SGLT2 Inhibitors for Heart Failure

The approved indications for empagliflozin have been updated to include the treatment of symptomatic heart failure with reduced ejection fraction, as an adjunct to standard of care therapy. Empagliflozin is now the second sodium-glucose co-transporter 2 (SGLT2) inhibitor approved for this indication, following the approval of dapagliflozin in 2020.

SGLT2 inhibitors were originally approved only for the treatment of type 2 diabetes. However, randomised clinical trials demonstrate that these agents may improve cardiovascular outcomes. The EMPA-REG OUTCOME trial investigated the effect of empagliflozin on cardiovascular morbidity and mortality in patients with diabetes and high cardiovascular risk. Compared to placebo, patients in the empagliflozin group showed a 38% relative risk reduction for cardiovascular death (3.7% versus 5.9%) and a 35% relative risk reduction for heart failure hospitalisation (2.7% versus 4.1%).

The reduction in risk of hospitalisation for heart failure is observed early after randomisation in clinical trials, suggesting that the mechanism may be independent of the glucose-lowering ability of these agents. While many trials have studied these cardioprotective effects in patients with diabetes, more recent studies have explored the use of SGLT2 inhibitors in patients without diabetes.

The EMPA-TROPISM study investigated the effect of empagliflozin on cardiovascular outcomes in people with heart failure with reduced ejection fraction (HFrEF) who do not have diabetes. Empagliflozin was associated with a significant reduction in left ventricular end-diastolic volume and left ventricular end-systolic volume, as well as improvements in peak oxygen consumption, 6-minute walk test, and quality of life.

The mechanism of the cardiac benefits associated with SGLT2 inhibitors is not completely understood. One theory relates to energy metabolism. Significant changes occur in energy metabolism in patients with heart failure. There is typically a progressive decline in mitochondrial oxidative metabolism, which can result in a cardiac energy deficit. In an animal model, SGLT2 inhibitors were shown to increase the utilisation of ketone bodies as a cardiac energy source. This may improve overall cardiac efficiency.

However, many other potential mechanisms have been proposed, including:

• Reduction in blood pressure (these effects are typically modest and thought unlikely to completely explain the magnitude of benefits seen);
• Diuretic effect (SGLT2 inhibitors more selectively target the interstitial volume and have less effect on intravascular volume than traditional diuretics. This limits reflex neurohormonal stimulation of the sympathetic nervous system and renin-angiotensin-aldosterone system);
• Weight loss (which is thought to improve myocardial insulin sensitivity. However, this is unable to completely explain the magnitude of effect as other weight loss strategies are not as effective in reducing heart failure severity);
• Inhibition of the sympathetic nervous system (may be secondary to a reduction in renal stress);
• Prevention of adverse cardiac remodelling (short-term exposure to SGLT2 inhibitors can promote reverse cardiac remodelling);
• Increased haematocrit (SGLT2 inhibitors may increase erythropoietin secretion leading to improved oxygen delivery);
• Reduced oxidative stress; and
• Improved vascular function.

Ongoing studies continue to investigate the mechanisms involved in the cardioprotective effects of SGLT2 inhibitors. These include studies on the effects of remodelling, lipolysis, myocardial calcium use, and ketone production. Improved understanding of the mechanisms involved may lead to further advances in the treatment of heart failure and the development of specific therapies to target these pathways.