Introduction

Patients with heart failure (HF) and other forms of cardiovascular diseases (CVD), or kidney disease are at an increased risk of developing insulin resistance and metabolic impairment, thus putting them at a high risk for the development and adverse health effects of diabetes. Prevention or delay of diabetes is thus a critical treatment priority in these high-risk patient subgroups. Currently, sodium-glucose co-transporter 2 inhibitors (SGLT2i) is a core component of the pharmacotherapy for HF patients irrespective of the left ventricular ejection fraction (LVEF). Studies have demonstrated that SGLT2is have beneficial metabolic effects of relevance for insulin sensitivity and diabetes risk. Hence, optimal treatment with SGLT2i in HF patients renders a substantial opportunity to reduce the risk of diabetes.

Aim

To determine the impact of SGLT2i on incident diabetes in HF patients across the LVEF spectrum and across the broader spectrum of CVD or kidney disease.

Patient Profile

• Patients with HF with New York heart association (NYHA) functional class II–IV symptoms, LVEF > 40%, evidence of structural heart disease, and elevated serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations.
• Participants with no history of diabetes, baseline glycated hemoglobin (HbA1c) <6.5%, and not using glucose-lowering therapy (GLTs) at baseline were included in the pooled analysis. Study subjects were further classified as having pre-diabetes (HbA1c 5.7%–6.4%) and normoglycemia (HbA1c <5.7%) at baseline as per the American Diabetes Association definitions.

Methods

Study Design

• The study was divided into two parts as follows:
  • A participant-level pooled analysis of 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
  • A broader trial-level meta-analysis of seven complementary CVD and kidney disease outcomes trials (summarize the effects of SGLT2i on new-onset diabetes).

  Treatment Strategy

• Patients in the DAPA-HF and DELIVER trial were randomized 1:1 to receive dapagliflozin (10 mg once a day) or placebo.

  Outcomes

• The incidence of new-onset diabetes

  Results

• The pooled analysis of DAPA-HF and DELIVER included 5623 participants with HF but without diabetes or GLT use at baseline.
• A total of 164 (2.9%) participants developed new-onset diabetes requiring GLT during a median follow-up of 22 months [incidence rate: 1.58; 95% confidence interval (CI): 1.35–1.84 per 100 person-years]. Of these, 121 (74%) had pre-diabetes at baseline. The incidence rate of new-onset diabetes was similar in DAPA-HF trial (incidence rate: 1.51; 95% CI: 1.16–1.96 per 100 person-years) and DELIVER trial (incidence rate: 1.61; 95% CI: 1.34–1.95 per 100 person years).
• Fewer patients treated with dapagliflozin developed new-onset diabetes, requiring GLT (2.3% vs. 3.5%; incidence rate: 1.26 vs. 1.89 per 100 person-years). This translated into a significant 33% reduction in the incidence of new-onset diabetes with dapagliflozin [hazard ratio (HR): 0.67; 95% CI: 0.49–0.91; P =0.012], as compared with placebo (Fig. 1).

• Treatment effects of dapagliflozin on incident diabetes remained consistent between the clinical trials (P_interaction =0.67) and between participants with normoglycemia (HR: 0.83; 95% CI 0.46–1.05) and pre-diabetes (HR: 0.62; 95% CI 0.43–.90) at baseline (P_interaction = 0.43).
• Benefits of dapagliflozin were also consistent across age, sex, race, LVEF category, baseline glycemic status, and estimated glomerular filtration rate (eGFR) category. The treatment effect of dapagliflozin vs. placebo exhibited no heterogeneity across the spectrum of continuous LVEF or key subgroups.
• Regardless of the treatment assignment, the incidence of serious adverse safety events was higher among participants who developed new-onset diabetes vs. those who did not. However, neither subgroup experienced major hypoglycemia events (i.e. all participants without diabetes and no GLT use at baseline).
• The meta-analysis of CV and renal events was based on the data from the DELIVER, DAPA-HF, EMPEROR-Preserved, EMPEROR- Reduced, DAPA-CKD, EMPA-KIDNEY, and DAPA-MI trials (n=17855; SGLT2i group: n=8938; placebo group: n=8917).
• Fewer patients treated with SGLT2i developed new-onset diabetes, compared to those treated with placebo (4.2% vs. 5.5%).
• Treatment with either dapagliflozin or empagliflozin was associated with a 26% lower rate of new-onset diabetes (HR: 0.74; 95% CI .65–.85; P < 0.001), the treatment effect being consistent across trials.

Conclusions

• The comprehensive meta-analysis examined the totality of evidence from all CV and kidney outcome trials of SGLT2i that have been conducted in HF patients without diabetes.
• Treatment with SGLT2i reduced incident diabetes requiring the initiation of GLT in HF patients across the LVEF spectrum, without excess risk of major hypoglycemia.
• Treatment with SGLT2i was associated with a reduced incidence of new-onset diabetes, requiring the initiation of GLT among individuals with CVD or kidney disease.
• Early implementation of SGLT2i may have an important additional benefit on prevention or delay of diabetes in this high-risk patient population.

Eur Heart J. 2024 Nov 21 (Online ahead of print):ehae780. doi: 10.1093/eurheartj/ehae780.