GLP-1 Side Effects: What the STEP and SURMOUNT Trials Actually Reported

Every GLP-1 ad shows the weight-loss curve. Almost none show the adverse-event table sitting a few pages later in the same FDA label. Both numbers come from the same trials, and you're entitled to both before you pick a drug or a provider. Here's what the pivotal obesity trials — STEP for semaglutide, SURMOUNT for tirzepatide — actually reported, sourced to the trial publications and the current FDA-approved labeling rather than to marketing copy.

How to read an adverse-event table

One thing worth understanding before the numbers: these percentages come from placebo-controlled trials, meaning the placebo group also received lifestyle counseling and often reported meaningful side effects of their own — the 16% nausea rate on Wegovy's placebo arm and the 8% rate on Zepbound's aren't zero. The relevant number isn't the raw rate on the drug, it's the gap between drug and placebo, since some baseline rate of nausea, fatigue, or GI upset shows up in any trial regardless of what's being tested. Reading the gap rather than the raw percentage is the difference between an accurate picture and an inflated one.

Where these numbers come from

The headline results for injectable semaglutide (branded Wegovy) come from the STEP 1 trial, a 68-week randomized, placebo-controlled study in adults with overweight or obesity¹. The headline results for tirzepatide (branded Zepbound) come from SURMOUNT-1, a similarly designed 72-week trial². Both drugs' current FDA-approved labels report the full adverse-event tables from these and supporting trials, and that's the source for the percentages below.

Semaglutide: the gastrointestinal numbers

Per the current Wegovy prescribing information, gastrointestinal adverse reactions were the dominant complaint in the placebo-controlled obesity trials³:

- Nausea: 44% on semaglutide vs. 16% on placebo - Diarrhea: 30% vs. 16% - Vomiting: 24% vs. 6% - Constipation: 24% vs. 11%

Severe gastrointestinal adverse reactions were reported in 4.1% of semaglutide-treated patients versus 0.9% on placebo. Overall, 6.8% of semaglutide patients permanently discontinued treatment because of an adverse reaction, versus 3.2% on placebo — with nausea, vomiting, and diarrhea named as the most common reasons for stopping³.

Tirzepatide: the gastrointestinal numbers

The current Zepbound label reports adverse-event rates by dose from the pooled SURMOUNT obesity trials⁴:

| Reaction | Placebo | 5 mg | 10 mg | 15 mg | |---|---|---|---|---| | Nausea | 8% | 25% | 29% | 28% | | Diarrhea | 8% | 19% | 21% | 23% | | Vomiting | 2% | 8% | 11% | 13% | | Constipation | 5% | 17% | 14% | 11% |

Discontinuation due to adverse reactions ran 4.8%, 6.3%, and 6.7% at the 5 mg, 10 mg, and 15 mg doses respectively, versus 3.4% on placebo; discontinuation specifically for gastrointestinal reactions ran 1.9%–4.3% across doses versus 0.5% on placebo⁴. For a closer dose-by-dose comparison against semaglutide's own numbers, see semaglutide vs tirzepatide: comparing side effects and tolerability.

Beyond nausea: the non-GI reactions that get skipped over

GI symptoms dominate the conversation, but they aren't the only reactions the labels report. On Wegovy, headache affected 14% of patients (vs. 10% on placebo), fatigue 11% (vs. 5%), and dizziness 8% (vs. 4%)³. Cholelithiasis — gallstones, a known risk with rapid weight loss regardless of the drug causing it — occurred in 1.6% of Wegovy-treated adults³; a much larger pooled trial dataset breaks that specific risk down further in GLP-1 and gallbladder disease: what the meta-analysis of 76 trials shows. On Zepbound, injection site reactions ran 6%–8% across doses (vs. 2% on placebo), fatigue 5%–7% (vs. 3%), and hair loss 4%–5% (vs. 1%); the label specifically notes that hair loss on Zepbound tracked with the amount of weight lost and was more common in women, which is consistent with hair shedding being a known side effect of rapid weight loss generally rather than a drug-specific mechanism⁴ — see does GLP-1 cause hair loss? What the evidence actually shows for the fuller dermatology literature behind that single line. None of these are as common as the headline GI numbers, but they're worth knowing about before you assume nausea is the only thing to watch for.

Two more specific reactions deserve their own space rather than a one-line mention: what "GI side effects" don't cover is a documented, if uncommon, dry-mouth effect, covered in GLP-1 and dental side effects: what "Ozempic teeth" claims actually have behind them, and the class-wide boxed warning plus a newer, non-label safety signal are covered in full in GLP-1 boxed warnings: what the label actually says. Weight loss itself also isn't cost-free from a body-composition standpoint — see GLP-1 and muscle loss: what the body-composition data actually shows for what the DXA-scan evidence actually measured, and GLP-1 and bone density: what the evidence shows for the separate, more reassuring bone-health data from the same kind of trials.

What the pattern actually means

Two things stand out. First, GI side effects aren't rare edge cases — on both drugs, nausea alone affects roughly a quarter to nearly half of patients at some point in a year-plus trial, which is worth knowing before you assume the first month will feel normal. Second, most people who start don't quit: even at semaglutide's highest discontinuation rate, over 93% of patients stayed on treatment through the trial. The side-effect profile is real, but it's usually tolerable and usually front-loaded during dose increases — which is exactly why how GLP-1 dosing and titration actually works matters as much as the drug itself: a slower titration is one of the few levers you and a prescriber can actually pull.

Why this belongs in your provider decision

A program's medical intake should ask about your GI history, current medications, and comfort with a gradual titration — not just collect a card number. That's part of why we score prescriber quality as its own factor in our Value Score methodology, separate from price. It's also why side effects don't disappear once you're established: what happens if you stop is its own evidence base, covered in what happens when you stop GLP-1 medication.

Putting this next to price

Tolerability and cost aren't separate questions — a program that lets you titrate slowly, adjust dose, or pause without penalty is worth more than its sticker price suggests. Compare that kind of flexibility across providers using our semaglutide price ranking and tirzepatide price ranking, and read the flexibility notes in our provider reviews alongside the price.

This piece sits in our research index alongside every other sourced explainer we publish — the trials, the compounding rules and the pricing mechanics, grouped by the question each one answers.