GLP-1 drugs: a complete guide to semaglutide and beyond

Few molecules changed medicine as much in a decade as the GLP-1 receptor agonists. They started as a type 2 diabetes treatment, became the most effective drug therapy for obesity, and now have hard-outcome trials in the heart, the kidney and sleep apnea^3171819. This guide puts in one place what a physician needs to know: what the hormone is, how the drugs work, what the human trials say, how semaglutide, tirzepatide and the next generation compare, which risks are documented and which questions remain open. Each section links to our articles that go deeper.

What GLP-1 is, and why the natural hormone can't be a drug

Glucagon-like peptide-1 (GLP-1) is a gut hormone released by L cells in the ileum and colon after a meal. It stimulates insulin secretion in a glucose-dependent way, suppresses glucagon, slows gastric emptying and reduces appetite¹. In essence, it is one of the signals the gut uses to tell the pancreas and the brain that food has arrived.

The problem is its half-life. The enzyme dipeptidyl peptidase 4 (DPP-4) cleaves the first two amino acids of GLP-1 and inactivates it within minutes; the resulting truncated fragment is the main metabolite circulating in the blood². That is why the natural hormone cannot be used as a medicine: it would have to be infused continuously. The whole pharmacological history of this class is about solving that problem³⁴.

For the historical context, from insulin to today's analogs, see A century of peptide therapeutics: from insulin to semaglutide.

Mechanism of action: how a weekly GLP-1 was engineered

Liraglutide was the first big step: an analog with a fatty-acid chain that binds plasma albumin, which delays its clearance and allows once-daily dosing⁴. Semaglutide took the idea further: an amino-acid substitution at position 8 that protects it from DPP-4 and a fatty-acid chain with an optimized linker that binds albumin more strongly, designed for once-weekly administration⁵.

Physiologically, GLP-1 receptor agonists act on several organs at once: the pancreas (more insulin when glucose is high, less glucagon), the stomach (slower emptying) and the brain, in regions that regulate appetite and satiety¹³. That central effect explains much of the weight loss, and it is also why they are being studied in addiction and neurological disease, topics we cover in Semaglutide and alcohol: three trials and a warning removed and in GLP-1s and the brain: Parkinson's, Alzheimer's and mood.

Slower gastric emptying has a practical consequence that surprised anesthesiologists: patients with a full stomach despite fasting. We explain it in Full stomach despite fasting: GLP-1s, sedation and the 2024 reversal.

Semaglutide and liraglutide: what the obesity trials show

In the SCALE trial (3,731 adults with obesity or overweight), liraglutide 3.0 mg daily was associated with a mean loss of 8.4 kg at 56 weeks vs 2.8 kg with placebo; 63.2% lost at least 5% of their body weight, vs 27.1% with placebo, and 33.1% lost more than 10%, vs 10.6%⁶. The most reported adverse events were mild or moderate nausea and diarrhea, and serious events occurred in 6.2% vs 5.0% with placebo⁶. It was the first GLP-1 approved for obesity, but its efficacy was moderate.

Weekly semaglutide changed the scale. In STEP 1 (1,961 adults without diabetes), semaglutide 2.4 mg was associated with a −14.9% change in body weight at 68 weeks vs −2.4% with placebo; half of the participants (50.5%) lost 15% or more⁷. Nausea and diarrhea were the most frequent adverse events, generally transient and mild to moderate⁷.

Tirzepatide: the dual GIP/GLP-1 agonist

Tirzepatide is a single peptide that activates two receptors: the GLP-1 receptor and the receptor for glucose-dependent insulinotropic polypeptide (GIP), the other incretin⁸. That adding GIP worked was a surprise, because for years the hormone was thought to promote obesity; the paradox and its explanations are in Tirzepatide and the GIP paradox.

In SURMOUNT-1 (2,539 adults without diabetes), tirzepatide was associated with body-weight changes of −15.0%, −19.5% and −20.9% on 5, 10 and 15 mg at 72 weeks, vs −3.1% with placebo; on 10 and 15 mg, 50% and 57% of participants lost 20% or more of their body weight, vs 3% with placebo⁹. And in the first head-to-head obesity trial, SURMOUNT-5 (751 participants), tirzepatide reached −20.2% vs −13.7% with semaglutide at 72 weeks, with gastrointestinal effects as the most common adverse event in both groups¹⁰.

