What the large randomized trials found for the heart, kidneys, liver and joints, and what those results don’t tell you.
Enter your email to be alerted when new articles are posted. It’s free, and no more than a few emails a month.
Semaglutide became famous as a weight-loss drug. But since 2023, a run of large, randomized trials has asked a harder question: does it change what actually happens to people’s health? Not just the number on the scale, but heart attacks, kidney failure, liver scarring and everyday pain.
This article walks through that evidence trial by trial, with the actual numbers. It also covers the parts that tend to get left out of social media posts: which doses were tested, in which patients, and what the trials can’t tell you about any product outside them.
Semaglutide was first approved in 2017 as Ozempic, a weekly injection for type 2 diabetes. The higher 2.4 mg dose was then tested specifically for obesity in the STEP program, which led to the approval of Wegovy in 2021.1,2
Average change in body weight from the start of the trial.
These are averages. Some people lost much more and some lost little. The STEP trials also showed that the effect depends on staying on treatment: in STEP 4, people who switched to placebo after 20 weeks regained 6.9% of their body weight over the following year, while those who continued lost another 7.9%.3
Weight, blood sugar and blood pressure are what researchers call surrogate markers. They’re useful, but they aren’t the same as the events people actually fear. A drug can improve a number on a lab report without preventing a single heart attack. Outcome trials settle that question directly: they enroll thousands of people, follow them for years, and count the events that matter.
The trials below are that kind of evidence. Most are Phase 3, all are randomized and placebo-controlled, and all were published in major peer-reviewed journals.
Share of people who had a heart attack, stroke or cardiovascular death. Hazard ratio 0.80, a 20% lower risk.
SELECT was the first trial to show that a weight-management drug reduces cardiovascular events in people without diabetes. It’s the basis for the March 2024 FDA label expansion that lets Wegovy be prescribed to reduce cardiovascular risk in this group.4
What makes SELECT interesting is that the benefit doesn’t appear to be explained by weight loss alone. Average weight loss was a more modest 9.4% (versus 0.9% on placebo), the benefit was similar across every starting weight, and a later analysis found that how much weight people lost early on didn’t predict their later heart risk.5 Researchers think effects on inflammation, blood vessels and blood pressure are likely part of the story, but that isn’t settled.
HFpEF is the form of heart failure most tied to obesity, aging and metabolic disease. The heart pumps normally but is stiff, leaving people breathless and exhausted. It has historically had few effective treatments.
Change in six-minute walking distance.
Symptom scores on the Kansas City Cardiomyopathy Questionnaire improved by 16.6 points with semaglutide versus 8.7 with placebo. Weight fell 13.3% versus 2.6%. C-reactive protein, a blood marker of inflammation, dropped 43.5% versus 7.3%, and serious adverse events were less common in the semaglutide group.6
Share of people with a major kidney event: kidney failure, a 50% or greater loss of kidney function, or death from kidney or heart causes. Hazard ratio 0.76, a 24% lower risk.
Kidney function declined more slowly with semaglutide, by about 1.2 mL/min per year. The trial also found 18% fewer major cardiovascular events, 29% fewer cardiovascular deaths and 20% lower death from any cause.7 FLOW led to a January 2025 label expansion for Ozempic in people with type 2 diabetes and chronic kidney disease.
Note the population and dose. FLOW studied people with diabetes and existing kidney disease at the 1.0 mg diabetes dose. It doesn’t show that semaglutide protects healthy kidneys.
Metabolic dysfunction-associated steatohepatitis, or MASH (formerly called NASH), is fat buildup in the liver that has progressed to inflammation and scarring. It’s common in people with obesity and diabetes and can lead to cirrhosis, liver cancer and transplant.
Share of people whose liver inflammation resolved without the scarring getting worse.
