What Is Semaglutide and How Does It Work?
Semaglutide is the most commercially successful peptide drug in history. Sold under the brand names Ozempic, Wegovy, and Rybelsus, it generated over $20 billion in revenue for Novo Nordisk in 2024 alone. It has been prescribed to millions of people worldwide for type 2 diabetes and obesity.
Semaglutide is the most commercially successful peptide drug in history. Sold under the brand names Ozempic, Wegovy, and Rybelsus, it generated over $20 billion in revenue for Novo Nordisk in 2024 alone. It has been prescribed to millions of people worldwide for type 2 diabetes and obesity. It's reshaped how medicine thinks about weight management, spawned a cultural phenomenon, and prompted conversations about everything from food addiction to beauty standards.
But what is semaglutide, exactly? How does a peptide originally designed to help diabetics control blood sugar become the most sought-after weight loss drug in decades? And is it as good as the headlines suggest?
Here's the complete picture.
Table of Contents
- What Semaglutide Is
- How Semaglutide Works: The Mechanism of Action
- FDA-Approved Uses and Brand Names
- How Semaglutide Works for Weight Loss
- How Semaglutide Works for Diabetes
- Cardiovascular Benefits: The SELECT Trial
- Side Effects: What to Expect
- Cost and Access
- Semaglutide vs. Other GLP-1 Drugs
- What Happens When You Stop
- Frequently Asked Questions
- The Bottom Line
- References
What Semaglutide Is
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. In plainer language: it's a synthetic version of a hormone your gut already makes, modified to last much longer in your body.
Your intestines naturally release GLP-1 after you eat. This hormone tells your pancreas to produce insulin, tells your liver to reduce glucose output, slows stomach emptying, and signals your brain that you've eaten enough. The problem is that natural GLP-1 breaks down in about 2 minutes. It's destroyed almost as fast as it's made by an enzyme called DPP-4.
Semaglutide is engineered to resist that breakdown. Novo Nordisk's scientists made three key modifications to the natural GLP-1 molecule:
- An amino acid substitution at position 8 (alanine replaced with alpha-aminoisobutyric acid) that resists DPP-4 degradation
- A C-18 fatty acid chain attached via a linker at position 26 that binds to albumin (a blood protein), creating a circulating reservoir
- An amino acid substitution at position 34 that prevents fatty acid attachment at the wrong site
The result: semaglutide has a half-life of approximately 7 days, compared to 2 minutes for natural GLP-1. One injection per week maintains therapeutic levels. That's a 5,000-fold increase in duration. For a deeper look at the pharmacology, see the semaglutide pharmacology guide.
How Semaglutide Works: The Mechanism of Action
Semaglutide works by binding to GLP-1 receptors throughout the body. These receptors are found in the pancreas, brain, gut, heart, and other organs. Activation of these receptors triggers several parallel effects:
In the Pancreas:
- Stimulates insulin secretion from beta cells (but only when blood sugar is elevated — this is glucose-dependent, which reduces the risk of hypoglycemia)
- Suppresses glucagon secretion from alpha cells (glucagon raises blood sugar, so suppressing it lowers it)
- May support beta cell preservation and proliferation over time
In the Brain:
- Acts on GLP-1 receptors in the hypothalamus, which regulates appetite and satiety
- Reduces hunger and food cravings through central nervous system signaling
- May reduce reward-driven eating by acting on the mesolimbic dopamine system (this is why some users report reduced interest in alcohol and other addictive behaviors)
In the Gut:
- Slows gastric emptying — food moves more slowly from the stomach into the small intestine
- This contributes to feeling full longer after meals and reducing overall food intake
In the Heart and Blood Vessels:
- Reduces inflammation in arterial walls
- May improve endothelial function
- Reduces blood pressure modestly (2-5 mmHg systolic in clinical trials)
This multi-organ mechanism explains why semaglutide affects much more than blood sugar alone.
