Metformin has run to cure heart failure again? The latest research data is published

Previous studies have confirmed that different hypoglycemic drugs have different effects on the risk of heart failure (hereinafter referred to as heart failure). For example, a sodium-glucose synergistic transporter 2 inhibitor (SGLT2i) is effective in preventing heart failure in patients with type 2 diabetes mellitus and improves clinical outcomes in patients with heart failure (HFrEF) with reduced ejection fraction or heart failure (HFpEF) with preserved ejection fraction.

Although there is growing evidence to support the widespread use of SGLT2i, metformin and sulfonylureas remain the most commonly used oral hypoglycemic agents, and are no exception in patients with type 2 diabetes mellitus with heart failure. In addition, due to pathophysiological differences in HFrEF and HFpEF, the effect of metformin and sulfonylurea on cardiovascular risk may vary due to differences in ejection fraction (EF). To develop a better treatment plan for this subset of patients, it is critical to understand the effects of metformin and sulfonylureas on cardiovascular outcomes and risk of heart failure events.

Recently, the latest data from the GWTG-HF (Get With The Guidelines-Heart Failure) registered study, published in JACC Heart Fail, evaluated and compared the effects of metformin and sulfonylureas on the clinical outcomes of elderly diabetic patients in the United States who were hospitalized for heart failure, and also evaluated the difference in the effects of the two drugs on HFrEF patients and HFpEF patients.

Research methodology

The study included diabetic patients hospitalized for heart failure registered with GWTG-HF from 2006 to 2014, none of whom had a history of metformin or sulfonylureas prior to admission. In a parallel separate analysis of metformin and sulfonylureas, patients who began taking the above drugs within 90 days after discharge were compared with those who did not. The researchers used a multivariate model to assess the association between drug therapy and mortality and hospitalization for heart failure at 12 months. Pre-specified subgroup analyses were stratified according to EF≤40% and EF>40%.

Effective endpoints included a combination of all-cause mortality, hospitalization for heart failure, all-cause death, and hospitalization for heart failure. Negative control endpoints included hospitalization for urinary tract infection, hospitalization for gastrointestinal bleeding, and influenza vaccination.

Research results

Of the 5852 registered patients, within 90 days of discharge, 454 (7.8%) started using metformin for the first time and 504 (8.6%) started using sulfonylureas for the first time. The median age of these patients was 75 years (69-82 years), of which 51.6% were female, 73.0% were of white ethnicity, the median ejection fraction was 45% (41.9% of patients had EF ≤ 40%), and the median eGFR at discharge was 60 mL/min/1.73 m2.

Initiation of metformin was independently associated with a reduction in the combined risk of all-cause death and heart failure hospitalization (HR, 0.81; 95% CI, 0.67-0.98; P=0.03), but there was no statistically significant association with a single all-cause death or heart failure hospitalization risk. In 40% of patients with EF>, initiation of metformin was associated with a reduced compound risk of all-cause death and heart failure hospitalization (HR, 0.68; 95% CI, 0.52 to 0.90) and associated with a reduced risk of hospitalization for heart failure (HR, 0.58; 95% CI, 0.40 to 0.85) (p-values for interactions were all ≤0.04). For 40% of patients with EF≤, the use of metformin was not found to be associated with reduced risk.

Sulfonylureas were associated with an increased risk of all-cause death (HR, 1.24; 95% CI, 1.00-1.52; P = 0.045) and the risk of hospitalization for heart failure (HR, 1.22; 95% CI, 1.00-1.48; P = 0.050), and an increased risk of compound risk of all-cause death and hospitalization for heart failure (HR, 1.17; 95% CI, 1.00-1.37; P = 0.047). Moreover, the use of sulfonylureas was associated with an increased risk of hospitalization for death and heart failure, regardless of the size of the EF (p-values for interactions were > 0.11). Neither metformin nor sulfonylureas were associated with negative control endpoints.

Conclusions of the study

The GWTG-HF registry study found that for 40% of elderly patients with diabetes who were hospitalized for heart failure with EF>, the use of metformin was independently associated with a significant improvement in clinical outcome at 12 months. In contrast, initiation of sulfonylureas, regardless of EF value, was associated with an increased risk of hospitalization for death and heart failure. The findings support metformin's potential for use in diabetic patients with HFpEF, and that sulfonylureas are best avoided in people with diabetes with heart failure.

discuss

Lead author of the study, Dr. Stephen J. Greene, said the GWTG-HF registry study was an observational study with inherent limitations and that more randomized controlled trials were needed to further validate the effects of metformin in diabetic patients with heart failure. SGLT2i is the oral hypoglycemic agent of choice for diabetic patients with heart failure, and metformin may be considered if further blood glucose reduction is required. In addition, the results of the GWTG-HF registry study and other observational studies have shown that the use of sulfonylureas is harmful in patients with heart failure. Many other hypoglycemic agents with favorable or no effect on heart failure outcomes are available, so the use of sulfonylureas in diabetic patients with associated heart failure should be avoided as much as possible.

Dr. Alice Y.Y. Cheng, an endocrinologist at the University of Toronto, believes that while this study supports the use of metformin in patients with type 2 diabetes with heart failure, SGLT2i remains the mainstay of treatment for patients with HFrEF and HFpEF, and metformin cannot replace SGLT2i or delay the use of SGLT2i. In addition, since 40% of LVEF patients in the metformin group ≤ only 193, clinicians should look with caution the conclusions drawn from these data.

There have been previous studies that suggest that metformin has the potential to treat HFpEF. An animal experiment showed that metformin can improve myocardial compliance and improve cardiac pumping function in HFpEF phenotype mice by N2B-mediated increase in phosphate groups in myocardial muscle-linked proteins (titins). In addition, a meta-analysis of four observational studies showed that metformin reduced mortality in patients with HFpEF or HFrEF (β = -0.2; 95% CI, -0.3 to -0.1; p = 0.02), and the protective effect was more significant when EF > 50% (p = 0.003). The role of metformin in patients with heart failure is worth looking forward to.

bibliography:

1.Khan MS, Solomon N, DeVore AD, et al. Clinical Outcomes With Metformin and Sulfonylurea Therapies Among Patients With Heart Failure andDiabetes. JACC Heart Fail. 2021 Nov 30:S2213-1779(21)00538-2.

2.Mitchel L. Zoler. Metformin Benefits Patients Hospitalized for Heart Failure. Medscape. December 14, 2021.

3.Slater RE, Strom JG, Methawasin M, et al. Metformin improves diastolic function in an HFpEF-like mouse model by increasing titin compliance. J Gen Physiol. 2019 Jan 7; 151(1): 42-52.

4.Halabi A, Sen J, Huynh Q, Marwick TH. Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis. Cardiovasc Diabetol. 2020 Aug 5; 19(1): 124.