The next generation: retatrutide, CagriSema and orforglipron

The race is no longer only about amplifying the GLP-1 signal, but about combining hormonal signals or changing the route of administration. This is how the main obesity trials in adults without diabetes compare (with the caveat that duration, population and statistical method differ between them)^79121314:

• Semaglutide 2.4 mg weekly (GLP-1 agonist, STEP 1): −14.9% at 68 weeks vs −2.4% with placebo⁷.
• Tirzepatide 15 mg weekly (dual GIP/GLP-1 agonist, SURMOUNT-1): −20.9% at 72 weeks vs −3.1%⁹.
• Cagrilintide + semaglutide (amylin + GLP-1, REDEFINE 1, 3,417 adults): −20.4% at 68 weeks vs −3.0%¹³.
• Retatrutide 12 mg weekly (triple GIP/GLP-1/glucagon agonist, TRIUMPH-1, 2,339 adults): −25.0% at 80 weeks vs −3.9%¹².
• Orforglipron 36 mg daily by mouth (small molecule, non-peptide, ATTAIN-1, 3,127 adults): −11.2% at 72 weeks vs −2.1%¹⁴.

Retatrutide adds the glucagon receptor. In phase 2 (338 adults), the 12 mg dose was associated with −24.2% at 48 weeks¹¹; in the phase 3 TRIUMPH-1 trial it reached −25.0% at 80 weeks and also reduced knee-osteoarthritis pain and apnea events in the subgroups with those conditions¹². As of this guide it does not appear among the FDA's 2026 novel drug approvals¹⁵.

More efficacy does not mean better tolerability. In the retatrutide phase 2 trial, gastrointestinal events were dose-related and partly mitigated by a lower starting dose (2 mg vs 4 mg), and heart rate rose in a dose-dependent way¹¹. In ATTAIN-1, adverse events led to stopping orforglipron in 5.3% to 10.3% of participants vs 2.7% with placebo, although 54.6% of those on 36 mg lost 10% or more of their body weight, vs 12.9% with placebo¹⁴.

The cagrilintide-semaglutide (CagriSema) combination adds an analog of amylin, another satiety hormone; gastrointestinal events affected 79.6% vs 39.9% with placebo, mostly transient¹³. We cover it in Cagrilintide and amylin: the other satiety hormone.

Orforglipron is the first oral GLP-1 receptor agonist that is not a peptide; the FDA approved it on April 1, 2026 to reduce excess body weight and maintain weight reduction long term in adults with obesity¹⁵. Its profile is in Orforglipron: the first GLP-1 pill that is not a peptide, and the critical comparison of the whole next generation (and why numbers across trials cannot be compared directly) is in After semaglutide: CagriSema, orforglipron, MariTide and the estimand trap.

Beyond weight: heart, kidney and sleep apnea

What made this class a cornerstone of cardiometabolic medicine was not just the scale but the hard-outcome trials. In LEADER (9,340 patients with type 2 diabetes), liraglutide reduced the composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke: 13.0% vs 14.9% with placebo over a median follow-up of 3.8 years; cardiovascular death was 4.7% vs 6.0% (HR 0.78)¹⁶.

In SELECT (17,604 adults with established cardiovascular disease and overweight or obesity, without diabetes), semaglutide 2.4 mg reduced major cardiovascular events: 6.5% vs 8.0% (HR 0.80; 95% CI 0.72–0.90)¹⁷. In FLOW (3,533 patients with type 2 diabetes and chronic kidney disease), it reduced major kidney events by 24% (HR 0.76), cardiovascular death (HR 0.71) and death from any cause by 20%; the annual decline in glomerular filtration rate was also 1.16 ml/min/1.73 m² slower¹⁸. The trial was stopped early after a prespecified interim analysis¹⁸.

Tirzepatide reduced the apnea-hypopnea index by about 20–24 more events per hour than placebo in the two SURMOUNT-OSA trials¹⁹, and in SURPASS-CVOT (13,299 patients with diabetes and atherosclerotic disease) it was noninferior to dulaglutide for major cardiovascular events (12.2% vs 13.1%; HR 0.92), without showing superiority²⁰. The full review of these trials, including heart failure, fatty liver and osteoarthritis, is in GLP-1s beyond weight: the hard-outcome trials.

