Best GLP-1 Drugs Ranked by Evidence (2026)
Which GLP-1 or incretin drug is the best one to take?
Tirzepatide, at 6.1, then semaglutide at 6.0, then orforglipron at 5.8 if you want the pill. All three are approved, all three have real trial evidence, and all three are obtainable. The six drugs below them score lower on evidence maturity and legal supply, not on how much weight they actually take off.
- Tirzepatide 6.1 and semaglutide 6.0 lead. Everything else scores 5.8 or below.
- The drug with the largest published weight loss ranks 8th. CagriSema hit about 22.7% on-treatment in REDEFINE 1, and still scores 5.1, because it is not approved anywhere and has no heart-outcomes data.
- Only two of the nine are prescribable in the US as injectables today. A third, orforglipron, is an approved oral pill. The other six arrive as research or cross-border vials with vendor-dependent purity.
- The top two take every scored use case between them. That is a statement about evidence depth, not about biology.
- Two members are worth knowing for one organ each: survodutide for biopsy-confirmed liver disease, mazdutide for raw liver-fat clearance.
- The ranking is the live score. When a member's score moves, this page moves with it.
The Ranking
9 interventions ranked by live BioHarmony score.
Rank 1: Tirzepatide
6.1 / 10 Worth tryingDual GIP and GLP-1 agonist. FDA approved. BioHarmony 6.1, worth trying.
Rank 2: Semaglutide
6.0 / 10 Worth tryingSecond by a tenth of a point, and first on almost every non-scale endpoint. It holds the highest blood-sugar subrating in the category at 9.5, the highest cardiovascular at 8.0 behind a 20% reduction in 3-point MACE (Lincoff 2023), and a kidney-outcome win in type 2 diabetes with CKD (Perkovic 2024). Pick it over tirzepatide when the reason you are here is cardiovascular or renal risk rather than the number on the scale. Complete regain within about a year of stopping is the same trade.
GLP-1 agonist. FDA approved. BioHarmony 6.0, worth trying.
Rank 3: Orforglipron (Foundayo)
5.8 / 10 Worth tryingThe pill. Approved for obesity in April 2026, non-peptide, once daily, no food or water timing rules, and it cut body weight about 11.2% at 72 weeks in ATTAIN-1 (Wharton 2025). It also beat oral semaglutide on both weight and HbA1c head to head (ACHIEVE-3). It ranks third rather than first because 11.2% trails injectable semaglutide by about 4 points and tirzepatide by about 10, and its dedicated cardiovascular outcomes trial is years out. Pick it when a needle is the thing stopping you.
Non-peptide oral GLP-1 agonist. FDA approved April 2026. BioHarmony 5.8, worth trying.
Rank 3: VK2735 (Viking Therapeutics)
5.8 / 10 Worth tryingSame score as orforglipron, arrived at from the opposite direction: a strong signal on the thinnest file in the batch. The peer-reviewed VENTURE Phase 2 injectable trial reported about 14.7% weight loss, with roughly 89% of the 15 mg arm losing at least 10% of body weight (Bays 2026). Every dataset is 13 weeks or shorter, nothing is approved, and there is no cardiovascular or long-term safety data at all. Its own report rates confidence low. Worth tracking, not worth sourcing.
Investigational dual GLP-1 and GIP agonist. BioHarmony 5.8, worth trying.
Rank 3: Cagrilintide (AM833)
5.8 / 10 Worth tryingThe only non-incretin in the ranking, and the reason it is here is tolerability. Amylin signaling produced about 11.8% weight loss as monotherapy at 68 weeks in REDEFINE 1 (Garvey 2025) with no hypoglycemia and less nausea than the GLP-1 drugs. That matters if gastrointestinal side effects are what ended your last attempt. It still loses to semaglutide alone on effect, has zero cardiovascular data, and exists only as the amylin half of CagriSema. Choose it for the mechanism, not the supply.
Long-acting amylin analogue. Investigational. BioHarmony 5.8, worth trying.
Rank 6: Mazdutide (IBI362)
5.6 / 10 🤷 NeutralApproved in China for obesity in June 2025, which makes it the only member besides the top three with a real regulatory label anywhere. GLORY-1 showed about 14.84% weight loss at 48 weeks (Ji 2025) and the strongest published liver-fat reduction in the class, roughly 72 to 80% in high-baseline participants. Neutral rather than worth trying because the glucagon arm raises heart rate, no cardiovascular outcomes trial exists, and outside China the supply is gray market.
Dual GLP-1 and glucagon agonist. Approved in China only. BioHarmony 5.6, neutral.
