DAPA HF - analysis of risk of new onset type 2 diabetes in patients with HFrEF

DAPA-HF trial demonstrated that SGLT2i dapagliflozin reduced CV death and worsening HF in patients with HFrEF (1)

A prespecified exploratory analysis of DAPA-HF evaluated whether dapagliflozin could reduce incidence of new T2DM in patients with HFrEF without diabetes at baseline (2):

Exclusions from analysis:

• individuals who had a diagnosis of T2DM at baseline were excluded from this subanalysis
• individuals whose HbA1c was >=6.5% (>=48 mmol/mol) at both the enrollment and randomization visits (i.e., repeated and confirmed and therefore considered a diagnosis of T2D) were excluded from this analysis

Study cohort:

• participants (n=2605) with normoglycemia (HbA1c <5.7%, n= 857 [33%]) or with prediabetes (HbA1c between 5.7 and 6.4%, n=1748 [67%])
• 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
• 157 (6.0%) developed T2DM during follow-up (median 18.2 months), of whom 150 (95.5%) had prediabetes (based on the ADA definition (HbA1c 5.7-6.4%) at baseline
• compared to those whose HbA1c remained in the nondiabetic range, participants with new-onset T2DM had:
  • higher HbA1c at baseline,
  • higher BMI at baseline,
  • lower eGFR (61.5+/-17.4 vs. 68.2+/-19.3 mL/min/1.73 m²),
  • more commonly using a statin (72% vs. 61%, P=0.006)
    
    
• Of those who developed T2DM - 4.9% (64 of 1298) were treated with dapagliflozin versus 7.1% (93 of 1307) treated with placebo
• Dapagliflozin reduced the risk of incident T2DM by 32% (HR 0.68, 95%CI 0.50-0.94, P=0.019). Detection of divergence of the event curves was apparent by the 4-month visit
• it was noted that risk of death from any cause was higher in patients who developed new-onset T2DM to those who did not develop T2DM (adjusted HR 1.70, 95%CI 1.04-2.80, P=0.035)

Commentary (3):

DAPA-HF is a trial which showed benefit of an SGLT2 inhibitor (dapagliflozin) in reducing both CV death and worsening HF in patients with heart failure with reduced ejection fraction (HFrEF).DAPA-HF included patients with and without Type 2 Diabetes (T2DM) with HFrEF.

However, SGLT2 inhibitors were first developed as glucose lowering drugs in Type 2 Diabetes (T2DM) and the question then arises 'How does the use of SGLT2 inhibitors in patients with HFrEF, who do not have T2DM, affect subsequent T2DM risk?' This important analysis of the DAPA-HF data by Inzucchi et al (2) addresses this question. The study results have shown that that there was a significant (32%) reduction in risk of new onset T2DM in the dapagliflozin treated group in comparison to placebo. This significant effect was seen during a relatively short trial period (median 18.2 months) and the divergence of incidence of new onset T2DM was apparent from the 4-month trial visit. Other points of interest include the higher incidence of diabetes seen with patients with a lower eGFR at baseline; and a higher risk on statins versus those not on statins.

Reference:

1. 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; 381:1995-2008.
2. Inzucchi SE, Docherty KF, Kober L et al.Dapagliflozin and the Incidence of Type 2 Diabetes in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis From DAPA-HF Diabetes Care. 2021 Feb;44(2):586-594. doi: 10.2337/dc20-1675.
3. Commentary - Dr Jim McMorran (Editor in Chief GPnotebook); February 20th 2021