# What are GLP-1 medications like semaglutide and tirzepatide?

> GLP-1 medications mimic a gut hormone that helps control blood sugar and appetite; after large trials, the FDA approved semaglutide and tirzepatide products for type 2 diabetes, weight management and other uses. Digestive side effects are common and weight tends to return after stopping; compounded versions are not FDA-approved and were not tested in those trials.

The journal is published by Rovere, a telehealth service that sells some of the treatments discussed here. Articles are general information, not medical advice. Only a licensed clinician can say whether a treatment is right for you.

- Topic: Compounds
- Web page: https://roverehealth.com/journal/glp-1-medications

## Key points

- Semaglutide and tirzepatide are peptides, short chains of amino acids, usually injected under the skin. They switch on cell receptors for GLP-1, a hormone the gut releases after meals. Tirzepatide also switches on receptors for GIP, another gut hormone.
- Semaglutide and tirzepatide products, not compounded versions, are FDA-approved for type 2 diabetes, weight management and lowering heart risk. Semaglutide also has approvals for diabetic kidney disease and, under accelerated approval, the liver disease MASH; tirzepatide for sleep apnea.
- Nausea and other digestive side effects are common. The labels warn about pancreatitis (inflammation of the pancreas), gallbladder disease and thyroid tumors seen in rodents, and in November 2026 the FDA required a warning about a rare optic nerve condition.
- In trials where people switched from semaglutide or tirzepatide to a placebo, they regained much of the weight they had lost.
- Compounded semaglutide and tirzepatide are not FDA-approved and were not tested in the trials behind the approvals. Retatrutide, an experimental drug that acts on GIP, GLP-1 and glucagon receptors, is not approved for any use and cannot legally be compounded.

## At a glance

| Compound | Kind | How it is taken | FDA status | Research in people |
| --- | --- | --- | --- | --- |
| Semaglutide | GLP-1 receptor agonist (peptide) | Injection under the skin, or a tablet taken by mouth | Specific semaglutide products are FDA-approved; compounded versions are not FDA-approved, and the FDA does not review them for safety, effectiveness or quality before they are sold. (checked 2026-11-14) | Large trials in people. In randomized trials, FDA-approved semaglutide led to more weight loss than placebo (STEP 1, 1,961 adults) and fewer combined heart attacks, strokes and cardiovascular deaths (SELECT, 17,604 adults with cardiovascular disease); none tested a compounded version. |
| Tirzepatide | GIP and GLP-1 receptor agonist (peptide) | Injection under the skin | Specific tirzepatide products are FDA-approved; compounded versions are not FDA-approved, and the FDA does not review them for safety, effectiveness or quality before they are sold. (checked 2026-11-14) | Large trials in people. In randomized trials, FDA-approved tirzepatide led to more weight loss than placebo (SURMOUNT-1, 2,539 adults) and was no worse than dulaglutide, an older GLP-1 drug, on heart attacks, strokes and cardiovascular deaths (SURPASS-CVOT, 13,299 adults with type 2 diabetes); none tested a compounded version. |
| Liraglutide | GLP-1 receptor agonist (peptide) | Injection under the skin | Specific liraglutide products, from the original maker and, since December 2024, other companies, are FDA-approved; compounded versions are not FDA-approved. (checked 2026-11-14) | Large trials in people. In randomized trials, FDA-approved liraglutide led to more weight loss than placebo (SCALE Obesity and Prediabetes, 3,731 adults without diabetes) and fewer combined heart attacks, strokes and cardiovascular deaths (LEADER, 9,340 adults with type 2 diabetes); none tested a compounded version. |
| Retatrutide (also: LY3437943) | GIP, GLP-1 and glucagon receptor agonist (peptide) | Injection under the skin (in trials) | Not FDA-approved for any use; the FDA says it is not a component of any approved drug and cannot be used in compounding under federal law. (checked 2026-11-14) | Large trials in people. Phase 3 obesity trials, TRIUMPH-1 (2,339 adults) and TRIUMPH-2 (1,152 adults with type 2 diabetes), found more weight loss than placebo over 80 weeks, with more digestive side effects; effects on heart and kidney events and long-term safety are unknown. |
| Cagrilintide (also: AM833) | Amylin analog (peptide) | Injection under the skin (in trials) | Not FDA-approved for any use; the FDA says it is not a component of any FDA-approved drug and cannot be used in compounding under federal law. (checked 2026-11-14) | Large trials in people. Combined with semaglutide, it led to more weight loss than placebo in phase 3 trials REDEFINE 1 (3,417 adults, 68 weeks) and REDEFINE 2 (1,206 adults with type 2 diabetes); phase 3 trials designed to test it alone are due to finish in 2027. |
| Orforglipron | GLP-1 receptor agonist (small molecule, not a peptide) | Tablet taken by mouth | FDA-approved on April 1, 2026, for chronic weight management in adults with obesity, or with overweight and a weight-related condition; not approved for any other use. (checked 2026-11-13) | Large trials in people. In ATTAIN-1, a randomized trial of 3,127 adults with obesity but not diabetes, orforglipron led to more weight loss than placebo over 72 weeks, and more people stopped it because of side effects; it did not test a compounded version. |

