Among patients with heart failure (HF) and type 2 diabetes mellitus (DM), metformin initiation is independently associated with substantial improvement in 12-month clinical outcomes in those with ejection fraction (EF) of greater than 40%, and sulfonylurea initiation is associated with an increased risk of death and hospitalization. These findings were published in JACC: Heart Failure.

Researchers identified Medicare beneficiaries who were hospitalized for HF in the Get With The Guidelines–Heart Failure (GWTG-HF) registry from January 1, 2006, to December 31, 2014, and were discharged with a diagnosis or history of DM. All participants also had a medication fill for any antidiabetic medication from January 1, 2006, to December 31, 2015.

The study authors evaluated the effectiveness of metformin and sulfonylurea therapies separately in identical parallel analyses. Patients who had a medication fill were compared with those who did not have a medication fill for the respective therapy.


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All-cause mortality, hospitalization for HF, and the composite of all-cause mortality or HF hospitalization were the prespecified clinical outcomes and were assessed for 12 months, beginning at day 91 postdischarge.

A total of 5852 patients from 367 US hospitals were included in the primary analysis, of whom 7.8% were newly prescribed metformin, 8.6% were newly prescribed sulfonylurea, and 2.3% were newly initiated on both therapies. Participants were median aged 75 (IQR, 69-82) years, 51.6% were women, and 73.0% were White.

Adjusted analysis showed that metformin initiation was significantly associated with a lower risk of composite all-cause mortality or HF hospitalization at 12 months (hazard ratio [HR], 0.81 [95% CI, 0.67-0.98]; P =.032). The associations between initiation of metformin and all-cause mortality (HR, 1.06 [95% CI, 0.85-1.33]; P =.59) and HF hospitalization (HR, 0.80 [95% CI, 0.63-1.02]; P =.072) were not statistically significant after adjustment.

The associations with a substantially reduced risk for both endpoints were limited to patients with EF of greater than 40% (HF hospitalization HR, 0.58 [95% CI, 0.40-0.85]; composite endpoint HR, 0.68 [95% CI, 0.52-0.90]), with no suggestion of reduced risk occurring in patients with EF of 40% or less.

Sulfonylurea initiation was associated with a statistically significant increased risk of all-cause mortality after adjustment (HR, 1.24 [95% CI, 1.00-1.52]; P =.045). Adjusted analyses showed that initiation of sulfonylurea therapy was also associated with an increased risk of composite all-cause mortality or HF hospitalization (HR, 1.17 [95% CI, 1.00-1.37]; P =.047) and HF hospitalization (HR, 1.22 [95% CI, 1.00-1.48]; P =.050), and both had marginal statistical significance.

The investigators noted that their observational analysis cannot definitively prove cause-effect relationships and residual and unmeasured confounding are possible. Also, the study did not assess postdischarge adherence or persistence of metformin or sulfonylurea therapy or the role of these factors in clinical outcomes. Furthermore, the analysis excluded patients with severe chronic kidney disease and was limited to Medicare beneficiaries aged 65 years or older.

“These findings support the potential use of metformin among patients with HF with preserved ejection fraction and DM, and the need for confirmatory randomized clinical trials,” wrote the researchers. “In addition, in the context of multiple alternative antidiabetic medications being available with favorable or neutral effects on cardiovascular outcomes, these findings suggest that sulfonylureas may best be avoided among patients with HF and DM.”

Disclosure: The GWTG-HF program is provided by the American Heart Association and sponsored, in part, by Novartis, Boehringer Ingelheim and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Khan MS, Solomon N, DeVore AD, et al. Clinical outcomes with metformin and sulfonylurea therapies among patients with heart failure and diabetes. JACC Heart Fail. Published online February 28, 2022. doi: 10.1016/j.jchf.2021.11.001