Across the roster, GI AEs cluster during dose escalation and are partially mitigated by slower/lower-starting-dose titration; explicit titration-mitigation evidence...
Full findingAcross the roster, GI AEs cluster during dose escalation and are partially mitigated by slower/lower-starting-dose titration; explicit titration-mitigation evidence strongest for retatrutide (2 vs 4 mg start), stated for orforglipron and survodutide.
PopulationSynthesis across SURMOUNT-1, retatrutide phase 2, ATTAIN-1, survodutide phase 2
Fundingindustry - multiple, each disclosed per component: Eli Lilly / Boehringer Ingelheim
Scope limitsCross-cutting observation, not a single-trial result. 'Decrease' denotes mitigation of GI burden, not a drug-effect direction.
Comparatorsplacebo
GLP-1 RA classMARKETED
Gastrointestinal tolerabilityIncrease
Moderate evidence
GLP-1 RAs added to insulin in T1D roughly tripled nausea and vomiting and doubled early treatment withdrawal - a substantial early gastrointestinal burden that eases...
SourceKateel R, Parida A, Chogtu B, Holla SN. Safety of GLP-1 receptor agonists in type 1 diabe...Source
Full findingGLP-1 RAs added to insulin in T1D roughly tripled nausea and vomiting and doubled early treatment withdrawal - a substantial early gastrointestinal burden that eases after about six months, requiring slow dose titration and careful patient selection.
PopulationGLP-1 RA T1D safety/tolerability meta-analyses (Kateel et al., 25 studies; corroborated by Tan et al. GI-AE OR 2.96, PMC10797415).
Fundingacademic/government (Kasturba Medical College, Manipal; Dept of Health Research, India)
Scope limitsTextbook GLP-1 GI tolerability - kept in tolerability-gi (distinct from the safety-other hypo/ketosis signals). The early-withdrawal RR 2.02 is the clinically meaningful consequence; improves after ~6mo, supporting stepwise titration.
Comparatorsplacebo (insulin background)
GLP-1 RA classMARKETED
Gastrointestinal tolerabilityIncrease
Moderate evidence
FOLK-CLAIM VERDICTS (GI cluster): (1) 'Nausea is near-inevitable' = OVERSTATED - real and the top AE but ~25-44% (not inevitable), mostly mild-moderate, concentrated...
SourceWharton S et al. Gastrointestinal tolerability of semaglutide 2.4 mg (pooled STEP 1-3). D...Source
Full findingFOLK-CLAIM VERDICTS (GI cluster): (1) 'Nausea is near-inevitable' = OVERSTATED - real and the top AE but ~25-44% (not inevitable), mostly mild-moderate, concentrated at titration. (2) 'Constipation is more common than diarrhoea' = FALSE/MIXED - for semaglutide diarrhoea (29.7%) >= constipation (24.2%), and the balance is DRUG-SPECIFIC (sema/lira constipation-leaning, tirzepatide diarrhoea-leaning). (3) 'Fatigue, especially after each dose increase' = TRUE as a recognised (labelled) AE, but the per-step-spike mechanism is OVERSTATED - fatigue is largely secondary to reduced intake/dehydration/electrolytes during the nausea-prone escalation window, not a proven per-step pharmacological effect.
PopulationPooled STEP 1-3 (semaglutide) GI-tolerability analysis + SURMOUNT (tirzepatide) + a class network meta-analysis.
