SGLT2 inhibitors lower risk of incident diabetes in patients with CVD or kidney disease

SGLT2 inhibition reduced the incidence of new-onset diabetes by 26% to 33% compared with placebo in patients with CVD or CKD, as shown by a pooled analysis of the DELIVER and DAPA-HF trials and a meta-analysis of 7 RCTs.

This summary is based on the publication of Ostrominski JW, Højbjerg Lassen MC, Claggett BL, et al. - Sodium-glucose co-transporter 2 inhibitors and new-onset diabetes in cardiovascular or kidney disease. Eur Heart J. 2024 Nov 21:ehae780 [Online ahead of print]. doi: 10.1093/eurheartj/ehae780

Introduction and methods

Background

In patients with HF, other forms of CVD, or kidney disease, prevention or delay of diabetes is important to improve health outcomes in these high-risk populations.

Aim of the study

The study aim was to determine the effects of SGLT2 inhibitors on incident diabetes in HF patients across the LVEF spectrum and across the broader spectrum of CVD or CKD.

Methods

To assess the effects of dapagliflozin (10 mg once daily) versus placebo on new-onset diabetes in HF across the LVEF spectrum, the authors conducted a participant-level pooled analysis of 2 international, multicenter, double-blind, placebo-controlled, phase 3 RCTs: the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials [1,2]. Major inclusion criteria included NYHA class II–IV HF symptoms, LVEF ≤40% (DAPA-HF) or >40% (DELIVER), and elevated NT-proBNP levels. In the current analysis, 5623 participants with HbA1c <6.5%, no history of diabetes, and no glucose-lowering therapy at baseline were included.

To examine the composite effects of SGLT2 inhibitors versus placebo on new-onset diabetes, the authors performed a systematic search in PubMed and Embase to identify RCTs comparing SGLT2 inhibitors (dapagliflozin or empagliflozin) with placebo in ≥1000 adult patients with CVD or kidney disease published between January 1, 2015, and January 1, 2024. They then conducted a trial-level meta-analysis with inverse-variance weighting of the included complementary CV and kidney outcomes trials (n=17,855). These were trials in HF patients (DELIVER, DAPA-HF, EMPEROR-Preserved, and EMPEROR-Reduced) [1-5], CKD patients (DAPA-CKD and EMPA-KIDNEY) [6,7], or post–acute MI patients (DAPA-MI) [8].

Outcomes

In the pooled analysis of the DAPA-HF and DELIVER trials, the endpoint was the incidence of new-onset diabetes, defined as the new initiation of glucose-lowering therapy during follow-up. In the meta-analysis of the 7 trials, the definition of new-onset diabetes differed between trials.

Main results

Participant-level pooled analysis of DAPA-HF and DELIVER

• In the pooled analysis of the DAPA-HF and DELIVER trials, dapagliflozin reduced the incidence of new-onset diabetes compared with placebo during a median follow-up time of 22 months (2.3% vs. 3.5%; HR: 0.67; 95%CI: 0.49–0.91; P=0.012; estimated number needed to treat (NNT): 83).
• The treatment effect of dapagliflozin on incident diabetes was similar between the 2 trials (P for interaction=0.67).
• Subgroup analysis showed generally consistent results across subgroups stratified by age, sex, LVEF category, baseline glycemic status, or eGFR category (all P for interaction>0.05).
• When LVEF was analyzed as a continuous variable, there was no evidence of heterogeneity in the treatment effect of dapagliflozin versus placebo on new-onset diabetes across the LVEF spectrum (P for interaction=0.98).
• The frequency of serious adverse events was higher among patients who developed new-onset diabetes compared with those who did not (71.3% vs. 37.1%), regardless of the assigned treatment arm (P for interaction=0.54). However, no ketoacidosis or major hypoglycemic events were observed in either treatment group.

Trial-level meta-analysis of CV and kidney outcomes trials

• The meta-analysis of 7 RCTs showed SGLT2 inhibition reduced the rate of new-onset diabetes compared with placebo during a median follow-up range of 11.6 months to 2.4 years (HR: 0.74; 95%CI: 0.65–0.85; P<0.001; P for heterogeneity=0.42; estimated NNT: 77).

Conclusion

In a participant-level pooled analysis of the DAPA-HF and DELIVER trials, dapagliflozin reduced the incidence of new-onset diabetes by 33% compared with placebo in HF patients, irrespective of baseline HbA1c level, LVEF, or eGFR and without increasing the risk of hypoglycemia. In addition, a trial-level meta-analysis of 7 large-scale RCTs showed SGLT2 inhibitors reduced the rate of incident diabetes by 26% compared with placebo in patients with CVD, such as HF, or CKD. The authors conclude “these findings extend understanding of the wide-ranging cardiovascular–kidney–metabolic benefits of SGLT2 [inhibitors], highlighting the potential of robust implementation efforts to reduce the burden of diabetes across the HF spectrum.”

Find this article online at Eur Heart J.

References

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