Semaglutide: the complete evidence-based guide

Semaglutide is the drug that made the GLP-1 class mainstream. It was the first once-weekly GLP-1 agonist to show >10% average weight loss in obesity trials, and its generic names (Ozempic for type-2 diabetes, Wegovy for obesity) have become shorthand for the whole class. Understanding semaglutide is understanding the baseline everything else in the GLP-1 conversation compares against.

What semaglutide is#

Semaglutide is a synthetic peptide analogue of native glucagon-like peptide-1 (GLP-1). Native GLP-1 is broken down in minutes by the enzyme dipeptidyl peptidase-4 (DPP-4). Semaglutide is engineered with three key modifications that resist DPP-4 degradation and extend the half-life to approximately one week, enabling once-weekly subcutaneous dosing.

Mechanistically, semaglutide activates GLP-1 receptors in three key locations:

• Hypothalamus and brainstem: suppresses appetite signalling, promotes satiety
• Gastrointestinal tract: slows gastric emptying, reduces post-meal glucose spikes
• Pancreatic beta cells: stimulates glucose-dependent insulin release (no hypoglycaemia in normal-glucose states)

This is single-receptor pharmacology. Semaglutide does not activate GIP, glucagon, or any other incretin receptor. That's the pharmacological difference from tirzepatide and retatrutide.

The efficacy data#

Obesity: STEP 1. In the STEP 1 trial (Wilding et al., NEJM 2021), semaglutide 2.4 mg weekly produced 14.9% mean body-weight reduction at 68 weeks in adults with obesity. Placebo: 2.4%. Approximately 86% of participants achieved ≥5% weight loss; 50% achieved ≥15%; 32% achieved ≥20%.

Type-2 diabetes: SUSTAIN programme. Across the SUSTAIN trials, semaglutide consistently reduced HbA1c by 1.0–1.8 percentage points depending on dose and comparator. It also produced meaningful weight loss as a secondary outcome in T2D patients.

Cardiovascular outcomes: SELECT. The landmark SELECT trial (Lincoff et al., NEJM 2023) enrolled adults with obesity and established cardiovascular disease. Studies have shown semaglutide reduces the risk of major adverse cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death) by 20% over placebo. This is the first obesity drug where cardiovascular benefit has been shown in a dedicated outcomes trial, a finding that reshapes how obesity pharmacotherapy is positioned in clinical practice.

MASLD. Semaglutide has shown meaningful liver-fat reductions in Phase 2 trials for metabolic dysfunction-associated steatotic liver disease. Phase 3 trials are enrolling.

Dosing and titration#

Semaglutide for obesity (Wegovy) follows a standardised 16-week escalation before reaching target dose:

Phase	Weekly dose	Duration
Start	0.25 mg	Weeks 1–4
Step 1	0.5 mg	Weeks 5–8
Step 2	1.0 mg	Weeks 9–12
Step 3	1.7 mg	Weeks 13–16
Target	2.4 mg	Weeks 17+

For type-2 diabetes (Ozempic), target doses are typically lower (0.5 mg, 1.0 mg, or 2.0 mg weekly) and titration is slower. The Klarovel titration calculator builds a custom schedule for any target dose.

Reconstitution for research-grade vials: a 5 mg semaglutide vial reconstituted with 2 mL of bacteriostatic water yields 2.5 mg/mL. A 0.25 mg starting dose equals 0.1 mL = 10 syringe units. The peptide calculator handles any vial-and-dose combination.

Side effects and tolerability#

Gastrointestinal events dominate, as they do across the GLP-1 class:

• Nausea (~44% at the 2.4 mg dose in STEP 1)
• Diarrhoea (~30%)
• Vomiting (~24%)
• Constipation (~24%)
• Abdominal pain (~20%)

Most events are mild to moderate, concentrate during dose escalation, and diminish over time. Discontinuation rates due to adverse events ran ~5–7% in STEP 1, meaningful but lower than discontinuation due to lack of efficacy in placebo arms.

Less common but class-relevant signals:

• Gallbladder disease, associated with elevated risk as a class effect
• Pancreatitis (rare; class warning)
• Injection-site reactions
• Diabetic retinopathy worsening in pre-existing retinopathy (T2D population)
• Thyroid C-cell tumours in rodents (not confirmed in humans; absolute contraindication in patients with personal or family history of MTC/MEN 2)

Regulatory status and access#

Semaglutide is approved and marketed globally. In Norway, DMP has approved both:

• Ozempic: type-2 diabetes indication
• Wegovy: chronic weight management in adults with obesity or overweight with weight-related comorbidities

Norwegian reimbursement through blå resept applies to type-2 diabetes under standard clinical criteria. Obesity-indication reimbursement (Wegovy) is more restrictive; full out-of-pocket cost via hvit resept is common for obesity-only prescriptions.

Shortages have affected semaglutide supply globally from 2023 onwards, particularly for the 2.4 mg obesity formulation. As of April 2026, supply has largely stabilised but remains regionally variable.

Semaglutide vs tirzepatide vs retatrutide#

Semaglutide sits at the first receptor tier of the GLP-1 class:

Drug	Receptors	Weight loss	Timepoint
Semaglutide 2.4 mg	GLP-1	14.9%	68 weeks
Tirzepatide 15 mg	GIP + GLP-1	22.5%	72 weeks
Retatrutide 12 mg	GIP + GLP-1 + glucagon	28.7%	68 weeks

For newcomers to GLP-1 pharmacology, semaglutide remains the most common first choice: longest real-world track record, best-established cardiovascular benefit, broadest clinical familiarity. Tirzepatide's efficacy advantage is real but comes with less long-term real-world safety data. For the detailed head-to-head, see semaglutide vs tirzepatide.

Practical considerations#

Three things matter for anyone considering a semaglutide protocol:

1. Titration discipline. The GLP-1 class rewards patience. Staying at each step for the full 4 weeks before escalating is the single best predictor of tolerability. The titration calculator builds the schedule.
2. Bloodwork baseline and follow-up. HbA1c, lipid panel, TSH, and liver enzymes at baseline. Repeat at 12 and 24 weeks. Any new retinopathy symptoms (in T2D patients) warrant an ophthalmology check.
3. Realistic weight-loss expectations. Average weight loss is 14–15% at the highest dose over 14–16 months. Individual variation is wide: some people lose more than 20%, some lose less than 8%. Response is not fully predictable from baseline characteristics.

For the class-level mechanism, see the GLP-1 class explained. For the pharmacology ceiling of the class, see the retatrutide guide. Klarovel's questionnaire is the right starting point: it screens for class-level contraindications and maps results against the approved-drug profile.

Semaglutide is the drug that changed the conversation. For well-screened patients, it works. The discipline is in the screening, the titration, and the bloodwork.