Explore studies of side effects.
GLP-1 receptor agonists upregulate mucin expression in airways via p38 MAPK, exacerbating emphysematous phenotypes in obstructive lung disease models.
Nohara, Hirofumi; Nakashima, Ryunosuke; Kamei, Shunsuke; Fujikawa, Haruka; Ueno-Shuto, Keiko; Kawakami, Taisei; Eto, Yuka; Suico, Mary Ann; Li, Jian-Dong; Kai, Hirofumi; Shuto, Tsuyoshi · Animal
Semaglutide demonstrated cardiovascular superiority in SUSTAIN 6, with a safety profile typical of GLP-1RAs. The only concerning signal was increased diabetic retinopathy events, likely related to rapid glucose lowering rather than direct drug toxicity.
Peter, Rajesh; Bain, Steve C · Review
Combination of CGRP mAbs with onabotulinumtoxinA reduced monthly headache days by an additional 3.5-4.0 beyond Botox alone, with 45.1% achieving meaningful disability improvement.
Blumenfeld, Andrew M; Frishberg, Benjamin M; Schim, Jack D; Iannone, Ashley; Schneider, Gary; Yedigarova, Larisa; Manack Adams, Aubrey · Observational
5.3% of migraine patients with Raynaud phenomenon experienced microvascular complications from CGRP antagonists, including rare but serious events like gangrene requiring digit amputation.
Breen, Ilana D; Brumfiel, Caitlin M; Patel, Meera H; Butterfield, Richard J; VanderPluym, Juliana H; Griffing, Leroy; Pittelkow, Mark R; Mangold, Aaron R · Observational
ADA prevalence ranged from <1% to ~18% and neutralizing ADA from 0-12% across CGRP mAbs, with adverse events related to ADA formation rare across all four approved migraine antibodies.
Cohen, Joshua M; Ning, Xiaoping; Kessler, Yoel; Rasamoelisolo, Michele; Campos, Verena Ramirez; Seminerio, Michael J; Krasenbaum, Lynda J; Shen, Honglue; Stratton, Jennifer · Review
Combining GLP-1 RA and DPP-4 inhibitor provides only a small incremental reduction in HbA1c and weight loss, with the benefit unlikely to offset potential pancreatitis risk and additional cost.
Cowart, Kevin; Updike, Wendy H; Lloyd, Andie; Bullers, Krystal · Systematic Review
In 112 adolescents, CGRP mAbs reduced headache frequency by 2.0 days/month (95% CI -0.8 to -3.2). 29.5% perceived significant benefit. 31% reported functional improvement. Side effects were mild and similar to adults. 4.5% discontinued for side effects.
Greene, Kaitlin A; Gentile, Carlyn P; Szperka, Christina L; Yonker, Marcy; Gelfand, Amy A; Grimes, Barbara; Irwin, Samantha L · Retrospective Cohort
GLP-1 receptor agonists were proposed to cause hypoglycemia in healthy normoglycemic subjects, challenging the assumption of purely glucose-dependent action. The FDA evaluated all 12 marketed GLP-1 RAs for potential hypoglycemia safety signals. Risk appears dependent on individual factors.
Ja'arah, Daria; Al Zoubi, Mazhar Salim; Abdelhady, Gamal; Rabi, Firas; Tambuwala, Murtaza M · Review
A cell-based MRGPRX2 assay reliably identified peptide compounds causing injection site histamine release and edema in ex vivo skin samples, serving as a replacement for postmortem animal evaluation.
John, Linu M; Dalsgaard, Charlotte M; Jeppesen, Claus B; Conde-Frieboes, Kilian W; Baumann, Katrine; Knudsen, Niels P H; Skov, Per S; Wulff, Birgitte S · Drug Development/Validation Study
Across all 9 trials, tirzepatide did not increase the risk of cancer overall or any specific cancer type. This held true regardless of what the comparison drug was. However, the authors stress this is preliminary. The trials were short (36 to 72 weeks), which is not long enough to detect most drug-related cancer signals. Cancer takes years to develop, and these studies were designed to measure diabetes outcomes, not cancer risk.
Popovic, Djordje S; Patoulias, Dimitrios; Popovic, Lazar S; Karakasis, Paschalis; Papanas, Nikolaos; Mantzoros, Christos S · Meta Analysis
Meta-analyses of long-term randomized controlled trials show DPP-4 inhibitors carry a small increased risk of acute pancreatitis, but GLP-1 receptor agonists and GLP-1/GIP co-agonists do not. GLP-1 receptor agonists and co-agonists are associated with higher rates of cholecystitis and cholelithiasis (gallbladder inflammation and gallstones). No incretin-based drug class is associated with increased pancreatic cancer risk.