## What they are

GLP-1 medications mimic GLP-1 (glucagon-like peptide-1), a hormone the gut releases after meals. GLP-1 is a peptide, a short chain of amino acids (the building blocks of proteins). The enzyme DPP-4 and the kidneys clear half of it from the blood within 1 to 2 minutes. [1, 2]

Semaglutide and tirzepatide are receptor agonists: they bind to a hormone’s receptor on cells and switch it on. Semaglutide closely matches human GLP-1 but is modified to resist DPP-4. Liraglutide, an earlier GLP-1 medication, is also modeled on human GLP-1. Tirzepatide is built on GIP (glucose-dependent insulinotropic polypeptide), a second gut hormone, and acts on both GIP and GLP-1 receptors. [3, 4, 5, 57]

Retatrutide, code name LY3437943, is an experimental peptide that acts on three receptors: GIP, GLP-1 and glucagon. Glucagon is a pancreatic hormone that raises blood sugar. Cagrilintide is an experimental peptide modeled on amylin, a pancreatic hormone that makes people feel full. [6, 7, 8, 61, 62]

## How they work

The semaglutide and tirzepatide labels say both drugs make the pancreas release more insulin and less glucagon when blood sugar is high. They slow how fast food leaves the stomach. GLP-1 receptors are also found in brain areas that control appetite, and both drugs lower calorie intake, likely by affecting appetite. [3, 9, 10]

## How they are taken

Semaglutide, tirzepatide and liraglutide are injected under the skin (a subcutaneous injection), from prefilled pens, syringes or vials. Semaglutide also comes as a tablet. [3, 4, 9, 11, 57, 58]

Orforglipron, also a GLP-1 tablet, is not a peptide but a small molecule, a compact chemical. [12, 13, 14]

## What the research in people shows

Most trials below supported FDA approvals; the drug’s maker paid for each. [14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 32, 59, 60, 63, 64]

Selected randomized trials (people assigned by chance), oldest first. Unless stated, the comparison was a placebo (a dummy treatment). [3, 4, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 32, 59, 60, 63, 64]

| Trial (year published) | Who took part | How long | What it found |
| --- | --- | --- | --- |
| SCALE Obesity and Prediabetes (2015) | 3,731 adults with obesity or overweight, without diabetes | 56 weeks | More weight loss with liraglutide |
| LEADER (2016) | 9,340 adults with type 2 diabetes at high cardiovascular (heart and blood vessel) risk | Median 3.8 years | Fewer combined heart attacks, strokes and cardiovascular deaths with liraglutide |
| STEP 1 (2021) | 1,961 adults with obesity or overweight, without diabetes | 68 weeks | More weight loss with semaglutide |
| SURMOUNT-1 (2022) | 2,539 adults with obesity or overweight, without diabetes | 72 weeks | More weight loss with tirzepatide |
| SELECT (2023) | 17,604 adults with cardiovascular disease and overweight or obesity, without diabetes | About 40 months (average) | Fewer combined heart attacks, strokes and cardiovascular deaths with semaglutide |
| FLOW (2024) | 3,533 adults with type 2 diabetes and chronic kidney disease | Median 3.4 years | Fewer combined kidney failures, large losses of kidney function and kidney or cardiovascular deaths with semaglutide |
| SURMOUNT-OSA (2024) | 469 adults with obesity and moderate to severe obstructive sleep apnea | 52 weeks | Fewer breathing pauses and shallow-breathing episodes during sleep with tirzepatide |
| ESSENCE (2025) | 1,197 adults with MASH (metabolic dysfunction-associated steatohepatitis), an inflamed fatty liver, and moderate to advanced scarring | 72 weeks (interim results, first 800 people) | On liver biopsy, the inflammation cleared in more people on semaglutide, and scarring lessened in more |
| SURMOUNT-5 (2025) | 751 adults with obesity, without diabetes | 72 weeks | More weight loss with tirzepatide than with semaglutide. Participants knew which drug they took |
| REDEFINE 1 and 2 (2025) | Adults with obesity or overweight: 3,417 without diabetes and 1,206 with type 2 diabetes | 68 weeks | More weight loss with cagrilintide plus semaglutide |
| ATTAIN-1 (2025) | 3,127 adults with obesity, without diabetes | 72 weeks | More weight loss with orforglipron tablets; more people stopped because of side effects |
| SURPASS-CVOT (2025) | 13,299 adults with type 2 diabetes and cardiovascular disease | About 4 years (median) | Tirzepatide no worse than dulaglutide, an older GLP-1 drug approved to lower heart risk, on combined heart attacks, strokes and cardiovascular deaths; not shown better |
| TRIUMPH-1 (2026) | 2,339 adults with obesity, without diabetes | 80 weeks | More weight loss with retatrutide. In 574 people with knee osteoarthritis (wear-and-tear arthritis), less knee pain but more serious health problems |
| TRIUMPH-2 (2026) | 1,152 adults with obesity and type 2 diabetes | 80 weeks | More weight loss with retatrutide |