Rank 6: Retatrutide
5.6 / 10 🤷 NeutralThe most ambitious molecule in the category and the one most often bought on the wrong evidence. Jastreboff 2023 reported up to 24.2% body-weight loss at 48 weeks in Phase 2, and an indirect network meta-analysis of 27 RCTs ranked it first of seven agents (Xie 2024). None of that is a Phase 3 publication. FDA states it has not been found safe and effective for any condition and cannot be used in compounding, so outside a Lilly trial every supply is a not-for-human-use vial. The score is an evidence and access discount, not a verdict on the biology.
Investigational GLP-1, GIP and glucagon triple agonist. BioHarmony 5.6, neutral.
Rank 8: CagriSema (Cagrilintide + Semaglutide)
5.1 / 10 🤷 NeutralEighth with the biggest number on the page. About 22.7% weight loss on-treatment at 68 weeks in REDEFINE 1 (Garvey 2025), roughly 5 to 6 points better than semaglutide alone, and 74% of type 2 diabetics reaching HbA1c at or below 6.5% in REDEFINE 2 (Kahn 2025). It still scores 5.1: it lost a head-to-head against tirzepatide, carries the heaviest gastrointestinal load in the batch, has no heart-outcomes data, and is not approved anywhere. This row is the clearest illustration of what the ranking measures.
Investigational amylin plus GLP-1 combination. BioHarmony 5.1, neutral.
Rank 8: Survodutide (BI 456906)
5.1 / 10 🤷 NeutralLast on the composite and first on one organ. In a 48-week biopsy-confirmed Phase 2 trial, 62% of patients on 4.8 mg saw MASH improve with no worsening of fibrosis, against 14% on placebo (Sanyal 2024), and Phase 3 topline reports up to 16.6% weight loss. Its liver subrating of 6.3 is the highest of any member scored on direct hepatic outcomes rather than inferred from weight loss. Pick it only if serious fatty liver disease is the reason you are reading, and even then, not from a vial.
Investigational dual GLP-1 and glucagon agonist. BioHarmony 5.1, neutral.
Best Pick by Use Case
| Use Case | Winner | Runner-Up | Why |
|---|---|---|---|
| Body Composition | Tirzepatide 9.0 | Retatrutide 7.5 | Tirzepatide's 9.0 comes from a pivotal Phase 3 with about 15% mean loss. Retatrutide's larger headline number sits at 7.5 because 24.2% came from a Phase 2 trial. CagriSema's 22.7% scores 6.8 for the same reason. Nothing here protects lean mass on its own. |
| Blood Sugar | Semaglutide 9.5 | Tirzepatide 9.2 | A 0.3 gap between the two approved injectables, which in practice means pick either. Orforglipron's 6.0 is the one to watch: it beat oral semaglutide on HbA1c head to head, and its diabetes indication is pending. |
| Cardiovascular | Semaglutide 8.0 | Tirzepatide 7.8 | The only row where a completed outcomes trial exists on either side. Semaglutide cut 3-point MACE by 20% in SELECT. Six of the nine members score below 4.0 here, and every one of those scores means the same thing: no cardiovascular outcome trial has reported. |
| Metabolic Health | Semaglutide 9.0 | Tirzepatide 8.7 | Retatrutide's 8.5 is close behind on mechanism, and the four newest members cluster at 5.0 to 5.6 because their metabolic marker data is real but short. VK2735's 78% return to normal glucose is a 13-week readout. |
| Liver Detox | Tirzepatide 8.3 | Retatrutide 8.0 | Read this row carefully. Tirzepatide's 8.3 is inferred from weight loss and insulin-resistance reduction. Survodutide's lower 6.3 rests on biopsy-confirmed MASH improvement, and mazdutide's 5.8 on 72 to 80% liver fat clearance. If the liver is the reason you are here, the highest score is not the most direct evidence. Cagrilintide and VK2735 are not scored for this use case. |
| Longevity | Semaglutide 7.0 | Tirzepatide 6.5 | Both top scores are event-risk proxies, not lifespan data. The other seven members score 1.5 to 3.0 and their reports all say the same thing in different words: nothing has been measured against aging or mortality endpoints. |
| Anti Inflammatory | Semaglutide 7.5 | Tirzepatide 6.2 | A weight-loss-mediated effect on both, not a direct anti-inflammatory mechanism. The seven investigational members score 1.5 to 5.0 with no dedicated inflammatory endpoints. |
| Energy | Tirzepatide 6.2 | Semaglutide 5.0 | The lowest-value row in the table and worth saying so. Nobody takes these drugs for energy, and early titration usually costs you some. Every investigational member sits at 2.0 to 3.0. |
| Endurance Cardio | Tirzepatide 5.5 | Semaglutide 5.5 | A dead heat. Tirzepatide and semaglutide are level at 5.5, so read this row as a tie rather than a win. Endurance improves because you are carrying less mass, not because anything in the drug helps the engine. Losing lean mass can move this the other way. |
At a Glance
Tirzepatide
- Efficacy 5.0
- Breadth 4.8
- Evidence 4.4
- Speed 4.2
- Durability 2.0
- Bioindividuality 4.4
- Safety Risk 4.0
- Side Effects 2.4
- Cost 2.2
- Effort 1.6
- Opportunity Cost 2.1
- Dependency 3.5
- Reversibility 1.7
- Blood Sugar
- Body Composition
- Metabolic Health
- Liver Detox
Dual GIP and GLP-1 agonist. FDA approved. BioHarmony 6.1, worth trying.
