The incretin drugs — semaglutide, tirzepatide, and the investigational retatrutide — have produced the largest sustained weight loss ever seen from medication rather than surgery. They started as diabetes treatments, but the weight effect turned out to be the headline. This guide covers how they work, the real numbers from the pivotal trials, and the parts people tend to gloss over: the muscle you lose alongside the fat, the nausea, and what happens when you stop.
The short version: these drugs work mainly by making you eat less. They are not fat burners in the metabolic sense. They turn down appetite and slow the stomach, so you take in fewer calories almost without trying. That is a genuinely powerful lever, but it also explains most of the trade-offs.
How they actually work
GLP-1 (glucagon-like peptide-1) is a hormone your gut releases after eating. It tells the pancreas to release insulin, slows how fast the stomach empties, and acts on appetite centres in the brain to make you feel full sooner and stay full longer. These drugs are engineered versions of that hormone that resist breakdown, so a single weekly injection keeps the signal running for days.
- Semaglutide agonises the GLP-1 receptor alone.
- Tirzepatide is a dual agonist: it hits both GLP-1 and GIP (another incretin hormone), which appears to add efficacy.
- Retatrutide is a triple agonist — GLP-1, GIP, and glucagon. The glucagon arm may raise energy expenditure on top of appetite suppression, which is one theory for why its trial numbers are the highest so far.
The practical effect is the same across all three: you are less hungry, food is less interesting, and you stop eating sooner. The weight comes off because of the calorie deficit that creates.
What the trials actually show
These are real numbers from the pivotal phase 3 trials, at the top studied doses, over roughly 16 months:
- Semaglutide 2.4 mg (STEP 1, adults with obesity, no diabetes): mean weight loss of about 14.9% versus 2.4% on placebo over 68 weeks.
- Tirzepatide 15 mg (SURMOUNT-1): mean weight loss of about 20.9% versus 3.1% on placebo over 72 weeks.
- Retatrutide 12 mg (phase 2, 48 weeks): mean weight loss of about 24.2%. This is phase 2 data — larger phase 3 trials (the TRIUMPH programme) were ongoing, so treat the figure as promising but not yet confirmed at scale.
For context, those are averages. Some people lose far more, some much less. Roughly a third of tirzepatide 15 mg participants lost at least a quarter of their body weight — territory that used to require bariatric surgery.
Semaglutide also has the SELECT trial behind it, which showed a 20% reduction in major cardiovascular events in people with heart disease and obesity but not diabetes. That is a hard clinical outcome, not just a number on a scale.
The muscle-loss trade-off
This is the part fitness-minded users care about most and the drugs' own marketing tends to skip. When you lose weight rapidly through a calorie deficit, a meaningful fraction of what you lose is lean mass, not just fat. In GLP-1 trials where body composition was measured, lean mass has typically accounted for somewhere around a quarter to 40% of total weight lost, depending on the study, the population, and how it was measured.
That is not unique to these drugs — any large, fast weight loss does this, including dieting and surgery. But because the appetite suppression is so strong, people often eat far too little protein and do no resistance training, which makes the lean-mass loss worse than it needs to be. Two things blunt it: keeping protein intake high (roughly 1.6 g/kg of target body weight or more) and lifting weights throughout. Neither eliminates it, but both help preserve strength and metabolic rate.
Side effects and tolerability
The dominant side effects are gastrointestinal and follow directly from slowed stomach emptying:
- Nausea, vomiting, diarrhoea and constipation — most common early and during dose escalation, usually fading over weeks.
- Reduced appetite so strong that some people struggle to eat enough protein or stay hydrated.
- Less commonly, gallbladder problems (rapid weight loss raises gallstone risk) and pancreatitis, which is rare but a reason to stop and seek care if severe abdominal pain occurs.
Doses are escalated slowly for exactly this reason: starting low and stepping up over months keeps most people below the threshold where nausea becomes intolerable. Rushing the titration is the most common self-inflicted problem.
What happens when you stop
These are appetite drugs, not permanent metabolic resets. When you stop, appetite returns. The STEP 4 extension study of semaglutide showed that people who came off the drug regained a large share of the lost weight over the following year. This is not a moral failing — it is the pharmacology. The signal keeping appetite down is gone, so intake rises again.
The honest implication is that these are, for most people, long-term or indefinite treatments if the goal is to keep the weight off, much like blood-pressure medication. Anyone framing them as a short course to "reset" is misunderstanding how they work.
Bottom line
GLP-1 and multi-agonist drugs produce weight loss that no previous medication has matched — roughly 15% for semaglutide, 21% for tirzepatide, and possibly more for retatrutide once phase 3 confirms it. They do it by cutting appetite, which is powerful but also explains the costs: real gastrointestinal side effects, meaningful lean-mass loss unless you actively defend it with protein and training, and weight regain when you stop. Used with eyes open — high protein, resistance training, and a long-term mindset — they are a genuinely effective tool. Treated as a quick fix, they disappoint.