GLP-1 receptor agonists reduce kidney failure risk and cardiovascular events

With evidence from 85,373 participants across 11 trials, GLP-1 receptor agonists significantly reduced kidney failure risk and cardiovascular events, showing consistent benefits across diabetes and non-diabetes populations.

In a recent study published in The Lancet Diabetes Endocrinology, researchers evaluate the effects of glucagon-like peptide-1 (GLP-1) receptor agonists on kidney and cardiovascular outcomes.

Improving kidney and cardiovascular outcomes

Non-communicable diseases account for nearly 70% of global deaths, with diabetes and chronic kidney disease (CKD) among the top causes.

CKD affects over 850 million people worldwide and is projected to become the fifth leading cause of death by 2050, driven primarily by the obesity epidemic and rising type 2 diabetes prevalence. These conditions, which are collectively referred to as cardiovascular-kidney-metabolic syndrome, are strongly interlinked, with overlapping risk factors contributing to poor outcomes.

Although sodium-glucose cotransporter-2 (SGLT2) inhibitors and GLP-1 receptor agonists show promise in reducing cardiovascular and kidney risks, the potential for GLP-1 receptor agonists to prevent kidney failure remains unclear. Thus, further research is needed to clarify the role of these medications in broader populations and long-term outcomes.

About the study

The current study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with the protocol registered in the International Prospective Register of Systematic Reviews (PROSPERO). Eligible randomized controlled trials included at least 500 participants with type 2 diabetes, compared GLP-1 receptor agonists to placebo over at least 12 months, and reported clinical kidney or cardiovascular outcomes.

Trials involving dual-acting GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonists or surrogate outcomes were excluded. Post hoc, the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial, which was the first to assess GLP-1 receptor agonists in participants without diabetes, was incorporated into the analysis.

A search of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) through March 2024 identified eligible studies. The risk of bias was assessed using the Cochrane Risk of Bias 2 tool.

Primary outcomes included a composite kidney outcome, which comprised kidney failure, 50% or more estimated glomerular filtration rate (eGFR) decline, or death from kidney disease. Major adverse cardiovascular events (MACE) like cardiovascular death, nonfatal myocardial infarction, or stroke were also considered primary study outcomes.

Statistical analyses used hazard ratios (HRs) with random-effects models, heterogeneity was assessed through I², and evidence was graded using Grading of Recommendations Assessment, Development, and Evaluation (GRADE).

Study findings

Database searches identified 5,136 records, with four additional records identified from other sources. After removing 1,066 duplicates, 4,074 records were screened, and 176 full-text articles were assessed for eligibility.

Ultimately, the meta-analysis included 11 trials from 21 articles. These studies comprised 85,373 participants, with a median sample size of 6,068.

Five trials focused on participants with cardiovascular disease or risk factors, three trials included participants with cardiovascular disease alone, one trial enrolled those with cardiovascular or kidney disease and additional risk factors, and one included participants regardless of cardiovascular history. Ten trials involved patients with type 2 diabetes, whereas one SELECT trial included individuals without diabetes.

Baseline characteristics were balanced across GLP-1 receptor agonist and placebo groups, with a median follow-up period of 25.2 months. The mean baseline eGFR was 77.2 mL/min/1.73 m², with 22.7% of participants having eGFR values below 60 mL/min/1.73 m².

Eight trials administered interventions weekly, whereas others used daily dosing or continuous infusions. Most studies included MACE as the primary cardiovascular outcome, whereas kidney outcomes varied across studies.

GLP-1 receptor agonists reduced the composite kidney outcome risk by 18% in study participants with type 2 diabetes, with consistent effects observed when the SELECT trial was included. Kidney failure risk and worsening kidney function were reduced by 16% and 21%, respectively.

MACE risk was reduced by 13% in individuals with diabetes and 14% when SELECT was included in the analysis. Subgroup analyses identified consistent treatment effects across different groups, with no significant heterogeneity observed by diabetes status for most outcomes.

GLP-1 receptor agonists also reduced the risk of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and all-cause mortality, with high-certainty evidence. Hospitalization for heart failure was reduced by 13%.

Serious adverse events were similar between groups, although treatment discontinuation due to adverse events was more frequently reported in the GLP-1 receptor agonist group. There was no increased incidence of pancreatic or thyroid cancers, acute pancreatitis, severe hypoglycemia, or retinopathy.

Conclusions

The current study identifies an 18% reduction in composite kidney outcomes, a 16% decrease in kidney failure, and a 13% reduction in MACE risk in patients with type 2 diabetes prescribed GLP-1 agonists. Importantly, these benefits extended to cardiovascular death, myocardial infarction, stroke, and all-cause mortality.

GLP-1 receptor agonists were effective across a wide range of patient subgroups and exhibited consistent results regardless of diabetes status. Although treatment discontinuation due to adverse effects was reported, no significant differences were observed in major adverse events, thus emphasizing the safety and clinical utility of these medications.

Journal reference:

• Badve, S. V., Bilal, A., Lee, M. M. Y., et al. (2024). Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. The Lancet Diabetes Endocrinology. doi:10.1016/S2213-8587(24)00271-7