FDA-Approved Uses and Brand Names
Semaglutide is sold under three brand names, each approved for different indications:
| Brand Name | Form | FDA Approval | Indication |
|---|---|---|---|
| Ozempic | Weekly subcutaneous injection (0.25, 0.5, 1.0, 2.0 mg) | December 2017 | Type 2 diabetes |
| Rybelsus | Daily oral tablet (3, 7, 14 mg) | September 2019 | Type 2 diabetes |
| Wegovy | Weekly subcutaneous injection (0.25, 0.5, 1.0, 1.7, 2.4 mg) | June 2021 | Chronic weight management |
Ozempic and Wegovy contain the same molecule — the only differences are the dose escalation schedule and the approved indication. Wegovy reaches a higher maximum dose (2.4 mg vs. 2.0 mg for Ozempic) because the weight loss indication typically requires more drug.
Rybelsus uses a special absorption enhancer (SNAC, or sodium N-[8-(2-hydroxybenzoyl) amino] caprylate) to protect the peptide from stomach acid and facilitate absorption through the stomach lining. Oral bioavailability is still only about 1%, which is why the oral dose (14 mg) is much higher than the injectable dose (2.4 mg) despite being the same drug.
For the differences between brands, see the Ozempic vs. Wegovy breakdown.
How Semaglutide Works for Weight Loss
The STEP (Semaglutide Treatment Effect in People with Obesity) clinical trial program is the most comprehensive weight loss drug trial series ever conducted. The results:
- STEP 1 (n=1,961): 2.4 mg weekly semaglutide produced mean weight loss of 14.9% at 68 weeks, vs. 2.4% with placebo. One-third of participants lost more than 20% of their body weight.
- STEP 2 (n=1,210, patients with type 2 diabetes): Mean weight loss of 9.6% at 68 weeks.
- STEP 3 (n=611, with intensive behavioral therapy): Mean weight loss of 16.0%.
- STEP 5 (n=304, 2-year data): Weight loss maintained at approximately 15% over 104 weeks with continued treatment.
To put these numbers in context: previous weight loss medications typically produced 5-8% weight loss. Semaglutide roughly doubled that. For the complete trial breakdowns, see the STEP study analysis.
How the weight comes off: Semaglutide's weight loss is driven primarily by reduced caloric intake, not increased metabolism. Studies using doubly labeled water methods show that participants on semaglutide eat approximately 20-35% fewer calories per day — not because they're forcing themselves to eat less, but because they feel satisfied sooner and experience fewer cravings. The slowed gastric emptying contributes to this, but the central brain effects appear to be the primary driver.
Body composition concern: Approximately 40% of weight lost on semaglutide is lean mass (muscle), not fat. This ratio is similar to weight loss through calorie restriction alone and is a legitimate concern, particularly for older adults. Resistance training during semaglutide treatment is strongly recommended to preserve muscle mass.
How Semaglutide Works for Diabetes
For type 2 diabetes, semaglutide's effects are substantial:
- HbA1c reduction: 1.5-1.8% in clinical trials (SUSTAIN program). An HbA1c drop of 1.5% can mean the difference between uncontrolled and well-controlled diabetes.
- Fasting glucose reduction: Significant decreases from baseline.
- Weight loss: 4-6 kg in the diabetes trials (using lower doses than the weight management trials).
- Cardiovascular protection: See the SELECT trial results below.
The glucose-dependent mechanism is particularly important. Semaglutide only stimulates insulin when blood sugar is elevated, which means the risk of hypoglycemia (dangerously low blood sugar) is minimal when used as monotherapy. This is a meaningful advantage over older diabetes drugs like sulfonylureas, which can cause hypoglycemia regardless of blood sugar levels.
Cardiovascular Benefits: The SELECT Trial
In November 2023, the SELECT trial (n=17,604) demonstrated that semaglutide 2.4 mg weekly reduced major adverse cardiovascular events (MACE — heart attack, stroke, or cardiovascular death) by 20% in overweight or obese adults without diabetes.
This was groundbreaking. Previous weight loss drugs had never shown cardiovascular protection. The SELECT results suggested that semaglutide's cardiovascular benefits extend beyond its effects on weight and blood sugar — likely involving direct anti-inflammatory effects on blood vessels.
Based on SELECT, the FDA expanded Wegovy's indication to include cardiovascular risk reduction in March 2024, making it the first weight management drug approved specifically to prevent heart attacks and strokes.
