medwireNews: Research published in JAMA supports a beneficial cardiovascular safety profile for metformin relative to sulfonylureas in people with mild or moderate kidney dysfunction.
The journal released the paper concurrently with the CAROLINA study, which was previously reported at the ADA Scientific Sessions in June this year. CAROLINA showed that the sulfonylurea glimepiride had an equivalent cardiovascular safety profile to the dipeptidyl peptidase-4 inhibitor linagliptin, which has an established neutral cardiovascular safety profile compared against placebo.
CAROLINA was a randomized controlled trial, whereas the current study is a retrospective analysis of data from 24,679 metformin users and 24,799 sulfonylurea users (glyburide, glipizide, or glimepiride). All participants had continued taking the medications after being diagnosed with reduced kidney function and follow-up started from this point of diagnosis. The two groups were matched on the propensity to continue taking metformin or sulfonylurea despite reduced kidney function.
Study author Christianne Roumie (Vanderbilt University Medical Center, Nashville, Tennessee, USA) and colleagues note that “[a]lthough there is consensus that metformin is first-line diabetes treatment, metformin is discontinued in many patients when kidney disease develops.”
The data were sourced from the Veterans Health Administration, so the participants were mostly men (98.0%) and White (81.8%). Median follow-up time was 1.0 years for metformin users and 1.2 years for sulfonylurea users, with changes in medication the most common reason for follow-up ending.
During follow-up, major adverse cardiovascular events (MACE) occurred at a rate of 23.0 versus 29.2 per 1000 person–years’ use of metformin and sulfonylureas, respectively, equating to a significant 20% relative risk reduction with metformin use.
The cumulative probability of having an endpoint event was lower for the metformin versus sulfonylurea groups throughout follow-up, at 1.9% versus 2.5% at 1 year, 3.4% versus 4.4% at 3 years, and 3.8% versus 4.9% at 4 years.
The main MACE endpoint comprised acute myocardial infarction, stroke or transient ischemic attack, and cardiovascular death. The benefits in favor of metformin were consistent for the individual endpoint outcomes and for the composite outcome with transient ischemic attack excluded.
“The study further supports the use of metformin as the first-line treatment to which other diabetes medications are added, even as early chronic kidney disease develops,” says Deborah Wexler (Massachusetts General Hospital, Boston, USA) in an editorial that accompanies both papers.
The researchers stress that their study cannot distinguish a protective effect of metformin from a detrimental effect of sulfonylureas, although the aforementioned CAROLINA trial suggests a neutral cardiovascular safety profile at least for glimepiride.
They also caution against over-generalization, saying that “the study population was mostly elderly white men, and may not be representative of the larger population of patients with diabetes and reduced kidney function.”
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JAMA 2019; doi:10.1001/jama.2019.13206
JAMA 2019; doi:10.1001/jama.2019.14533