive evidence of macrovascular risk reduction with any of these 3 agents or with any other antidiabetic drug

√

Warnings and precautions Acute pancreatitis Acute pancreatitis cases have been reported postmarketing If pancreatitis is suspected, promptly discontinue treatment Hypersensitivity

Additional warnings and precautions for alogliptin/metformin Lactic acidosis Patients should be warned against excessive alcohol intake Alogliptin/metformin is not recommended in patients with hepatic impairment Alogliptin/metformin is contraindicated in renal impairment Vitamin B12 deficiency

√

Metformin may lower vitamin B12 levels Monitor hematologic parameters annually Radiologic studies

√

Alogliptin/metformin should be temporarily discontinued in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids

√

Additional warnings for alogliptin/pioglitazone Congestive heart failure Fluid retention may occur and can exacerbate or lead to congestive heart failure Combination use with insulin and use in patients with NYHA stage I or II congestive heart failure may increase risk Monitor patients for signs and symptoms of congestive heart failure Edema

√

Dose-related edema may occur Fractures Increased incidence of fractures in female patients has been reported Current standards of care for assessing and maintaining bone health should be applied Bladder cancer

√

Preclinical and clinical trial data, and results from an observational study suggest an increased risk of bladder cancer in pioglitazone users The observational data further suggest an increased risk with duration of use Alogliptin/pioglitazone should not be used in patients with active bladder cancer, and used with caution in patients with a history of bladder cancer Macular edema

√

Macular edema has been reported in some patients taking pioglitazone Regular eye exams are recommended, with prompt evaluation for acute visual changes Ovulation

√

Therapy with pioglitazone, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women

√

NYHA indicates New York Heart Association. Sources: Nesina (alogliptin) tablets prescribing information. 2013; Kazano (alogliptin and metformin) tablets prescribing information; 2013; Oseni (alogliptin and pioglitazone) tablets prescribing information; 2013.

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Drug Update production, decreases intestinal ab sorption of glucose, and improves in sulin sensitivity by increasing periph eral glucose uptake and utilization. Metformin does not produce hypo glycemia in patients with type 2 dia betes or in healthy persons, except in special circumstances, and does not cause hyperinsulinemia. With met formin therapy, insulin secretion re mains unchanged and fasting insulin levels and day-long plasma insulin response may actually decrease.8

Clinical Studies The FDA approval of alogliptin/ metformin was based on 4 clinical studies in more than 2500 patients with type 2 diabetes.7 The FDA re quired that 2 postmarketing studies be conducted with alogliptin/met formin to monitor for liver abnormal ities, serious cases of pancreatitis, and severe hypersensitivity reactions through an enhanced pharmacovigi lance program. A pediatric safety and efficacy study under the Pediatric Research Equity Act was also re quired by the FDA.7 Type 2 diabetes inadequately controlled with diet and exercise. A 26week, double-blind, placebo-controlled study assessed the safety and efficacy of alogliptin/metformin coadministra tion in patients whose type 2 diabetes was inadequately controlled with diet and exercise alone. A total of 784 pa tients (mean baseline A1c, 8.4%) were randomized to 1 of 7 treatment groups. Significant improvements in A1c levels were demonstrated in the 2 com bination treatment arms—alogliptin 12.5 mg/metformin 500 mg, and alogliptin 12.5 mg/metformin 1000 mg compared with the respective individ ual component regimens of alogliptin alone and metformin alone (Table 4). Significant improvements in fast ing plasma glucose were also demon strated in the 2 treatment arms of alogliptin/metformin versus the re spective individual component regi mens of each drug alone (Table 4).8 Type 2 diabetes inadequately controlled with metformin alone. In a 26-week, double-blind, placebo-con trolled study, 527 patients already receiving metformin (mean baseline A1c 8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily. During the treatment period, patients continued to use a stable dose of metformin (median daily dose, 1700 mg). Alogliptin 25 mg in combination with metformin showed statistically significant improvements from base line in A1c and fasting plasma glucose levels at week 26 compared with pla cebo (Table 5).8 VOL. 6

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Table 4 Glycemic Parameters: Alogliptin, Metformin, and Alogliptin/Metformin Combination, at Week 26 Alogliptin/metformin Metformin Alogliptin Alogliptin 12.5 mg/ Alogliptin 12.5 mg/ 12.5 mg 500 mg 1000 mg metformin 500 mg metformin 1000 mg Glycemic parameters Placebo twice daily twice daily twice daily twice daily twice daily (N = 102) (N = 104) (N = 103) (N = 108) (N = 102) (N = 111) A1c, %a Mean baseline A1c

8.5

8.4

8.5

8.4

8.5

8.4

Change from baseline (adjusted meanb)