Scarring improved in 36.8% of people on semaglutide versus 22.4% on placebo, and both improved together in 32.7% versus 16.1%. Weight fell 10.5% versus 2.0%.8 In August 2025, the FDA granted accelerated approval for Wegovy in adults with MASH and moderate to advanced scarring, the first GLP-1 liver indication. The second part of ESSENCE, which tracks cirrhosis and other liver outcomes over several years, is still underway.
Weight loss on its own is known to improve liver biopsies, so how much of this effect is specific to the drug is still debated.9
Change in WOMAC knee pain score, on a 0–100 scale where lower is better.
Physical function scores improved by 12.0 points versus 6.5, and weight fell 13.7% versus 3.2%.10 Less weight means less load on the knee, and that likely explains most of the effect. Whether semaglutide also calms joint inflammation directly is plausible but unproven.
Not every hoped-for benefit has held up. Early observational data suggested GLP-1 drugs might protect the brain, which led to two large trials of oral semaglutide in people with early Alzheimer’s disease, EVOKE and EVOKE+. In November 2025, both trials missed their main goal of slowing cognitive decline.11 Claims that semaglutide improves memory or prevents dementia aren’t supported by the trial evidence.
| Area | Result vs placebo | Trial and dose |
|---|---|---|
| Weight (obesity) | −14.9% vs −2.4% | STEP 1 · 2.4 mg · 68 weeks |
| Heart attack, stroke, CV death | 20% lower risk | SELECT · 2.4 mg · ~40 months |
| Heart failure (HFpEF) | Better symptoms; +21.5 m vs +1.2 m walk | STEP-HFpEF · 2.4 mg · 52 weeks |
| Kidneys (T2D with CKD) | 24% lower risk of major kidney events | FLOW · 1.0 mg · 3.4 years |
| Liver (MASH) | Resolved in 62.9% vs 34.3% | ESSENCE · 2.4 mg · 72 weeks |
| Knee osteoarthritis | Pain −41.7 vs −27.5 points | STEP 9 · 2.4 mg · 68 weeks |
| Alzheimer’s disease | No benefit | EVOKE / EVOKE+ · oral semaglutide |
Every trial above used FDA-approved semaglutide made by the manufacturer, at 2.4 mg or 1.0 mg weekly. Compounded semaglutide is prepared by licensed pharmacies for individual prescriptions. It is not FDA-approved and has not been evaluated by the FDA for safety, effectiveness or quality, and none of these trials studied it.
Lower “microdose” regimens are a separate question. There are no published outcome data for sub-therapeutic doses, and none of the results above should be attributed to them.
They apply to the people studied. SELECT enrolled people who already had heart disease. FLOW enrolled people with diabetes and kidney disease. ESSENCE required biopsy-proven liver disease. A result in one of those groups doesn’t automatically carry over to a healthy adult who wants to lose 15 pounds.
The benefits last only while treatment continues. As STEP 4 showed, weight returns when the drug stops. Long-term treatment is the model the trials tested, much like blood-pressure or cholesterol medication.
Side effects are real. Nausea, vomiting, diarrhea and constipation are common, especially while the dose is increasing, and are the most frequent reason people stop. Less common but serious risks include pancreatitis, gallbladder disease, low blood sugar when combined with insulin or sulfonylureas, and kidney injury from dehydration. Semaglutide carries a boxed warning about thyroid C-cell tumors seen in rodents, and it shouldn’t be used by people with a personal or family history of medullary thyroid cancer or MEN 2. Only a licensed clinician who knows your history can weigh these for you.
Visit ajpeptide.com to see current compounded GLP-1 options and start a provider evaluation.
ajpeptide.comThe companion article: tirzepatide’s trials, approvals and head-to-head results against semaglutide.
Tirzepatide, not just for weight lossPrescription required. Provider evaluation at no charge. A licensed clinician determines eligibility, dosing and monitoring for every patient. Individual results vary. This article is for education and is not medical advice. Wegovy and Ozempic are registered trademarks of Novo Nordisk A/S; AJ Peptide is not affiliated with Novo Nordisk.
