Dapagliflozin Prevents T2D in Adults With Heart Failure

Prophylactic treatment with a sodium-glucose co-transporter 2 (SGLT-2) inhibitor slashed the risk of developing type 2 diabetes (T2D), according to a new study.

In a prespecified exploratory analysis from the DAPA-HF trial, once-daily treatment with 10 mg of dapagliflozin (Farxiga) reduced the risk of new-onset diabetes by 32% (HR 0.68, 95% CI 0.50-0.94, P=0.019), reported Silvio Inzucchi, MD, of Yale School of Medicine in New Haven, Connecticut.

Of the 2,605 participants who were free of diabetes at study entry, a total of 157 developed diabetes during a median follow-up of 18.2 months.

This included 93 of those on placebo (93 of 1,307; 7.1%) and 64 of those on dapagliflozin (64 of 1,298; 4.9%), Inzucchi explained during a presentation at the American Diabetes Association (ADA) virtual meeting.

“While the major role of dapagliflozin in patients with [heart failure with reduced ejection fraction] is to reduce cardiovascular mortality and worsening heart failure, decreasing the incidence of type 2 diabetes may be considered an additional benefit, especially since incident diabetes is associated with greater mortality,” said Inzucchi.

“In contrast to other diabetes prevention trials with glucose-lowering medications, HbA1c was minimally reduced by dapagliflozin in the non-diabetic patients at baseline,” he noted, adding that this “may dispel concerns about merely masking the development of diabetes, which has been raised with other diabetes prevention trials using glucose-lowering medications.”

Certain clinical factors were predictive of progression to T2D, one of the strongest being prediabetes at baseline: an HbA1c between 5.7% to 6.4%. In total, 95.5% of those who developed incident diabetes during follow-up had prediabetes at baseline, the study showed.

Even a more restrictive definition of prediabetes — a baseline HbA1c between 6.0% to 6.4% — was also predictive, as 87% of those who developed diabetes had their baseline A1c fall within this range.

Overall, when compared with those who remained free of diabetes throughout follow-up regardless of treatment, the top three factors that were predictive of progression to diabetes were higher average baseline HbA1c, elevated body mass index (BMI), and lower estimated glomerular filtration rate (eGFR):

  • Baseline A1c: 6.2 ±0.3 for new-onset T2D vs 5.7 ±0.4% for those who remained free of T2D
  • Greater BMI: 28.5 ±5.9 for new-onset T2D vs 27.1 ±5.7 remained free of T2D
  • Lower eGFR: 61.5 ±17.4 for new-onset T2D vs 68.2 ±19.3 ml/min/1.73 m2 remained free of T2D

First approved in 2014 as a treatment for T2D, dapagliflozin also gained an indication in October 2019 for heart failure hospitalization risk-reduction in adults with T2D at elevated risk due to established cardiovascular disease or multiple risk factors. And most recently, in May 2020, the FDA approved dapagliflozin for the treatment of heart failure with reduced ejection fraction, even in people without diabetes, based on the main findings of the DAPA-HF trial.

To be included in the study, all participants had to have a left ventricular ejection fraction of 40% or lower, a New York Heart Association symptom class of II, III, or IV, as well as the biomarker of N-terminal pro b-type natriuretic peptide (NT-proBNP) of 600 pg/mL or more. Those with T2D, renal failure defined by an eGFR below 30 ml/min/1.73 m2, or a systolic blood pressure under 95 mmHg were excluded.

For this prespecified analysis, HbA1c testing was performed at baseline and at each study visit during follow-up. Incident diabetes during follow-up was defined as an HbA1c of 6.5% or higher at two consecutive visits or by a diagnosis of T2D by the participant’s healthcare provider marked with a new prescription of a glucose-lowering medication.

Certain subgroups also saw a significantly greater protective benefit with daily dapagliflozin. Specifically, younger individuals — age 65 and younger — saw a 56% reduced risk for developing incident T2D (HR 0.44, 95% CI 0.26-0.75). Also, those who fell below the median for baseline NT-proBNP levels had a 58% reduced risk of developing diabetes (HR 0.42, 95% CI 0.26-0.69).

Interestingly, those who fell into the median upper half for NT-proBNP levels didn’t see any protective benefit from dapagliflozin for new-onset diabetes risk (HR 1.02, 95% CI 0.66-1.56).

Not surprisingly, those who did develop incident diabetes during follow-up had a significant increase in their cardiovascular risk. This included a 70% (adjusted HR 1.70, 95% CI 1.04-2.80) increased risk for all-cause mortality and a 77% (aHR 1.77, 95% CI 1.04-3.02) increased risk of cardiovascular death after developing diabetes.

Regarding study limitations, Inzucchi said he and his colleagues did not assess fasting plasma glucose or perform oral glucose tolerance testing — something that is typically used in traditional diabetes prevention trials. In addition, the findings are applicable only to patients with heart failure with reduced ejection fraction.

“It’s unknown if the effect of this medication on incident type 2 diabetes would be durable over time,” he said, noting that the trial was a relatively short 18 months, since it was an event-driven trial.

Inzucchi concluded by highlighting that dapagliflozin is the first medication that showed reduction in both incident T2D and mortality in a single trial. However, he said, further research is still needed to see whether those treatment effects are linked.

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    Kristen Monaco is a staff writer, focusing on endocrinology, psychiatry, and dermatology news. Based out of the New York City office, she’s worked at the company for nearly five years.


The DAPA-HF study was funded by AstraZeneca.

Inzucchi reported grant funding from the National Institute of Diabetes and Digestive and Kidney Diseases, and financial relationships with AstraZeneca, Boehringer-Ingelheim, Sanofi/Lexicon, Novo Nordisk, vTv Therapeutics, Abbott, and Merck.