People on these drugs lose lean mass, which includes muscle, along with fat. In a 2025 SURMOUNT-1 substudy, X-ray scans (DXA) of 160 participants after 72 weeks showed most weight lost was fat, on tirzepatide or placebo, though people on tirzepatide lost more of both. A 2026 meta-analysis found lean mass fell consistently with GLP-1 drugs across 28 studies, on low-certainty evidence, and called effects on muscle function unclear. [67, 68]

## What happens after stopping

In STEP 4 (2021), 803 adults taking semaglutide were randomly assigned to continue it or switch to placebo for about a year. SURMOUNT-4 (2024) did the same with 670 adults taking tirzepatide. In both, those switched to placebo regained much of the lost weight, and those who continued kept losing weight. [26, 27]

A 2026 review of 37 studies with 9,341 adults found weight returned faster after stopping a weight-management medicine, including semaglutide and tirzepatide, than after diet and exercise programs ended. [28]

## Side effects and risks

Digestive side effects are the most common. Nausea affected 44 in 100 people on semaglutide injections in the three main weight-management trials, lasting up to 68 weeks, against 16 in 100 on placebo. Two tirzepatide trials lasting up to 72 weeks found 25 to 29 in 100, against 8. Diarrhea, vomiting and constipation were also more common. [9, 10]

Most were mild to moderate and eased over time. In those trials, about 7 in 100 people on semaglutide and 5 to 7 in 100 on tirzepatide stopped because of side effects, against about 3 on placebo. Other common effects include stomach pain, indigestion, tiredness, dizziness, hair loss and, with semaglutide, abnormal skin sensations (dysesthesia). [9, 10, 17, 18]

Every semaglutide, tirzepatide and liraglutide label carries a boxed warning, which the FDA can require for serious risks, even ones seen only in animals. In rodents, all three drugs caused tumors of the thyroid’s C-cells (cells that make the hormone calcitonin), including cancers. The drugs must not be used by anyone with a personal or family history of medullary thyroid cancer, or with multiple endocrine neoplasia type 2 (MEN 2), an inherited tumor syndrome. Nor may anyone who has had a serious allergic reaction to the drug use it. The labels also warn about: [3, 4, 9, 10, 11, 29, 30, 57, 58]

- Pancreatitis (inflammation of the pancreas), sometimes fatal; warning signs include persistent or severe stomach pain that may reach the back.
- Gallbladder disease, such as gallstones.
- Low blood sugar, especially with insulin or a sulfonylurea, a pill that makes the pancreas release insulin.
- Kidney injury, sometimes needing dialysis, mostly after dehydration from vomiting or diarrhea.
- Severe digestive reactions; the drugs are not recommended with severe gastroparesis, a very slow-emptying stomach.
- A blocked or stalled bowel (intestinal obstruction or ileus) and severe constipation, reported since approval.
- Serious allergic reactions, including anaphylaxis (a sudden, life-threatening whole-body reaction) and swelling under the skin (angioedema).
- Worsening diabetic eye disease (retinopathy); in SUSTAIN-6, a 2016 trial of 3,297 adults with type 2 diabetes, complications affected about 3 in 100 people on semaglutide and 2 in 100 on placebo.
- Rarely, inhaling food left in the stomach into the lungs under general anesthesia or deep sedation, even after fasting.
- A faster resting heart rate, listed on the semaglutide and liraglutide weight-management labels.
- Blood-borne infections if a pen that holds several doses is shared, even with a new needle.

