Metformin lowers all-cause mortality but not CV death, MI or stroke in T2D patients

In patients with both type 2 diabetes (T2D) and an elevated cardiovascular risk, metformin lowers the risk of all-cause mortality but does little to protect against CV death, MI or ischemic stroke, a new evaluation of the SAVOR-TIMI 53 trial has found.

In a post-hoc analysis of 12,156 patients enrolled in SAVOR-TIMI 53, Brian Bergmark, MD, and colleagues at Brigham and Women’s Hospital and Harvard Medical School examined whether metformin—the recommended first-line therapy for T2D in both the U.S. and Europe—is safe in patients with additional CV risk factors, like prior heart failure (HF) or chronic kidney disease (CKD). 

While it’s the gold standard for treating T2D, in reality, we’re not sure how it affects the cardiovascular system.

“Based on recent randomized controlled trials, several of the new diabetes medications have now been granted an indication for cardiovascular risk reduction by the U.S. FDA, something metformin does not have,” Bergmark et al. said in Circulation, where their findings were published July 31. “Because professional societies’ recommendations for metformin as the first-line agent for T2D are based on wide availability, an absence of serious side effects, and low cost rather than efficacy for macrovascular outcomes, its place is now legitimately in question.”

SAVOR-TIMI 53 was a multinational randomized controlled CV outcomes trial that compared the DPP-4 inhibitor saxagliptin with placebo in 16,492 patients with T2D and CVD or an elevated CV risk. Bergmark and his colleagues extracted data from 12,156 of those patients who had baseline biomarker samples, classifying them as either having been exposed to metformin or never having taken the drug.

Nearly three-quarters of their patient pool was exposed to metformin, the authors reported, and an additional 13% and 11% had prior heart failure or at least moderate CKD, respectively.

Bergmark et al. said metformin use wasn’t associated with any difference in risk for his team’s composite endpoint of CV death, MI or ischemic stroke, but the drug was linked to a 25% lower risk of all-cause mortality. The researchers didn’t find any significant relationship between metformin use and the composite endpoint or all-cause mortality in patients with prior HF or moderate to severe CKD; in fact, metformin’s positive effects were most pronounced in patients without those comorbidities.

“While the findings from SAVOR-TIMI 53, the REACH registry and the meta-analysis are compelling in their consistency, if a potential causal relationship is to be posited, it would be helpful for there to be a biologically plausible mechanism for decreased mortality in the absence of reduction in MI or ischemic stroke,” the authors wrote. “At present, no single mechanism of this nature exists.”

Bergmark and co-authors said that since their analysis is retrospective and observational, they can’t exclude the possibility of unmeasured confounders between the metformin-exposed and metformin-unexposed groups. They also acknowledged their patient population included “relatively few” patients with prior HF or CKD.

“These findings emphasize the need for an adequately powered randomized trial in these high-risk patients,” they wrote.