Semaglutide didn't just become a blockbuster drug — it changed the entire framing of what obesity treatment can look like. Before semaglutide, "lifestyle intervention" was the polite way of saying "we don't have much for you." After the STEP trials, it became clear that a weekly injection could do what decades of dieting couldn't.
It's worth understanding what semaglutide actually is. It's a synthetic analog of GLP-1 (glucagon-like peptide-1), a hormone your gut produces naturally when you eat. GLP-1 does several things: tells your pancreas to release insulin, tells your liver to stop dumping glucose, slows how fast food leaves your stomach, and sends satiety signals to your brain. Semaglutide mimics all of these effects — but it's been engineered to last a week instead of minutes, which is why a once-weekly injection works.
The results in clinical trials are numbers the obesity medicine field had never seen before. In the STEP 1 trial (2,000+ participants, 68 weeks), the average weight loss was 14.9% of body weight on 2.4mg/week. About a third of participants lost 20% or more. For context, orlistat — the previous best non-surgical weight loss drug — averaged about 3%. Bariatric surgery averages 25–30% but comes with significant surgical risk. Semaglutide sits in a new category.
How Semaglutide Works
Appetite and "food noise" suppression. This is what users describe most consistently — and it's not willpower, it's pharmacology. Semaglutide activates GLP-1 receptors in the hypothalamus and brainstem, the parts of the brain that regulate hunger and reward. The "food noise" that people with obesity often describe — the constant background thoughts about food, cravings, urges to eat when not hungry — gets turned down dramatically. Many users report being able to walk past food they previously couldn't resist without a second thought.
Delayed gastric emptying. Food leaves your stomach more slowly on semaglutide. This keeps you feeling full longer after meals, reduces post-meal blood sugar spikes, and changes the whole rhythm of eating. Smaller portions feel satisfying in a way they didn't before.
Insulin secretion and glucose regulation. Semaglutide triggers insulin release in a glucose-dependent way — meaning it only activates when blood sugar is actually elevated. This is why hypoglycemia is rare with GLP-1 agonists compared to older diabetes drugs.
Cardiovascular protection. The SELECT trial (2023) — 17,600 participants, 5 years — showed semaglutide reduced major cardiovascular events (heart attack, stroke, cardiovascular death) by 20% in people with obesity but without diabetes. This is a landmark finding that extends semaglutide's significance beyond just weight loss.
What the Clinical Evidence Shows
The evidence base for semaglutide is among the strongest for any drug in recent history. The STEP program (STEP 1–5) consistently showed 10–17% weight loss across different populations. SUSTAIN trials demonstrated robust A1c reduction in type 2 diabetes. The FLOW trial showed kidney disease progression slowed. SELECT showed cardiovascular benefit. This is not a drug with one positive trial — it has a deep, converging body of evidence.
The Ozempic vs. Wegovy distinction matters: they're the same molecule, different doses. Ozempic (up to 2mg) is dosed for diabetes; Wegovy (up to 2.4mg) for weight loss. The difference in approved max dose explains some of the results gap between them.
The Titration Schedule Matters
Semaglutide's side effect profile — primarily nausea, vomiting, constipation, and diarrhea — is almost entirely a dose-titration problem. The approved schedule starts at 0.25mg/week for 4 weeks, then slowly escalates over months to the maintenance dose. People who rush the titration get hit with significant GI side effects. People who follow the schedule, or titrate even slower, typically report manageable or no nausea by week 6–8.
This is the single most common reason people stop early: they or their prescriber rush the dose escalation. The titration schedule isn't optional — it's how the drug works tolerably.
Who Semaglutide Is Not For
Semaglutide has a black box warning for thyroid C-cell tumors, which appeared in rodent studies. People with personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 should not take it. History of pancreatitis is a contraindication. It's also not appropriate during pregnancy.
The compounded semaglutide market (which exploded during the Ozempic shortage) is a different story entirely. Compounded versions have no FDA oversight for purity or dosing accuracy, and there have been documented hospitalizations from miscalculated doses. If you're going off-label, that risk is real and worth understanding.
The Rebound Question
The most important thing that doesn't get enough honest discussion: weight tends to return when semaglutide is stopped. The STEP 1 extension study showed that participants regained two-thirds of lost weight within a year of stopping. This doesn't mean semaglutide "doesn't work" — it means obesity is a chronic disease that, for most people, requires ongoing treatment. That's not unique to semaglutide; it's true of blood pressure medication too. But it's a crucial piece of information for anyone deciding whether to start.