Fundingindustry - Novo Nordisk A/S (sponsor of the underlying STEP 1-3 trials and the load-bearing Wharton 2022 pooled GI-tolerability analysis)
Scope limitsBelief-vs-reality: nausea is a large-minority, mostly-mild, titration-linked event (not inevitable); the 'these drugs back you up' rule is wrong-way-round for semaglutide and is drug-specific; fatigue is real but intake-mediated. Frequency anchors (self-report) are in C-CLASS-TOLGI-REDDIT-FREQ-01. Cross-ref C-TIRZ-VS-SEMA-TOLGI-01 (tirz-gentler) and the existing tolerability-gi rows. [REASONED CAVEAT + OPEN QUESTION (OQ-FOLK-GI-01), 2026-06-22, NOT a settled finding: the constipation-vs-diarrhoea split likely reflects an ASYMMETRY - constipation is the more DRUG-INTRINSIC outcome (slowed transit -> the colon reabsorbs more water -> hard, dry stool; happens largely independent of diet, even on small intake), whereas diarrhoea is the more DIET/BEHAVIOUR-MODULATED one (the drug, especially tirzepatide's GIP-driven effect on fat handling, primes fat and bile to reach the colon where they trigger a secretory/osmotic flush, but it needs a fatty/difficult-to-digest meal to actually fire). The DRUG component of the diarrhoea tilt is REAL (it appears in the SURMOUNT-5 head-to-head and meta-analyses, not only in self-report), but its MAGNITUDE is diet- and population-modulated - and the real-world tirzepatide diarrhoea signal is further confounded as the drug reaches a broader, less-screened, less-diet-coached population (the same confound that grades the self-report rows very-low). Testable prediction: a high-fat-meal challenge or a diet-controlled comparison should move the diarrhoea rate while barely touching the constipation rate.]
Comparatorsplacebo
GLP-1 RA classMARKETED
Gastrointestinal tolerabilityNot directional
Very low evidence
REAL-WORLD ONLINE SELF-REPORT context for the GI/other folk frequencies. This is a SIGNAL-DETECTION / pharmacovigilance-adjacent dataset, NOT prevalence, NOT...
SourceSehgal NKR, Tronieri J, Ungar L, Guntuku SC. Self-reported side effects of semaglutide an...Source
Full findingREAL-WORLD ONLINE SELF-REPORT context for the GI/other folk frequencies. This is a SIGNAL-DETECTION / pharmacovigilance-adjacent dataset, NOT prevalence, NOT incidence, NOT causal - self-selected communities, no denominator, no controls, no titration timing (the authors state they cannot say GLP-1s cause these symptoms). Use it to gauge how COMMON a BELIEF/report is, never to estimate true rates. The sema-vs-tirz nausea split is a text-mining ratio, not a randomised comparison.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsGRADE very-low (self-selected online self-report; reporting != incidence). Verified to exist (Nature Health 2026) but NOT PubMed-indexed - findable via Nature/medRxiv preprint (10.64898/2026.03.12.26348253)/arXiv 2603.12341. Captured as the frequency-of-belief layer per the Director's instruction; heavily fenced. Anchors the frequency tags throughout the folk-claims register.
GLP-1 RA classMARKETED
Gastrointestinal tolerabilityNot directional
Low evidence
FOLK-CLAIM VERDICT ('sulfur burps' / rotten-egg belches): UNPROVEN - this is the clearest GENUINE EVIDENCE GAP in the GI cluster. The phenomenon is a widespread,...
SourceNo indexed literature on GLP-1-associated sulfur eructation/hydrogen-sulfide belching loc...
Full findingFOLK-CLAIM VERDICT ('sulfur burps' / rotten-egg belches): UNPROVEN - this is the clearest GENUINE EVIDENCE GAP in the GI cluster. The phenomenon is a widespread, recognisable community 'class signal' with a plausible mechanism (delayed gastric emptying -> fermentation -> hydrogen sulfide), but there is NO trial, case series or mechanistic paper formally characterising or quantifying it. Real-world reports + coherent mechanism, but no formal evidence base.
Populationn/a - documents the absence of formal literature; online self-report (eructation ~6.9%) is the only frequency anchor.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsGRADE very-low (no evidence base; verdict is 'unstudied', not 'refuted'). Belief-vs-reality: patients treat sulfur burps as a known class signature; the science has barely looked. A genuine open research question (the one true gap in the GI set). Cross-ref C-CLASS-TOLGI-FOLKVERDICT-01.
DulaglutideMARKETED
Gastrointestinal tolerabilityIncrease
High evidence
Across the AWARD programme, dulaglutide's most common adverse events are gastrointestinal (nausea, diarrhoea, vomiting), dose-related and mostly mild-to-moderate and...
