The expanding use of GLP-1 receptor agonists (RAs) requires careful evaluation of efficacy, tolerability, and safety across diverse populations, particularly because adverse effects and discontinuation rates remain clinically relevant considerations, suggests Dr Paolo Spriano in Medscape Medical News.
Spriano writes:
Obesity is recognised as a chronic disease and a central component of the cardiometabolic spectrum. Evidence supports the clinical benefits of GLP-1 RAs for weight management and improvement in cardiovascular and metabolic risk profiles, and the therapeutic role of this drug class is therefore extending beyond glycaemic control and weight loss.
Although these agents were developed to mimic peripheral GLP-1 activity, their effects on weight reduction depend largely on reduced energy intake mediated through central nervous system pathways.
GLP-1 RAs exert anti-inflammatory effects across multiple organ systems, including the lungs, cardiovascular system, liver, intestine, kidneys, joints, and central nervous system. Preclinical and clinical evidence supports these effects in the cardiovascular system, liver, kidneys, and joints.
Neuroprotective mechanisms include reduced protein aggregation, enhanced autophagy, improved mitochondrial function, suppression of neuroinflammation, and preservation of synaptic integrity.
Epidemiologic analyses suggest a reduced incidence of dementia, Parkinson disease, and multiple sclerosis among long-term users. However, anti-inflammatory effects in the central nervous system, lungs, and intestine remain incompletely defined and require further study, particularly in the context of safety and tolerability.
Therapeutic tolerability
A systematic review of 39 randomised controlled trials demonstrated a class effect, with increased risk for nausea, vomiting, diarrhoea, and constipation compared with placebo in individuals without diabetes.
Gastrointestinal adverse events frequently led to treatment discontinuation in both clinical trials and real-world settings.
Discontinuation rates were 6.5% among individuals receiving GLP-1 RAs compared with 3.6% of those receiving placebo. Nausea was the most common reason for discontinuation, followed by vomiting and diarrhoea. Risks for constipation, abdominal discomfort, and pain were lower. Slower and more flexible titration of dose improved adherence and reduced adverse events without compromising efficacy, although optimal titration strategies require further study.
GI symptom assessment
Most studies assessed symptoms through self-reporting by participants. Although practical, this approach has limitations. Future research should incorporate validated tools to assess upper gastrointestinal symptom severity.
GI motility
The incidence of retained gastric content was 56% of individuals receiving GLP-1 RAs compared with 19% of those not receiving these agents. Although studies reported an increased risk for retained gastric content leading to premature endoscopy discontinuation, no increased risk for aspiration pneumonia was identified.
These findings indicate a clear association between GLP-1 RA therapy and risk for gastric retention without evidence of increased aspiration risk.
This observation has prompted consideration of whether GLP-1 RA therapy should be modified or withheld before procedures associated with aspiration risk. Current multisociety guidance recommends an individualised approach.
Underlying mechanisms
Gastrointestinal adverse events associated with GLP-1 RAs reflect altered gastrointestinal function. GLP-1 receptor activation slows gastric emptying and suppresses small intestinal motility.
In addition, direct interaction with receptors in brainstem regions such as the area postrema and nucleus of the solitary tract may contribute to nausea through activation of the chemosensitive zone.
Biliary complications
A systematic review of 55 double-blind randomised controlled trials showed that treatment with GLP-1 RAs was associated with an increased risk for cholelithiasis compared with placebo (risk ratio, 1.46), but no increased risk for cholecystitis, cholangitis, or pancreatitis. Retrospective analyses suggest that early concerns linking GLP-1 RAs to acute pancreatitis were influenced by the diagnostic criteria applied.
These criteria require two of three features: severe upper abdominal pain radiating to the back, an elevated amylase or lipase level, and characteristic imaging findings.
Treatment with GLP-1 RAs is known to cause abdominal symptoms in many patients and may also lead to elevated amylase or lipase levels that do not predict clinical acute pancreatitis.
This context helps explain how misclassification may have occurred and supports the presence of reporting bias in adverse event databases, particularly when a serious safety signal emerges.
The findings underscore the need for robust pharmacovigilance research when evaluating suspected adverse events associated with newer therapies.
Thyroid cancer
An increased risk for medullary thyroid carcinoma with GLP-1 RAs has been hypothesised in susceptible individuals, although this signal has not been established in otherwise healthy populations.
An analysis of 93 phase 2 and 3 trials of liraglutide and semaglutide, supported by postmarketing surveillance data, found no association between GLP-1 RA use and the risk for thyroid cancer in adults.
However, a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 remains a contraindication to GLP-1 RA therapy.
Retinopathy and other vision problems
Subcutaneous semaglutide was associated with more retinopathy complications in the SUSTAIN-6 cardiovascular outcomes trial. A retrospective review suggests this may reflect the larger reductions in plasma glucose and A1c achieved with semaglutide compared with standard therapy. Ongoing studies are assessing its effects on retinopathy progression.
Nonarteritic anterior ischaemic optic neuropathy (NAION) is a sudden, painless cause of vision loss that occurs mainly in individuals with T2D. It results from hypoperfusion of the posterior ciliary arteries supplying the optic nerve head, leading to ischaemic injury and optic disc edema.
Risk increases with age and vascular comorbidities, including hypertension, T2D, hyperlipidemia, obstructive sleep apnoea, and optic disc abnormalities. Reported links with GLP-1 RAs are based on retrospective data, which do not establish causality and are prone to confounding.
The association may reflect underlying risk factors rather than drug effects. A meta-analysis of 20 randomised controlled trials found no association between GLP-1 RA use and risk for optic nerve or vision related events.
Depression and psychiatric outcomes
A systematic review of 80 randomised clinical trials found no association between GLP-1 RA use and major depression, suicide, or psychosis. Treatment with GLP-1 RAs was also associated with better mental health-related quality of life.
Effects in specific populations
Younger individuals
A meta-analysis of five studies in younger individuals with T2D showed higher adverse event rates with GLP-1 RAs, but low discontinuation rates.
Pregnancy
In animal studies, GLP-1 RA exposure was associated with reduced foetal growth, delayed skeletal ossification, and lower maternal weight gain and food intake. Use is not recommended during pregnancy or when planning pregnancy.
Severe renal impairment
Gastrointestinal adverse effects are more common in people with severe renal impairment, and use of GLP-1 RAs should be individualised after weighing risks and benefits.
Older adults
Discontinuation rates of GLP-1 RAs are high in this population. After 24 months, 68.2% of individuals under discontinued therapy, rising to 75.3% in those aged 65-74 and 82.6% in those aged 75 or older.
Reasons include cost, variable efficacy, patient preference, and adverse gastrointestinal effects. Bone loss has been reported with semaglutide, although exercise may reduce this risk. These risks should be balanced against cardiovascular benefit, which increases with age.
Muscle mass reduction
Weight loss with GLP-1 RAs includes loss of lean body mass, raising concern for sarcopenia. Evidence linking this to reduced physical function remains limited. Caution is warranted in higher-risk groups, including older adults and those with low physical activity, low protein intake, or rapid weight loss.
Spriano is a physician/internist based in Varese, Italy. This story was translated from Univadis Italy, part of the Medscape Professional Network.
Medscape article – GLP-1 Drugs Under Scrutiny: How Real Are the Risks? (Open access)
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