Peptides for weight loss: Semaglutide vs Tirzepatide

Semaglutide is a long-acting analogue of GLP-1, a gut hormone released after eating. It slows gastric emptying, amplifies glucose-dependent insulin release, suppresses glucagon, and — most importantly for weight — signals satiety in the hypothalamus. The result is smaller portions, longer satiety, and a quieter "food noise" loop.

Tirzepatide adds a second receptor: GIP. GIP alone is a weak weight-loss signal, but combined with GLP-1 it appears to improve insulin sensitivity, enhance lipid handling, and blunt some of the nausea seen with pure GLP-1 agonism. In practice this translates to more weight loss at each equivalent dose step.

STEP 1 (Wilding et al., NEJM 2021) randomised 1,961 adults with obesity to semaglutide 2.4 mg weekly or placebo. At 68 weeks the semaglutide arm lost 14.9% of body weight vs 2.4% with placebo; 86% lost ≥5%.

SURMOUNT-1 (Jastreboff et al., NEJM 2022) randomised 2,539 adults to tirzepatide 5, 10, or 15 mg weekly vs placebo. At 72 weeks the 15 mg arm lost 20.9% of body weight; 91% lost ≥5%, and 57% lost ≥20%.

SURMOUNT-5 (2025) is the first direct head-to-head: tirzepatide beat semaglutide by roughly 5–6 percentage points of weight loss over 72 weeks. SELECT showed a 20% reduction in major adverse cardiovascular events on semaglutide 2.4 mg in patients with established cardiovascular disease and overweight — the strongest outcome data in the class so far.

Both molecules are titrated slowly — the goal is not to reach the "top" dose but to reach the lowest effectivedose that produces steady weight loss with acceptable side effects. Faster titration is the single most common reason patients quit.

• Semaglutide: 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg weekly, stepping up every 4 weeks.
• Tirzepatide: 2.5 → 5 → 7.5 → 10 → 12.5 → 15 mg weekly, stepping up every 4 weeks.
• Hold or reduce the dose if GI side effects are severe — momentum matters more than speed.
• Preserve lean mass: prioritise 1.6–2.2 g/kg protein daily and resistance training 2–3× weekly.

The reconstitution & pen calculator handles unit-mark conversions for both molecules.

The commonest issues are gastrointestinal — nausea, constipation, reflux, occasional diarrhoea — mostly during titration. Serious but rare risks include pancreatitis, gallbladder disease, and gastroparesis. GLP-1 / GIP agonists are contraindicated in personal or family history of medullary thyroid carcinoma or MEN 2, and should be paused before elective surgery per anaesthesia guidance. Pregnancy and active severe GI disease are also exclusions.

Baseline and follow-up labs typically include HbA1c, fasting insulin, lipid panel, liver enzymes, renal function, and — where indicated — lipase. The Bloodwork Interpreter lists the markers most relevant to this class.

• Retatrutide — a triple agonist (GLP-1 / GIP / glucagon) in phase 3; early data suggests weight loss beyond tirzepatide.
• Tesamorelin — targets visceral adipose tissue specifically; useful adjunct, not a systemic weight loss agent.
• AOD-9604 — a GH fragment marketed for fat loss; evidence is thin compared with the incretin class.
• MOTS-c and MQ-NAD-C — mitochondrial and metabolic support; helpful alongside GLP-1s, not a substitute.

The full Fat Loss protocol shows how these molecules stack in practice.