Semaglutide
- Efficacy 4.8
- Breadth 4.8
- Evidence 4.4
- Speed 3.8
- Durability 2.0
- Bioindividuality 4.3
- Safety Risk 4.0
- Side Effects 2.5
- Cost 2.1
- Effort 1.5
- Opportunity Cost 2.2
- Dependency 3.5
- Reversibility 1.7
- Blood Sugar
- Metabolic Health
- Cardiovascular
- Liver Detox
GLP-1 agonist. FDA approved. BioHarmony 6.0, worth trying.
Orforglipron (Foundayo)
- Efficacy 4.6
- Breadth 4.4
- Evidence 4.0
- Speed 4.2
- Durability 2.4
- Bioindividuality 4.4
- Safety Risk 4.0
- Side Effects 2.5
- Cost 2.0
- Effort 1.6
- Opportunity Cost 2.0
- Dependency 3.5
- Reversibility 1.8
- Body Composition
- Blood Sugar
- Metabolic Health
- Cardiovascular
Non-peptide oral GLP-1 agonist. FDA approved April 2026. BioHarmony 5.8, worth trying.
VK2735 (Viking Therapeutics)
- Efficacy 5.0
- Breadth 4.8
- Evidence 3.5
- Speed 4.2
- Durability 2.0
- Bioindividuality 4.4
- Safety Risk 4.0
- Side Effects 2.4
- Cost 3.1
- Effort 1.6
- Opportunity Cost 2.1
- Dependency 3.5
- Reversibility 1.7
- Body Composition
- Metabolic Health
- Blood Sugar
- Energy
Investigational dual GLP-1 and GIP agonist. BioHarmony 5.8, worth trying.
Cagrilintide (AM833)
- Efficacy 4.0
- Breadth 3.5
- Evidence 4.0
- Speed 3.4
- Durability 2.0
- Bioindividuality 3.5
- Safety Risk 2.5
- Side Effects 2.6
- Cost 3.0
- Effort 2.8
- Opportunity Cost 2.4
- Dependency 3.3
- Reversibility 1.8
- Body Composition
- Metabolic Health
- Blood Sugar
- Longevity
Long-acting amylin analogue. Investigational. BioHarmony 5.8, worth trying.
Mazdutide (IBI362)
- Efficacy 4.8
- Breadth 4.5
- Evidence 3.9
- Speed 3.6
- Durability 2.0
- Bioindividuality 4.2
- Safety Risk 4.0
- Side Effects 2.6
- Cost 2.8
- Effort 1.6
- Opportunity Cost 2.1
- Dependency 3.5
- Reversibility 1.7
- Body Composition
- Liver Detox
- Blood Sugar
- Metabolic Health
Dual GLP-1 and glucagon agonist. Approved in China only. BioHarmony 5.6, neutral.
Retatrutide
- Efficacy 5.0
- Breadth 4.0
- Evidence 3.4
- Speed 3.8
- Durability 2.0
- Bioindividuality 4.8
- Safety Risk 4.0
- Side Effects 2.6
- Cost 2.4
- Effort 1.5
- Opportunity Cost 2.2
- Dependency 3.6
- Reversibility 1.7
- Metabolic Health
- Liver Detox
- Blood Sugar
- Body Composition
Investigational GLP-1, GIP and glucagon triple agonist. BioHarmony 5.6, neutral.
CagriSema (Cagrilintide + Semaglutide)
- Efficacy 4.8
- Breadth 4.3
- Evidence 3.9
- Speed 3.8
- Durability 2.0
- Bioindividuality 3.8
- Safety Risk 4.0
- Side Effects 3.4
- Cost 3.5
- Effort 3.0
- Opportunity Cost 2.3
- Dependency 3.5
- Reversibility 1.8
- Body Composition
- Blood Sugar
- Metabolic Health
- Cardiovascular
Investigational amylin plus GLP-1 combination. BioHarmony 5.1, neutral.
