Weight Beneficial Treatments for Type 2 Diabetes

S P E C I A L F E A T U R E R e v i e w Weight Beneficial Treatments for Type 2 Diabetes L. F. Meneghini, D. Orozco-Beltran, K. Khunti, S. Caputo, T. Damçi, A. Liebl, and S. A. Ross Context: The close link between type 2 diabetes and excess body weight highlights the need to consider the weight effects of different treatment regimens. We examine the impact of “weight-friendly” type 2 diabetes pharmacotherapies and suggest treatment strategies that mitigate weight gain. Evidence Acquisition: Evidence was identified via PubMed search by class and agent and in bibliographies of review articles, with final articles for inclusion selected by author consensus. Evidence Synthesis: Substantial evidence confirms the weight benefits of metformin and shows that, of the newer available agents, glucagon-like peptide-1 (GLP-1) agonists and amylin analogs promote weight loss. Dipeptidyl peptidase-4 (DPP-4) inhibitors and bile acid sequestrants are weight-neutral. Liraglutide and exenatide appear to have similar effects on weight; however, recent research suggests a potentially greater effect of liraglutide on glycemic control compared to exenatide, when used as a second-line therapy. Mounting evidence suggests that insulin detemir may provide the most favorable weight benefits of available insulins. Conclusions: Weight-beneficial agents should be considered in patients, particularly obese patients, who fail to reach glycemic targets on metformin therapy. We propose the following treatment choices based on potential weight benefit and blood glucose increment: long-acting GLP-1 agonists (liraglutide), DPP-4 inhibitors, bile acid sequestrants, amylin analogs, and basal insulin for patients with elevated fasting plasma glucose; and short-acting (exenatide) or long-acting GLP-1 agonists, amylin analogs, DPP-4 inhibitors, acarbose, and bile acid sequestrants for patients with elevated postprandial glucose. The weight-sparing effects of insulin detemir, notably in patients with high body mass index, should also be considered when initiating insulin therapy. (J Clin Endocrinol Metab 96: 3337–3353, 2011) U ntil recently, only two drugs available for type 2 diabetes (T2D) treatment could be considered weight-neutral: metformin and acarbose (1). Although weight is a modifiable risk factor and an integral part of T2D management, weight control is particularly challenging when treatments such as sulfonylureas (SU), thiazolidinediones (TZD), and/or insulin are introduced to achieve glycemic targets. In addition, both weight gain and weight loss can be self-perpetuating. Beyond the psychological implications, weight gain increases insulin resistance, which in turn leads to escalating insulin requirements and eventual intensification of therapy (2). Because these effects could be reversible with adequate weight reduction (3), treatment decisions should ideally incorporate weight-friendly strategies in the management plan. ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2011 by The Endocrine Society doi: 10.1210/jc.2011-1074 Received March 23, 2011. Accepted August 10, 2011. First Published Online September 7, 2011 Abbreviations: BMI, Body mass index; CI, confidence interval; DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; HbA1c, hemoglobin A1c; OAD, oral antidiabetic agent; PPG, postprandial glucose; RCT, randomized control trial; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione. J Clin Endocrinol Metab, November 2011, 96(11):3337–3353 jcem.endojournals.org 3337 Diabetes Research Institute (L.F.M.), University of Miami Miller School of Medicine, Miami, Florida 33136; Cathedra of Family Medicine (D.O.-B.), Clinical Medicine Department, University Miguel Hernandez, 03550 San Juan de Alicante, Spain; Department of Health Sciences (K.K.), University of Leicester, Leicester LE1 7RH, United Kingdom; Servizio di Diabetologia (S.C.), Policlinico Gemelli, Università Cattolica, 00168 Rome, Italy; Istanbul University (T.D.), Cerrahpasa Medical Faculty, Department of Endocrinology, Diabetes and Metabolism, 34378 Istanbul, Turkey; Center for Diabetes and Metabolism (A.L.), 83670 Fachklinik Bad Heilbrunn, Germany; and University of Calgary (S.R.), Alberta, Canada AB T2N 1N4 3338 Meneghini et al. Weight Beneficial Treatments for Type 2 Diabetes Methods This review includes a comprehensive selection of representative clinical trials covering all agents with data available to report weight change in T2D. The literature search for articles to include in this review started with the bibliographies of several relevant review articles (4 – 6) for reports of T2D clinical trials reporting weight as an outcome. Articles deemed appropriate were included, and additional references were identified using the “related citations” search option on PubMed. This was judged by the authors to be a preferable approach to starting the literature review with a term search on PubMed. In particular, the authors were concerned that using the search term “weight” might produce results only for agents showing consistent weight benefits, which could lead to biased results. Alternatively, excluding the search term “weight” would have likely produced an unworkably large number of articles, with only a minor proportion of relevant trials for inclusion in this paper. Additional PubMed searches were performed by class or agent using the following search terms (‘All fields’): “incretin,” “DPP4 inhibitor,” “biguanide,” “amylin analog,” “bile acid sequestrant,” “␣ glucosidase inhibitors,” “colesevelam,” “acarbose,” or “insulin,” limited to clinical trials in type 2 diabetes [MeSH term]. At each stage of the search, each author provided expert opinion on which articles to include or exclude; this was done to prevent bias. Generally, articles summarizing nonrandomized studies were excluded in cases where insulin was evaluated in combination with regimens no longer commonly prescribed; these decisions were made based on author expert opinion regarding clinical relevance. The final selection of studies considered suitable for inclusion was based on author consensus. Results Pharmacological treatments in T2D providing weight benefit: clinical trials Metformin monotherapy and combination therapy The biguanide insulin-sensitizing agent, metformin, is thought to decrease hepatic glucose production and en- hance peripheral tissue sensitivity to insulin. Metformin, along with lifestyle intervention, typically achieves reduction in hemoglobin A1c (HbA1c) of approximately 1.0% (7) and is the recommended first-line treatment of T2D in all current management guidelines (8 –10). Metformin is weight-neutral, or associated with modest weight loss, particularly in obese patients (11). The weight benefits of metformin monotherapy have been demonstrated in several trials reporting a 0.6- to 2.9-kg weight reduction in treatment-naive patients followed for 6 months to (...truncated)