Diabetes Obes MetabSide Effects & SafetyMeta-AnalysisDecember 15, 2025

Injection-site and dermatologic reactions associated with glucagon-like peptide-1 receptor agonists: Insights from meta-analysis of randomised controlled trials and real-world evidence.

Taj S, Zuber M, Rashid M, Chhabra M, Undela K, Rawal S, Villa Zapata L

Key Finding

GLP-1 medications increase injection-site reaction risk by 3.5 times compared to other treatments, with exenatide and dulaglutide showing the highest rates of injection-site bleeding.

What This Study Found

Think of injection-site reactions like your body's security system being a bit too enthusiastic - when you inject GLP-1 medications under your skin, sometimes your immune system treats it like an unwelcome visitor and creates local inflammation, redness, or irritation. This study analyzed 14 clinical trials involving 4,861 patients and found that 396 people experienced these reactions. It's like having a bouncer at a club who's overly cautious - most of the time everything is fine, but occasionally they make a fuss over harmless guests. The researchers also dove into real-world data from the FDA's adverse event database, which is like a massive complaint box where doctors and patients report problems. They found that exenatide (an older, twice-daily GLP-1 drug) and dulaglutide (Trulicity) were particularly associated with injection-site bleeding - imagine these medications are like slightly rougher needles that occasionally cause tiny bruises at the injection spot.

Statistics Decoded

Risk ratio of 3.55 means if 10 people on placebo had injection-site reactions, about 35 people on GLP-1s would - like comparing a gentle spring rain to a moderate downpour. The 95% confidence interval of 2.35-5.36 means we're pretty sure the real increase is somewhere between 2.4 times and 5.4 times higher risk. The I2 of 41.4% indicates moderate variation between studies - like different weather stations reporting slightly different rainfall amounts. For exenatide's injection-site bleeding, PRR of 27.6 means this side effect was reported 27 times more often than expected by chance - that's definitely not a coincidence, like finding 27 four-leaf clovers when you'd normally find 1.

Why This Matters

This matters because injection-site reactions can make patients stop taking these highly effective diabetes and weight-loss medications - it's like having a great car but avoiding driving because the seat is uncomfortable. Doctors now have specific data to warn patients that skin reactions are common but usually manageable, helping set proper expectations and prevent unnecessary treatment discontinuation.

Original Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used for type 2 diabetes mellitus and obesity, with once-weekly dosing that supports adherence. However, injection-site reactions (ISRs) and dermatologic events have been recognised, ranging from mild local events to rare systemic hypersensitivity reactions that may cause discontinuation. To evaluate dermatologic and ISR safety of GLP-1 RAs through a meta-analysis of randomised controlled trials (RCTs) and disproportionality analysis of data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). PubMed, Embase and Web of Science were searched through December 2024 to identify RCTs reporting ISR or dermatologic outcomes for GLP-1 RAs. Random-effects meta-analysis synthesised trial evidence. A retrospective disproportionality analysis of FAERS data evaluated all approved GLP-1 RAs. Lower bound reporting odds ratios (LB ROR), proportional reporting ratios (PRR) and information components (IC) were calculated. The pooled meta-analysis of 14 RCTs that reported ISRs (4861 patients; 396 ISR events) showed increased ISR risk with GLP-1 RAs versus comparators (risk ratio 3.55; 95% confidence interval, 2.35-5.36; I2 = 41.4%). Dermatologic events were infrequent and not significantly elevated. FAERS data analysis revealed potential ISR signals for exenatide and dulaglutide. Exenatide was associated with injection-site haemorrhage (PRR: 27.6; LB ROR: 29.4; IC025: 4.6). Dulaglutide showed disproportionate reporting for injection-site haemorrhage (PRR: 11.5; LB ROR: 11.5; IC025: 3.4). GLP-1 RAs are consistently linked to higher ISR risk, especially with exenatide and dulaglutide, while generalised dermatologic events are rare. Clinicians should counsel patients about ISR risk to support adherence and optimise outcomes.