The benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with heart failure were serendipitously discovered years ago during index trials in patients with type 2 diabetes. These data suggested that SGLT2 inhibitors provided a degree of cardiovascular protection in patients with type 2 diabetes, because many of those enrolled did not have a comorbid diagnosis of heart failure.1 Researchers soon began to redirect their attention toward the efficacy of SGLT2 inhibitors in reducing cardiovascular events and heart failure-related hospitalizations. Over the past 5 years, numerous trials have provided compelling safety and efficacy data in favor of SGLT2 inhibitor use in patients with type 2 diabetes and heart failure with reduced ejection fraction. This ultimately led to the completion of the DAPA-HF trial, evaluating SGLT2 inhibitors as an independent therapy for patients with heart failure with reduced ejection fraction.1 In 2020, the FDA approved dapagliflozin as a novel therapeutic agent to reduce cardiovascular disease (CVD) risk and hospitalization rates in patients with heart failure with reduced ejection fraction who have New York Heart Association (NYHA) functional class II through IV symptoms, regardless of whether or not they carry a comorbid diagnosis of type 2 diabetes.2

THERAPEUTIC MECHANISMS

In a physiologically normal kidney, glucose is coupled with sodium for transport into the proximal convoluted tubule by way of an electrochemical gradient.3 SGLT1 and SGLT2 facilitate the reentry of sodium and glucose into the cell.3 Ninety percent of glucose is reabsorbed in the proximal convoluted tubule via SGLT2, leaving the remaining 10% to be reabsorbed via SGLT1 more distally.3 Therefore, inhibiting SGLT2 increases urinary excretion of glucose and sodium. This in turn reduces cardiac preload, pulmonary and systemic congestion, and the sodium content in skin and muscle.3 Notably, the degree of sodium retention in these tissues is believed to be closely correlated with the development of left ventricular (LV) hypertrophy in patients with chronic kidney disease.4 Additional cardiovascular benefits include reduced oxidative stress secondary to better glycemic control, tempered activation of the renin-angiotensin-aldosterone system (RAAS), and a shift in cardiac fuel consumption from carbohydrates to fatty acids and ketone bodies.3

CLASS EFFECT OF SGLT2 INHIBITORS

Multiple glucose-lowering therapies such as thiazolidinediones and sulfonylureas have historically been associated with deleterious cardiovascular risks, including hospitalization for heart failure, myocardial infarction (MI), and CVD-related death.5 The FDA now requires cardiovascular outcome trials (CVOTs) to be performed on any novel antihyperglycemic agent. SGLT2 inhibitors have been broadly examined in CVOTs to evaluate their respective risk of CVD-related death, nonfatal MI, and nonfatal stroke. Empagliflozin, canagliflozin, and dapagliflozin have each demonstrated considerable cardiovascular risk reduction compared with placebo.5 Additionally, multiple trials have demonstrated a 30% to 35% reduction in heart failure-related hospitalizations in patients treated with SGLT2 inhibitors compared with placebo.6 Packer and colleagues make an important distinction that this risk reduction cannot be attributed to better blood glucose control alone, because other antihyperglycemic agents lack favorable CVD outcomes.7 Packer and colleagues studied empagliflozin in patients with NYHA class II through IV heart failure symptoms and LV ejection fraction of 40% or less (EMPEROR-Reduced trial).7 Combined risk for CVD-related death or heart failure-hospitalization was 25% lower in patients randomized to empagliflozin compared with those on placebo, regardless of the patient's background heart failure therapies or diabetes status.7 This article focuses on dapagliflozin therapy. However, other SGLT2 inhibitors may soon find a role in CVD management.

Box 1RESULTS FROM THE DAPA-HF TRIAL

McMurray and colleagues' landmark multicenter, multinational randomized controlled trial evaluated SGLT2 inhibitor use in patients with heart failure with reduced ejection fraction, with and without a comorbid diagnosis of type 2 diabetes.1 Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure—also known as DAPA-HF—enrolled 4,744 patients with NYHA functional class II through IV heart failure symptoms, LV ejection fraction of 40% or less, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) of at least 600 pg/mL (or 400 pg/mL if the patient had been hospitalized for heart failure within 12 months of enrollment).1 These patients were randomized to receive dapagliflozin (10 mg once daily) or placebo over 18 months in addition to appropriate underlying guideline-directed medical therapy (GDMT) for heart failure and type 2 diabetes. At the time of screening, 42% of patients in both the treatment and placebo groups had an underlying diagnosis of type 2 diabetes. Patients were evaluated at 14 days, 60 days, 120 days, and in 4-month intervals thereafter to assess their volume status, heart failure symptoms, renal function, potassium levels, and any adverse medication reactions. The primary endpoints were defined as worsening heart failure necessitating hospitalization or urgent IV therapy and death related to a cardiovascular event. Among those enrolled, 502 patients (21%) in the placebo arm of the study experienced worsening heart failure or CVD-related death compared with 386 patients (16.3%) in the dapagliflozin group (hazard ratio 0.74; 95% CI; P < .001).1 A substantial percentage of patients enrolled in the dapagliflozin arm (58.3% versus 50.9% in the placebo arm) experienced subjectively improved heart failure symptoms when surveyed with the Kansas City Cardiomyopathy Questionnaire as a secondary composite outcome.1

