Dapagliflozin as a Possible Diabetes Prevention Drug?

Study finds incidence of type 2 diabetes reduced by 32% in participants taking dapagliflozin vs. placebo, suggesting a possible prevention role.  

Diabetes mellitus affects more than 34 million Americans, and 90-95% of these have type 2 diabetes. The prevalence of type 2 diabetes continues to increase over time, and most of the people diagnosed with the condition are over 45 years old. Symptoms of type 2 diabetes can be present for a long time before the patient notices them and begins to manage the health condition. The disease can progress and lead to severe damage, especially cardiovascular events and even death, if the patient doesn’t make lifestyle modifications. Due to the high incidence of diabetes, prevention is essential in the population. Some analyses have been performed to evaluate the incidence of cardiovascular events and hyperglycemia, but limited data exist on the effect of anti-diabetic medication in the prevention of diabetes. 

In this recent cohort study, researchers studied the effect of dapagliflozin on incident type 2 diabetes in patients without diabetes enrolled in the “Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure” (DAPA-HF) trial. DAPA-HF was a randomized controlled trial that included 4,744 patients with Heart Failure Reduced Ejection Fraction (HFrEF). They included HF class II-IV patients based on NYHA and Left Ventricular Ejection Fraction (LVEF) ≤40%. They excluded patients with prior history of type 1 diabetes and those with eGFR <30ml/min/1.73m2. Patients in the dapagliflozin group were using 10mg once daily or matching placebo orally. These patients were followed up for two weeks, two months, and four months until trial completion. As primary outcomes, researchers looked at cardiovascular death or worsening heart failure. As secondary outcomes, they looked for heart failure hospitalization (primary or recurrent) or cardiovascular death and changes in heart failure symptoms from baseline to 8 months. All these patients underwent HbA1C testing at baseline and during each follow-up. Those previously diagnosed with type 2 diabetes and those with HbA1C ≥6.5% were excluded from this cohort study. From the 4,744 participants in the randomized clinical trial, only 2,605 were included in this cohort study. These 2,605 were participants with prediabetes (HbA1C: 5.7-6.4%) and with normoglycemia (HbA1C: <5.7%). During this study, clinicians performed Cox proportions analysis to obtain hazard ratios and 95% CI to evaluate dapagliflozin compared to placebo on incident diabetes. They also adjusted for HbA1c at baseline to assess the consistency of data. Time-to-event was assessed based on the time from randomization to new-onset diabetes. New-onset diabetes was defined as the date of the first HbA1C of ≥6.5%. 

During the study, the median duration of follow-up was 18.2 months. 502 participants achieved the primary outcome from the placebo group, whereas this occurred in 386 participants in the dapagliflozin group. The relative risk was reduced by 26% (HR: 0.74, 95% CI: 0.65-0.85: p<0.001). Of the 2,605 participants, 1,748 had prediabetes, and 857 participants had normoglycemia. Researchers found some differences between patients with prediabetes and normoglycemia. These differences include age: the mean age was 67.1 in the prediabetic group vs. 64.5 years in the normoglycemia group (p<0.001). Also, BMI of 27.4 vs. 26.8 kg/m2 (p=0.023) and HbA1c of 6.0% vs. 5.3% (p<0.001) for prediabetic group vs. normoglycemia. At baseline, the patients without diabetes had an HbA1C of 5.8% in the placebo group vs. 5.7% in the dapagliflozin group. At eight months follow-up, the HbA1C did not vary. For the prediabetic group, the mean baseline HbA1c level was 5.9% for those taking dapagliflozin vs. 6.0% for those in the placebo group. Results showed that for the group using dapagliflozin, the HbA1C decreased -0.08% (95% CI: -0.10 to -0.06) compared to a decrease in -0.04% (95% CI: -0.07 to -0.02) in the placebo group. On the other hand, for the normoglycemic group, when comparing the HbA1c at baseline and eight months, the HbA1C increases by 0.10% with dapagliflozin and 0.15% with placebo. 

Moreover, from the 2,605 participants without diabetes at baseline, 157 developed type 2 diabetes during follow-up. Of those 157 participants, 95.5% had prediabetes. Researchers noticed that those with incident type 2 diabetes had a higher HbA1c at baseline 6.2% vs. 5.7% (p<0.001), higher BMI (28.5 vs. 27.1 (p<0.003), and lower eGFR (61.5 vs. 68.2 (p<0.001), and were commonly using statins, versus those who remained without diabetes. Of the 157 participants who developed type 2 diabetes, 93 belonged to the placebo group, and 64 were in the dapagliflozin group. The use of dapagliflozin led to a 32% reduction in diabetes incidence (HR: 0.68, 95% CI: 0.50-0.94; p=0.019). After diagnosing type 2 diabetes in these patients, the death rate from any cause increased more than 2-fold that of patients who did not develop diabetes. 

If diabetes is prevented, patients will have lower risks of developing micro and macrovascular complications. This study showed that dapagliflozin could prevent the incidence of diabetes. The results showed that the incidence of diabetes was reduced by 32% with dapagliflozin. Diabetes prevention is essential to decrease cardiovascular events. There is no FDA-approved medication to prevent diabetes, but more studies can be performed on this drug for potential FDA indication in the future. As for now, diabetic prevention includes lifestyle modifications and increased physical activity. 

Practice Pearls: 

• The risk of incident diabetes is decreased by 32% with dapagliflozin.  
• Dapagliflozin is used in patients with HFrEF for the reduction in cardiovascular mortality and worsening of heart failure. Still, this study showed that it could decrease the incidence of new diabetes. 
• Diabetic prevention studies focused on the progression of hyperglycemia, but limited data exist on the effect of diabetic prevention and chronic vascular complications. 

Inzucchi, S, 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)  

Laura Martínez López, PharmD. Candidate 2021, Lake Erie College of Osteopathic Medicine, College of Pharmacy