Survodutide (BI 456906)
- Efficacy 4.5
- Breadth 4.5
- Evidence 3.5
- Speed 3.8
- Durability 2.0
- Bioindividuality 4.0
- Safety Risk 4.0
- Side Effects 3.0
- Cost 3.2
- Effort 2.8
- Opportunity Cost 2.2
- Dependency 3.5
- Reversibility 1.8
- Liver Detox
- Body Composition
- Metabolic Health
- Blood Sugar
Investigational dual GLP-1 and glucagon agonist. BioHarmony 5.1, neutral.
Cost Comparison
| Intervention | Monthly Cost | Notes |
|---|---|---|
| Tirzepatide | $299 to $449 | ESTIMATE, priced 2026-09-07, manufacturer self-pay channel. LillyDirect self-pay Zepbound vials are $299 per 28 days at 2.5 mg, $399 at 5 mg and $449 at 7.5 through 15 mg, which covers the whole standard titration. Branded pharmacy retail without coverage is far higher. |
| Semaglutide | $199 to $349 | ESTIMATE, priced 2026-09-07, manufacturer self-pay channel. NovoCare Pharmacy self-pay Wegovy is $199 a month for the first two fills at 0.25 to 0.5 mg and $349 a month thereafter across the rest of the titration. Branded cash retail is $1,000 to $1,350. |
| Orforglipron (Foundayo) | $149 to $299 | Published self-pay pricing, checked 2026-09-08. LillyDirect runs $149 a month at the 0.8 mg starting tier up to $299 at the 36 mg maintenance dose this report scores. Commercially insured patients may pay $25 a month through Lilly's savings card. The cheapest approved option here. |
| Mazdutide (Xinermei) | $400 to $420 | A real pharmacy price, in the wrong country. Innovent's NMPA-approved list price is about 2,920 yuan, roughly $411 a month, for four 6 mg pens, checked 2026-09-08. There is no legal US or EU channel, so a Western buyer is paying an unpriced gray-market or cross-border route instead. |
| Survodutide | $300 to $500 | ESTIMATE, priced 2026-09-08, research-vial channel. Vials run about $150 to $250 per 6 to 10 mg; at the 4.8 mg weekly dose that produced the MASH result, roughly 19.2 mg a month, that is $300 to $500. No pharmacy exists, and purity is vendor-dependent. |
| Retatrutide | $130 to $960 | ESTIMATE, priced 2026-09-07, research-vial channel. 10 mg vials run about $80 to $200. At 4 mg weekly that is $128 to $320; at the 12 mg weekly dose behind the headline weight loss it is $384 to $960. The dose that works is the one that costs more than the approved drugs. |
| VK2735 | $100 to $400 | ESTIMATE and UNVERIFIED, priced 2026-09-08. No VK2735-specific vial listing was found, because the drug is unmarketed. This range is inferred from comparable GLP-1 and GIP research vials at about $80 to $200 per 10 mg, run at 2.5 to 5 mg weekly. Treat it as an order of magnitude, not a price. |
| CagriSema | $80 to $160 | ESTIMATE, priced 2026-09-08, research-vial channel. Blend vials run about $40 to $80 per 5 mg plus 5 mg; at 2.4 mg of each weekly that is $80 to $160 a month. The largest published weight loss in the category at the second-lowest estimated price, which is exactly the trap this ranking exists to describe. |
| Cagrilintide | $70 to $170 | ESTIMATE, priced 2026-09-08, research-vial channel. Vials run about $35 to $90 per 5 to 10 mg; at 2.4 mg weekly maintenance, roughly 9.6 mg a month, that is $70 to $170. Cheapest line on the table and the one with no legal route at all. |
| The difference | $70 to $960, and the spread is not about potency | Four of the nine have a real published price: three US self-pay programs and mazdutide's Chinese list price. The other five are estimated research-vial costs.The cheapest lines on this table are the drugs you cannot legally buy, and the one that costs the most, retatrutide at its effective dose, is also a vial with no product standard. Orforglipron at $149 to $299 is the cheapest thing here that arrives with a label. Every figure carries a pricing date because this channel moves. |
Who Should Pick What?
Adult with obesity who wants to start treatment this month
Tirzepatide
Body composition 9.0, the largest approved effect in the category, and a manufacturer self-pay channel that does not depend on insurance. Waiting for a better molecule costs you a year of untreated metabolic disease, and the better molecules are not obtainable.
Type 2 diabetes with established cardiovascular or kidney disease
Semaglutide
Cardiovascular 8.0 and blood sugar 9.5, both the highest in the category, and it is the only member with a completed MACE outcome trial (Lincoff 2023) plus a kidney-outcome win (Perkovic 2024). This is the row where the outcome data, not the weight loss, decides.
