How they work: one, two or three receptors
GLP-1 and GIP are incretins, hormones the gut releases after eating. Activating the GLP-1 receptor helps release insulin when blood sugar is high, lowers glucagon, slows stomach emptying and acts on brain areas that control hunger and fullness. Semaglutide acts on this receptor only. It is a modified 31-amino-acid version of GLP-1 with a fatty acid side chain that lets it last far longer than the natural hormone.
Tirzepatide is a 39-amino-acid peptide built on the GIP sequence that activates both the GIP and GLP-1 receptors, so it is called a dual agonist. Researchers think GIP adds to the effects on insulin and appetite, though exactly how is still debated. Retatrutide adds a third target, the glucagon receptor. In animal and early human research, glucagon signaling increased energy use and fat breakdown in the liver, while the GLP-1 and GIP effects are thought to offset glucagon's push on blood sugar.
Approval status
Semaglutide, made by Novo Nordisk, is the active ingredient in Ozempic, an injection for type 2 diabetes, Rybelsus, a tablet for type 2 diabetes, and Wegovy, for long-term weight management. Tirzepatide, made by Eli Lilly, is the active ingredient in Mounjaro for type 2 diabetes and Zepbound for weight management. Retatrutide, also from Eli Lilly, is investigational and in clinical trials as of 2026, so much less is known about it. The semaglutide profile and the retatrutide profile go deeper.
What the trials looked at
Results from separate trials, with different participants and lengths, cannot be compared directly, so claims that one drug is stronger than another should be read with care. The head-to-head trials above are the fairest comparison between two of these drugs. Results also varied from person to person, and in a follow-up of one large semaglutide weight trial, participants regained much of the weight within a year of stopping.
- Semaglutide
- The SUSTAIN and PIONEER programs studied type 2 diabetes, the STEP trials studied body weight, SELECT studied heart attacks and strokes in people with heart disease and overweight or obesity but no diabetes, and FLOW studied kidney disease in type 2 diabetes.
- Tirzepatide
- The SURPASS trials studied type 2 diabetes, and the SURMOUNT trials studied body weight in adults with obesity or overweight. The SURMOUNT-OSA trials also studied obstructive sleep apnea in adults with obesity.
- Tirzepatide vs semaglutide
- Two trials compared them directly. In SURPASS-2, in type 2 diabetes, average drops in HbA1c and weight were larger with tirzepatide. In SURMOUNT-5, in adults with obesity, average weight loss was larger with tirzepatide.
- Retatrutide
- Phase 2 trials in obesity and in type 2 diabetes, published in 2023, reported larger average drops in weight, and in the diabetes trial HbA1c, than placebo. Since late 2025, Eli Lilly has reported phase 3 TRIUMPH results, not all yet fully published.
Side effects and cautions
In trials of all three, the most common side effects were digestive: nausea, diarrhea, vomiting and constipation. They were most frequent early in treatment and often eased, but some participants stopped because of them. Severe vomiting or diarrhea can lead to dehydration, which has been linked to sudden kidney injury. A much smaller appetite can make it harder to eat enough protein and nutrients, and in this drug class part of the weight lost is lean tissue. Anyone with health questions should talk to a qualified clinician.
- Thyroid
- The US labels for semaglutide and tirzepatide carry a boxed warning because these drugs caused thyroid C-cell tumors in rodents. Whether this happens in people is not known.
- Pancreas and gallbladder
- Pancreatitis and gallbladder problems, including gallstones, are known risks for approved drugs in this class, and researchers watch for them with retatrutide.
- Low blood sugar
- The risk rises when these drugs are combined with insulin or sulfonylurea diabetes drugs.
- Birth control pills
- Tirzepatide's label notes that it may make birth control pills less effective for a time, because it slows stomach emptying.
- Retatrutide unknowns
- Its trials reported rises in heart rate and dysesthesia, an altered sense of touch on the skin. Because it is investigational, its full side effect profile is not yet known.
- Product content
- Health agencies have warned about counterfeit semaglutide, and products sold online as retatrutide outside trials may not contain what their labels say.
Where cagrilintide fits
Cagrilintide is often mentioned alongside these three, but it is not a GLP-1 drug. It is an investigational, long-acting version of amylin, a hormone the pancreas releases with insulin after meals, and it acts on amylin and calcitonin receptors. Novo Nordisk is testing it mainly together with semaglutide, a pairing called CagriSema. The cagrilintide profile covers that research.
