Semaglutide
Ozempic · Wegovy · Rybelsus
The most rigorously studied GLP-1 receptor agonist for weight and glycemic control.
Class
GLP-1 receptor agonist
Half-life
~7 days (once-weekly dosing)
Evidence
Randomized human trials
Randomized human trials
Supported by randomized controlled trials in humans. Several compounds at this level are FDA-approved for specific indications.
Overview
Semaglutide is a long-acting analogue of glucagon-like peptide-1 (GLP-1), a hormone your gut releases after eating. Structural modifications — a substituted amino acid at position 8 and a fatty-acid chain that binds albumin — make it resistant to the DPP-4 enzyme that destroys natural GLP-1 within minutes, extending its half-life from roughly two minutes to about a week.
It is among the most thoroughly evidenced compounds in this entire library. The STEP program demonstrated mean body weight reduction of roughly 15% over 68 weeks at 2.4 mg weekly, and the SELECT trial showed a 20% reduction in major adverse cardiovascular events in people with overweight and established cardiovascular disease — the first weight-management drug to prove cardiovascular benefit.
The trade-off is that its effects are largely maintenance-dependent. Withdrawal studies consistently show substantial weight regain after discontinuation, which is why it is framed clinically as a chronic therapy rather than a course of treatment.
How it works
- Agonises GLP-1 receptors in pancreatic beta cells, amplifying glucose-dependent insulin secretion — insulin release scales with blood glucose, which is why monotherapy rarely causes hypoglycemia.
- Suppresses glucagon secretion from pancreatic alpha cells, reducing hepatic glucose output.
- Slows gastric emptying, prolonging satiety and blunting post-meal glucose excursions.
- Acts on GLP-1 receptors in the hypothalamic arcuate nucleus and area postrema, directly reducing appetite and food-reward signalling.
What the research shows
Researched effects
- Mean 14.9% body weight reduction at 68 weeks (STEP 1, 2.4 mg weekly)
- HbA1c reduction of roughly 1.5–1.8 percentage points in type 2 diabetes
- 20% relative risk reduction in major adverse cardiovascular events (SELECT)
- Improvement in hepatic steatosis and NASH resolution in phase 2 trials
- Reduced progression to type 2 diabetes in prediabetic cohorts
Limitations & what it won't do
- Roughly two-thirds of lost weight is regained within a year of stopping (STEP 4 extension).
- Between 25–40% of total weight lost is lean mass unless resistance training and adequate protein intake are maintained.
- Does not improve — and may transiently worsen — diabetic retinopathy in people with pre-existing retinal disease and rapid glucose correction.
Dosing protocols
These ranges reflect published trials and community protocols. They are reference information, not a prescription. Doses are per injection unless noted.
Standard clinical titration (weight management)
0.25 mg → 2.4 mg0.25 mg weeks 1–4, 0.5 mg weeks 5–8, 1.0 mg weeks 9–12, 1.7 mg weeks 13–16, then 2.4 mg maintenance. Titration exists to manage GI side effects, not to build efficacy.
Type 2 diabetes (Ozempic labelling)
0.25 mg → 2.0 mgLower ceiling than the weight-management indication.
Low-dose maintenance
0.5–1.0 mgMany people hold at a sub-maximal dose once at goal weight rather than pushing to 2.4 mg. Discuss with a prescriber.
Reconstitution & measuring your dose
Handling
- Typical vial sizes
- 10 mg
- Suggested BAC water
- 2 mL
- Storage
- Unreconstituted lyophilised powder: refrigerate at 2–8 °C, protected from light. Commercial pens: refrigerate before first use.
- After reconstitution
- Reconstituted: roughly 28–56 days refrigerated depending on preservative. Never freeze. Discard if cloudy or particulate.
Why 2 mL? HTX carries semaglutide as a 10 mg vial. In 2 mL that yields 5 mg/mL, so 0.25 mg lands on 5 units of a U-100 syringe and 2.4 mg lands near 48 units — every titration step falls on a readable mark.
