A recent study published in Nature Medicine evaluated the effects of semaglutide with or without the use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (SGLT2i) in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).
Study: Effect of semaglutide with or without an SGLT2 inhibitor in patients with type 2 diabetes and chronic kidney disease in the FLOW trial. Image credit: Caroline Ruda / Shutterstock
Patients with CKD or T2D are at increased risk for cardiovascular complications and renal failure. Preliminary trials of SGLT2i versus glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) have evaluated cardiovascular outcomes in patients with high cardiovascular risk and T2D. Some of these trials have found benefits for both drug classes.
The “Weekly Semaglutide to Assess Renal Function” (FLOW) trial was the first to conduct kidney-specific outcomes in patients with CKD and T2D. It found clear benefits of semaglutide treatment on renal and cardiovascular outcomes and survival. GLP-1 RAs have a significant effect on CKD or cardiovascular outcomes, heart failure, and death.
Similarly, SGLT2i are also effective in preventing heart failure and cardiovascular disease. The combined use of both drug classes may further improve clinical outcomes. However, no studies have examined the effects of the two drug classes on cardiovascular and renal disease in patients with CKD and T2D.
About the Research
In this study, researchers evaluated the potential safety and benefits of semaglutide with and without an SGLT2i in patients with CKD and T2D. Patients with CKD and T2D were randomized to receive once-weekly semaglutide or a matching placebo. Participants were adults (aged 18 years or older) with T2D, impaired renal function, and treatment with a renin-angiotensin-aldosterone inhibitor.
Subjects were excluded if they had hypersensitivity to the study drug, stroke, myocardial infarction, uncontrolled/unstable diabetic retinopathy, hereditary/congenital renal disease, solid organ transplant, use of GLP-1 RA within 30 days, etc. The primary endpoint was a composite of a ≥50% decline in estimated glomerular filtration rate (eGFR) from baseline sustained for at least 28 days or death from cardiovascular or renal causes.
In addition, the team evaluated kidney-specific outcomes that were identical to the primary endpoint, except for cardiovascular death. Secondary outcomes included rate of kidney function decline, major adverse cardiovascular events (MACE), and all-cause mortality. Time-to-event endpoints were examined with Cox proportional hazards models.
Investigation result
The researchers screened more than 5,500 patients and randomized 3,533, of whom 550 reported baseline SGLT2i use. Vital status was available for 98.2% of subjects who were SGLT2i users at baseline and 98.6% of those who were not. Baseline SGLT2i users were younger, less likely to be female, had lower systolic blood pressure, and higher eGFR. Except for metformin, rates of hypoglycemic medication use were similar between SGLT2i users and nonusers.
Use of renin-angiotensin system inhibitors was reported by 97% of SGLT2i users and 95% of non-SGLT2i users. There was an increase in non-SGLT2i users initiating SGLT2i use during the study, especially in the placebo group. During a median follow-up of 3.4 years, among those using SGLT2i at baseline, primary outcome events occurred in 14.8% of semaglutide and 13.9% of placebo users, respectively. Corresponding estimates in non-users were 19.5% and 24.9%, respectively.
Renal-specific composite outcomes occurred in 11.6% and 9.9% of semaglutide and placebo patients, respectively, in the baseline SGLT2i use subgroup. In non-users, renal-specific outcomes were recorded in 12.5% ​​of semaglutide patients and 15.6% of placebo patients. MACE was less frequent in the semaglutide group, regardless of baseline SGLT2i use.
All-cause mortality was also lower in the semaglutide group and did not differ between subgroups of subjects who used SGLT2i drugs at baseline and those who did not.Among subjects in the semaglutide and placebo groups who used SGLT2i drugs at baseline or initiated an SGLT2i drug during the trial, primary endpoint events occurred in 14.6% and 16.6%, respectively. In contrast, in subjects who did not use an SGLT2i drug at baseline or initiated an SGLT2i drug during the trial, the corresponding estimates were 20.7% and 27.2%, respectively.
Conclusion
The results suggest that the cardiovascular and renal effects of semaglutide are not affected by concomitant SGLT2i use. The effect of semaglutide on mortality and MACE did not differ between baseline SGLT2i users and non-users. The results suggest that the survival or cardiovascular effects of semaglutide are independent of SGLT2i. Given the efficacy and acceptable safety profile, the combination of semaglutide with an SGLT2i may be considered for patients with CKD and T2D.
Journal References:
Mann JFE, Rossing P, Bakris G, et al. “Effects of semaglutide with or without concomitant SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease in the FLOW trial.” Nat Med, 2024, DOI: 10.1038/s41591-024-03133-0, https://www.nature.com/articles/s41591-024-03133-0
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