Over the past decade, in response to the 2008 US FDA guidelines that require cardiovascular safety data for antihyperglycemic medications undergoing approval, we have seen an escalation of cardiovascular outcome trials of these agents. Prior studies have focused on the impact of glycemic control on microvascular or macrovascular outcomes. However, with several studies demonstrating adverse cardiovascular outcomes with certain classes of medications in patients with diabetes, and with cardiovascular disease being prevalent, there has been a shift towards looking at cardiovascular safety of these drugs1,2. As seen in the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) study, sodium glucose cotransporter-2 (SGLT-2) inhibitors were among the first class of antihyperglycemic medications to demonstrate cardiovascular benefit as well as safety.3 Since then, several other clinical trials involving SGLT-2 inhibitors have also demonstrated cardiovascular benefits, as summarized in the table below.
SGLT-2 inhibitors block the reabsorption of glucose from the renal proximal tubules leading to glycosuria as well as natriuresis. The osmotic diuresis from glycosuria causes reduction in intravascular volume and lowers ventricular preload and oxygen consumption by the myocardium. Natriuresis leads to a modest reduction in blood pressure. Glycosuria also leads to loss of calories, with a beneficial effect on weight. There is a shift in cardiac energy production, with more efficient energy obtained through hepatic ketone production. SGLT-2 inhibitors also inhibit sodium-hydrogen exchanger 1 (NHE-1) found in cardiomyocytes. The inhibition of NHE-1 leads to increase in mitochondrial calcium and subsequent adenosine triphosphate production.8,9 Moreover, several studies have also shown that SGLT-2 inhibitors improve left ventricular mass index as well as left ventricular dysfunction.10
SGLT-2 inhibitors have recently been recognized not only as antihyperglycemic medications, but also as an effective treatment for heart failure in patients with and without diabetes. The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial found that over a median of 18.2 months, the primary outcome of worsening heart failure or death from cardiovascular cause was reduced by 26% in the group taking dapagliflozin in addition to standard therapy (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). Standard therapy included a heart failure device (an implantable cardioverter–defibrillator, cardiac resynchronization therapy, or both) and drug therapy consisting of either an angiotensin-converting–enzyme inhibitor or angiotensin-receptor blocker, or sacubitril–valsartan plus a beta-blocker. Subgroup analysis showed this benefit was seen in both patients with diabetes (HR = 0.75; 95% CI, 0.63-0.9) and those without diabetes (HR = 0.73; 95% CI, 0.6-0.88).11 Similar findings were reported from the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction (EMPEROR-Reduced). Both studies recruited patients with chronic heart failure with an ejection fraction of ≤40%, however the latter trial included patients with more advanced heart failure and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP), 1926 versus 1446 pg/mL. Primary outcome, which was a composite of heart failure hospitalization and death from cardiovascular cause, was reduced by 25% in the empagliflozin group (HR 0.75; P<0.001).12 Dapagliflozin has since been approved by the FDA for treatment of heart failure with reduced ejection fraction in both patients with and without diabetes; empagliflozin is pending review.
The use of SGLT-2 inhibitors has also been studied in the setting of acute heart failure. The Effects of Empagliflozin on Clinical Outcomes in Patients with Acute Decompensated Heart Failure (EMPA-RESPONSE-AHF) trial, which looked at the use of empagliflozin in 80 patients, found no difference in visual analogue scale dyspnea score, diuretic response, and length of stay or NT-proBNP levels compared to the placebo arm. It was safe for use in the acute setting with no adverse effect on blood pressure or renal function. Investigators also found a reduction in combined endpoint of in-patient worsening of heart failure (intensification of intravenous therapy or mechanical ventilatory, renal or circulatory support), rehospitalization for heart failure or death at 60 days compared with placebo (4 [10%] vs. 13 [33%]; P = 0.0140.13 Sotagliflozin, a dual inhibitor of SGLT-1 and 2, was also examined for use in acute heart failure in the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure Trial (SOLOIST-WHF). Although the study ended prematurely, leading to revision of the primary end point to increase the power of the trial, a total of 1,222 patients were followed for a median of 9.2 months. Patients were randomly assigned to receive sotagliflozin before or within three days following discharge. Sotagliflozin was found to reduce the composite of total cardiovascular deaths, hospitalizations for HF and urgent HF visits by 33% (HR, 0.67; P<0.001).14
Patients with diabetes and concomitant heart failure are known to have poorer outcomes than those with heart failure alone. The development of SGLT-2 inhibitors has not only provided an additional treatment option for improving glycemic control, but also offers cardiovascular as well as renal benefits, findings that will be discussed in subsequent columns. The story of SGLT-2 inhibitors is still ongoing as we await the outcomes of further studies on the effects of these agents in patients with heart failure and preserved ejection fraction.
- Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-71.
- Huupponen R. Adverse cardiovascular effects of sulphonylurea drugs. Clinical significance. Med Toxicol. 1987;2(3):190-209.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-28.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-57.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-57.
- Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020 Oct 8;383(15):1425-35.
- Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129-39.
- Brown E, Rajeev SP, Cuthbertson DJ, et al. A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium‐glucose co‐transporter‐2 inhibitors. Diabetes Obes Metab. 2019;Suppl 2:9-18.
- Rotkvić PG, Berković MC, Bulj N, et al. Sodium-glucose cotransporter 2 inhibitors’ mechanisms of action in heart failure. World J Diabetes. 2020;11(7):269-279.
- Lan NS, Fegan PG, Yeap BB, et al. The effects of sodium‐glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions. ESC Heart Fail. 2019;6(5):927-35.
- McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995-2008.
- Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-24.
- Damman K, Beusekamp JC, Boorsma EM et al. Randomized, double‐blind, placebo‐controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA‐RESPONSE‐AHF). Eur J Heart Fail. 2020;22(4):713-22.
- Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384:117-28.
Any editorial comments about this article can be sent to: Jane.Savio@worldwidediabetes.org