Dose calculator
Draw to
5units
= 0.05 mL · 50 mcg per unit
Concentration
5000 mcg/mL
Doses per vial
40
Side effects
Common
- Nausea (most common; typically peaks after each dose increase then subsides)
- Constipation or diarrhoea
- Vomiting, especially with high-fat meals
- Fatigue and reduced exercise capacity in the first weeks
- Injection-site reactions
- "Sulfur burps" and reflux
Serious / rare
- Acute pancreatitis (rare — severe persistent abdominal pain radiating to the back requires immediate care)
- Gallbladder disease and gallstones, particularly with rapid weight loss
- Bowel obstruction / severe gastroparesis
- Acute kidney injury secondary to dehydration from vomiting
- Worsening diabetic retinopathy with rapid glycemic correction
Contraindications & interactions
Do not use if you have
- Medullary thyroid carcinoma or MEN2 (personal or family)
Rodent studies showed dose-dependent thyroid C-cell tumours. Personal or family history of medullary thyroid carcinoma or MEN2 is an absolute contraindication on the FDA boxed warning.
- Pregnant, breastfeeding, or trying to conceive
Contraindicated in pregnancy. Guidance is to discontinue at least 2 months before a planned pregnancy given the long half-life.
- Pancreatitis history
Prior pancreatitis is a contraindication in most prescribing guidance — GLP-1 agonists carry a pancreatitis signal.
Use caution if you have
- Gastroparesis or delayed gastric emptying
Semaglutide slows gastric emptying by design. Layering it on existing gastroparesis can cause severe retention and vomiting.
- Gallbladder disease or gallstones
Rapid weight loss substantially raises gallstone risk. Existing gallbladder disease compounds it.
- Diabetic retinopathy or eye disease
Rapid HbA1c correction transiently worsened retinopathy in the SUSTAIN-6 trial. Baseline retinal exam is advised.
- Type 1 diabetes
Not indicated for type 1 diabetes. Any use is off-label and requires close insulin adjustment to avoid ketoacidosis.
- Kidney disease
Dehydration from GI side effects can precipitate acute kidney injury on a compromised baseline.
- Mood or psychiatric condition
Post-marketing reports of mood changes and suicidal ideation exist; regulatory reviews have not confirmed causation, but monitoring is prudent.
Medication interactions
- avoidInsulin — Combining without supervised dose reduction risks severe hypoglycemia. Insulin doses typically need cutting by 20% or more at initiation — this must be managed by a prescriber.
- avoidSulfonylureas — Sulfonylureas drive insulin release independent of glucose. Stacked with a GLP-1 the hypoglycemia risk is significant and requires prescriber-managed dose reduction.
- avoidGLP-1 / GIP agonists — Never stack two GLP-1 receptor agonists. There is no additive benefit and the GI and pancreatitis risk compounds.
- monitorMetformin — Commonly co-prescribed and generally well tolerated. Watch for additive GI upset.
- cautionHormonal contraceptives / HRT — Delayed gastric emptying and vomiting can reduce oral contraceptive absorption. A backup method is advisable during titration.
- monitorThyroid hormone — Altered gastric emptying can change levothyroxine absorption. Recheck TSH after reaching a stable dose.
Don't stack with
- Tirzepatide — Both are GLP-1 receptor agonists — overlapping mechanism, compounding GI and pancreatitis risk.
- Retatrutide — Overlapping incretin agonism with no additive benefit and additive risk.
- Liraglutide — Duplicate GLP-1 agonism.
What to monitor
- Baseline and periodic HbA1c and fasting glucose
- Baseline retinal exam if diabetic
- Lipase/amylase if abdominal pain develops
- Body composition — track lean mass, not just scale weight
- Protein intake (target ≥1.6 g/kg) and resistance training to defend lean mass
Commonly combined with
References
- STEP 1 — Once-Weekly Semaglutide in Adults with Overweight or ObesityNEJM 2021;384:989-1002
- SELECT — Semaglutide and Cardiovascular OutcomesNEJM 2023;389:2221-2232
- SUSTAIN-6 — Semaglutide and Cardiovascular Outcomes in T2DNEJM 2016;375:1834-1844
Research & educational information only — not medical advice.
You must be 18 or older to use this site. The peptides described are presented as research chemicals intended for research purposes only. Most are not approved by the FDA for human use. Dosing ranges reflect what has appeared in the scientific literature or community protocols and are not prescriptions. Nothing here replaces evaluation by a licensed physician who knows your full medical history.
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