Patients with diabetes and HF on Metformin and Sulfonylurea show improved clinical outcomes

In patients with type 2 diabetes mellitus, composite mortality/HHF was significantly lower in patients taking metformin versus those taking sulfonylurea.

The rising global burden of diabetes and its complications in recent years has called for new Prevention and control programs and alternative treatment approaches for existing treatments based on evidence-based treatment modalities. The main goal of therapy in patients with type 2 diabetes mellitus (T2DM) is to recommend drugs that demonstrate effective glycemic control and a safe cardiovascular profile. However, there has been an increased interest in therapeutic agents that can provide a reno-cardioprotective effect. For example, several recent clinical trials have demonstrated the emerging role of antihyperglycemic agents such as Glucagon-like peptide 1 (GLP-1) agonists (e.g., dulaglutide, semaglutide, liraglutide), and Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors (e.g., canagliflozin, dapagliflozin, and empagliflozin) in lowering the Cardio-Nephroprotection risk in patients T2DM. 

Metformin and sulfonylurea (e.g., glibenclamide, gliclazide, and glimepiride) are two commonly prescribed oral antihyperglycemic agents that are considered the mainstay of therapy for patients with T2DM. Metformin is recommended as initial therapy with continued lifestyle modifications for all patients with T2DM unless they present with an A1C ≥9%. It is safe, effective, relatively inexpensive, and may reduce the risk of cardiovascular events and death.

Until recently, the use of metformin was contraindicated in heart failure patients because of concerns over lactic acidosis. Subsequent evidence, however, revealed a small risk of lactic acidosis initially observed with the older biguanide, phenformin. Currently, available evidence suggests that metformin, a highly effective and usually well-tolerated oral agent, in patients with T2DM, may be associated with favorable clinical outcomes among diabetic patients who also have a history of heart failure due to its effect in reducing collagen accumulation, potentially reducing left ventricular hypertrophy, and improving diabetic myocardial diastolic function  

A recent parallel analysis of metformin and sulfonylurea was conducted to investigate the associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes. The study endpoint was composite mortality and hospitalization for HF (HHF) at 12 months by ejection fraction (EF) using a multivariable model within 90 days of discharge evaluated associations between prescription of therapy and mortality and hospitalization for HF (HHF) during a 12-month period. The study included 5,852 patients; 454 (7.8%) and 504 (8.6%) were prescribed metformin and sulfonylurea, respectively, within 90 days of discharge and were compared with patients not prescribed therapy.

The study showed a significant reduction in the risk of composite mortality/HHF in patients who were prescribed metformin (HR: 0.81; 95% CI: 0.67-0.98; P = 0.03), but no statistical significance was observed in individual components. Mortality/HHF in patients with EF>40% showed similar results (HR: 0.68; 95% CI: 0.52-0.90) and HHF (HR: 0.58; 95% CI: 0.40-0.85) with P for interaction ≤0.04. Patients on sulfonylurea on the other hand, showed an increased risk of mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) and HHF (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) with P for interaction >0.11. The study concluded that in HF hospitalized adults with comorbid diabetes; metformin use was linked to significant improvements in 12-month clinical outcomes in patients with an EF > 40%. On the other hand, Sulfonylurea use was linked to an increased risk of death and HF hospitalization, regardless of EF.

Practice Pearls:

• HF patients who have T2D with newly prescribed metformin within 90 days of discharge showed significant improvements compared with patients who were not prescribed therapy. 

• The study results suggest that metformin may be associated with a reduction in the risk of composite mortality among heart failure patients with comorbid diabetes and who are prescribed metformin as well as patients with EF>40% 
• Initiation of sulfonylurea in HF patients showed a significant risk increase in mortality and HF hospitalization.

References:

Khan, Muhammad Shahzeb, et al. “Clinical Outcomes with Metformin and Sulfonylurea Therapies among Patients with Failure and Diabetes.” JACC: Heart Failure, 2021, https://doi.org/10.1016/j.jchf.2021.11.001.

Halabi, Amera et al. “Metformin treatment in heart failure with preserved ejection fraction: a systematic review and meta-regression analysis.” Cardiovascular diabetology vol. 19,1 124. 5 Aug. 2020, doi:10.1186/s12933-020-01100-w

Elmoataz Elmamoun

PharmD Candidate, 2022, South College School of Pharmacy