SGLT2 Inhibitor, GLP-1 RA Combination Improves Cardiovascular, Kidney Outcomes in Diabetes

Findings from a recent study are providing support for the combined use of sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists to optimize cardiovascular and kidney outcomes in patients with diabetes.¹

The collaborative meta-analysis examined 12 randomized controlled trials included in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium (SMART-C) and found consistent effects of SGLT2 inhibitors on cardiovascular and kidney outcomes, regardless of GLP-1 receptor agonist use.¹

“Given the rapidly expanding indications for the use of GLP-1 receptor agonists, it was important to look at their effects with SGLT2 inhibitors,” Brendon Neuen, MBBS, PhD, nephrologist and director of the Kidney Trials Unit at Royal North Shore Hospital, said in a press release.² “This study represents the largest and most comprehensive assessment of clinical outcomes for this combination of medicines.”

To evaluate the benefits of SGLT2 inhibitors with and without the use of GLP-1 receptor agonists, investigators conducted a collaborative meta-analysis using data from trials participating in SMART-C, which comprises completed, randomized, double-blind, placebo-control­ led, event-driven trials assessing the effects of an SGLT2 inhibitor on a primary clinical outcome in adults ≥ 18 years of age, restricted to trials with > 500 participants in each group and with a follow-up of ≥ 6 months. In this analysis, investigators focused on trials enrolling patients with diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease.¹

In total, 12 trials from SMART-C were assessed, with the analysis cohort restricted to trials exclusively enrolling participants with diabetes, and participants with diabetes enrolled in the following heart failure and chronic kidney disease trials: DAPA-CKD, EMPA-KIDNEY, DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER. Treatment effects from individual trials were obtained from Cox regression models and pooled using inverse variance weighted meta-analysis.¹

The main cardiovascular outcomes were major adverse cardiovascular events, defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, and hospitalization for heart failure or cardiovascular death. The main kidney outcomes were chronic kidney disease progression, defined as ≥40% decline in estimated glomerular filtration rate (eGFR), kidney failure (eGFR <15 mL/min/1·73 m², chronic dialysis, or kidney transplantation), or death due to kidney failure, and the rate of change in eGFR over time. Investigators also assessed safety outcomes, focusing primarily on serious adverse events since this outcome was available in all trials using common serious adverse event criteria for reporting.¹

Across the 12 trials included in the present study, 73,238 (82.1%) of 89,183 participants had diabetes, 3065 (4.2%) of whom were using GLP-1 receptor agonists at baseline. Investigators noted GLP-1 receptor agonist use varied across all trials, with a range of 2.8-4.4% in the atherosclerotic cardiovascular disease trials, 4.2-11.1% in the chronic kidney disease progression trials, and 1.0-2.2% in the heart failure trials.¹

In total, 7187 (9.8%) participants had a major adverse cardiovascular event, including 268 (3.7%) who were receiving GLP-1 receptor agonist and 6919 (96.3%) who were not receiving a GLP-1 receptor agonist at baseline. Investigators pointed out the incidence of major adverse cardiovascular events was greatest in the heart failure trials compared with all other trials and noted the effect of SGLT2 inhibitors on major adverse cardiovascular events was consistent in participants both receiving and not receiving GLP-1 receptor agonists (hazard ratio [HR], 0.81; 95% CI, 0.63–1.03 vs HR, 0.90; 95% CI, 0.86–0.94; P-heterogeneity = .31).¹

Overall, 6260 (8.5%) participants were hospitalized for heart failure or died due to cardiovascular disease, the majority of whom were not receiving a GLP-1 receptor agonist at baseline (n = 6049; 96.6%). Similar to major adverse cardiovascular events, the incidence was greatest in the heart failure trials. Of note, the effect of SGLT2 inhibitors on hospitalization for heart failure or cardiovascular death (HR, 0.77; 95% CI, 0.74-0.81) was consistent in participants receiving GLP-1 receptor agonists (HR, 0.76; 95% CI, 0.57-1.01) and those not receiving GLP-1 receptor agonists (HR, 0.78; 95% CI, 0.74-0.82; P-heterogeneity = .90).¹

Regarding the composite kidney outcome, investigators noted the incidence was greatest in the chronic kidney disease trials, with 3294 (4.5%) participants experiencing chronic kidney disease progression, including 3164 (96.1%) patients who were not receiving a GLP-1 receptor agonist at baseline. SGLT2 inhibitors reduced the risk of chronic kidney disease progression (HR, 0.67; 95% CI, 0.62-0.72), with similar efficacy in participants receiving and not receiving GLP-1 receptor agonists (HR, 0.65; 95% CI, 0.46-0.94 vs HR, 0.67; 95% CI, 0.62-0.72; P-heterogeneity = .81).¹

Investigators pointed out fewer serious adverse events occurred with SGLT2 inhibitors compared with placebo, irrespective of GLP-1 receptor agonist use (relative risk, 0.87; 95% CI, 0.79-0.96 vs relative risk, 0.91; 95% CI, 0.89-0.93; P-heterogeneity = .41).¹

Investigators outlined several limitations to these findings, some of which included the limited number of outcomes for patients using GLP-1 receptor agonists; the inability to derive estimated treatment effects from one-stage meta-analysis; the lack of time-updated analyses beyond baseline; and the grouping of all GLP-1 receptor agonists without consideration for different agents within the class.¹

“SGLT2 inhibitors have clear protective effects against heart failure and chronic kidney disease, while GLP-1 receptor agonists can reduce the risk of heart attack, stroke, and also kidney disease - as recently demonstrated in the landmark FLOW trial,” Neuen concluded.² “Our findings support using this combination to further improve outcomes in patients with type 2 diabetes who meet guideline recommendations for both therapies.”

References

1. ^{Apperloo EM, Neuen BL, Fletcher RA, et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials. The Lancet Diabetes & Endocrinology. https://doi.org/10.1016/S2213-8587(24)00155-4}
2. ^{George Institute for Global Health. Combining popular diabetes drugs offers complementary heart and kidney benefits. EurekAlert! July 8, 2024. Accessed July 9, 2024. https://www.eurekalert.org/news-releases/1050506}