Sources for the list above: [3, 4, 9, 10, 11, 16, 57, 58]

In November 2026 the FDA required a warning about a potential increased risk of NAION (non-arteritic anterior ischemic optic neuropathy) on all GLP-1 medications. NAION is sudden, painless vision loss in one eye from reduced blood flow to the optic nerve, and it can be permanent. [2]

In the FDA’s analysis of 126 randomized trials, there were 6.4 NAION cases for every 100,000 people treated for a year with a GLP-1 drug, against 3.8 with comparison treatments. Those rates rest on 15 probable cases. The FDA’s own study of adults with type 2 diabetes, and well-designed published ones, found higher risk than with some other diabetes drugs. NAION is more likely to recur in people who have had it, and the FDA advises clinicians to consider stopping the drug if it occurs. [2]

In February 2026 the weight-management labels dropped a warning about suicidal thoughts and behavior, at the FDA’s request. Its review of 91 placebo-controlled trials with 107,910 people found no increased risk. [9, 10, 31, 58]

The weight-management labels say to stop once a pregnancy is recognized. The semaglutide labels advise stopping at least 2 months before a planned one. Tirzepatide can make birth-control pills less reliable, so its labels advise a non-oral or added barrier method for 4 weeks after starting and after each dose increase. The semaglutide tablet labels advise against breastfeeding. [4, 9, 10, 11, 58]

By slowing stomach emptying, the drugs can change how other medicines taken by mouth are absorbed. The labels advise closer checks on drugs with a narrow safe range, such as the blood thinner warfarin. Semaglutide tablets raised exposure to the thyroid medicine levothyroxine by about a third in one study. The weight-management labels advise against combining them with other GLP-1 medicines. [4, 9, 10, 11, 58]

Retatrutide’s and cagrilintide’s side effects were also mostly digestive. In TRIUMPH-2, up to 6 in 100 people on retatrutide had low blood pressure and up to 7 in 100 abnormal skin sensations, against 1 in 100 or fewer on placebo. Serious health problems were more common with retatrutide in two 2026 knee osteoarthritis trials. [25, 32, 62, 63]

## FDA status

The FDA has approved semaglutide and tirzepatide products for the uses below. Liraglutide products were approved for type 2 diabetes in 2010, chronic weight management in 2014, and lowering heart risk in adults with type 2 diabetes and cardiovascular disease in 2017. Other companies’ liraglutide products have been approved since December 2024. No approval covers a compounded version of any of them, one made by a compounding pharmacy rather than the approved product’s manufacturer. [3, 4, 33, 34, 35, 36, 53, 54, 55, 57, 58]

FDA-approved uses as of November 13, 2026, and the year each was approved. [3, 4, 9, 10, 11, 33, 35, 37, 38, 39, 40]

| Use | Semaglutide | Tirzepatide (injection) |
| --- | --- | --- |
| Type 2 diabetes | Adults: injection (2017) and tablet (2019) | Adults (2022); children 10 and older (2025) |
| Chronic weight management | Injection: adults (2021) and ages 12 and older (2022). Tablet: adults (2025) | Adults (2023) |
| Lowering the risk of heart attack, stroke or cardiovascular death | Injection: adults with type 2 diabetes and cardiovascular disease (2020); adults with cardiovascular disease and obesity or overweight (2024). Tablet: adults with type 2 diabetes at high risk (2025); adults with cardiovascular disease and obesity or overweight (2025) | Adults with type 2 diabetes at high risk (2026) |
| Chronic kidney disease in type 2 diabetes | Adults: injection (2025) | Not approved |
| Moderate to severe obstructive sleep apnea with obesity | Not approved | Adults (2024) |
| MASH with moderate to advanced liver scarring, but not cirrhosis (the most advanced scarring) | Adults: injection (2025), accelerated approval | Not approved |

