Reduced new-onset T2D: Another benefit of dapagliflozin

Dapagliflozin reduced the incidence of new-onset type 2 diabetes (T2D) in patients with heart failure and reduced ejection fraction (HFrEF), according to a prespecified exploratory analysis of the DAPA-HF* trial.

“While the major role of dapagliflozin is to reduce cardiovascular (CV) mortality and worsening of HF, decreasing incident diabetes could be considered an additional benefit,” said study author Professor Silvio E. Inzucchi from the Yale University School of Medicine and Yale Diabetes Center, New Haven, Connecticut, US, who presented the findings at ADA 2020.

“In this very high-risk population, the safety profile of dapagliflozin was excellent, the treatment well-tolerated with low discontinuation rates,” he added.

Of the 4,744 patients with HFrEF (NYHA class II–IV and LVEF** ≤40 percent) enrolled in the DAPA-HF trial, 55 percent (n=2,605) were without T2D at baseline (mean age 66.2 years, 75.7 percent male, mean BMI 27.2 kg/m², mean HbA_1c 5.8 percent). They were randomized to receive once-daily doses of dapagliflozin (10 mg) or placebo. Median follow-up was 18.2 months.

A total of 157 patients (6.0 percent) developed T2D, 95.5 percent of whom (n=150) had pre-diabetes at baseline (HbA_1c 5.7–6.4 percent).

There was a 32 percent significant reduction in the incidence of new-onset T2D, defined as HbA_1c ≥6.5 percent at two consecutive assessments or initiation of glucose-lowering medication, among those assigned to dapagliflozin vs placebo (4.9 percent vs 7.1 percent; hazard ratio [HR], 0.68, 95 percent confidence interval, 0.50–0.94; p=0.019). [ADA 2020, abstract 271-OR]

Compared with those who did not develop T2D, those who did had a higher baseline HbA_1c (mean 6.2 vs 5.7; p<0.001), higher BMI (mean 28.5 vs 27.1 kg/m²; p=0.003), and lower estimated glomerular filtration rate (eGFR; mean 61.5 vs 68.2 mL/min/1.73 m²; p<0.001), with a greater proportion with eGFR <60 mL/min/1.73 m² (48.4 percent vs 35.5 percent; p=0.001).

The effects of dapagliflozin in reducing new-onset T2D appeared greater among patients aged ≤65 vs >65 years (HR, 0.44 and 0.89, respectively; p=0.04) or with below vs above median NT-proBNP levels (HR, 0.42 and 1.02; p=0.01).

Exploratory analysis suggested an increased risk of all-cause mortality (HR, 1.70; p=0.035) and CV death (HR, 1.77; p=0.035) with new-onset T2D vs non-diabetics. 

Inzucchi noted that the findings only applied to patients with HFrEF, and that the lack of oral glucose tolerance testing or fasting plasma glucose assessments were limitations. “We will need to do more studies to see if this effect extends to patients without HFrEF and to evaluate how durable the benefit might be and how long diabetes prevention persists after the discontinuation of therapy.”

“DAPA-HF was the first trial to show the effectiveness of an SGLT2*** inhibitor (dapagliflozin) to improve clinical outcomes in patients with HFrEF with or without T2D,” pointed out Inzucchi. This was previously demonstrated with a reduction in a composite of CV death and worsening HF with dapagliflozin vs placebo (HR, 0.74; p=00001), a result consistent regardless of whether patients did or did not have T2D (HR, 0.75 and 0.73, respectively). [N Engl J Med 2019;38:1995-2008]

“DAPA-HF is [also] the first trial to demonstrate a “diabetes prevention” effect from an SGLT2 inhibitor,” he added. He noted that the minimal reduction in HbA_1c with dapagliflozin in those without diabetes at baseline “may dispel concerns about merely masking the development of T2D.”