Saxagliptin (Onglyza) fails to reach primary endpoint in a CV outcome study of type 2 diabetic patients

On June 19, 2013 Bristol-Myers Squibb (BMS) announced top-line results of the phase IV study, named SAVOR-TIMI-53. In this study of adult patients with type 2 diabetes with either a history of established cardiovascular disease or multiple risk factors, Onglyza met the primary safety objective of non-inferiority, and did not meet the primary efficacy objective of superiority, for a composite endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal ischemic stroke, when added to a patient’s current standard of care (with or without other anti-diabetic therapies), as compared to placebo.  The full findings will be presented September 2, 2013 at the European Society of Cardiology (ESC) 2013 Congress in Amsterdam. Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor approved in the US, Canada, Europe, and elsewhere as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Non-randomized analyses had suggested that DPP-4 ihbitors might have a CV-protective effect in diabetic patients [see here].

Saxagliptin was the first new diabetes drug to receive FDA approval after the issuance of new agency guidelines in July 2009, requiring companies to perform CV-outcomes studies with new diabetes drugs [see here]. The drug’s clinical development program had been completed before the guidance, but because of the new rule, the company launched SAVOR-TIMI 53. The four-year-long trial had a target enrollment of 16 500 patients [Source: Heartwire].

Commentary.  Prior to approval of saxagliptin, BMS provided an analysis of the phase 2b/3 data, based on  4607 subjects, 3356 of whom had received saxagliptin [see here].  This retrospective analysis, using the newly issued FDA Guidance, showed no increased risk of major adverse cardiac events (MACE) or other CV events.  The upper limit of 95% CI of hazard ratio of point estimates for FDA-defined MACE or acute CV events remained at or below 1.8 for saxagliptin compared to placebo controls [see presentation here].  This information was subsequently published and the authors suggested that saxagliptin may actually lower CV risk in patients with type 2 DM [see Cobble & Frederich].  Other, non-randomized analyses had raised hopes that this class of drugs might provide protective effect on the vasculature of diabetes patients [see here and here] and also published by [Monami et al.] and by [Frederich et al.]. Based on these encouraging data, the sponsors undertook the large phase 4 study named (SAVOR-TIMI-53], a randomized, double-blind, placebo-controlled trial that involved 16,500 patients in 25 countries with type 2 diabetes who had a history of established cardiovascular disease or multiple risk factors, with or without renal impairment [see].  Failure to show superiority compared to standard of care, does not affect Onglyza‘s ability to remain on the market.  However, it removes the possibility of Bristol-Myers and AstraZeneca to update the label to claim an advantage in reducing CV risks in patients with type 2 diabetes. The inability to differentiate Onglyza from competitors could have financial consequences [see here].  As detailed elsewhere on this website, demonstrating cardiovascular benefit in post-approval studies has been an elusive goal for many drugs, which in non-randomized studies or retrospective analyses had shown such benefits.  Recent examples include the TREAT study, the ALTITUDE study, and the EVOLVE  study.

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