0.1

–0.6

–0.7

–1.1

–1.2

–1.6

Difference from metformin (adjusted meanb with 95% CI)

—

–0.6c (–0.9 to –0.3)

–0.4c (–0.7 to –0.2)

Difference from alogliptin (adjusted meanb with 95% CI)

—

–0.7c (–1.0 to –0.4)

–1.0c (–1.3 to –0.7)

% of patients who achieved A1c ≤7%d

47c

59c

(N = 106)

(N = 110)

(N = 106)

(N = 112)

Fasting plasma glucose, g/dLa (N = 105) (N = 106) Mean baseline

187

177

180

181

176

185

Change from baseline (adjusted meanb)

–10

–12

–32

–46

Difference from metformin (adjusted meanb with 95% CI)

—

–20c (–33 to –8)

–14c (–26 to –2)

Difference from alogliptin (adjusted meanb with 95% CI)

—

–22c (–35 to –10)

–36c (–49 to –24)

Intent-to-treat population using the last observation on study before discontinuation of double-blind study medication or sulfonylurea rescue therapy for patients needing rescue. b Least squares means adjusted for treatment, geographic region, and baseline value. c P <.05 compared with metformin and alogliptin alone. d Compared using logistic regression. CI indicates confidence interval. Source: Kazano (alogliptin and metformin) tablets prescribing information; 2013. a

Type 2 diabetes inadequately controlled with metformin plus pioglitazone. A 52-week study with 803 patients showed that alogliptin 25 mg, in combination with pioglitazone and metformin, was statistically su perior in lowering A1c and fasting plasma glucose levels compared with the titration of pioglitazone from 30 mg to 45 mg at week 26 and at week 52 in patients whose disease was in adequately controlled with pioglita zone 30 mg and metformin.8

Table 5 Glycemic Parameters at Week 26: Alogliptin as Add-on to Metformin Alogliptin 25 mg + Placebo + Glycemic parameters metformin metformin (N = 203) (N = 103) A1c, %

Adverse Reactions The most common adverse reac tions reported in clinical trials in ≥4% of patients using alogliptin/met formin were upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, back pain, and urinary tract infection.8 Table 3 lists the warnings and pre cautions associated with alogliptin/ metformin, based on clinical studies, as well as in postmarketing studies.

Fasting plasma glucose, mg/dL

Boxed Warning Alogliptin/metformin was ap proved with a boxed warning about lactic acidosis, a rare but serious com plication that can occur from met formin accumulation. The risk in creases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impair

Mean baseline A1c

7.9

Change from baseline (adjusted meana)

8.0

–0.6

–0.1

–0.5 (–0.7 to –0.3)

—

Difference from placebo (adjusted meana with 95% confidence interval)

—

% of patients who achieved A1c ≤7%b

44b

(N = 204)

(N = 104)

172

180

–17

–17 (–26 to –9)

—

Difference from metformin (adjusted meana with 95% confidence interval)

Mean baseline Change from baseline (adjusted mean ) a

Difference from placebo (adjusted mean with 95% confidence interval)

Least squares means adjusted for treatment, baseline value, geographic region, and baseline metformin dose. b P <.001 compared with placebo. Source: Kazano (alogliptin and metformin) tablets prescribing information; 2013. a

ment, and acute congestive heart fail ure. If acidosis is suspected, alogliptin/metformin should be dis continued and the patient should be hospitalized immediately.

Contraindications Alogliptin/metformin is contrain dicated in patients with renal impair ment; normal renal function should be verified before initiating treatment with this medication, and at least an

nually thereafter. The use of alogliptin/metformin is also contraindicated in patients with metabolic acidosis, including diabetic ketoacidosis. In addition, alogliptin/metformin is contraindicated in patients with a his tory of a serious hypersensitivity reac tion to alogliptin or to metformin (the components of alogliptin/metformin), such as anaphylaxis, angioedema, or severe cutaneous adverse reactions.

august 2013

Continued on page 22

www.AHDBonline.com

Drug Update Nesina, Kazano, and Oseni: Three Alogliptin-Based Agents... lycemic Parameters at Week 26: Alogliptin and Pioglitazone Table 6 G Coadministration Alogliptin Pioglitazone Alogliptin 25 mg + Glycemic parameters 25 mg 30 mg pioglitazone 30 mg (N = 160) (N = 153) (N = 158) A1c, % Mean baseline A1c

8.8

Change from baseline (adjusted meana)

–1

–1.2

–1.7

Difference from alogliptin 25 mg (adjusted meana with 95% CI)

–0.8b (–1 to –0.5)

Difference from pioglitazone 30 mg (adjusted meana with 95% CI)

–0.6b (–0.8 to –0.3)

% of patients who achieved A1c ≤7%

63b

(N = 162)

(N = 157)

(N = 162)

