Are SGLT2 Inhibitors Only Suitable for the Treatment of Diabetes?
SGLT2 inhibitors, or gliflozins, are effective antidiabetic drugs that have shown nephroprotective and cardioprotective effects in diabetics, repeatedly demonstrated in clinical trials. At the European Cardiology Congress in September 2019 in Paris, results were presented from the DAPA-HF study, where dapagliflozin became the first SGLT2 inhibitor to show benefits in patients with heart failure with reduced ejection fraction of the left ventricle, regardless of whether they had type 2 diabetes or not. The study thus offered a completely new perspective on the treatment of heart failure.
Cardioprotective Effects of Antidiabetic Drugs
Type 2 diabetes mellitus is a serious cardiovascular risk factor, and it is therefore necessary to have proven cardioprotective effects not only in new antidiabetic drugs but also in existing ones. Newly designed studies with antidiabetic drugs are therefore focused both on monitoring parameters related to hyperglycemia and on the cardiovascular safety of therapy. An example of a classical antidiabetic with proven reduction in cardiovascular risk is metformin, which has long been and rightly remains the first-line drug for type 2 diabetes, as confirmed in the latest therapeutic guidelines review from December 2019.
Previous studies with gliflozins have also shown that cardiovascular risk in diabetics is not only not increased but even reduced. This reduction was largely due to the influence on heart failure, raising the clear question of whether gliflozins can influence heart failure in patients without diabetes. This question was addressed by the aforementioned DAPA-HF study.
The DAPA-HF Study
Study Population, Course, and Objectives
DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a multicentric randomized study that enrolled 4,744 patients from 20 countries worldwide, including the Czech Republic. All had diagnosed heart failure according to NYHA (New York Heart Association) class II, III, or IV with reduced left ventricular ejection fraction (< 40%) and elevated NT-proBNP values. The average age of the participants was 66 years, predominantly men (approximately 77%), with most in NYHA class II, an average LV ejection fraction of 31%, and an NT-proBNP value around 1400 pg/ml at study entry.
Patients with and without diabetes were randomized into groups receiving dapagliflozin (10 mg once daily) or placebo in addition to optimized heart failure treatment according to current guidelines.
The primary endpoint was a composite of cardiovascular mortality and worsening heart failure, defined as unplanned hospitalization or urgent clinic visit requiring intravenous heart failure treatment.
Findings
Patients were followed for an average of 18.2 months. The primary endpoint occurred in 16.3% of the dapagliflozin group and 21.2% of the placebo group (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.65–0.85; p < 0.001), indicating a significant 26% reduction with dapagliflozin treatment. Dapagliflozin users experienced significantly lower rates of each individual endpoint: worsening heart failure (10.0% vs. 13.7%; HR 0.70; 95% CI 0.59–0.83), cardiovascular mortality (9.6% vs. 11.5%; HR 0.82; 95% CI 0.69–0.98), and overall mortality (11.6% vs. 13.9%; HR 0.83; 95% CI 0.71–0.97). Importantly, the positive effect of dapagliflozin was observed in both diabetic and non-diabetic patients.
Dapagliflozin was well tolerated. The number of participants who discontinued treatment was comparable in both groups: 249 in the dapagliflozin group and 258 in the placebo group.
Discussion and Conclusion
Dapagliflozin demonstrated that gliflozins are not only very effective antidiabetics but could also be successfully used in other areas of medicine in the future. Findings from the DAPA-HF study could soon be implemented into real-world clinical practice for the treatment of heart failure with reduced LV ejection fraction.
A currently unanswered question is whether this treatment effect will also be observed in patients with preserved LV ejection fraction and whether it is a so-called class effect. Answering these questions will require several more years, as additional studies with gliflozins are currently underway in patients with both reduced and preserved LV ejection fraction.
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Source: McMurray J. J. V., Solomon S. D., Inzucchi S. E. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995−2008, doi: 10.1056/NEJMoa1911303.
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