SourceLudvik B, Frias JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitor...Source
Full findingAcross the AWARD programme, dulaglutide's most common adverse events are gastrointestinal (nausea, diarrhoea, vomiting), dose-related and mostly mild-to-moderate and transient, with low study-drug discontinuation.
PopulationAWARD programme phase-3 double-blind randomised trials: AWARD-10 (N=424, vs placebo, on SGLT2i) and the open-label AWARD-6 (N=599, vs liraglutide, on metformin); GI adverse-event incidence and discontinuation.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsNET-NEW gather (WI-5). Opens the dulaglutide tolerability-gi cell with a per-drug GI/discontinuation record (dulaglutide GI was previously inherited only via the SURPASS-CVOT comparator arm). AWARD-10 (placebo-controlled) and AWARD-6 (vs liraglutide) GI percentages confirmed from abstracts; AWARD-6 discontinuation 6%/6% confirmed. Observation only; the dose-relation of nausea (15% at 1.5 mg vs 5% at 0.75 mg in AWARD-10) is recorded as an observation. Industry (Eli Lilly). Council interpretive review not yet run.
Comparatorsplacebo; liraglutide
DulaglutideMARKETED
Gastrointestinal tolerabilityNo change
Moderate evidence
In the AWARD-6 head-to-head, study or study-drug discontinuation because of adverse events was the same for once-weekly dulaglutide and once-daily liraglutide.
SourceDungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglu...Source
Scope limitsPMID confirmed. Maintenance-phase tolerability after switching from injectables.
Comparatorsplacebo
OrforglipronINVESTIGATIONAL
Gastrointestinal tolerabilityIncrease
High evidence
GI AEs most common, mostly mild-to-moderate, concentrated in escalation; per-symptom rates and AE-related discontinuation dose-related.
SourceLilly ATTAIN-1 (NEJM 2025) and ATTAIN-2 resultsSource
PopulationATTAIN-1: adults with obesity (no diabetes); phase 3 RCT, orforglipron 6/12/36 mg vs placebo
Fundingindustry - Eli Lilly
Scope limitsidentifier not fully verified; no outcome data yet (ongoing)
Comparatorsplacebo
OrforglipronINVESTIGATIONAL
Gastrointestinal tolerabilityIncrease
Low evidence
Review-channel: safety profile consistent with GLP-1 class, dominated by manageable GI events mitigated by slow escalation; small mild-pancreatitis signal noted...
SourcePillai AA et al., Cardiol Rev 2025 (orforglipron review)Source
Full findingReview-channel: safety profile consistent with GLP-1 class, dominated by manageable GI events mitigated by slow escalation; small mild-pancreatitis signal noted (logged as class context).
PopulationACHIEVE-3 (T2D) and ATTAIN-2 (obesity+T2D) programme; phase 3
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Scope limitsPer-symptom GI rates not quantified here (see C-ORF-SAFETY-GI05).
Comparatorsoral semaglutide; placebo
RetatrutideINVESTIGATIONAL
Gastrointestinal tolerabilityIncrease
Moderate evidence
GI AEs most common, dose-related, mostly mild-to-moderate; partially mitigated by a lower 2 mg (vs 4 mg) starting dose. Nausea showed a clear dose gradient.
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
GI effects (esp. nausea, vomiting) most frequent AEs across the PIONEER programme; mild-to-moderate, faded with time. PIONEER 1 trial-product discontinuations...
SourceAroda VR et al., Diabetes Care 2019 (PIONEER 1)Source
Full findingGI effects (esp. nausea, vomiting) most frequent AEs across the PIONEER programme; mild-to-moderate, faded with time. PIONEER 1 trial-product discontinuations dose-related.
PopulationPIONEER 1: 703 adults with T2D on diet/exercise; 26 weeks; phase 3a RCT, oral semaglutide 3/7/14 mg vs placebo
Fundingindustry-Novo Nordisk
Scope limitsPMID/DOI and discontinuation range CONFIRMED directly via PubMed (corrects fork's earlier review-channel tag). Per-symptom nausea rates (e.g. 16.0% on 14 mg) from broader PIONEER reporting.
