# GLP-1 / Anti-Obesity Medications Status: cross-verified ## Scope checklist - [x] Collect guideline and review-level framing - [x] Pull flagship RCT and meta-analysis effect sizes - [x] Compare weight-loss durability and maintenance - [x] Document discontinuation/regain data - [x] Document adverse effects / discontinuation rates - [x] Rank by practical usefulness for keeping a downcycle going - [x] Separate current practical options from investigational / frontier agents ## Key takeaways - For routine practical use in adults without diabetes, the strongest current evidence still supports `tirzepatide > semaglutide > phentermine/topiramate ~= liraglutide > naltrexone/bupropion > orlistat` for average weight-loss effect size, with the biggest practical split between the modern injectables and the older oral agents. - The biggest correction to internet discourse is still that these are not clean "finish the cut, then stop" drugs. Withdrawal data repeatedly show meaningful regain, often with reversal of some cardiometabolic gains, so the evidence base fits chronic therapy better than short-course therapy. - The summary needed a frontier section. `Retatrutide`, `CagriSema / cagrilintide`, `mazdutide`, and likely `orforglipron` matter in 2026, but they belong in an investigational or emerging-options section rather than being mixed uncritically into the practical ranking. - The main tolerability cost is gastrointestinal, not a proven large suicidality signal. As of January 10, 2026, FDA said it found no increased risk of suicidal thoughts or behavior and requested removal of that warning from Wegovy, Saxenda, and Zepbound labels. - Semaglutide still matters even though tirzepatide is usually stronger for weight loss: semaglutide has obesity-specific cardiovascular-outcomes evidence from SELECT and an FDA obesity label expansion dated March 8, 2024. ## Current practical ranking for keeping a downcycle going ### 1. Tirzepatide - Best average efficacy among routine approved options. - Flagship effects: SURMOUNT-1 showed `-15.0%`, `-19.5%`, and `-20.9%` at 72 weeks for 5 mg, 10 mg, and 15 mg versus `-3.1%` with placebo. - Direct comparison: SURMOUNT-5 reported `-20.2%` at week 72 with tirzepatide versus `-13.7%` with semaglutide. - Maintenance: strong while continued, weak after stopping. In SURMOUNT-4, participants who continued tirzepatide from week 36 to week 88 lost another `5.5%`; those switched to placebo regained `14.0%`. - Main drawbacks: GI adverse effects, injectable route, cost/access, and less obesity-specific hard-outcomes evidence than semaglutide as of April 13, 2026. ### 2. Semaglutide 2.4 mg - Slightly weaker on average weight loss than tirzepatide, but still a major-effect drug and more proven on cardiovascular outcomes in obesity. - Flagship effects: STEP 1 showed `-14.9%` at 68 weeks versus `-2.4%` with placebo. STEP 5 showed `-15.2%` at 104 weeks versus `-2.6%` with placebo. - Meta-analytic effect: a 2023 updated meta-analysis found about `-11.80 percentage points` versus placebo in non-diabetic overweight/obese adults. - Outcomes edge: SELECT supported a `20%` reduction in major adverse cardiovascular events in adults with overweight/obesity and established cardiovascular disease but without diabetes; FDA announced the related label expansion on `2024-03-08`. - Main drawback for downcycle use: stopping leads to regain. In STEP 4, people who switched to placebo after the run-in regained `6.9%` over 48 weeks, versus another `7.9%` loss if semaglutide was continued. ### 3. Phentermine/topiramate - Best older non-GLP-1 option for pure weight-loss effect size. - Trial effects: placebo-subtracted loss around `9.3%` in EQUIP, `8.6%` in CONQUER, and `8.7%` in SEQUEL. - Practical role: useful when an oral option is required or cost/access block GLP-1/GIP therapy. - Main drawbacks: stimulant-type side effects, insomnia/anxiety risk, teratogenic risk, REMS requirements, and the need to taper rather than stop abruptly. ### 4. Liraglutide 3.0 mg - Clearly effective, but generally displaced by weekly semaglutide/tirzepatide because it is weaker and requires daily injection. - Trial effects: about `8.0%` versus `2.6%` placebo in SCALE Obesity and Prediabetes; after initial diet-induced loss, SCALE Maintenance showed an additional `6.2%` loss versus `0.2%` with placebo. - Practical role: still evidence-based, but hard to rank above semaglutide unless supply, cost, or individual tolerability changes the decision. ### 5. Naltrexone/bupropion - Modest efficacy and more of a niche fit than a first-line downcycle support drug. - Trial effects: COR-I reported `6.1%` mean loss versus `1.3%` placebo; behavioral-program versions can do somewhat better. - Main drawbacks: nausea, insomnia, headache, blood-pressure concerns, seizure risk, and contraindications in eating-disorder and opioid-use contexts. ### 6. Orlistat - Low-effect option with the biggest adherence penalty from GI side effects. - Practical role: mainly when patients want a non-central, non-injectable, long-term option and accept modest effects. - Main drawback: oily stool/fecal urgency and related GI burden are the main reasons people discontinue it. ## Investigational / frontier agents that were missing ### Retatrutide - This was a real omission from the earlier summary. - Mechanistically, retatrutide is a triple agonist (`GIP + GLP-1 + glucagon`) and is one of the main reasons the frontier obesity-drug landscape now extends beyond tirzepatide. - Earlier obesity-phase data already suggested very high efficacy; as of `2026-03-19`, Lilly reported first Phase 3 diabetes topline data from TRANSCEND-T2D-1 with up to `16.8%` weight loss at 40 weeks and said the obesity program remains in Phase 3. - Practical ranking logic: if retatrutide reaches approval with Phase 3 obesity efficacy and tolerability close to earlier signals, it may outrank tirzepatide on weight-loss effect