Starting metformin treatment in patients with type 2 diabetes shortly after they were hospitalized for heart failure was linked with a reduced rate of repeat hospitalization for heart failure (HHF) during the subsequent year when their left ventricular ejection fraction (LVEF) was greater than 40%, report the authors of an observational study of more than 5800 Medicare patients.
When a sulfonylurea was started instead, the incidence of a repeat HHF was neutral when their LVEF was greater than 40%. But their HHF rate increased by a significant 48% relative to patients who did not receive a sulfonylurea when the index LVEF was 40% or less.
These results “are provocative,” but as they come from an observational study they are “hypothesis-generating and not definitive,” cautioned Stephen J. Greene, MD, senior author of the study, which was recently published in JACC: Heart Failure.
“To change practice with metformin for patients with heart failure and diabetes we need a randomized trial to definitively prove cause and effects,” said Greene, a cardiologist at Duke University in Durham, North Carolina.
Signal of Harm for HF: Best to Avoid a Sulfonylurea
“However, with regards to sulfonylureas, these results and findings from other observational studies have shown a signal of harm for heart failure. With many other oral treatments for diabetes to choose from with either very favorable or neutral effects on heart failure outcomes in randomized trials, I think it’s best to avoid treatment with a sulfonylurea in these patients, if at all possible,” Greene said in an interview.
Existing evidence “makes agents from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class the first choice as an oral glucose-lowering agent for these patients, with metformin a consideration if additional lowering of glucose is needed,” he added.
Other experts agree with the study’s conclusions.
“The general findings that metformin was associated with a lack of harm or benefit is consistent with current recommendations to preferentially use metformin and SGLT2 inhibitors in patients with [diabetes and] heart failure,” commented Alice Y.Y. Cheng, MD, an endocrinologist at the University of Toronto, Ontario, Canada.
“There were only 193 people with an LVEF of 40% or less in the metformin group, so I would be very cautious about drawing any conclusions from these data,” she added, agreeing that the findings are hypothesis-generating.
She also highlighted that the report did not address patients who were not hospitalized for heart failure, “so it does not contribute to the discussion of metformin use” in patients without a history of HHF.
Metformin Can‘t Replace or Delay an SGLT2 Inhibitor
“SGLT2 inhibitors must be part of the treatment regimen for patients with heart failure of any type. This report supports also using metformin in those with type 2 diabetes and heart failure, but not in place of an SGLT2 inhibitor or to delay start of an SGLT2 inhibitor,” Cheng said in an interview.
Darren K. McGuire, MD, a cardiologist and professor at Dallas-based UT Southwestern Medical Center, also urged caution when considering the study’s findings.
“While these observations may influence decision-making around metformin and sulfonylureas in patients with [diabetes and] heart failure, they are not definitive,” McGuire said.
“I don’t think these findings in any way contribute to considerations about using SGLT2 inhibitors” in patients like the ones studied, he added in an interview.
“The consensus among cardiologists is that SGLT2 inhibitors should be one of the pillars of treatment for patients with heart failure, with both reduced and preserved ejection fraction, independent of glucose control and independent of metformin treatment. Some, but not yet most, endocrinologists are beginning to have the same thought.”
Metformin: A Significant 19% Reduction in the Combined Primary Endpoint
The new study published in JACC: Heart Failure and conducted by Greene and colleagues used data collected during 2006-2014 by the Get With the Guidelines—Heart Failure registry, a program sponsored and organized by the American Heart Association that now involves more than 500 US hospitals and has enrolled more than 125,000 patients.
The researchers focused on Medicare patients in this cohort who were hospitalized for heart failure and discharged with a history, or a current diagnosis, of type 2 diabetes and at least one prescription fill for an antidiabetic medication. The analysis excluded patients with an estimated glomerular filtration rate less than 45 mL/min/1.73m2 because metformin use is discouraged in such patients.
This resulted in a study cohort of 5852 patients, including 454 (8%) patients who started metformin while hospitalized or during the subsequent 90 days and 504 (9%) patients who began taking a sulfonylurea during the same period.
The analysis had prespecified primary outcomes of all-cause death, HHF, and combined HHF or all-cause death during the 12-month period that began on the 91st day following hospital discharge, immediately after the window closed for starting either of the two drug classes.
Patients started on metformin had a significant 19% reduction in 12-month incidence of all-cause death or HHF relative to other patients in the study in an analysis that adjusted for 29 potential confounders.
HHF was reduced by 20% in those who started metformin compared with those who did not, a difference that fell slightly short of statistical significance (P = .072). The incidence of all-cause death was similar in those who received metformin and those who did not.
A more granular analysis that divided patients by LVEF during their index hospitalization showed metformin use was linked with a significant 42% lower incidence of HHF and a significant 32% lower rate of HHF or all-cause death in patients with an LVEF of more than 40%. (Roughly 58% of all patients in the study had an LVEF of more than 40%.)
Metformin treatment showed no significant link with any of the three primary outcomes in patients with an LVEF of 40% or less.
Signal of Harm From Sulfonylureas
Patients who started on a sulfonylurea showed borderline significant increases in incidence rates of all three primary outcomes relative to those not receiving a sulfonylurea in the fully adjusted model. Sulfonylurea treatment was linked with a 24% relative increase in all-cause death (P = .045), a 22% relative increase in HHF (P = .05), and a 17% relative increase in incidence of the combined endpoint (P = .047).
When broken down by baseline LVEF, significant differences were linked with sulfonylurea use by patients with an LVEF of 40% or less who were hospitalized for HF. All-cause death was 29% higher in those taking a sulfonylurea with a lower LVEF at baseline.
The lack of any benefit from metformin among patients with an LVEF of 40% or less at time of HHF in the study “adds support for prioritizing SGLT2 inhibitors before metformin as first-line therapy for type 2 diabetes in the setting of heart failure with reduced ejection fraction,” write Greene and his co-authors.
Data from several trials have shown “substantial clinical benefits” of an SGLT2 inhibitor for these types of patients, they stress.
Their report also highlights the “especially relevant” signal of harm from sulfonylureas shown in this study. “Clinicians often choose sulfonylureas as the initial choice of drug for patients with diabetes” because they have no gastrointestinal adverse effects, are easy to titrate, are low cost, and clinicians are generally comfortable with the class.
“The suggestion of harm with sulfonylureas in the current study supports prioritizing use of alternative antidiabetic medications in patients with heart failure, if at all possible,” the authors reiterate.
The study received no commercial funding. Get With the Guidelines—Heart Failure is sponsored in part by several drug companies. Greene has reported no relevant financial relationships. Cheng and McGuire have each received personal fees from numerous companies.
JACC Heart Fail. Published online December 8, 2021. Abstract
Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler
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