Side Effects: What to Expect
Semaglutide's side effects are well-documented from clinical trials involving tens of thousands of participants:
Very Common (>10% of users):
- Nausea (40-44% at some point during treatment; usually peaks during dose escalation and improves)
- Diarrhea (30%)
- Vomiting (24%)
- Constipation (24%)
- Abdominal pain (20%)
Common (1-10%):
- Headache
- Fatigue
- Dyspepsia (indigestion)
- Dizziness
- Injection site reactions
Uncommon but Important:
- Pancreatitis: Occurs in approximately 0.3% of users in clinical trials. Symptoms include severe, persistent abdominal pain radiating to the back.
- Gallbladder disease: Rapid weight loss increases gallstone risk. Approximately 1.6% of Wegovy users developed gallbladder problems vs. 0.7% on placebo.
- "Ozempic face": Not a medical side effect but a visible one — loss of facial fat that can create a gaunt appearance, particularly in people who lose a large amount of weight. This affects some users more than others.
Boxed Warning (serious):
- Thyroid C-cell tumors: In rodent studies, semaglutide caused thyroid C-cell tumors. This has not been confirmed in humans, but semaglutide carries a boxed warning and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
For detailed guidance on managing these effects, see how to manage GLP-1 side effects.
Cost and Access
Semaglutide's cost is a major barrier for many patients:
- Ozempic: Approximately $900-1,000/month without insurance (US list price)
- Wegovy: Approximately $1,300-1,400/month without insurance (US list price)
- Rybelsus: Approximately $900-1,000/month without insurance
Insurance coverage: Medicare historically did not cover weight loss drugs, though this changed with the FDA's cardiovascular indication for Wegovy. Private insurance coverage varies widely — some plans cover it for diabetes but not weight management, some cover it for both, some cover neither.
Compounded semaglutide: Until the FDA crackdown in 2024-2025, compounding pharmacies offered semaglutide at $200-400/month. The compounded semaglutide controversy significantly impacted access for patients who couldn't afford brand-name pricing.
Global pricing: Semaglutide costs vary dramatically by country. In the UK, Wegovy costs approximately £150-200/month. In some countries, it's covered by national health systems; in others, it's entirely out-of-pocket. See the global GLP-1 pricing comparison for specifics.
Supply issues: Semaglutide has faced repeated shortages since 2022, driven by demand outpacing manufacturing capacity. The situation has improved but supply constraints remain for certain doses. Current shortage status is worth checking.
Semaglutide vs. Other GLP-1 Drugs
Semaglutide is not the only GLP-1 drug available. Here's how it compares to the main alternatives:
| Drug | Frequency | Weight Loss | HbA1c Reduction | Notes |
|---|---|---|---|---|
| Semaglutide (Ozempic/Wegovy) | Weekly injection | ~15% | ~1.5-1.8% | Most prescribed GLP-1 |
| Tirzepatide (Mounjaro/Zepbound) | Weekly injection | ~20-22% | ~2.0-2.4% | Dual GIP/GLP-1 agonist; more effective but newer |
| Liraglutide (Victoza/Saxenda) | Daily injection | ~8% | ~1.0-1.2% | Older; requires daily dosing |
| Dulaglutide (Trulicity) | Weekly injection | ~5-6% | ~1.0-1.5% | Primarily for diabetes |
| Oral semaglutide (Rybelsus) | Daily oral | ~5-7% | ~1.0-1.3% | No injection needed; lower efficacy |
Tirzepatide (Mounjaro/Zepbound) has produced larger weight loss in head-to-head comparisons and may become the preferred option for weight management. See the semaglutide vs. tirzepatide comparison for the full analysis.
What Happens When You Stop
This is one of the most important questions about semaglutide, and the data is sobering:
The STEP 1 extension study showed that participants who stopped semaglutide after 68 weeks regained approximately two-thirds of their lost weight within one year. They also saw increases in cardiovascular risk factors (blood pressure, lipids, blood sugar) that had improved during treatment.
