Semaglutide

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist developed by Novo Nordisk. It is one of the most commercially successful drugs in pharmaceutical history and is widely credited with launching the current wave of interest in weight loss medications. It is available under three brand names: Ozempic (for Type 2 diabetes), Wegovy (for chronic weight management), and Rybelsus (an oral formulation for diabetes).

Originally developed for Type 2 diabetes management, semaglutide's significant weight loss effects observed in diabetes trials led to its development and eventual FDA approval as a dedicated anti-obesity medication. The drug mimics the naturally occurring GLP-1 hormone but has been modified to resist enzymatic degradation, giving it a half-life of approximately one week — long enough for convenient once-weekly dosing.

Semaglutide has also demonstrated significant cardiovascular benefits, becoming the first anti-obesity medication to show a reduction in major adverse cardiovascular events (heart attack, stroke, cardiovascular death) in the landmark SELECT trial, further broadening its clinical significance beyond weight management.

Semaglutide works by mimicking GLP-1, a hormone naturally produced in the gut in response to food intake:

Appetite suppression (brain): Semaglutide crosses the blood-brain barrier and acts on GLP-1 receptors in the hypothalamus and other brain regions that regulate appetite. This reduces hunger, increases feelings of fullness, and decreases food cravings — including cravings for high-fat and high-sugar foods. Many users report a fundamental shift in their relationship with food.

Slowed gastric emptying (gut): Semaglutide delays the rate at which food leaves the stomach, leading to prolonged feelings of fullness after meals and reduced overall food intake.

Improved insulin signaling (pancreas): In a glucose-dependent manner, semaglutide enhances insulin secretion and suppresses glucagon release, improving blood sugar regulation. This glucose-dependent mechanism means it rarely causes hypoglycemia on its own.

Cardiovascular effects: Beyond weight loss, semaglutide appears to reduce systemic inflammation, improve lipid profiles, lower blood pressure, and may have direct beneficial effects on blood vessel function. The SELECT trial demonstrated a 20% reduction in major adverse cardiovascular events.

Emerging neurological effects: Ongoing research is investigating semaglutide's potential benefits for Alzheimer's disease, Parkinson's disease, and addiction, based on the widespread distribution of GLP-1 receptors in the brain.

STEP 1 (Obesity, no diabetes): 1,961 participants. At 68 weeks, semaglutide 2.4 mg produced mean weight loss of -14.9% vs -2.4% placebo. 86.4% of participants lost at least 5% body weight, and 32% lost at least 20%.

STEP 2 (Obesity with diabetes): Mean weight loss of -9.6% at 68 weeks with semaglutide 2.4 mg.

STEP 3 (With intensive behavioral therapy): Mean weight loss of -16.0%, demonstrating that combining semaglutide with lifestyle modifications enhances results.

SELECT (Cardiovascular outcomes): 17,604 participants followed for a mean of 33 months. Semaglutide reduced major adverse cardiovascular events by 20% compared to placebo — a landmark finding making it the first anti-obesity medication to demonstrate cardiovascular risk reduction.

STEP 5 (Long-term, 2 years): Sustained weight loss of -15.2% at 104 weeks, demonstrating durability of effect with continued treatment.

FLOW (Kidney outcomes): Semaglutide demonstrated a 24% reduction in clinically important kidney disease outcomes in patients with Type 2 diabetes and chronic kidney disease.

Wegovy (weight management) escalation:

Month	Weekly Dose	Duration
Month 1	0.25 mg	4 weeks
Month 2	0.5 mg	4 weeks
Month 3	1.0 mg	4 weeks
Month 4	1.7 mg	4 weeks
Month 5+	2.4 mg	Maintenance

Ozempic (diabetes) escalation: Starts at 0.25 mg weekly for 4 weeks, then 0.5 mg. Can increase to 1 mg then 2 mg based on glycemic response.

Rybelsus (oral): 3 mg daily for 30 days, then 7 mg daily, with optional increase to 14 mg. Must be taken on an empty stomach with no more than 4 oz of water, at least 30 minutes before food or other medications.

Administration: Subcutaneous injection in the abdomen, thigh, or upper arm. Rotate injection sites. Can be administered at any time of day, with or without food. Inject on the same day each week; if a dose is missed, take it within 5 days of the missed dose.

Common side effects (>5%): Nausea (up to 44% initially, decreasing over time), diarrhea (30%), vomiting (24%), constipation (24%), abdominal pain (20%), headache, fatigue, and injection site reactions.

Gastrointestinal side effects are the most common reason for discontinuation but are generally worst during dose escalation and improve significantly with continued use. Eating smaller meals, avoiding high-fat foods, and staying hydrated can help manage these effects.

Serious warnings:

• Thyroid C-cell tumors — boxed warning based on rodent data. Contraindicated with personal/family history of medullary thyroid carcinoma or MEN 2.
• Pancreatitis — rare but serious. Discontinue if suspected.
• Gallbladder disease — rapid weight loss increases gallstone risk.
• Diabetic retinopathy — rapid improvements in blood sugar can temporarily worsen diabetic eye disease.
• Muscle mass loss — approximately 25-40% of weight lost may be lean mass. Resistance training and adequate protein intake are recommended to mitigate this.

Weight regain after stopping: The STEP 1 extension trial showed that participants regained approximately two-thirds of lost weight within one year of stopping semaglutide, highlighting that the drug manages rather than cures obesity.