Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been used in the treatment of type 2 diabetes mellitus (T2DM) to inhibit renal glucose reabsorption and thereby increase urinary glucose loss.¹Kashiwagi A et al. J Diabetes Investig. Published online June 20, 2020. Recent landmark clinical trials of these inhibitors have also found that they confer cardiovascular benefits, including reductions in major adverse cardiovascular events, cardiovascular death, composite renal outcome, and heart failure (HF) hospitalisation.¹Kashiwagi A et al. J Diabetes Investig. Published online June 20, 2020. Notably, the latter is a major determinant of the prognosis of diabetes patients.¹Kashiwagi A et al. J Diabetes Investig. Published online June 20, 2020.

Dapagliflozin, an SGLT2 inhibitor, has been found to reduce HF hospitalisation in patients with T2DM.²Seferović PM et al. Eur J Heart Fail. n/a(n/a). The phase 3 DAPA-HF trial randomised 4,744 patients with and without T2DM and with New York Heart Association (NYHA) Class II, III, or IV HF and an ejection fraction ≤40% to receive standard-of-care (SOC) treatment plus either dapagliflozin 10mg once daily or matching placebo. The primary outcome was a composite endpoint of worsening HF – defined as unplanned hospitalisation or an urgent visit resulting in intravenous therapy for HF – or death due to any cardiovascular cause.³McMurray JJV et al. N Engl J Med. Published online September 19, 2019.

Approximately 42% of patients were known to have baseline T2DM, and an additional 3% of patients in each treatment group received a new diagnosis of T2DM during the course of the study.³McMurray JJV et al. N Engl J Med. Published online September 19, 2019. Results of the DAPA-HF trial reported showed that SOC plus dapagliflozin reduced the risk of worsening HF or death by 26% as compared to SOC plus placebo (p<0.001).[mfn referencenumber=3]McMurray JJV et al. N Engl J Med. Published online September 19, 2019.[/mfn] This effect was generally consistent over prespecified subgroups, which included patients without diabetes at baseline.³McMurray JJV et al. N Engl J Med. Published online September 19, 2019. The benefits were observed early after randomisation, and also seen in patients receiving other recommended therapies for HF.³McMurray JJV et al. N Engl J Med. Published online September 19, 2019. Serious adverse events (SAEs) related to volume depletion and serious renal events occurred in 1.2% and 1.6% of patients receiving dapagliflozin, respectively.³McMurray JJV et al. N Engl J Med. Published online September 19, 2019. Only 4.7% of patients discontinued therapy due to adverse events.³McMurray JJV et al. N Engl J Med. Published online September 19, 2019.

The results of a prespecified secondary analysis of DAPA-HF were recently presented at the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) Discoveries 2020.⁴Docherty KF. Late-Breaking Science Session 6 – Pharmacotherapy presented at the: HFA Discoveries 2020; June 19, 2020. The new analysis added “outpatient intensification of HF therapy” to the trial’s composite primary endpoint of cardiovascular death, HF hospitalisation, and urgent HF visit.⁴Docherty KF. Late-Breaking Science Session 6 – Pharmacotherapy presented at the: HFA Discoveries 2020; June 19, 2020.

Outpatient intensification of HF therapy was defined as a diuretic dosage increase, or new addition of an evidence-based HF medication.⁴Docherty KF. Late-Breaking Science Session 6 – Pharmacotherapy presented at the: HFA Discoveries 2020; June 19, 2020. Intensification was provided to 8.6% of the trial population and was associated with a 2-3x increased mortality risk in the adjusted analysis.⁴Docherty KF. Late-Breaking Science Session 6 – Pharmacotherapy presented at the: HFA Discoveries 2020; June 19, 2020. The analysis showed that the composite primary outcome was met by 16.5% per 100 patient-years (PY) of patients receiving dapagliflozin compared with 22.6% per 100 PY with placebo.⁴Docherty KF. Late-Breaking Science Session 6 – Pharmacotherapy presented at the: HFA Discoveries 2020; June 19, 2020. Dapagliflozin reduced the risk of the expanded composite outcome by 27%, and the number-to-treat (NTT) was 16.⁴Docherty KF. Late-Breaking Science Session 6 – Pharmacotherapy presented at the: HFA Discoveries 2020; June 19, 2020. The results of the prespecified secondary analysis indicate that the clinical benefits of dapagliflozin may be greater than previously thought.⁴Docherty KF. Late-Breaking Science Session 6 – Pharmacotherapy presented at the: HFA Discoveries 2020; June 19, 2020.

At the ESC Congress 2020, the results the EMPEROR-Reduced trial investigating empagliflozin in patients with heart failure with reduced ejection fraction (HFrEF) also showed a statistically different 25% reduction in the incidence of cardiovascular death or HF hospitalisation, consistent with the results of the DAPA-HF trial previously mentioned.⁵Packer M et al. N Engl J Med. doi: 10.1056/NEJMoa2022190 A secondary outcome of rate of eGFR decline over the trial duration also showed slower decline with empagliflozin than placebo (-0.55mL/min/1.73m² vs. -2.28mL/min/1.73m²; p<0.001). These benefits were observed regardless of patients receiving currently recommended drugs for HF, including sacubitril-valsartan.⁵ However, uncomplicated genital tract infection was reported more frequently with empagliflozin than placebo.⁵Packer M et al. N Engl J Med. doi: 10.1056/NEJMoa2022190

The consistent results of EMPEROR-Reduced solidify the class effects of SGLT2 inhibitors in reducing HF hospitalisations, and SGLT2 inhibitors could be recommended in the future to reduce the risk of HF hospitalisation in T2DM patients with established cardiovascular disease or who are at high cardiovascular risk.^2,5Seferović PM et al. Eur J Heart Fail. n/a(n/a).
Packer M et al. N Engl J Med. doi: 10.1056/NEJMoa2022190.