SGLT2i reduces new-onset T2DM in patients with HFrEF
Dapagliflozin and the Incidence of Type 2 Diabetes in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis From DAPA-HF
Introduction and methods
T2DM is preceded by prediabetes, a prolonged asymptomatic phase with mild hyperglycemia . Strategies to prevent transition from prediabetes to T2DM include lifestyle changes, bariatric surgery or several glucose-lowering or weight loss medications . SGLT2i induce glucosuria and thereby lower blood glucose and HbA1c concentrations. In addition, outcome trials have shown that SGLT2i reduce MACE, HF hospitalization and progression of CKD in patients with T2DM at high CV or renal risk . The DAPA-HF trial demonstrated that SGLT2i dapagliflozin reduced CV death and worsening HF in patients with HFrEF . It remained unknown whether dapagliflozin could prevent incident T2DM in this population. This prespecified exploratory analysis of DAPA-HF evaluated whether dapagliflozin could reduce incidence of new T2DM in patients with HFrEF without diabetes at baseline.
In DAPA-HF [4,5], 4744 patients with HFrEF were randomized to receiving dapagliflozin (10 mg, once daily) or matching placebo. All patients underwent HbA1c testing at baseline and at each study visit (at 2 weeks, 2 months, and 4 months after randomization and then every 4 months until completion of the trial). For this analysis, individuals with a prior diagnosis of T2DM or with HbA1c ≥6.5% at both enrollment and randomization visits were excluded. The remaining cohort comprised of participants (n=2605) with normoglycemia (HbA1c <5.7%, n= 857 [33%]) or with prediabetes (HbA1c between 5.7 and 6.4%, n=1748 [67%]). The exploratory endpoint of this analysis was a new diagnosis of T2DM, defined as either HbA1c ≥6.5% on two consecutive follow-up visits or clinical diagnosis of diabetes outside the trial setting leading to initiation of a glucose-lowering agent. Median follow-up was 18.2 months (IQR 14.2-21.5).
- Of the 2605 participants in this analysis, 157 (6.0%) developed T2DM during follow-up, of whom 150 (95.5%) had prediabetes (based on the ADA definition) at baseline.
- Compared to those whose HbA1c remained in the nondiabetic range, participants with new-onset T2DM had higher HbA1c at baseline (mean±SD: 6.2%±0.3% vs. 5.7%±0.4%, P<0.001), higher BMI (28.5±5.9 kg/m² vs. 27.1±5.7, P=0.003), lower eGFR (61.5±17.4 vs. 68.2±19.3 mL/min/1.73 m²), and were more commonly using a statin (72% vs. 61%, P=0.006).
- New-onset T2DM occurred in 7.1% (93 of 1307) of patients in the placebo group and in 4.9% (64 of 1298) of patients in the dapagliflozin group. A Cox proportional hazards model showed that dapagliflozin reduced the risk of incident T2DM with 32% (HR 0.68, 95%CI 0.50-0.94, P=0.019). Divergence of the event curves was detectable by the 4-month visit.
- Risk of death from any cause was higher in patients who developed new-onset T2DM compared to those who did not develop T2DM (adjusted HR 1.70, 95%CI 1.04-2.80, P=0.035).
This exploratory analysis of DAPA-HF showed that dapagliflozin, compared to placebo, reduced the risk of new-onset T2DM in patients with HFrEF without T2DM at baseline. Most patients who developed T2DM during follow-up had prediabetes at baseline. Patients who developed new-onset T2DM had higher subsequent mortality compared to those who did not develop T2DM. Trials of longer duration and in people without HF are needed to confirm the potential benefit of dapagliflozin in reducing new-onset T2DM.