A new overview review reveals how GLP-1 therapies influence cardiovascular, renal, and metabolic outcomes in type 2 diabetes, while highlighting drug-specific advantages and the need to control gastrointestinal risks.
Study: Efficacy and safety of glucagon-like peptide-1 receptor agonists on all health outcomes in type 2 diabetes: an overview and evidence map of randomized controlled trials. Image Credit: zimmytws/Shutterstock
In a recent study published in the journal Diabetes, Obesity, and Metabolism, researchers conducted an overview to examine the efficacy and safety of glucagon-like peptide 1 receptor agonists, GLP-1RA, on all health outcomes in type 2 diabetes, T2D.
Multifaceted Physiological Effects and Safety Concerns
GLP-1RAs are established as a cornerstone therapy for type 2 diabetes as they improve glycemic control by suppressing glucagon, delaying gastric emptying, and improving insulin secretion.
A growing body of evidence suggests that GLP-1RAs may offer benefits beyond glycemic control, such as protective effects on the cardiovascular, renal, hepatic, and endocrine systems.
The wide-ranging effects are thought to arise from the broad expression of glucagon-like peptide-1 receptors in extrapancreatic tissues. However, the widespread distribution of these receptors raises concerns about possible unwanted physiological effects associated with GLP-1RAs.
Clinical trials have identified increased risks of gastrointestinal (GI) events, such as pancreatitis, intestinal obstruction, biliary disease, and gastroparesis.
Overview review and evidence selection approach
Researchers comprehensively evaluated health outcomes associated with GLP-1RA treatment in patients with type 2 diabetes. A literature search in Embase, CINAHL, Google Scholar, PubMed, and MEDLINE identified meta-analyses of randomized controlled trials (RCTs) evaluating the effects of GLP-1RAs.
We excluded studies that were network meta-analyses, that compared GLP-1RA alone with placebo, that used non-human models, that duplicated results, or that 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 qualification of evidence
Individual estimates from the included meta-analyses were reanalyzed using fixed-effects and random-effects models. Heterogeneity was quantified with the I-squared statistic. The certainty of the evidence was assessed using the GRADE methodology.
Cardiovascular and metabolic benefits identified
The searches identified 3145 records, and after screening, 17 meta-analyses of 432 RCTs were included, covering 65 outcomes in cardiovascular, metabolic, oncology, renal, gastrointestinal and other clinical domains. GLP-1RA use was associated with a reduced risk of peripheral arterial disease and heart failure, although certainty was low.
No class-level associations were found for myocardial infarction, composite cardiovascular 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.
Specific Effects of Drugs on Blood Pressure and Organ Health
Semaglutide and exenatide were associated with reductions in systolic blood pressure. Semaglutide was also associated with a reduction in cerebrovascular outcomes, a pattern that was not observed at the class level.
For renal outcomes, GLP-1RAs were associated with a lower risk of kidney-specific composite outcomes, nephropathy, and albuminuria, although certainty was low. GLP-1RAs have been associated with metabolic improvements, including reductions in visceral and liver fat, with moderate or low certainty.
These medications 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 analyzes showed no significant associations. In particular, GLP-1RAs were consistently associated with an increase in gastrointestinal adverse effects, such as nausea, dyspepsia, and constipation, with high or moderate certainty. GLP-1RA use was not associated with retinopathy, macular edema, or cerebrovascular outcomes at the class level.
The drugs were associated with reduced levels of C-reactive protein, while most adipokines and cytokines did not show consistent patterns.
GLP-1RAs were associated with increased bone mineral density in the lumbar spine, hip, and neck, and were not associated with influenza, all-cause adverse events, or nasopharyngitis.
General implications for type 2 diabetes treatment and safety monitoring
Overall, GLP-1RAs were associated with better glycemic control and reduced renal, metabolic, and cardiovascular risks, without increasing cancer risk, supporting their use in people with cardiorenal comorbidities. However, gastrointestinal adverse effects, particularly nausea, constipation, and dyspepsia, remain important considerations.
The study emphasizes that the 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 the use of GLP-1RA in the treatment of type 2 diabetes.