Needle aversion is the thing that has stopped you
Orforglipron (Foundayo)
An approved once-daily oral GLP-1 with no food or water timing rules, at about 11.2% weight loss over 72 weeks. You give up roughly 4 points against injectable semaglutide and about 10 against tirzepatide. A pill you actually take beats an injection you do not.
Nausea and vomiting ended your last GLP-1 attempt
Cagrilintide (AM833)
Mechanistically it is the right answer: amylin signaling produced about 11.8% loss with less nausea and no hypoglycemia. Practically it is not obtainable, so the actionable version is a slower titration on an approved drug with your prescriber. Do not buy the mechanism you want from a vial.
Biopsy-confirmed MASH or high measured liver fat
Survodutide (BI 456906)
It has the most direct hepatic evidence in the category, 62% MASH improvement with no fibrosis worsening at 48 weeks. It is also investigational with no legal supply, so treat this as the drug to ask your hepatologist about rather than the one to start. Tirzepatide is the liver answer you can actually fill today.
You want the biggest weight-loss number available
Tie
The honest answer is that you cannot have it. CagriSema at 22.7% and retatrutide at 24.2% are the two largest published effects and neither is approved anywhere. A research vial has no product standard behind its label. Take the approved drug and add the resistance training you were going to skip.
Metabolically healthy and chasing a cosmetic 15 pounds
Tie
None of the nine. Every report in this category restricts the risk-benefit to real metabolic pathology, all nine exclude prior pancreatitis, eight of nine exclude a medullary thyroid carcinoma or MEN2 history, and none protects lean mass on its own. This is the row where the answer is to not start.
You are already on one and it has stalled
Tirzepatide
Before switching, check that you ran a full 16-week window at the top tolerated dose with protein and progressive resistance training in place, because that is the most common reason a stall is not a drug failure. If the stall is real and you are on semaglutide, tirzepatide is the only approved step up in effect size.
How This Ranking Is Built
- Ranked by
- the live BioHarmony overall score
- What is included
- Every published BioHarmony report whose primary mechanism is agonism at one or more incretin or amylin receptors: GLP-1, GIP, glucagon, or amylin receptor complex, including combination products. Appetite drugs via another pathway are out; tesofensine is excluded despite sharing the search cluster. Embargoed reports wait until embargo lifts; a new report in this boundary adds a row.
- Kept current
- Positions and scores are read live from each intervention report on every page load, so the order re-renders the moment any member is rescored. Membership is rebuilt nightly against the inclusion rule above.
The order on this page is the live BioHarmony overall score, read from each member's report when the page renders. It is not an editorial ranking, and nothing about it is fixed. When a member's score changes, the row moves that night.
Ties are shown as ties. Three drugs sit at 5.8 and two pairs sit at 5.6 and 5.1. Within a tie the order is by upside total, which is the sum of the benefit dimensions before risk is subtracted. That is a tiebreak, not a ranking: treat tied members as equivalent.
What the score measures is the part most rankings skip. The BioHarmony overall combines effect size with evidence quality, safety, access, cost and practicality.
A drug that works brilliantly in a Phase 2 trial and can only be bought as a research vial scores below an approved drug with a smaller effect. That is by design, not an oversight: it is why CagriSema's 22.7% weight loss ranks eighth and tirzepatide's 15% ranks first.
The consequence is that the two approved injectables take every scored use case between them. That is not evidence they are biologically superior.
They are the only two members with a complete 66-use-case subrating set built on Phase 3 trials and completed outcome studies. The seven investigational drugs are scored across roughly 10 use cases each, and score low on most of them because the trials have not run, not because the drugs failed.
Costs in the table are ESTIMATES with a pricing date, and for the investigational members they are the price of a vial labelled not for human use, with vendor-dependent purity on top. Treat them as channel estimates, not quotes.
Eloralintide is a published report held out of this ranking under embargo until 2026-09-13. Tesofensine is excluded because it is a monoamine reuptake inhibitor rather than an incretin, and liraglutide has no report yet.
Research Highlights
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Mechanism Difference
Four mechanisms are represented in this category and they are not interchangeable. GLP-1 agonism alone is semaglutide and orforglipron. Adding GIP gives you tirzepatide and VK2735, which is the combination behind the largest approved weight effect.Adding glucagon instead gives you mazdutide and survodutide, and glucagon is the arm that raises hepatic fat oxidation, which is why both of those drugs have the most interesting liver data and both raise heart rate.Retatrutide runs all three. Cagrilintide runs none of them: it is an amylin analogue, a separate satiety pathway that produces less nausea and no hypoglycemia, and CagriSema is that amylin arm bolted onto semaglutide. Reading the ranking as one drug class getting progressively better misses the point. These are three or four different bets on how to make someone eat less.