GLP-1 side effects and safety

Gastrointestinal. Nausea, vomiting, diarrhea and constipation are the most frequent events in every trial, especially during dose escalation⁷⁹¹⁰. In a database study, GLP-1s used for weight loss were associated with more pancreatitis (HR 9.09), bowel obstruction (HR 4.22) and gastroparesis (HR 3.67) than bupropion-naltrexone, with wide confidence intervals²³.

Rebound after stopping. In the STEP 1 extension, one year after stopping semaglutide participants regained two-thirds of the weight they had lost, and most cardiometabolic improvements drifted back toward baseline²¹. In SURMOUNT-4, those switched from tirzepatide to placebo regained 14.0% of body weight between weeks 36 and 88, while those who stayed on the drug lost another 5.5%; at week 88, 89.5% of those who continued kept at least 80% of their initial loss, vs 16.6% on placebo²². In the STEP 1 extension (327 participants), the net loss at 120 weeks was 5.6% after a 17.3% loss during treatment²¹.

Lean mass. In the SURMOUNT-1 body-composition substudy, about a quarter of the weight lost was lean mass, a proportion similar to placebo²⁴. Eyes: the European Medicines Agency concluded in 2025 that non-arteritic anterior ischemic optic neuropathy (NAION) is a very rare side effect of semaglutide that may affect up to 1 in 10,000 people²⁵. These topics are in GLP-1s: muscle, rebound, eyes and pancreas, and interactions with oral contraceptives, bone and micronutrients in GLP-1s: interactions, bone, micronutrients and the "microdosing" fad.

Thyroid. In rats and, to a lesser extent, mice, GLP-1 agonists activate thyroid C cells and cause hyperplasia; in primates receptor expression in those cells is low, and 20 months of liraglutide at more than 60 times human exposure did not cause C-cell hyperplasia in monkeys²⁶. In a Scandinavian cohort of 145,410 GLP-1 users there was no increase in thyroid cancer risk vs DPP-4 inhibitors (HR 0.93; 95% CI 0.66–1.31) over a mean follow-up of 3.9 years; the upper limit of the interval rules out a relative-risk increase greater than 31%, and for medullary carcinoma the HR was 1.19 with a very wide interval (0.37–3.86)²⁷. In patients treated with liraglutide for 2 years, mean calcitonin stayed at the low end of the normal range²⁶. Even so, the semaglutide obesity label keeps the boxed warning on C-cell tumors and the contraindication in a history of medullary thyroid carcinoma or MEN2²⁸. The details are in GLP-1s and thyroid cancer: from rat C-cells to Nordic registries.

In aesthetics, rapid loss of facial volume gave its name to a phenomenon of its own; we analyze it in The "GLP-1 face": what the studies show.

Quality and purity: the risk of products outside the approved supply chain

Semaglutide and tirzepatide are long peptides with chemical modifications, such as fatty-acid chains attached to the molecule⁵⁸; producing them with the purity, potency and stability of the trial product is not trivial. In a pharmacovigilance analysis covering 2018 to 2024 (707 of 81,078 GLP-1 reports involved compounded products), those products showed more reports of preparation errors (ROR 48.9), contamination (ROR 19.0) and manufacturing issues (ROR 8.5), and higher odds of hospitalization (ROR 2.35) than approved products²⁹. Another analysis, authored by researchers from tirzepatide's manufacturer, found a new, widespread impurity in compounded tirzepatide combined with vitamin B12, formed by a chemical reaction between tirzepatide and certain B12 analogs; its clinical effects are unknown³⁰.

Salts, impurities and immunogenicity are explained in Compounded GLP-1s: salts, impurities and antibodies.

Open questions about GLP-1 drugs

• Lifelong treatment? Withdrawal trials show the weight returns after stopping²¹²²; how to maintain the result with less drug still has no firm answer.
• Which one is "best"? There is only one large head-to-head obesity trial (SURMOUNT-5)¹⁰; the other comparisons cross trials with different populations and estimands^79121314.
• What do glucagon or amylin add long term? Retatrutide and CagriSema show more weight loss¹²¹³, but their cardiovascular outcome trials are still missing.
• Muscle and function? DXA lean mass is not the same as strength or physical function²⁴.
• Rare risks? Pancreatitis, NAION and thyroid are still being monitored with cohort studies and pharmacovigilance²³²⁵²⁷.