Most GLP-1 headlines are built on a single trial. One study, one drug, one number. That’s useful, but it leaves out the question most people actually have: across everything that’s been tested, what does the overall picture look like?
A systematic review published September 1 in Annals of Internal Medicine tries to answer that for one specific group, adults with overweight or obesity who do not have diabetes. It’s an update of a review the same McGill University team published in early 2025, and it’s worth reading closely, both for what it found and for the limits the authors put on it themselves.
What the researchers did
The team searched three major medical databases for randomized controlled trials published between October 2024 and March 2026, lasting at least 16 weeks, that tested GLP-1 receptor agonists or newer “co-agonists” (drugs that act on GLP-1 plus one or more other hormone pathways) in adults without diabetes.
Combined with the earlier review, that brought the total to 38 randomized trials covering 25,816 participants. Fourteen of those trials, with about 11,000 participants, were new since the last version. Two reviewers extracted the data independently, and the review reports no funding source.
What it found
The headline measure is placebo-subtracted weight change: the difference between the drug group and the placebo group in the same trial. Among products the authors classed as commercially available, the largest placebo-subtracted reductions reported were:
- Liraglutide: up to about 5.8%
- Oral semaglutide: up to about 14.3%
- Injectable semaglutide: up to about 14.8%
- Orforglipron: up to about 12.4%
- Tirzepatide: up to about 19.0%
Investigational multi-agonists that are still in development showed numerically larger reductions, including about 23.9% for amycretin and about 22.1% for retatrutide. Where trials compared drugs directly, tirzepatide and the cagrilintide-semaglutide combination produced greater reductions than semaglutide, and semaglutide produced greater reductions than liraglutide.
The broader takeaway the authors drew is simple: the evidence base for this class in people without diabetes has grown substantially, and so has the range of options being studied, including pills and drugs that target several pathways at once.
On tolerability, gastrointestinal side effects such as nausea were common: 76.0% of participants on a GLP-1 medication reported one, versus 40.1% on placebo. Stopping treatment because of side effects happened in 10.7% versus 3.4%, and was numerically higher with some oral agents. Serious adverse events were 6.5% versus 5.2%. Those figures are a reminder that these are real medications with real trade-offs, which is exactly why dose decisions and monitoring belong with a licensed provider.
How to read “up to”
That phrase is doing a lot of work, and it’s easy to skim past.
These are the best results for each drug, not typical ones. “Up to 19.0%” is the largest placebo-subtracted figure across the tirzepatide trials in the review, usually at the highest dose and longest duration. Other trials of the same drug, at lower doses or shorter timeframes, reported smaller differences.
Placebo-subtracted is not the same as total weight change. Participants on placebo in these trials typically also received lifestyle counseling and often lost some weight. Subtracting that out isolates the drug’s added effect, which is the right number for comparing drugs, but not the number a participant would have seen on their own scale.
An average is not a prediction. Every figure above is a group average. Inside each trial, some people responded far more than the average and some far less. Nothing in a pooled review tells you which of those you’d be.
What the review does not establish
The authors are direct about its limits, and they’re worth repeating.
The trials couldn’t be statistically combined. The studies differed too much in dose, duration, population, and design for a pooled meta-analysis, so the review reports ranges from individual trials rather than a single combined estimate. That means the numbers above shouldn’t be treated as a clean ranking. Two drugs that were never tested head to head, in different populations over different timeframes, can’t be compared precisely by lining up their best results.
Safety reporting was inconsistent. The authors note that trials didn’t report adverse events the same way, which limits how confidently they can be compared across studies. The review reported no new safety signals, but “not seen in the trials reviewed” is a narrower statement than “ruled out.”
It covers people without diabetes only. Results in people with type 2 diabetes are generally different and aren’t part of this analysis.
It’s about trial conditions. Randomized trials enroll selected participants, follow them closely, and track adherence. Real-world use tends to look different, with more people stopping early or never reaching the doses studied.
The part that applies to compounded medications
Every trial in this review tested a branded, manufactured product made by its manufacturer, or an investigational drug in development. None tested a compounded preparation.
Compounded semaglutide and tirzepatide, the medications NoBsRx provides provider-guided access to, are prepared by state-licensed pharmacies for an individual patient. Compounded medications are not FDA-approved, and they have not been through the trials summarized here. The evidence in this review covers the branded products that were studied, and it does not transfer to a compounded preparation.
We say that plainly because it’s routinely blurred. If a company cites a pooled figure like “up to 19%” to sell a compounded product, it’s borrowing evidence the product doesn’t have. The honest framing is narrower: the active ingredients have a large trial record, the specific compounded preparation does not, and whether any of it is appropriate for you is a clinical question.
Why this matters anyway
A review like this is still useful, because it moves the conversation away from a single headline trial and toward the whole body of evidence. It also makes clear that the field is no longer one or two drugs. There are more options, in more forms, with different trade-offs.
That’s why the useful starting point isn’t a percentage, it’s an assessment. At NoBsRx, every treatment decision is made by an independent licensed provider who reviews your history, current medications, and goals, and who can decline to prescribe if treatment isn’t appropriate for you. If you have questions about how that works, our FAQ covers the process in more detail.
This post is general information, not medical advice. It does not describe a benefit of any NoBsRx program and it is not a claim that any medication will produce a specific result. Compounded medications are not FDA-approved. Treatment is never guaranteed. Eligibility and every treatment decision are made by independent licensed providers based on an individual clinical assessment, and availability varies by state. Do not start, stop, or change any medication based on an article. If you have questions about weight-management treatment, talk to a licensed clinician.