Mean baseline

189

185

Change from baseline (adjusted meana)

–26

–37

–50

Fasting plasma glucose, mg/dL

Difference from alogliptin 25 mg (adjusted meana with 95% CI)

–25b (–34 to –15)

Difference from pioglitazone 30 mg (adjusted meana with 95% CI)

–13b (–22 to –4)

Least squares means adjusted for treatment, geographic region, and baseline value. P <.01 compared with alogliptin 25 mg or pioglitazone 30 mg. CI indicates confidence interval. Source: Oseni (alogliptin and pioglitazone) tablets prescribing information; 2013. a

Oseni (alogliptin/pioglitazone)

Dosing Alogliptin/pioglitazone (Oseni) is an oral tablet available in several strengths: alogliptin 25 mg/pioglita zone 15 mg, alogliptin 25 mg/pioglit azone 30 mg, alogliptin 25 mg/pio glitazone 45 mg, alogliptin 12.5 mg/ pioglitazone 15 mg, alogliptin 12.5 mg/ pioglitazone 30 mg, and alogliptin 12.5 mg/pioglitazone 45 mg. The starting dose of alogliptin/pi oglitazone should be individualized based on the patient’s current regi men and concurrent medical condi tion but should not exceed a daily dose of alogliptin 25 mg and pioglita zone 45 mg. Alogliptin/pioglitazone can be taken with or without food. In patients with New York Heart Association (NYHA) class I or II heart failure, the initial dose of pioglitazone should be limited to 15 mg once daily. In patients with moderate renal impairment, the dose of alogliptin/ pioglitazone should be adjusted. Alogliptin/pioglitazone is not recom mended for patients with severe renal impairment or with end-stage renal disease that requires dialysis. In patients taking strong cytochrome (CY)P2C8 inhibitors (eg, gemfibrozil), the maximum recommended dose of pioglitazone is 15 mg once daily.10 Mechanism of Action The combination of 2 antihyper glycemic agents—alogliptin and pi

oglitazone—with 2 complementary and distinct mechanisms of action improves glycemic control in patients with type 2 diabetes.10 The alogliptin mechanism of action was discussed earlier (see page 19). Pioglitazone, a thiazolidinedione, is an agonist for peroxisome prolifer ator-activated receptor-gamma; acti vation of these nuclear receptors modulates the transcription of a num ber of insulin-responsive genes in volved in the control of glucose and lipid metabolism.10

Clinical Studies The FDA approval of alogliptin/ pioglitazone (Oseni) was based on 4 clinical studies in more than 1500 pa tients with type 2 diabetes.7 The FDA required an enhanced pharmacovigi lance program for alogliptin/pioglit azone to monitor for liver abnormali ties, serious cases of pancreatitis, and severe hypersensitivity reactions.7 Type 2 diabetes inadequately controlled with diet and exercise. Based on a 26-week, double-blind, active-con trolled study of 655 patients whose disease was inadequately controlled with diet and exercise alone, the coad ministration of alogliptin 25 mg with pioglitazone 30 mg showed a signifi cant improvement from baseline in A1c and fasting plasma glucose compared with alogliptin 25 mg alone or with pi oglitazone 30 mg alone (Table 6).10 Type 2 diabetes inadequately

American health & drug benefits

controlled with metformin alone. In a 26-week, double-blind, placebo-con trolled study, 1554 patients already receiving metformin (mean baseline A1c, 8.5%) were randomized to 1 of 12 groups—placebo; alogliptin alone (12.5 mg or 25 mg); pioglitazone alone (15 mg, 30 mg, or 45 mg); or alogliptin (12.5 mg or 25 mg) in combination with 15 mg, 30 mg, or 45 mg of pio glitazone. During the treatment peri od, patients continued to take a sta ble dose of metformin (median daily dose, 1700 mg). When added to metformin, the co administration of alogliptin and pio glitazone showed significant improve ments from baseline in A1c and fasting plasma glucose levels at week 26 com pared with placebo, with alogliptin alone, or with pioglitazone alone.10 Type 2 diabetes inadequately controlled with metformin plus pioglitazone. In a 52-week study of 803 patients, adding alogliptin 25 mg to pioglitazone used in combination with metformin was statistically su perior in lowering A1c and fasting plasma glucose levels compared with the titration of pioglitazone from 30 mg to 45 mg at weeks 26 and 52 in patients whose disease was inade quately controlled with pioglitazone 30 mg plus metformin.10

