Non-linear dose-response
The temptation in any weight-loss medication is to assume more is better, push the dose, get more weight loss. GLP-1 therapy doesn't quite work that way. The weight-loss curve is non-linear, with diminishing returns at higher doses, while the side-effect curve continues to rise.
Semaglutide curve
Approximate average weight loss at 68 weeks (STEP trials):
- 0.25 mg/week: ~3% (titration only)
- 0.5 mg: ~5%
- 1.0 mg: ~8%
- 1.7 mg: ~12%
- 2.4 mg: ~15%
Each step adds weight loss, but the increment from 1.7 to 2.4 is smaller than from 0.5 to 1.0. Side effects increase more steeply.
Tirzepatide curve
Approximate average weight loss at 72 weeks (SURMOUNT-1):
- 5 mg: ~15%
- 10 mg: ~19%
- 15 mg: ~21%
Tirzepatide's dose-response is similarly non-linear, with diminishing returns from 10 to 15 mg.
Side effect curve
Side effects (nausea, constipation, fatigue) increase roughly linearly with dose, and accelerate at the highest doses. Patients pushing maximum doses often struggle with tolerability without proportional weight benefit.
Finding personal optimal
The personal optimal dose is where:
- Weight loss is satisfactory for goals
- Side effects are minimal
- Adherence is sustainable long-term
For many patients, this is a mid-range dose, not the maximum. Patients should not feel pressure to push to maximum if they're achieving goals at lower doses.
Microdosing strategies
Some patients use lower doses than typical labeling, for body recomposition rather than dramatic weight loss, for maintenance after weight loss goals achieved, or for specific clinical effects (cravings reduction, glucose control) without aggressive weight effects.
Microdosing protocols typically range from 0.125 mg to 0.5 mg semaglutide weekly, achieving meaningful clinical effects at lower side-effect burden. covers protocols.
The clinical pearl: Push the dose only if results justify it. Patients losing weight steadily at 1.0 mg semaglutide don't need to escalate to 2.4 mg if they're tolerating it well and tracking toward goals. The maximum dose is for patients who need it, not for everyone.
Bottom line
GLP-1 dose-response is non-linear, diminishing weight loss benefit at higher doses, accelerating side effects. Most patients have an optimal personal dose somewhere mid-range. Escalation should be tolerability-paced, not calendar-paced. Microdosing strategies extend therapeutic options for specific use cases.