A new umbrella review reveals how GLP-1 therapies shape cardiovascular, renal, and metabolic outcomes in type 2 diabetes while highlighting drug-specific advantages and the need to manage gastrointestinal risks.

Study: Efficacy and safety of glucagon-like peptide 1 receptor agonists across all health outcomes in type 2 diabetes: An umbrella review and evidence map of randomised controlled trials. Image Credit: zimmytws / Shutterstock

Study: Efficacy and safety of glucagon-like peptide 1 receptor agonists across all health outcomes in type 2 diabetes: An umbrella review and evidence map of randomised controlled trials. Image Credit: zimmytws / Shutterstock

In a recent study published in the journal Diabetes, Obesity, and Metabolism, researchers conducted an umbrella review to examine the efficacy and safety of glucagon-like peptide 1 receptor agonists, GLP-1RAs, across all health outcomes in type 2 diabetes, T2D.

Multifaceted Physiological Effects and Safety Concerns

GLP-1RAs are established as a cornerstone therapy for T2D, improving glycemic control by suppressing glucagon, delaying gastric emptying, and enhancing insulin secretion.

An increasing body of evidence suggests that GLP-1RAs may offer benefits beyond glycemic control, such as protective effects across cardiovascular, renal, hepatic, and endocrine systems.

The wide-ranging effects are believed to stem from the broad expression of glucagon-like peptide-1 receptors in extrapancreatic tissues. Nonetheless, the widespread distribution of these receptors raises concerns about potential unintended physiological effects associated with GLP-1RAs.

Clinical trials have identified higher risks of gastrointestinal (GI) events such as pancreatitis, bowel obstruction, biliary disease, and gastroparesis.

Umbrella Review Approach and Evidence Selection

The researchers comprehensively assessed health outcomes associated with GLP-1RA treatment in patients with T2D. A literature search across Embase, CINAHL, Google Scholar, PubMed, and MEDLINE identified meta-analyses of randomized controlled trials (RCTs) evaluating the effects of GLP-1RAs.

Studies were excluded if they were network meta-analyses, compared GLP-1RAs only to placebo, used non-human models, duplicated outcomes, or did not isolate independent drug effects. Data on study characteristics, outcomes, and effect sizes were extracted.

Methodological quality was assessed using AMSTAR 2.

Analytical Framework and Evidence Grading

Individual estimates from included meta-analyses were re-analyzed using fixed-effect and random-effects models. Heterogeneity was quantified with the I-squared statistic. Certainty of evidence was evaluated using the GRADE methodology.

Cardiovascular and Metabolic Benefits Identified

Searches identified 3145 records, and after screening, 17 meta-analyses of 432 RCTs were included, covering 65 outcomes across cardiovascular, metabolic, oncologic, renal, GI, and other clinical domains. GLP-1RA use was associated with reduced risk of peripheral artery disease and heart failure, although certainty was low.

No class-level associations were found for myocardial infarction, cardiovascular composite outcomes, blood pressure, major adverse cardiovascular events, MACE, stroke, or heart rate.

Drug-specific findings showed that liraglutide, albiglutide, and dulaglutide were associated with a lower risk of MACE, myocardial infarction, and stroke, with moderate or high certainty.

Drug-Specific Effects on Blood Pressure and Organ Health

Semaglutide and exenatide were associated with reductions in systolic blood pressure. Semaglutide was also linked with reduced cerebrovascular outcomes, a pattern not observed at the class level.

Regarding renal outcomes, GLP-1RAs were associated with a lower risk of kidney-specific composite outcomes, nephropathy, and albuminuria, although certainty was low. GLP-1RAs were linked with metabolic improvements, including reductions in visceral and hepatic fat, with moderate or low certainty.

These drugs also reduced glycated hemoglobin and body weight. Semaglutide further decreased fasting plasma glucose, visceral adipose tissue, and body weight.

Gastrointestinal Risks and Neutral Findings in Cancer and Immunity

GLP-1RA use was not associated with overall cancer risk, and drug-specific analyses showed no significant associations. Notably, GLP-1RAs were consistently linked to increased GI adverse effects such as nausea, dyspepsia, and constipation, with high or moderate certainty. GLP-1RA use was not associated with retinopathy, macular edema, or class-level cerebrovascular outcomes.

The drugs were associated with reduced C-reactive protein levels, whereas most adipokines and cytokines showed no consistent patterns. 

GLP-1RAs were linked with increased bone mineral density in the lumbar spine and hip, neck, and were not associated with influenza, all-cause adverse events, or nasopharyngitis.

Overall Implications for T2D Treatment and Safety Monitoring

Overall, GLP-1RAs were associated with improved glycemic control and reduced renal, metabolic, and cardiovascular risks, without elevating cancer risk, supporting their use in individuals with cardiorenal comorbidities. However, adverse GI effects, particularly nausea, constipation, and dyspepsia, remain notable considerations.

The study emphasizes that cerebrovascular benefits observed with semaglutide do not generalize to the entire GLP-1RA class.

Future work should prioritize long-term safety and personalized therapeutic strategies to optimize GLP-1RA use in T2D management.