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Safety Comparison
Eight of the nine reports carry the same two hard exclusions: a personal or family history of medullary thyroid carcinoma, and MEN2. All nine exclude prior pancreatitis. Cagrilintide is the exception on the thyroid row, and for a real reason: it is an amylin analogue, and its report says the amylin class lacks the pancreatitis and thyroid signals that shadow the GLP-1 drugs.The drug-specific additions are where the mechanism shows. The three glucagon-containing members, mazdutide, survodutide and retatrutide, all list a raised or irregular resting heart rate as a reason not to start, because the glucagon arm pushes heart rate up in a way pure GLP-1 drugs do not.Retatrutide adds an active eating disorder and advanced kidney disease. CagriSema and semaglutide add gallbladder disease. And five of the nine name the same non-clinical exclusion: an inability to verify what is actually in the vial.
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Cost Comparison
The cost table splits along the approval line rather than along potency. Four members have a real published price: three US manufacturer self-pay programs, and mazdutide's Chinese list price of about $411 a month, which is a genuine pharmacy price in a country most readers do not live in.The other five have no pharmacy price because they have no pharmacy. Every figure quoted for those five is the estimated cost of a research vial sold not for human use, with vendor-dependent purity.In several cases the vial route looks cheaper at a low dose and costs more than the approved drug at the dose that produced the headline result. Cheaper here does not mean equivalent, and every number carries a pricing date because this channel moves.
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Evidence Maturity
The single most useful thing in this ranking is the gap between headline effect and rank. CagriSema produced about 22.7% weight loss on-treatment, the largest published figure in the category, and ranks eighth of nine. Retatrutide reported up to 24.2% and ranks sixth. Tirzepatide's roughly 15% ranks first.That inversion is the scoring model working as intended. The BioHarmony overall weighs evidence quality, safety exposure, access and cost alongside effect size, so a Phase 2 result you can only buy as a research chemical scores below a Phase 3 result you can fill at a pharmacy.If you want a ranking by raw weight loss, the use-case table's body-composition row is closer to it, and even there the maturity discount is visible.
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Editorial Verdict
For almost everyone reading this, the answer is tirzepatide or semaglutide, and which one depends on whether the scale or your cardiovascular risk is the reason you are here. Orforglipron is the third real answer and the first one if a needle is your barrier.The other six are worth understanding and not worth sourcing. Two of them, survodutide and mazdutide, do something clearly differentiated to the liver and are worth naming to a specialist.The rest are earlier versions of a bet the top two have already won. None of them is a reason to buy a vial labelled not for human use, and all of them will be easier to judge when their Phase 3 programs publish.
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Ranking Stability
This ranking is not an opinion that gets refreshed quarterly. The order is the live BioHarmony overall score for each member, resolved when the page loads, so a rescoring of any one report reorders the page that night without an editorial pass.Expect movement. Six of the nine are investigational, and the events that would move them are predictable: a Phase 3 publication, a cardiovascular outcomes readout, or an approval. Any one of those raises evidence quality and access at the same time, which is the combination that produces a large score change. The current gap between first and last is one point.
Frequently Asked Questions
- Which GLP-1 drug is the best?
- Tirzepatide, at a BioHarmony 6.1, with semaglutide a tenth of a point behind at 6.0. Tirzepatide wins on body composition, scoring 9.0 against 7.0. Semaglutide wins on blood sugar (9.5), cardiovascular risk (8.0) and kidney outcomes, and it is the only drug in the category with a completed MACE outcome trial. Both are approved, both require ongoing use, and both lead to substantial regain if you stop.
- Is retatrutide better than tirzepatide?
- On the published weight-loss number, yes: up to 24.2% at 48 weeks against roughly 15%. On the BioHarmony score, no, 5.6 against 6.1. The 24.2% came from a Phase 2 trial, retatrutide has no completed cardiovascular outcomes trial and no published Phase 3, and FDA states it cannot legally be compounded. Outside a Lilly trial the only supply is a research vial with vendor-dependent purity.
- Why does CagriSema rank near the bottom if it produced the most weight loss?
- Because the score weighs more than effect size. CagriSema's roughly 22.7% on-treatment loss is real and is the largest figure on this page. It also lost a head-to-head against tirzepatide, carries the heaviest gastrointestinal burden in the batch, has no cardiovascular outcome data, and is not approved anywhere. Those four facts are what pull a 6.8 body composition subrating down to a 5.1 overall.
