There is now a ranked table of how much weight each obesity drug takes off in a year. It was published in The BMJ, it pools 262 randomized trials and 99,791 participants across 19 drugs, and it is graded for certainty. The ranking is not the interesting part.
The interesting part is the second table — the one listing what each drug costs the people taking it.
The weight loss, first
Compared with lifestyle modification alone, at one year, with moderate to high certainty evidence:
- tirzepatide: −14.9% (95% CI −16.0 to −13.9)
- cagrilintide-semaglutide (CagriSema): −14.8% (−16.9 to −12.7)
- oral semaglutide: −10.9% (−12.7 to −9.1)
- orforglipron: −9.9% (−12.4 to −7.5)
- subcutaneous semaglutide: −9.8% (−10.6 to −9.1)
- phentermine-topiramate: −8.1% (−9.7 to −6.5)
Three newer agents — ecnoglutide, mazdutide and retatrutide — may land in the same range or higher, at 13.1% to 14.6%. That evidence is rated very low to low certainty, which is the review's way of saying the numbers may well move once more trials report.
Then the bill
People stopped taking them. Discontinuation because of adverse events was highest with orforglipron, naltrexone-bupropion, liraglutide, phentermine-topiramate, CagriSema and oral semaglutide — risk ratios between 1.9 and 4.2 compared with control. Moderate to high certainty. A drug nobody stays on does not produce the weight loss in the table.
Gastrointestinal problems. Most increased with naltrexone-bupropion, oral semaglutide, orforglipron and tirzepatide, risk ratios 3.1 to 4.2. The review reports these as one pooled category, so the split between nausea, vomiting and diarrhea is not visible at this level.
Fatigue, and this is the number worth staring at. With naltrexone-bupropion, the risk ratio for fatigue was 8.9 — an absolute increase of 331 more people per 1000 over a year. Roughly one in three users experiences tiredness they would not otherwise have had. Orforglipron came in at 3.4 (100 more per 1000) and CagriSema at 3.2 (92 more per 1000). Fatigue rarely makes headlines about these drugs. It should.
Fat came off, and so did lean mass. Tirzepatide reduced fat mass the most, by 25.7%. It also reduced lean mass the most, by 8.3%. Lean mass is muscle, organ tissue and bone-associated tissue — the part of body composition that predicts strength, mobility and how well someone tolerates the next decade. Losing some of it during rapid weight loss is expected; losing 8.3% of it is a meaningful subtraction, particularly for anyone already past midlife. This review was not designed to test whether resistance training or higher protein intake blunts that loss, so it cannot answer the obvious follow-up question.
Nobody felt better
This is the finding that will not fit in a headline. Across 43 trials with 45,663 participants, no drug produced a meaningful improvement in quality of life. Every mean difference came in under 5 points on scales where the minimally important difference — the smallest change a person actually notices — is 10.
People lost substantial weight and did not report feeling better in a way the instruments could detect. That does not make the weight loss worthless; blood pressure, blood sugar and joint load are real whether or not a questionnaire registers a mood shift. But it does undercut the promise these drugs are usually sold on.
No drug convincingly reduced kidney failure either.
Where the mortality benefit actually comes from
One drug in the analysis was associated with reduced all-cause mortality: subcutaneous semaglutide (risk ratio 0.81, 95% CI 0.72 to 0.93), which also reduced myocardial infarction (0.72, 0.61 to 0.85). Subcutaneous semaglutide (0.43) and tirzepatide (0.49) reduced heart failure risk.
Read the fine print on those estimates. They are largely informed by cardiovascular outcome trials conducted in high-risk populations — people with established heart disease or diabetes, not people taking a drug to lose 10 kilograms. Whether the same survival benefit extends to a healthier person with a BMI of 31 is not established by this evidence, and the review does not claim that it is.
How to read the table
The pattern the authors landed on is consistent across the whole analysis: larger weight loss generally arrives with greater harm and more discontinuation. The drug at the top of the efficacy list is also near the top of the lean-mass-loss list. The drug with the strongest mortality signal is mid-table for weight loss.
There is no single best answer in this data, which is exactly why the authors end on shared decision making rather than a recommendation. What the review does provide is an honest set of numbers to have that conversation with — including the ones that rarely come up, like fatigue and the quality-of-life null.
Medical note. This article is for general education and is not personal medical advice. Prescription decisions about obesity medication belong with your own clinician, who can weigh these trade-offs against your medical history. Do not start, stop or change a medication based on a news article.