Review ArticlesCardiovascular Safety and Benefits of Noninsulin Antihyperglycemic Drugs for the Treatment of Type 2 Diabetes Mellitus—Part 1Yandrapalli, Srikanth MD*; Jolly, George MD†; Horblitt, Adam MD‡; Pemmasani, Gayatri MBBS*; Sanaani, Abdallah MD*; Aronow, Wilbert S. MD*; Frishman, William H. MD*Author Information From the *Department of Medicine, Division of Cardiology, Westchester Medical Center and New York Medical College, Valhalla, NY †Division of Cardiology, Loma Linda University Medical Center, Loma Linda, CA ‡Division of Cardiology, Tulane Medical Center, New Orleans, LA. Disclosure: The authors have no conflicts of interest to report. Correspondence: Srikanth Yandrapalli, MD, Division of Cardiology, Department of Medicine, Westchester Medical Center and New York Medical College, 100 Woods Road, Macy Pavilion, Valhalla, NY 10595. E-mail: Srikanth.Yandrapalli@wmchealth.org. Cardiology in Review: July/August 2020 - Volume 28 - Issue 4 - p 177-189 doi: 10.1097/CRD.0000000000000308 Buy Metrics Abstract Cardiovascular disease (CVD) is a major contributor to the morbidity and mortality associated with type 2 diabetes mellitus (T2DM). With T2DM growing in pandemic proportions, there will be profound healthcare implications of CVD in person with diabetes. The ideal drugs to improve outcomes in T2DM are those having antiglycemic efficacy in addition to cardiovascular (CV) safety, which has to be determined in appropriately designed CV outcome trials as mandated by regulatory agencies. Available evidence is largely supportive of metformin’s CV safety and potential CVD risk reduction effects, whereas sulfonylureas are either CV risk neutral or are associated with variable CVD risk. Pioglitazone was also associated with improved CVD risk in patients with diabetes. The more recent antihyperglycemic medications have shown promise with regards to CVD risk reduction in T2DM patients at a high CV risk. Glucagon-like peptide-1 receptor agonists, a type of incretin-based therapy, were associated with better CV outcomes and mortality in T2DM patients, leading to the Food and Drug Administration approval of liraglutide to reduce CVD risk in high-risk T2DM patients. Ongoing and planned randomized controlled trials of the newer drugs should clarify the possibility of class effects, and of CVD risk reduction benefits in low-moderate CV risk patients. While metformin remains the first-line antiglycemic therapy in T2DM, glucagon-like peptide-1 receptor agonists should be appropriately prescribed in T2DM patients with baseline CVD or in those at a high CVD risk to improve CV outcomes. Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors are discussed in the second part of this review. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.