Boaz Hirshberg

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury. In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.

Owing to the close association of cardiovascular (CV) disease with type 2 diabetes and the uncertainty surrounding the CV safety of antidiabetes agents, in 2008 the Food and Drug Administration issued guidance for the demonstration of CV safety for new antidiabetes drugs. Recently the results from CV outcomes trials of three dipeptidyl peptidase-4 (DPP-4) inhibitors and a glucagon-like peptide-1 receptor agonist have been reported. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE) trial, and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the safety of saxagliptin, alogliptin, and sitagliptin, respectively, in patients with type 2 diabetes with CV disease or at high risk for CV disease. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) assessed the safety of lixisenatide in patients with type 2 diabetes and a recent acute coronary syndrome event. The results show that these agents neither increased nor deceased major adverse CV events (CV death, nonfatal myocardial infarction, and nonfatal stroke) compared with placebo. However, the resources needed to conduct these studies may detract from the ability to understand the potential long-term benefit and risk in the majority of patients that are candidates for use of these medications.