Semaglutide proves a game-changer for kidney and heart health in diabetes patients

By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Jun 25 2024

A recent study published in the journal Nature Medicine evaluated the effects of semaglutide with and without the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) in people with chronic kidney disease (CKD) and type 2 diabetes (T2D).

Study: Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Image Credit: Caroline Ruda / Shutterstock

People with CKD or T2D are at high risk for cardiovascular complications and kidney failure. Preliminary trials with SGLT2i and glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) in those with high cardiovascular risk and T2D were powered for cardiovascular outcomes. Some of these trials revealed benefits for both drug classes.

The “Evaluate Renal Function with Semaglutide Once Weekly” (FLOW) trial was the first trial with dedicated kidney outcomes in people with CKD and T2D. The trial revealed clear benefits of semaglutide treatment on kidney and cardiovascular outcomes and survival. GLP-1 RAs are substantially beneficial for CKD or cardiovascular outcomes, heart failure, and death.

Likewise, SGLT2i are also effective in preventing heart failure and cardiovascular outcomes. A combination of both drug classes might further augment clinical outcomes. However, no study has examined the effects of the two drug classes on cardiovascular and kidney outcomes in those with CKD and T2D.

About the study

In the present study, researchers evaluated the potential safety and benefits of semaglutide with and without SGLT2i use in people with CKD and T2D. Patients with CKD and T2D were randomized to receive semaglutide once weekly or a matched placebo. Eligible subjects were adults (≥ 18 years) with T2D, renal impairment, and treatment with renin-angiotensin-aldosterone inhibitors.

Subjects were excluded if they had hypersensitivity to trial products, stroke, myocardial infarction, uncontrolled/unstable diabetic retinopathy, hereditary/congenital kidney diseases, solid organ transplant, and GLP-1 RA use within ≤ 30 days, among others. The primary outcome was a composite of onset of ≥ 50% reduction in estimated glomerular filtration rate (eGFR) from baseline sustained for at least 28 days or death due to cardiovascular or kidney-related causes.

Besides, the team assessed a kidney-specific outcome identical to the primary outcome but without cardiovascular deaths. Secondary outcomes included the rate of kidney function loss, major adverse cardiovascular events (MACEs), and all-cause mortality. Cox proportional hazard models examined time-to-event endpoints.

Findings

The researchers screened over 5,500 patients and randomized 3,533 individuals; of these, 550 subjects reported baseline SGLT2i use. Vital status was confirmed for 98.2% of subjects using SGLT2i at baseline and 98.6% of those not using it. People who used SGLT2i at baseline were younger, less frequently female, had lower systolic blood pressure, and higher eGFR. The prevalence of glucose-lowering medication use was similar between SGLT2i users and non-users, except for metformin.

Renin-angiotensin system inhibitors use was reported by 97% of SGLT2i users and 95% of non-users of SGLT2i. An increasing number of non-SGLT2i users initiated SGLT2i use during the trial, especially in the placebo group. During a median of 3.4 years of follow-up, primary outcome events occurred in 14.8% of semaglutide and 13.9% of placebo recipients, respectively, in those with baseline SGLT2i use. The corresponding estimates among non-users were 19.5% and 24.9%, respectively.

The kidney-specific composite outcome occurred in 11.6% and 9.9% of semaglutide and placebo recipients in the subgroup with baseline SGLT2i use. Among non-users, the kidney-specific outcome was recorded in 12.5% of semaglutide subjects and 15.6% of placebo recipients. MACEs were less frequent in the semaglutide group regardless of baseline SGLT2i use.

All-cause death was also less frequent in the semaglutide group, with no differences between subgroups with and without baseline SGLT2i use. Primary outcome events occurred in 14.6% and 16.6% of semaglutide and placebo subjects, respectively, who used SGLT2i at baseline or initiated it during the trial. By contrast, the corresponding estimates were 20.7% and 27.2% in those who did not use SGLT2i at baseline or initiate it during the trial.

Conclusions

The findings suggest that the benefits of semaglutide on cardiovascular and kidney outcomes were unaffected by the concomitant use of SGLT2i. Semaglutide effects on mortality and MACE were not different between baseline SGLT2i users and non-users. The results suggest that the survival or cardiovascular benefits of semaglutide are independent of SGLT2i. Given the benefits and acceptable safety profile, the combination of semaglutide and SGLT2i could be considered for patients with CKD and T2D.