Empagliflozin Benefit in Heart Failure, With or Without Diabetes

Studies of empagliflozin and dapagliflozin have shown to reduce cardiovascular risk, indicating a class effect for heart failure patients.  

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce cardiac failure and hospital admission risk in patients with type 2 diabetes mellitus (T2DM). This benefit has not been demonstrated with other classes of T2DM treatments. SGLT2 inhibitors have been shown to reduce hospital admission due to cardiac failure by 30% compared to placebo. The most significant benefit was seen in patients with reduced left ventricular ejection fraction (EF). Also, SGLT2 inhibitors have been reported to reduce renal impairment progression by 45% compared to placebo. The mechanism of action of these effects has not yet been determined. Another study that looked at dapagliflozin cardiac risk reduction showed that mortality and hospitalization risks were reduced in patients without diabetes. 

This study aimed to assess empagliflozin’s effect on patients with chronic heart failure (CHF) with a reduced EF regardless of their diabetes diagnosis.  

The study is a randomized, double-blind, placebo-controlled trial that included patients 18 years or older with HF (classes II, III, or IV) based on the New York Heart Association (NYHA) classification. Plus, to be included in the study, patients had to have an EF of <40%. Included patients were on appropriate CHF treatment. Patients who met the criteria were randomized to empagliflozin 10mg per day or placebo at a 1:1 ratio. They will continue their CHF medication while receiving the study drug. The study dose was selected based on previous study results that were done in patients with T2DM. Initially, patients were screened for diabetes and renal function, followed up every three months to assess safety outcomes. The study identified the primary outcome of cardiovascular mortality or CHF related hospital admission. Recurrent CHF related admissions and glomerular filtration rate (GFR) reduction rate were considered secondary outcomes. 

The study period was from April 2017 to November 2019, with the last follow-up date set to April 2020. Around 3730 participants were randomized to the empagliflozin and placebo groups. Patients’ characteristics were similar between the groups. T2DM was identified in about 50% of the study population, and more than 70% have EF<30%. Approximately 0.6% of patients missed the follow-up towards the end of the trial due to COVID-19 related difficulties. Regarding the primary results, cardiovascular-related mortality or CHF-related hospital admission were 19.4% and 24.7% in the empagliflozin and the placebo groups, respectively, which is considered a statistically significant outcome (P<0.001). The results were similar between patients with or without T2DM.  

In terms of the secondary outcomes, total hospital admissions were significantly less in the empagliflozin group (388 admissions) than the placebo group (553 admissions). Similarly, the reduction of GFR was markedly slower in the empagliflozin group (reduced by 0.55ml/min/1.73m2 per year) compared to the placebo group (facilitated by 2.28ml/min/1.73m2 per year). On the other hand, mortality from other causes was nonsignificant between the groups. In terms of the safety outcomes, patients in the empagliflozin group had a higher rate of uncomplicated infections in the genital tract than placebo. Rates of hypoglycemia and amputations were not different between the groups. Other safety parameters were attributed to the CHF treatments.  

Compared to the DAPA-HF trial results, this study showed a more advanced CHF with EF<30%. Both studies have shown that SGLT2 inhibitors can reduce the rate of cardiovascular mortality and hospital admissions. 

This study findings show that there is a role in using SGLT2 inhibitors in patients with CHF, regardless if they have diabetes or not, because of their effect on the hospitalization and mortality rates and their renal protective outcomes. One strength of this study is its design: as a randomized controlled trial, the study design limits the potential for selection bias. Further studies could be considered comparing other SGLT2 inhibitors to identify the scope of their impact on patients without diabetes.   

Practice Pearls: 

• Empagliflozin reduces the rate of cardiovascular-related mortality or hospitalizations in patients with or without diabetes. 
• Empagliflozin showed a reduced rate of renal impairment when compared to placebo. 
• Both SGLT2 inhibitors empagliflozin and dapagliflozin have shown to significantly reduce cardiovascular risk compared to placebo, indicating a class effect. 

Packer, Milton et al. “Cardiovascular And Renal Outcomes With Empagliflozin In Heart Failure.” New England Journal Of Medicine, vol 383, no. 15, 2020, pp. 1413-1424. Massachusetts Medical Society, doi:10.1056/nejmoa2022190.  

Zelniker, Thomas A et al. “SGLT2 Inhibitors For Primary And Secondary Prevention Of Cardiovascular And Renal Outcomes In Type 2 Diabetes: A Systematic Review And Meta-Analysis Of Cardiovascular Outcome Trials”. The Lancet, vol 393, no. 10166, 2019, pp. 31-39. Elsevier BV, doi:10.1016/s0140-6736(18)32590-x.. 

McMurray, John J.V., et al. “Dapagliflozin In Patients With Heart Failure And Reduced Ejection Fraction.” New England Journal Of Medicine, vol 381, no. 21, 2019, pp. 1995-2008. Massachusetts Medical Society, doi:10.1056/nejmoa1911303.  

Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences

See more about heart failure, empagliflozin and other SGLT2 inhibitors in our therapy center.