Abstract
The constantly expanding population of heart failure (HF) patients over the last few decades in cardiology practice has successfully compelled cardiovascular (CV) research to evolve therapeutic strategies to reduce hospitalizations, improve quality of life, and enhance survival of these patients. Better understanding of the pathophysiology with parallel advances in pharmacotherapy has led to designing of constantly evolving optimal medical therapy. Over the years, the pharmacotherapy of HF has expanded by accumulation of unequivocal data with hard endpoints which has emphatically established aldosterone antagonists, beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blocker, and angiotensin receptor/neprilysin inhibitor to form the elements of the mandatory Guideline Directed Medical Therapy (GDMT). These medications have incrementally contributed to significantly improving clinical outcomes.
The newest and a strong contender for enrolment into this club is sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Introduced initially as oral hypoglycemic agents (OHA), Canagliflozin, Dapagliflozin, and Empagliflozin are the 3 drugs in this class which selectively block the SGLT-2 receptor in the proximal convoluted tubule of the kidney, promote glycosuria, and help in glycemic control. The existing vacuum of CV safety of OHA was undoubtedly addressed by these molecules as they demonstrated an encouraging reduction in HF hospitalization irrespective of presence of CV disease.1, 2 Mechanistically, this was attributed to osmotic diuresis and natriuresis leading to reduction in preload and after load, thus enhancing cardiac performance. The beneficial CV effects were unrelated to their effects on glycemic control showing their potential in usage in nondiabetic HF patients. This fact was abundantly evident by analysis of the 2 large trials DAPA-HF and EMPEROR-Reduced.3, 4 These trials included symptomatic HF patients with reduced ejection fraction (<40%) and elevated natriuretic peptides. In both the trials, patients were predominantly men with EMPEROR-R having worse left ventricular ejection fraction (LVEF) (31% vs 27±%) and higher NTProBNP (1,887 vs 1,428 pg/mL). Importantly, slightly over half of the patient population in both the trials was nondiabetic. More patients in EMPEROR-R were on ARNI (18.3% vs 10.5%). Among 8,474 patients in the 2 trials, the treatment effect for death was a 13% reduction in all-cause death (pooled hazard ratio [HR]: 0.87, 95% confidence interval: 0·77-0·98; P = .018) and 14% reduction in CV death (0.86, 0.76-0·98; P = .027). SGLT-2 inhibition was accompanied by a significant 26% reduction in the combined risk of CV death or first hospitalization for HF, a significant 25% decrease in the composite of recurrent hospitalizations for HF or CV death, and a significant 31% reduction in the risk of first hospitalization for HF. 5 Importantly, it was shown that dapagliflozin, compared with placebo, added to recommended therapy significantly reduced the risk of the primary composite outcome of a first episode of worsening HF or CV death in patients with diabetes (HR: 0.75) and in patients without diabetes (HR: 0.73) 6
The benefits of empagliflozin in HF patients were seen to extend to patients with preserved ejection fraction too. In a randomized double blind trial involving 5,988 patients with LVEF >40%, the composite of CV death or hospitalization for HF was seen in 13.8% in the empagliflozin arm compared to 17.1% in the placebo group, translating to a 21% relative risk reduction. 7 The CV benefits were similar in presence or absence of diabetes.
It is undoubtedly a challenge for a new drug to show a reduction in CV outcomes on top of current HF prescription. In this context, SGLT-2 is unique in demonstrating reduction of HF hospitalizations and modest reduction in mortality in both genders, across different ages, nondiabetics and diabetics, with or without concomitant administration of ARNI, and in patients with reduced and preserved ejection fraction. It is very tempting to speculate that primary prevention indications for implantable defibrillators may face a stiff challenge in the face of compliant GDMT which includes SGLT-2 inhibitors.