Adverse Events The most common adverse reac tions reported in ≥4% of patients receiving coadministration of alo gliptin 25 mg and pioglitazone 15 mg, 30 mg, or 45 mg in clinical trials were nasopharyngitis, back pain, and up per respiratory tract infection.10 Table 3 provides additional safety information, including the warnings and precautions associated with the use of alogliptin/pioglitazone, based on clinical trials, and in postmarket ing studies. Boxed Warning Alogliptin/pioglitazone was ap proved with a boxed warning, stating that thiazolidinediones, including pi oglitazone, cause or exacerbate con gestive heart failure in some patients. In addition, alogliptin/pioglitazone should be used with caution in pa tients with liver disease. Contraindications Alogliptin/pioglitazone is contra indicated in patients with a serious hypersensitivity reaction to alogliptin or pioglitazone, such as anaphylaxis, angioedema, or severe cutaneous ad verse reactions. Alogliptin/pioglitazone is also con

Continued from page 21

traindicated in patients with established NYHA class III or IV heart failure. Conclusion Three new oral treatment options for type 2 diabetes became available on January 25, 2013, with the FDA ap proval of alogliptin alone, alogliptin in combination with metformin, and alogliptin in combination with pio glitazone. These 3 independent agents are indicated as adjuncts to diet and exercise to improve glycemic control in patients with type 2 diabetes. They are not indicated for use in patients with type 1 diabetes or with diabetic ketoac idosis. Each of these 3 medications has unique benefits and potential adverse events and contraindications, based on the individual components of the spe cific medication. All 3 agents contain alogliptin, a novel DPP-4 inhibitor, with a positive safety profile. Of these new agents, the novel fixed-dose combination of alogliptin plus pioglitazone is the first treatment option in the United States to include a DPP-4 inhibitor and a thiazo lidinedione in a single tablet,11 provid ing patients with type 2 diabetes a new approach to glycemic control. In clinical studies that evaluated the efficacy of alogliptin alone, alogliptin/metformin combination, and alogliptin/pioglitazone combina tion plus other type 2 diabetes treat ments, all 3 agents demonstrated clin ically meaningful and significant improvements in patients’ HbA1c lev els versus comparators in patients with type 2 diabetes. n References

1. Centers for Disease Control and Prevention. Nation al diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. 2011. www.cdc.gov/diabetes/pubs/pdf/ ndfs_2011.pdf. Accessed April 15, 2013. 2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US population: dynamic modeling of incidence, mortality, and predia betes prevalence. Popul Health Metr. 2010;8:29. 3. American Diabetes Association. Economic costs of dia betes in the US in 2012. Diabetes Care. 2013;36:1033-1046. 4. Huang ES, Basu A, O’Grady M, Capretta JC. Projecting the future diabetes population size and related costs for the US. Diabetes Care. 2009;32:2225-2229. 5. American Diabetes Association. Implications of the United Kingdom prospective diabetes study. Diabetes Care. 1998;21:2180-2184. 6. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD). Management of hyper glycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379. Erra tum in Diabetes Care. 2013;36:490. 7. US Food and Drug Administration. FDA approves three new drug treatments for type 2 diabetes. News release; January 25, 2013. Updated January 28, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnoun cements/ucm336942.htm. Accessed April 16, 2013. 8. Kazano (alogliptin and metformin HCl) tablets [pre scribing information]. Deerfield, IL: Takeda Pharmaceu ticals America, Inc; 2013. 9. Nesina (alogliptin) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013. 10. Oseni (alogliptin and pioglitazone) tablets [prescrib ing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013. 11. Nordqvist J. Three type 2 diabetes pills from Take da approved by FDA. Medical News Today. January 27, 2013. www.medicalnewstoday.com/articles/255487.php. Accessed April 15, 2013.

I august 2013 VOL. 6 I

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Durst, RN; John Carlsen, MPH;e Lauren on, NMegan denKuchinski, Be conside eric MHA; t, Rei are mic b and o d . In mbL. urden withincause com red in RA utilizati f work p l AmJ. Harris, RN,J.BSN; Glenna addiDaniel Neves, BA; Stephanie ursTraiger, emen RN, MSN, CNS-BC ro om t Inte treatm months plication managem on are fa ductivity, ne.c Vol li ll ig n s ence, ctors Stakeholder Perspective 5by T. Kenney, Jr, RPh, MBA , NJames imme ent is co of disea of RA m ent. 4,5 DBo o2 th H at se on a l Marc w.A tion, diate sym nsidered set, y begin ww h/Ap c p e to de b ril 20 term ut also to toms of linically arly and velop 12 p n disab CLINICAL ility. 1,6,7slow disea ain associa ecessary aggressiv e to m ted w Histo se prog ana it re ricall 012 Benefits of Novel Oral Anticoagulant Agents for Thromboprophylaxis www y, est ssion to p h inflamm ge ril 2 .AHD imate re /Ap after Total Hip or Knee Arthroplasty Bon s of w vent lon aarch line.c M g o rk om disab 2 l Richard J. Friedman, MD, FRCSC l Am ili, No

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