This suggests semaglutide manages obesity rather than cures it — similar to how blood pressure medication manages hypertension. The drug works while you take it. When you stop, the underlying biology reasserts itself.
This has significant implications for cost (long-term or indefinite treatment) and for the weight management approach. Strategies for maintaining weight loss after stopping GLP-1 drugs exist, but they require significant lifestyle modifications.
Frequently Asked Questions
Is semaglutide a peptide? Yes. Semaglutide is a modified peptide — a 31-amino-acid chain based on the natural GLP-1 hormone (which is itself a peptide). It's produced through recombinant DNA technology in yeast cells (Saccharomyces cerevisiae). For a broader understanding of peptides, see what are peptides.
Can I get semaglutide without diabetes? Yes. Wegovy is FDA-approved specifically for chronic weight management in adults with a BMI of 30+ (obesity) or 27+ (overweight) with at least one weight-related comorbidity (high blood pressure, type 2 diabetes, high cholesterol). You don't need diabetes to qualify.
How fast does semaglutide work? Most people notice reduced appetite within the first week or two. Measurable weight loss typically begins within the first month. The dose escalation period (starting at 0.25 mg and increasing every 4 weeks) means full effects aren't reached until you're on the maintenance dose, which takes approximately 16-20 weeks.
Is semaglutide safe long-term? Clinical trials have studied semaglutide for up to 2 years, and post-marketing data now extends to 7+ years (since the 2017 Ozempic approval). No unexpected long-term safety signals have emerged, though monitoring continues. The thyroid tumor concern from rodent studies remains theoretical in humans.
Can I drink alcohol on semaglutide? Semaglutide doesn't directly interact with alcohol, but many users report significantly reduced desire for alcohol — sometimes dramatically. Slowed gastric emptying may also mean alcohol is absorbed differently. The medical advice is to moderate alcohol intake while on semaglutide, particularly given the nausea side effects.
What's the difference between Ozempic and Wegovy? Same drug, different dose and indication. Ozempic is approved for type 2 diabetes (max dose 2.0 mg/week). Wegovy is approved for weight management (max dose 2.4 mg/week). Prescribing Ozempic for weight loss in non-diabetic patients is off-label use.
The Bottom Line
Semaglutide is a genuinely effective medication for type 2 diabetes and obesity. The clinical data is extensive, the benefits are real, and the cardiovascular protection demonstrated in SELECT adds another dimension beyond weight and blood sugar control.
But it's not magic. Side effects are common, especially GI symptoms during dose escalation. Weight regain after stopping is the norm, not the exception. Cost remains prohibitive for many patients. And the 40% lean mass loss during weight reduction means exercise needs to be part of the equation.
Semaglutide works best as one component of a comprehensive approach — combined with dietary changes, resistance training, and ongoing medical monitoring. If you're considering it, start with your primary care physician or endocrinologist, who can evaluate whether you're a good candidate and help manage the process.
For those interested in how semaglutide fits into the broader peptide landscape, the beginner's guide to peptide therapy provides helpful context on what peptides can and can't do.
References
- Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." New England Journal of Medicine. 2021;384(11):989-1002. (STEP 1)
- Davies M, et al. "Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2)." The Lancet. 2021;397(10278):971-984.
- Wadden TA, et al. "Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity (STEP 3)." JAMA. 2021;325(14):1403-1413.
- Garvey WT, et al. "Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial." Nature Medicine. 2022;28(10):2083-2091.
- Lincoff AM, et al. "Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes." New England Journal of Medicine. 2023;389(24):2221-2232. (SELECT)
- Marso SP, et al. "Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes." New England Journal of Medicine. 2016;375(19):1834-1844. (SUSTAIN-6)
- Rubino DM, et al. "Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes." JAMA. 2022;327(2):138-150.
- Novo Nordisk. "Ozempic (semaglutide) Prescribing Information." FDA.gov. Updated 2025.
- Novo Nordisk. "Wegovy (semaglutide) Prescribing Information." FDA.gov. Updated 2025.
- Wilding JPH, et al. "Weight regain and cardiometabolic effects after withdrawal of semaglutide." Diabetes, Obesity and Metabolism. 2022;24(8):1553-1564.