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Diabetes Distilled: Dapagliflozin and new-onset type 2 diabetes in people with chronic kidney disease or heart failure

Kevin Fernando
The SGLT2 inhibitor dapagliflozin was tested on participants with heart failure with reduced ejection fraction in the DAPA-HF study and chronic kidney disease in the DAPA-CKD study. Both studies included people with and without type 2 diabetes. This new exploratory analysis of pooled data from the two studies aimed to assess the effects of dapagliflozin on new-onset type 2 diabetes. It found that treatment with dapagliflozin significantly reduced the incidence of new-onset type 2 diabetes in participants with heart failure and chronic kidney disease, without a reduction in HbA1c. While this provides a clear benefit in the management of those with these comorbidities, it is unclear whether dapagliflozin has a prevention effect in the broader population.

The seminal DAPA-HF study demonstrated that treatment with the SGLT2 inhibitor dapagliflozin resulted in a highly significant 26% relative risk reduction (RRR) in a primary composite endpoint of a worsening heart failure event (unplanned heart failure hospitalisation or an urgent heart failure visit requiring intravenous therapy) or cardiovascular death. Absolute risk reduction (ARR) was 4.9%, translating into a number needed to treat (NNT) of 21 over 1.5 years. DAPA-HF recruited individuals with heart failure with reduced ejection fraction, both with and without type 2 diabetes. Notably, treatment effects in individuals were similar irrespective of diabetes status.

Since more than half of DAPA-HF participants did not have type 2 diabetes at baseline, the authors took the opportunity to assess whether dapagliflozin might reduce the incidence of new-onset type 2 diabetes. This exploratory analysis of the DAPA-HF study concluded that dapagliflozin reduced the incidence of type 2 diabetes by 32% in 2605 individuals in DAPA-HF without type 2 diabetes at baseline, suggesting a preventative role for SGLT2 inhibitors in developing type 2 diabetes.

This is similar to the RRR of metformin reported in diabetes prevention studies, such as the Diabetes Prevention Program in the US (RRR 31%).

Of note, the effect of dapagliflozin on type 2 diabetes incidence was mainly driven by individuals with “pre-diabetes” (based on the American Diabetes Association’s definition of HbA1c 5.7–6.4% [39–46 mmol/mol]). Worryingly, those with new-onset diabetes were observed to have greater mortality.

The authors of this exploratory analysis did acknowledge several limitations, including the short 18-month duration of follow-up. Can we make meaningful conclusions about type 2 diabetes prevention within this timeframe? Furthermore, and like all exploratory analyses, this can only be hypothesis-generating.

The equally seminal DAPA-CKD study demonstrated that dapagliflozin also resulted in a highly significant 39% RRR in a primary composite endpoint of a decline of ≥50% in eGFR, new end-stage renal disease, renal death or cardiovascular mortality. ARR was 5.3%, translating into a NNT of 19 over 2.4 years. DAPA-CKD recruited individuals with chronic kidney disease (CKD), both with and without type 2 diabetes and, again notably, treatment effects in individuals were similar irrespective of diabetes status.

Similar to DAPA-HF, there was a numerical reduction in the number of people who developed type 2 diabetes during the DAPA-CKD trial, so a pooled analysis of the DAPA-CKD and DAPA-HF trials was undertaken to evaluate further the effect of dapagliflozin on new-onset type 2 diabetes. CKD and heart failure are well established as insulin-resistant states associated with a high incidence of type 2 diabetes.

4003 participants without type 2 diabetes at baseline were included from the DAPA-CKD and DAPA-HF trials. Half had received dapagliflozin and half had received placebo.

Over a median follow-up of 21.2 months, 6.3% of the placebo group and 4.3% of the dapagliflozin group developed type 2 diabetes. This translates into a 33% RRR in type 2 diabetes incidence with dapagliflozin. More than 90% of participants who developed type 2 diabetes had pre-diabetes at baseline (again based on the ADA definition). 

Moreover, there was no suggestion that the effect of dapagliflozin varied in pre-specified subgroups that included gender, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure and baseline cardiovascular medication use.

Importantly, mean HbA1c remained unchanged between those treated with dapagliflozin or placebo, both in those who did or did not develop type 2 diabetes. This suggests that the observed effect of dapagliflozin is separate to its glucose-lowering effects, perhaps an indirect effect on some of the underlying pathophysiological abnormalities seen in pre-diabetes, such as insulin resistance. The authors acknowledge one of the limitations of this study was that insulin sensitivity or resistance was not assessed.

Interestingly, in the EMPEROR-Reduced and EMPEROR-Preserved trials, empagliflozin was not observed to have a significant impact on new-onset type 2 diabetes in those without diabetes at baseline. Recruited participants in these studies were generally older and more obese than participants in DAPA-HF and DAPA-CKD, which may have contributed to this observation.

In conclusion, dapagliflozin has been demonstrated to reduce the incidence of new-onset type 2 diabetes in people living with heart failure and CKD, independent of its glucose-lowering effects. This is clearly advantageous when managing these comorbidities. However, it remains to be proven whether dapagliflozin has a diabetes prevention effect in a broader population of people living with pre-diabetes without significant comorbidities.

Click here to read the study in full.

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