PRACTICAL APPLICATIONS IN PATIENT CARE

The DAPA-HF trial suggested that dapagliflozin is equally efficacious in preventing heart failure readmissions and CVD-related death in patients without type 2 diabetes as it is in those with comorbid diabetes. Beyond that, most patients treated with dapagliflozin who had existing chronic kidney disease did not experience a meaningful decrement in renal function, contrary to initial concerns of acute kidney injury and hypovolemia from augmented diuresis.1 Clinicians should consider adding dapagliflozin for all patients with heart failure with reduced ejection fraction who are able to tolerate underlying goal doses of GDMT.

GDMT refers to the use of target treatment doses of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs)/angiotensin receptor-neprilysin inhibitors, and mineralocorticoid receptor antagonists in eligible patients—that is, those not limited by subjective intolerance, allergy, symptomatic hypotension, or renal dysfunction. Clinicians often fail to up-titrate medical therapies to goal doses: data gathered through the CHAMP-HF registry highlights these shortcomings.8 In a 12-month analysis of 2,558 patients with heart failure with reduced ejection fraction who qualified for beta-blockers, ACE inhibitor/ARB/angiotensin receptor-neprilysin inhibitor, and mineralocorticoid receptor antagonist therapy, fewer than 1% of patients reached stable target dosing.8 When considering the introduction of novel heart failure agents such as SGLT2 inhibitors, clinicians also must continue to prioritize up-titration of existing conventional therapies in tandem. This often can be accomplished with monthly BP checks coupled with routine laboratory work (basic metabolic panel), and a visit with a skilled clinician to incrementally increase doses of GDMT. Dapagliflozin can be started and up-titrated in conjunction with beta-blockers, ACE inhibitor/ARB/angiotensin receptor-neprilysin inhibitor, and mineralocorticoid receptor antagonist therapy as tolerated.

LIMITATIONS OF USE

SGLT2 inhibitors have been associated with dehydration, metabolic acidosis/ketoacidosis, Fournier gangrene, as well as yeast and urinary tract infections—specifically in patients who are older, hypotensive, or have some degree of renal insufficiency.1 The reported rates of volume depletion and serious renal adverse events in the DAPA-HF treatment group were noted to be 1.2% and 1.6%, respectively.1 Before initiating dapagliflozin, talk to patients about their risks and benefits of therapy.

CONCLUSION

Although SGLT2 inhibitors were originally designed to treat type 2 diabetes, they have since been proven to reduce hospitalization rates and CVD-related death in patients with heart failure with reduced ejection fraction, even in those who do not have diabetes. Dapagliflozin is now considered GDMT for patients with heart failure with reduced ejection fraction, along with beta-blockers, ACE inhibitor/ARB/angiotensin receptor-neprilysin inhibitor, and mineralocorticoid receptor antagonist therapy.

Reported rates of serious adverse reactions in the DAPA-HF treatment group were low, suggesting that most patients with heart failure with reduced ejection fraction can safely be started on dapagliflozin therapy with appropriate follow-up and clinical monitoring.

REFERENCES 1. McMurray JJ, 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. 2. US Food and Drug Administration. FDA approves new treatment for a type of heart failure. www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Accessed May 5, 2022. 3. Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors. J Am Coll Cardiol. 2020;75(4):422–434. 4. Schneider MP, Raff U, Kopp C, et al. Skin sodium concentration correlates with left ventricular hypertrophy in CKD. J Am Soc Nephrol. 2017;28(6):1867–1876. 5. Kluger AY, Tecson KM, Lee AY, et al. Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovasc Diabetol. 2019;18(1):99. 6. Zelniker TA, Wiviott SD, Raz I, 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. Lancet. 2019;393:31–39. 7. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413–1424. 8. Greene S, Fonarow G, DeVore A, et al. Longitudinal changes in medication dosing among patients with heart failure with reduced ejection fraction: from the Champ-HF registry. J Am Coll Cardiol. 2019;73(9):707.