- Is there an oral GLP-1 that actually works?
- Yes. Orforglipron was approved for obesity in April 2026 and cut body weight about 11.2% at 72 weeks in its Phase 3 trial, with no food or water timing restrictions. It beat oral semaglutide head to head on both weight and HbA1c. It scores 5.8, third in this ranking, because 11.2% trails injectable semaglutide by about 4 points and tirzepatide by about 10, and its cardiovascular outcomes trial has not run.
- Which one is best for fatty liver?
- Survodutide has the most direct evidence, with 62% of patients improving biopsy-confirmed MASH at 48 weeks against 14% on placebo, and mazdutide has the largest liver-fat reduction, roughly 72 to 80%. Neither is available in the US. Tirzepatide holds the highest liver subrating at 8.3, but that score is inferred from weight loss and insulin-resistance reduction rather than measured on the liver. It is the one you can actually fill.
- Do I keep the weight off after I stop?
- Mostly no, and this applies to all nine. The randomized withdrawal data on tirzepatide showed substantial regain after switching to placebo, and semaglutide's report describes near-complete regain within about a year of stopping. Every member of this category is priced and scored as ongoing therapy rather than a course you finish.
- How often does this ranking change?
- Whenever any member's score changes. The order is the live BioHarmony overall pulled from each report at render time, and a rescoring reorders the page that night with no editorial pass. Six of the nine drugs here are investigational, so a Phase 3 publication, an approval, or a cardiovascular readout on any of them will move the list.
- Are the gray-market versions the same drug?
- There is no way to know from the label. Six of the nine members have no legal pharmacy or compounding route, so the real-world supply is a vial sold not for human use with no product standard behind it and vendor-dependent purity. FDA has issued warning letters over unapproved GLP-1-like products. Purity verification is not an optional extra on that channel, and it is why those members score low on access regardless of their trial data.
Evidence Sources
- RCT Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) (2022) Pivotal Phase 3 obesity RCT; about 15% mean body-weight reduction versus placebo. The anchor for tirzepatide's 9.0 body-composition subrating.
- RCT Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2) (2021) Direct head-to-head. Greater HbA1c and body-weight reduction with tirzepatide than semaglutide 1 mg. About 1.5% HbA1c reduction in Phase 3.
- RCT Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity (2025) 731 participants; reduced composite endpoint or worsening heart-failure events and improved health status versus placebo.
- RCT Tirzepatide for Obesity Treatment and Diabetes Prevention (SURMOUNT-1 extension) (2025) 1,032 adults with obesity and prediabetes over 176 weeks; sustained weight loss and reduced progression to type 2 diabetes.
- RCT Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1) (2021) 14.9% mean weight loss at 68 weeks. The anchor for semaglutide's 7.0 body-composition subrating.
- RCT Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT) (2023) 20% lower 3-point MACE in adults with overweight or obesity and established cardiovascular disease. The only completed MACE outcome trial in this category.
- RCT Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW) (2024) Kidney-outcome benefit in type 2 diabetes with chronic kidney disease. Supports semaglutide's 7.0 longevity subrating.
- RCT Semaglutide 2.4 mg in Metabolic Dysfunction-Associated Steatohepatitis (ESSENCE) (2025) Phase 3 MASH data strengthening the liver case behind semaglutide's 7.5 liver subrating.
- RCT Orforglipron for Obesity: ATTAIN-1 Phase 3 trial (2025) 36 mg oral orforglipron cut body weight about 11.2% at 72 weeks versus roughly 2% on placebo. Basis for the FDA approval in April 2026.
- RCT Orforglipron versus oral semaglutide in type 2 diabetes (ACHIEVE-3) (2026) Direct head-to-head; orforglipron beat oral semaglutide on both HbA1c and body weight.
- RCT Orforglipron in early type 2 diabetes (ACHIEVE-1) (2025) 36 mg lowered HbA1c about 1.48% versus 0.41% on placebo. Supports the 6.0 blood-sugar subrating.
- RCT Cagrilintide and CagriSema in obesity: REDEFINE 1 (2025) Cagrilintide monotherapy about 11.8% weight loss at 68 weeks; CagriSema about 22.7% on-treatment, roughly 5 to 6 points above semaglutide alone.
- RCT CagriSema in type 2 diabetes: REDEFINE 2 (2025) 74% of participants reached HbA1c at or below 6.5%. Behind CagriSema's 5.6 metabolic-health subrating.
- RCT Mazdutide in Chinese adults with obesity: GLORY-1 Phase 3 (2025) About 14.84% weight loss at 48 weeks on 6 mg, and roughly 72 to 80% liver-fat reduction in high-baseline participants. The strongest published incretin liver-fat signal.
