Research Highlights Expanded Clinical Uses of SGLT2 Inhibitors

The first sodium-glucose cotransporter-2 (SGLT2) inhibitor, canagliflozin, received approval in 2013. Since then, several others, including dapagliflozin, ertugliflozin, and empagliflozin, have followed suit. These medications have demonstrated benefits for various conditions, such as type 2 diabetes, hypertension, heart failure, pulmonary diseases, and renal failure. Notably, trials like EMMY and DAPA-MI indicated potential advantages for SGLT2 inhibitors in patients post-acute myocardial infarction (AMI), however, their impacts on critical outcomes like heart failure and mortality remained unclear.

To further investigate, the EMPACT-MI trial was conducted as an international, double-blind, randomized, placebo-controlled study involving 6,522 patients hospitalized for AMI. Participants were randomized to receive either empagliflozin (10 mg/day) or placebo in addition to standard care. The primary endpoint assessed was a composite of hospitalization for heart failure or death from any cause over a median follow-up of 17.9 months. The trial included patients who had experienced AMI within the previous 14 days and either showed a left ventricular ejection fraction (LVEF) of less than 45% or exhibited signs of congestion.

Results showed that 8.2% of patients receiving empagliflozin experienced the primary endpoint compared to 9.1% in the placebo group, which was not statistically significant. Secondary endpoints similarly showed no meaningful differences between the two groups. The authors concluded that empagliflozin did not significantly reduce the risk of hospitalization for heart failure or death compared to placebo in the studied cohort.

While the trial's design was robust, the researchers note that several factors could have influenced the findings. Notably, funding was provided by the company marketing empagliflozin, and the initial sample size was increased to ensure sufficient power. Additionally, many patients had undergone medical optimization before randomization, likely impacting the event rates.

SGLT2 inhibitors target SGLT2 proteins in the kidneys to reduce glucose reabsorption, promoting glycosuria and slowing renal function decline. Their efficacy in improving cardiovascular outcomes has been well-documented in various trials, showing decreasing risks of cardiovascular death and heart failure hospitalization among patients, particularly those with type 2 diabetes.

Despite the negative findings of the EMPACT-MI trial, previous studies have consistently shown cardiovascular benefits associated with SGLT2 inhibitors. This prompted the FDA to expand dapagliflozin’s approval for patients with reduced and preserved ejection fraction heart failure in 2023. The question arises as to why these drugs, effective in other populations, did not demonstrate benefits in the AMI cohort. Differences in clinical management and the timing of treatment interventions may play a role, as patients experiencing AMI often receive rapid therapeutic interventions that could overshadow the potential benefits of SGLT2 inhibitors.

Long-term use of SGLT2 inhibitors has been linked to various positive cardiovascular outcomes, including decreased rates of hospitalization for heart failure and major adverse cardiac events. However, administering these drugs post-AMI may not capitalize on their protective effects, as many patients would have already experienced myocardial injury.

Additionally, the EMPACT-MI trial’s lack of granularity regarding heart failure severity and myocardial injury limits its findings. Therefore, the need arises for future studies to explore these parameters more thoroughly to understand better the potential benefits of SGLT2 inhibitors in this patient population.

"While the EMPACT-MI trial did not support the initiation of SGLT2 inhibitors post-AMI for reducing hospitalization or mortality risks, existing evidence highlights their cardiovascular advantages in broader patient groups. As such, SGLT2 inhibitors will continue to play a crucial role in managing patients at increased risk for cardiovascular complications," Richa Dhawan, Department of Anesthesia and Critical Care, the University of Chicago Medical Center, Chicago, and colleagues concluded.

Reference: https://www.jcvaonline.com/article/S1053-0770(24)00431-2/fulltext