Accelerated approval, used for serious conditions with an unmet medical need, rests on a measure thought to predict real benefit, here liver biopsy results. Keeping it may depend on a further trial confirming that benefit. [9, 41]

Orforglipron tablets were approved on April 1, 2026, only for chronic weight management in adults with obesity, or with overweight and a weight-related condition. [12, 13]

Retatrutide and cagrilintide are not FDA-approved or part of any approved drug. “Retatrutide and cagrilintide cannot be used in compounding under federal law,” the FDA says. It has warned telehealth companies for marketing retatrutide, ingredient distributors for selling it to compounders, and outsourcing facilities (FDA-registered compounders) for repackaging it. [34, 36]

## Compounded versions

The FDA does not review compounded drugs for safety, effectiveness or quality before they are sold. It says they “should only be used in patients whose medical needs cannot be met by an FDA-approved drug.” [34]

Federal law restricts compounding that copies an approved drug, but the restriction lifts while the drug is on the FDA’s shortage list. Semaglutide and tirzepatide, listed from 2022, came off in February 2025 and late 2024 respectively, so copying them is again restricted. A federal appeals court upheld both decisions in August 2026. Liraglutide injection has been listed since July 2023 and still was on November 14, 2026. [36, 42, 43, 44, 56]

A September 2026 FDA warning letter said a pharmacy’s tirzepatide with niacinamide, a B vitamin, and semaglutide with B12 appeared to be copies. It said ready-made menus of prescriber statements justifying such changes, on third-party technology platforms, call into question whether each decision was made for the individual patient. [42, 45]

By May 31, 2026, the FDA had received more than 1,700 reports of health problems with compounded semaglutide and tirzepatide. It says such problems are likely underreported, and it cannot always tell whether the drug caused them. [34]

A 2026 study of compounders’ websites, searched in February and March 2025, found 33 compounded semaglutide and tirzepatide products that differed from approved ones in strength, route or form. About half added ingredients such as vitamin B12, and most others were meant to dissolve under the tongue (sublingual). The authors found little evidence on their safety or effectiveness. [46]

FDA-approved semaglutide tablets contain an added ingredient that helps absorption in the stomach, yet their labels estimate no more than 2 parts in 100 reach the blood. In a May 2026 proposal on outsourcing facilities, the FDA found no basis to conclude that patients medically need semaglutide or tirzepatide held under the tongue or inside the cheek (buccal). [9, 11, 69]

## What isn’t known

- How compounded versions compare with approved ones; none was tested in the trials above.
- Effects beyond about four years, the length of the longest completed trials above.
- Whether GLP-1 drugs cause thyroid cancer in people. A 2023 French study comparing 2,562 people with diabetes and thyroid cancer against 45,184 without linked one to three years of use with higher risk. Studies following 145,410 users (2024) and 98,147 users (2025) for about two to four years found no clear increase, nor did a 2026 review of 48 short trials.
- Whether tirzepatide lowers heart risk in people with obesity or overweight but no diabetes; SURMOUNT-MMO, a trial of 15,374 adults, is due to finish in late 2027.
- Long-term effects on diabetic eye disease, which the semaglutide labels say have not been studied.
- Whether FDA-approved semaglutide prevents cirrhosis or other serious outcomes of MASH.
- Whether retatrutide lowers heart and kidney events; a trial of about 10,000 adults, expected to end in 2029, is testing this. Its long-term safety is also unknown.
- How well cagrilintide works alone, and its safety, over the long term. A 2021 trial of it alone lasted 26 weeks; RENEW 1 and 2, phase 3 trials of it alone, are due to finish in 2027.

Sources for the list above: [3, 9, 11, 22, 46, 47, 48, 49, 50, 51, 52, 62, 65, 66]

## Questions to ask a clinician

- Is there an FDA-approved GLP-1 medication for my condition, and if you suggest a compounded one instead, why?
- Does medullary thyroid cancer or MEN 2 in me or my family, or my history of pancreatitis, diabetic eye disease or sudden vision loss, change whether these drugs are right for me?
- Do my other medicines, such as insulin, birth-control pills, warfarin or thyroid medicine, need to change?
- What happens if I stop, and how would we plan for that?
- What should I tell a surgeon or anesthesiologist before a procedure?
- Which symptoms, such as severe stomach pain or sudden vision loss, need care right away?

Sources for the list above: [2, 3, 4]

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