A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes.
(Clinical Trial, Phase III;Journal Article)
OBJECTIVE: The objective was to assess the relative risk (RR) for cardiovascular (CV) events across all 8 randomized phase 2/3 trials evaluating saxagliptin in patients with type 2 diabetes mellitus. METHODS: Cardiovascular events (death, myocardial infarction [MI], stroke, revascularization procedures, and cardiac ischemia) were reported by investigators through standard adverse event reporting procedures and were systematically identified. Post hoc blinded adjudication of all deaths, MIs, and strokes was performed using prespecified endpoint definitions by an independent clinical events committee (CEC). RESULTS: A total of 4607 randomized and treated patients (n = 3356 treated with saxagliptin [2.5-100 mg/d]; n = 1251, comparator [n = 656, placebo; n = 328, metformin; n = 267, uptitrated glyburide]) were included. The median ages were 54 years (saxagliptin) and 55 years (comparator) (interquartile range, 47-61 each); 51% were female, 73% were white, 52% were hypertensive, 44% had hypercholesterolemia, 39% had a smoking history, 20% had a first-degree family member with premature coronary heart disease, and 12% had prior CV disease. Cardiovascular events were experienced by 61 patients (38 [1.1%], saxagliptin; 23 [1.8%], comparator), and CV death/MI/stroke events were reported by investigators in 41 patients: 23 (0.7%), saxagliptin; 18 (1.4%), comparator (relative risk, 95% confidence interval [CI], 0.44 [0.24-0.82]). The CEC reviewed 147 patients with potential CV events and identified a total of 40 patients with CV death/MI/stroke: 22 (0.7%), saxagliptin; 18 (1.4%), comparator (RR, 0.43 [0.23-0.80]). Component proportions for CV death, MI, and stroke were (saxagliptin vs comparator): 7 (0.2%) vs 10 (0.8%), 8 (0.2%) vs 8 (0.6%), and 11 (0.3%) vs 5 (0.4%), respectively. CONCLUSION: No increased risk of CV death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program. Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptin will be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptin compared with standard of care in patients with type 2 diabetes at increased risk for CV events.
Frederich, R; Alexander, JH; Fiedorek, FT; Donovan, M; Berglind, N; Harris, S; Chen, R; Wolf, R; Mahaffey, KW
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