SYSTEMATIC REVIEW Implications of incretin-based therapies on cardiovascular disease M. E. Rotz, 1 V. S. Ganetsky, 2 S. Sen, 2 T. F. Thomas 2 SUMMARY Background: Incretin-based therapies offer another treatment option for patients with type 2 diabetes. Agents that provide glycaemic control in addition to attenuat- ing cardiovascular disease (CVD) risk factors are important for diabetes management. This review will focus on the off-target effects of incretin-based therapies on CVD risk factors [body weight, blood pressure (BP), lipid profile and albuminuria], major adverse cardiovascular events (MACE), heart failure (HF) and beta-cell preservation. Methods: A literature search was conducted to identify English-language publica- tions for incretin-based therapies evaluating the following off-target end-points: body weight, BP, lipid profile, albuminuria, MACE, HF and beta-cell function. Randomised controlled trials (RCTs) were prioritised as the primary source of information. Results: Overall, incretin-based therapies have shown beneficial effects on CVD risk factors, and glucagon-like peptide 1 (GLP-1) receptor agonists appear to have a more pronounced effect compared with dipeptidyl peptidase-4 inhibitors. RCTs are being conducted to determine if these positive effects on CVD risk factors translate to a reduction in MACE. To date, these studies have not shown an increase in MACE. A signal of increased hospitalisations for HF was observed with saxagliptin, warranting continued evaluation and vigilance in high-risk patients. In addition, incretin-based therapies have shown positive effects on measures of beta-cell function supporting their durability in the management of diabetes. Conclusions: Incretin-based thera- pies are an important treatment option for patients with type 2 diabetes, offering beneficial effects on CVD risk factors without increasing MACE. Review criteria A literature search was conducted to identify English- language publications for incretin-based therapies evaluating the following end-points: body weight, blood pressure (BP), fasting lipid profile, albuminuria, major adverse cardiovascular event (MACE), heart failure (HF) and beta-cell function. Randomised controlled trials (RCTs) of patients with type 2 diabetes with a minimum duration of 12 weeks were prioritised as the primary source of information. Message for the clinic Clinical evidence demonstrates that incretin-based therapies have neutral to positive effects on the following outcomes, body weight, BP, fasting lipids, albuminuria, MACE and beta-cell preservation; however, evidence for HF has been conflicting. Clinicians should tailor the therapy based on patients’ individual needs. Introduction Incretin-based therapies, including the injectable glu- cagon-like peptide 1 (GLP-1) receptor agonists and oral dipeptidyl peptidase 4 (DPP-4) inhibitors, offer another treatment option for patients with type 2 dia- betes. GLP-1 receptor agonists mimic the effects of the endogenous incretin hormone, GLP-1, specifically, by stimulating insulin secretion in a glucose-dependent fashion, suppressing pancreatic glucagon output, slow- ing gastric emptying and decreasing appetite. DPP-4 inhibitors enhance circulating levels of GLP-1 and the incretin hormone, glucose-dependent insulinotropic peptide (GIP) (1). DPP-4 inhibitors decrease haemo- globin A1C by approximately 0.6–0.8% (2). The GLP-1 receptor agonists decrease haemoglobin A1C by approximately 1–1.5%, with greater decreases observed with liraglutide (1,3). The American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the American Associa- tion of Clinical Endocrinologists (AACE) recommend addition of GLP-1 receptor agonists or DPP-4 inhibi- tors to metformin as components of dual or triple therapy (1,4). The AACE guidelines also list GLP-1 receptor agonists and DPP-4 inhibitors as monothera- py options for patients with haemoglobin A1C < 7.5% (4). Other commonly used agents for diabetes, includ- ing sulfonylureas (SUs), thiazolidinediones (TZDs) and insulin, may adversely affect cardiovascular dis- ease (CVD) risk factors (1). Agents that provide gly- caemic control in addition to attenuating CVD risk factors are important in the therapeutic armamentar- ium of diabetes. This review will focus on the off- target effects of incretin-based therapies on body weight, blood pressure (BP), fasting lipid profile, albu- minuria, major adverse cardiovascular event (MACE), heart failure (HF) and beta-cell preservation. Methods A literature search was conducted with PubMed, International Pharmaceutical Abstracts and EMBASE ª 2014 John Wiley & Sons Ltd Int J Clin Pract, May 2015, 69, 5, 531–549. doi: 10.1111/ijcp.12572 531 1 Temple University School of Pharmacy, Philadelphia, PA, USA 2 Philadelphia College of Pharmacy at University of the Sciences, Philadelphia, PA, USA Correspondence to: Melissa E. Rotz, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA Tel.: +215 707 4943 Fax: +215 707 8326 Email: melissa.rotz@temple.edu Disclosures The authors report no conflicts of interest or financial disclosures.