In 2013, sodium-glucose cotransporter 2 (SGLT2) inhibitors burst onto the scene and quickly earned the title of blockbuster medications. After its 2014 approval, dapagliflozin topped $1 billion in annual revenue in just 3 years.1 The new wave of antihyperglycemic medications showed promise as an adjunctive treatment to help patients with type 2 diabetes control blood sugar and reign in their A1c.

Early on in clinical trials, researchers observed dapagliflozin reduced incidence of new heart failure (HF). This sparked research into whether SGLT2 inhibitors have glucose independent mechanisms for improving patient outcomes.

Now a study published in September 2019 in the New England Journal of Medicine has found that patients HF with reduced ejection fraction (HFrEF) receiving dapagliflozin decreased their risk of worsening HF or death from cardiovascular causes.2 These benefits were observed in all patients regardless of diabetes status. 

The phase 3 placebo-controlled clinical trial randomized 4744 patients with New York Heart Association (NYHA) class 1, 3, or 4 HF and reduced ejection fraction of less than 40%. The patient population was split with 45% of patients with type 2 diabetes and 55% without the disease. Patients received either dapagliflozin 10 mg once daily or placebo in addition to standard of care. A composite of worsening HF or cardiovascular death was the primary outcome.

Use of dapagliflozin was associated with fewer symptoms of HF as measured by a patient questionnaire. These benefits, which were both substantial and clinically significant, occurred early after randomization. The study also pointed out that dapagliflozin was as effective in patients with type 2 diabetes as in those without the disease. The most common adverse event in the treatment group was volume depletion (7.2%). Incidence of severe hypoglycemia was rare and occurred in less than 0.2% of patients receiving dapagliflozin.

The researchers were concerned about using dapagliflozin in patients without diabetes (as initial diuresis is common), especially in those who were already taking loop diuretics and mineralocorticoid receptor antagonists or had significant renal failure. For this reason, they monitored initial diuresis, volume depletion, and worsening of renal function. Initial diuresis volume depletion occurred at similar rates in all groups, and renal failure was rare and significantly less frequent in patients treated with dapagliflozin. Interestingly, only patients with diabetes experienced major hypoglycemia or diabetic ketoacidosis, and it was rare.

This demonstrates the cardiovascular benefit of SGLT2 inhibitors regardless of diabetic status, and reinforces the theory of other glucose independent mechanisms of action. Overall, this study supports expanding the indication of dapagliflozin to include  patients diabetes with HFrEF less than 40% who do not have diabetes.

A limitation of the trial was the lack of diversity in the patient population. The study included few black patients or elderly patients with comorbidities.

References
1. AstraZeneca. AstraZeneca Annual Report and Form 20-F Information 2017. Dec 31, 2017. AstraZeneca’s website. https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual-report-2017/annualreport2017.pdf    

2. McMurray JJV, Solomon SD, Inzucchi SE, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection
fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008.