Comparatorsplacebo
SemaglutideMARKETED
Gastrointestinal tolerabilityIncrease
High evidence
Nausea and diarrhoea most common AEs; transient, mild-to-moderate. More semaglutide than placebo participants discontinued for GI events.
SourceWilding JPH et al., NEJM 2021 (STEP 1)Source
GI AEs (nausea, diarrhoea, vomiting) markedly more frequent than placebo; dose-dependent, titration-managed; high AE-related discontinuation, mainly GI.
SourceSanyal et al., Phase 2 Survodutide in MASH and Fibrosis, NEJM 2024; Boehringer phase 3 pressSource
Fundingindustry - Boehringer Ingelheim (disclosed in publication)
Scope limitsidentifier not fully verified; no outcome data yet (ongoing)
Comparatorsplacebo
TirzepatideMARKETED
Gastrointestinal tolerabilityIncrease
High evidence
GI AEs most common, mostly mild-to-moderate, primarily during dose escalation; AE-related discontinuation dose-related. Per-symptom rates broadly dose-related (nausea...
SourceJuxtaposition of SURMOUNT-1 (NEJM 2022) and MariTide phase 2 (ADA 2025); see also LY35370...Source
Full findingGI AEs most common, mostly mild-to-moderate, primarily during dose escalation; AE-related discontinuation dose-related. Per-symptom rates broadly dose-related (nausea peaks at 10 mg).
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitsA separate Knop et al 2024 (Diabetes Obes Metab, DOI 10.1111/dom.15875) reported that adding a long-acting GIPR agonist improved GI tolerability of GLP-1RA therapy — consistent theme that GIPR agonism may be GI-sparing.
Comparatorsplacebo
MariTideMARKETED
Gastrointestinal tolerabilityIncrease
Moderate evidence
Gastrointestinal adverse events common but mitigated by lower starting dose and dose escalation.
SourceJastreboff AM et al. Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - ...Source
PopulationFull phase 2 population N=592; 52 wk; placebo comparator
Fundingindustry - Amgen
Scope limitsanimal data; human relevance uncertain; conference/abstract-level; identifier not fully verified; small sample (N~127)
Comparatorsplacebo
MazdutideINVESTIGATIONAL
Gastrointestinal tolerabilityIncrease
Low evidence
Mild-to-moderate GI TEAEs; no serious AEs in phase 1b
SourceJi L et al. EClinicalMedicine 2022;54:101691Source
Fundingindustry - Innovent / Eli Lilly (trial sponsor; inferred from registration trial)
Scope limitssmall sample (N~24)
Comparatorsplacebo
OrforglipronINVESTIGATIONAL
Gastrointestinal tolerabilityIncrease
High evidence
Predominantly mild-to-moderate GI adverse events, mostly during dose escalation; higher AE-related discontinuation than placebo/active comparators.
SourceHorn DB et al. Orforglipron... for obesity in people with type 2 diabetes (ATTAIN-2): a p...Source
PopulationPooled across ATTAIN-2, ACHIEVE-1, ACHIEVE-2 phase 3 RCTs
Fundingindustry-Eli Lilly
Scope limitsSafety profile stated as consistent with the GLP-1RA class. No drug-induced-liver-injury signal reported for orforglipron (contrast with Pfizer oral GLP-1s).
Comparatorsplacebo; dapagliflozin
PemvidutideINVESTIGATIONAL
Gastrointestinal tolerabilityIncrease
Low evidence
Well tolerated in MASLD study with no severe/serious AEs
SourceHarrison SA et al. J Hepatol 2024;82:7-17Source
PopulationMASLD phase 1b/2a (n=94), 12 wk
Fundingindustry - Altimmune (trial sponsor; inferred from registration trial)
Scope limitssmall sample (N~94)
Comparatorsplacebo
PetrelintideMARKETED
Gastrointestinal tolerabilityNo change
Very low evidence
Reported safe and well tolerated at all dose levels (company)
SourceZealand Pharma topline press release, 20 Jun 2024Source
The Echo Compendium