- RCT Survodutide in MASH: 48-week biopsy-confirmed Phase 2 trial (2024) 62% of patients on 4.8 mg improved MASH with no worsening of fibrosis, versus 14% on placebo. The most direct hepatic outcome evidence in the category.
- RCT Survodutide versus semaglutide in type 2 diabetes, 16 weeks (2024) Comparable blood-sugar lowering with more weight loss than semaglutide over 16 weeks.
- RCT VK2735 in obesity: VENTURE Phase 2 injectable trial (2026) About 14.7% weight loss at 13 weeks on 15 mg, with roughly 89% of that arm losing at least 10%. Every VK2735 dataset is 13 weeks or shorter.
- RCT Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial (2023) Up to 24.2% body-weight loss at 48 weeks, the largest single figure in this category, with dose-related heart-rate increases. Phase 2, not Phase 3.
- Meta-analysis Seven GLP-1 receptor agonists and polyagonists for weight loss: updated network meta-analysis (2024) 27 RCTs, 15,584 participants. Retatrutide ranked strongest for weight loss in an indirect comparison, which is not a direct head-to-head result.
- Regulatory FDA: medications containing semaglutide and unapproved GLP-1 drugs (2026) FDA states retatrutide cannot be used in compounding and has not been found safe and effective for any condition. Applies to the gray-market supply of every investigational member here.
- Systematic review Tirzepatide for adults living with obesity, Cochrane Database of Systematic Reviews (2025) 9 studies, 7,111 adults. Likely medium-term weight loss sustained beyond two years. All included studies manufacturer-funded.
- RCT Continued Treatment With Tirzepatide for Maintenance of Weight Reduction (SURMOUNT-4) (2023) Randomized withdrawal; switching to placebo led to substantial regain. The evidence behind the durability caveat that applies to every member.
Glossary
Quick reference for the medical and technical terms used in this comparison.
- GLP-1 Glucagon-Like Peptide-1
- The incretin hormone every drug in this ranking except cagrilintide targets. Raises glucose-dependent insulin release, slows gastric emptying and suppresses appetite.
- GIP Glucose-Dependent Insulinotropic Polypeptide
- The second incretin hormone. Added to GLP-1 in tirzepatide, VK2735 and retatrutide, and the combination behind the largest approved weight effect.
- GCGR Glucagon Receptor
- The third arm, used in mazdutide, survodutide and retatrutide to raise hepatic fat oxidation and energy expenditure. Also the reason those three raise heart rate.
- Amylin Amylin receptor analogue
- A separate satiety pathway, not an incretin. Cagrilintide is the only pure amylin drug here; CagriSema is that arm combined with semaglutide.
- HbA1c Glycated Hemoglobin
- A two to three month average of blood glucose, and the primary endpoint in every diabetes trial cited on this page.
- MACE Major Adverse Cardiovascular Events
- The composite outcome of cardiovascular death, heart attack and stroke. Semaglutide is the only member of this category with a completed MACE trial.
- MASH Metabolic Dysfunction-Associated Steatohepatitis
- The inflammatory stage of fatty liver disease, formerly NASH. The endpoint in survodutide's biopsy-confirmed Phase 2 trial.
- MASLD Metabolic Dysfunction-Associated Steatotic Liver Disease
- Fatty liver linked to metabolic dysfunction, formerly NAFLD. The broader condition behind the liver-detox use case.
- MTC Medullary Thyroid Carcinoma
- The rare thyroid cancer named in the boxed warning on the approved members. A personal or family history of it rules out every drug in this ranking.
- MEN2 Multiple Endocrine Neoplasia type 2
- A hereditary syndrome that raises MTC risk, and a hard contraindication on all nine source reports.
- Phase 2 vs Phase 3 Clinical trial phases
- Phase 2 tests dose and early efficacy in hundreds of people; Phase 3 tests it against a real comparator in thousands and is what regulators approve on. The distinction explains most of this ranking.
- Network meta-analysis Indirect comparison
- A statistical method that ranks drugs never tested against each other, by routing through shared comparators. Useful, and weaker evidence than a direct head-to-head trial.
First because it is the only drug here with a large approved effect, a pharmacy, and outcome trials in three organ systems. About 15% mean weight loss in SURMOUNT-1 (Jastreboff 2022), roughly 1.5% HbA1c reduction in Phase 3 diabetes (Frias 2021), reduced worsening heart-failure events in HFpEF with obesity (Packer 2025), and an approved obesity-related sleep apnea indication. Pick it over semaglutide when body composition is the goal, where it scores 9.0 against 7.0. The score is 6.1 rather than 8 because the benefit lasts as long as the injections do.