size. But as of `2026-04-13`, it remains investigational and is not yet a routine practical option. - Main caution: this is exactly the kind of drug internet discussion tends to talk about as if it were already interchangeable with approved treatments. It is not. ### CagriSema / cagrilintide - Cagrilintide monotherapy matters less than the combination with semaglutide. - Your peptides research correctly treats this as a meaningful frontier option: CagriSema produced about `20%` to `23%` body-weight loss in Phase 3 programs, which puts it in the same general performance band as tirzepatide and above semaglutide monotherapy. - Practical status point: it is still emerging rather than routine. It deserves mention because it is too important for a 2026 landscape summary to ignore, but it does not belong in the same bucket as established day-to-day prescribing options unless and until approval/access stabilize. - Head-to-head note: the existing comparison signal does not make it clearly superior to tirzepatide. ### Mazdutide - Mazdutide matters mostly as a serious emerging dual glucagon/GLP-1 option rather than a globally routine default recommendation. - Your peptides notes and verification file suggest it has stronger evidence than a typical obscure pipeline peptide and may be especially relevant in China, but it still has a much thinner practical evidence and access base than semaglutide or tirzepatide for a general audience. - It belongs in a frontier section, not omitted entirely, but also not mixed into the practical top-line ranking without a status label. ### Orforglipron - Not a peptide, but relevant to the 2026 obesity-med landscape because it is a serious oral GLP-1 contender. - Lilly reported in 2025-2026 that it is moving through Phase 3 and regulatory submission pathways. If approved, its main significance is convenience and oral delivery rather than clearly beating tirzepatide on effect size. - This is worth tracking because it could change the practical ranking for people who strongly prefer avoiding injections. ## Discontinuation and regain - The evidence is consistent across semaglutide, tirzepatide, and pooled GLP-1RA discontinuation studies: meaningful regain after stopping is common. - A 2025 systematic review/meta-analysis found pooled mean regain of `2.20 kg` after liraglutide discontinuation and `9.69 kg` after semaglutide/tirzepatide discontinuation. - This does not mean every patient regains everything immediately, but it does mean the "short course and you are done" model is not supported by the best current evidence. - Tirzepatide post hoc data also suggest regain is accompanied by backsliding in waist circumference, systolic blood pressure, HbA1c, fasting insulin, and non-HDL cholesterol. ## Adverse effects and discontinuation - The dominant class problem is gastrointestinal intolerance: nausea, vomiting, diarrhea, and constipation. - STEP 1 reported GI side effects in `74.2%` with semaglutide versus `47.9%` with placebo; serious adverse events were `9.8%` versus `6.4%`. - A 2025 systematic review/meta-analysis reported overall GI adverse events were `1.86x` higher with semaglutide/tirzepatide versus placebo, with higher relative GI risk for tirzepatide than semaglutide. - In STEP 4, adverse-event-related discontinuation during the randomized maintenance period was `2.4%` with continued semaglutide versus `2.2%` after switch to placebo, but this likely understates early intolerance because only run-in completers were randomized. - Frontier note: retatrutide and related next-wave agents may add distinct tolerability issues beyond ordinary GLP-1/GIP framing; those need separate tracking rather than being assumed identical to semaglutide. - Contraindication/practical caution themes that matter most in public-facing summaries: - GLP-1/GIP agents: GI intolerance; pregnancy planning; thyroid C-cell tumor warning context; gallbladder risk. - Phentermine/topiramate: pregnancy/teratogenicity, insomnia/anxiety, cardiovascular caution, taper requirement. - Naltrexone/bupropion: seizure risk, uncontrolled hypertension, opioid incompatibility, eating-disorder contraindications. - Orlistat: GI burden and fat-soluble vitamin malabsorption. ## Internet-claim corrections - `Claim correction:` "GLP-1s are a temporary cut drug you can stop once you hit goal weight." Reality: withdrawal trials and pooled discontinuation data show substantial regain is common. - `Claim correction:` "Semaglutide and tirzepatide are basically the same." Reality: direct randomized evidence currently favors tirzepatide for average weight-loss effect size. - `Claim correction:` "Older oral drugs work just as well." Reality: the better older agents are real but usually single-digit percentage-loss tools, not peers of semaglutide/tirzepatide. - `Claim correction:` "Retatrutide should already be treated like an available superior replacement for tirzepatide." Reality: retatrutide is highly important, but as of April 13, 2026 it is still investigational and should be ranked separately from routine practical options. - `Claim correction:` "GLP-1 obesity drugs have a confirmed suicidality signal." Reality: FDA's January 10, 2026 update said it found no increased risk and requested removal of that warning from Wegovy, Saxenda, and Zepbound labeling. ## Sources used for the main rankings - WHO obesity GLP-1 guideline news release, December 1, 2025. - Nature Medicine 2025 systematic review/meta-analysis of obesity pharmacotherapies. - SURMOUNT-1, SURMOUNT-4, and SURMOUNT-5 PubMed records / associated summaries. - STEP 1, STEP 4, STEP 5, SELECT, and semaglutide meta-analyses. - NCBI Endotext chapter `Pharmacologic Treatment of Overweight and Obesity in Adults`. - Eli Lilly retatrutide Phase 3 diabetes topline release, March 19, 2026. - Local `peptides` project notes and verification for cagrilintide/CagriSema, mazdutide, and retatrutide status framing.