Pratley, Richard; Saeed, Zeb I; Casu, Anna · Review
SGLT2 inhibitors with metformin reduced gout incidence by 25% compared to metformin alone (HR 0.75, p < 0.0001). SGLT2 inhibitors with insulin reduced gout by 17% versus insulin alone (HR 0.83, p < 0.0001). GLP-1 receptor agonists showed no significant difference in gout incidence versus either metformin or insulin controls. When SGLT2 inhibitors were compared directly to GLP-1 drugs, they had lower gout rates in both the metformin group (HR 0.77, p < 0.0001) and the insulin group (HR 0.82, p < 0.0001).
Preston, Frank G; Anson, Matthew; Riley, David R; Ibarburu, Gema H; Henney, Alexander; Lip, Gregory Y H; Cuthbertson, Daniel J; Alam, Uazman; Zhao, Sizheng S · Cohort Study
In the SUSTAIN-6 cardiovascular outcome trial, semaglutide was associated with approximately 75% increased risk of diabetic retinopathy (DR) worsening. This was a secondary endpoint, not the trial's primary focus. Cases were rare in absolute terms. Insulin icodec (a novel once-weekly insulin) also showed increased DR worsening compared to daily insulin. No other recent antihyperglycemic agent (SGLT2 inhibitors, DPP-4 inhibitors, other GLP-1 drugs) was associated with DR worsening. Importantly, after the SUSTAIN-6 finding, nearly all subsequent trials excluded patients with pre-existing diabetic retinopathy. This means the true risk in the most vulnerable population remains unclear. Dedicated semaglutide eye safety studies were underway at the time of publication. The most at-risk patients are those with pre-existing high-risk DR, poor baseline blood sugar (where rapid improvement could trigger worsening), and those using insulin.
Rajagopal, Rithwick; McGill, Janet B · Review
Compared to tirzepatide 5 mg: - 10 mg: additional 19% HbA1c reduction (MD: -0.19), additional 1.96 kg weight loss - 15 mg: additional 31% HbA1c reduction (MD: -0.32), additional 3.31 kg weight loss, and improved fasting glucose (MD: -6.71 mg/dL) The dose-response relationship was clear and consistent across the 10 studies. Higher doses produced incrementally better metabolic outcomes. For safety, gastrointestinal events were numerically higher with increasing doses but without reaching statistical significance. There were no significant differences across doses for death, nausea, diarrhea, vomiting, dyspepsia, decreased appetite, injection site reactions, hypoglycemia, treatment discontinuation, or serious adverse events.
Rangwala, Hussain Sohail; Fatima, Hareer; Ali, Mirha; Mustafa, Muhammad Saqlain; Shafique, Muhammad Ashir; Rangwala, Burhanuddin Sohail; Abbas, Syed Raza · Network Meta Analysis
Albuminuria was more consistently reduced by semaglutide than eGFR. The benefit was strongest in patients with macroalbuminuria (heavy protein loss). This suggests semaglutide may help slow the progression of diabetic kidney disease by reducing the protein that damages kidney filters. However, the impact on eGFR was variable. Some studies showed improvement, others showed no change, and some showed decrease. This inconsistency could reflect differences in patient populations, disease severity, and follow-up duration. Two case reports described acute kidney injury (AKI) associated with semaglutide, including one case of acute interstitial nephritis. This highlights the need for kidney monitoring during therapy, particularly in patients with advanced chronic kidney disease.
Rehman, Shuja Ur; Kolanu, Nikhil Deep; Mushtaq, Muhammad Muaz; Ali, Husnain; Ahmed, Zeeshan; Mushtaq, Maham; Liaqat, Maryyam; Sarwer, Muhammad Asad; Bokhari, Syed Faqeer Hussain; Ahmed, Fazeel; Bakht, Danyal · Systematic Review
GLP-1 receptor agonists achieve 10–20% weight reduction and reduce perioperative complications in hernia patients, but the delayed gastric emptying they cause creates anesthesia safety challenges requiring individualized fasting protocols.
Paduraru, Dan Nicolae; Palcau, Alexandru Cosmin; Ion, Daniel; Seicaru, Razvan · Narrative Review
A substantial proportion of patients on GLP-1 receptor agonists had high residual gastric contents before anesthesia despite standard fasting, suggesting current preoperative fasting guidelines may be inadequate for this population.
Pai, Sher-Lu; Nimma, Sindhuja R; Beam, W Brian; VanderWielen, Beth A; Kalagara, Hari K; Bettini, Layne M; Yu, Soojie; Sharpe, Emily E; Harbell, Monica W · Prospective Cohort
GLP-1 receptor agonists were associated with eustachian tube dysfunction, particularly the patulous variant, likely caused by rapid loss of soft tissue bulk around the eustachian tube opening.
Pak, Kaitlynne Y; Cutri, Raffaello M; Nadeem, Wasiq; Kothari, Dhruv; Wong, Yu-Tung; Wu, Arthur W; Miller, Mia E · Case Report