Tirzepatide, Weight Pharmacology & Emerging Agents
Dual Agonism · Weight Loss Biology · Pipeline · New Indications
2.46%
HbA1c reduction (tirzepatide 15 mg)
2.09%
HbA1c reduction (semaglutide 1 mg)
~22%
Body weight reduction (SURMOUNT-1)
62%
MASH resolution rate (SYNERGY-NASH)
- GLP-1 receptor agonism only
- Glucose-dependent insulin secretion ↑
- Glucagon suppressed
- Appetite suppressed via hypothalamus
- Gastric emptying slowed
- Weight loss: 10–15%
- MACE reduction: LEADER, SUSTAIN-6
- Dual GIP receptor + GLP-1 receptor agonism
- GIP amplifies insulin secretion & GLP-1 sensitivity
- Additive appetite suppression
- Superior postprandial glucose control
- Weight loss: 15–22% (diabetes); up to 22% (obesity)
- MACE superiority vs dulaglutide (SURPASS-CVOT)
- Approved: T2DM, obesity, MASH
| Agent | Class | Receptor Targets | Phase | Key Data |
|---|
| Retatrutide |
Triple agonist |
GLP-1 + GIP + Glucagon |
Phase 3 |
~24% weight loss in phase 2; adds energy expenditure via glucagon |
| CagriSema |
Amylin + GLP-1 combo |
Amylin + GLP-1 receptors |
Phase 3 |
~25% weight loss; complementary central mechanisms |
| Orforglipron |
Oral small molecule |
GLP-1 receptor only |
Phase 3 |
~9–10% weight loss; no absorption enhancer needed; lower cost potential |
- MASH (SYNERGY-NASH): 62% resolution vs 19% placebo
- HFpEF + obesity (SUMMIT): reduced worsening heart failure events
- Obstructive sleep apnea: trials ongoing
- SURPASS-CVOT: MACE superiority over dulaglutide
- GLP-1 receptor agonists lower the defended body weight set point
- Weight loss is maintained only with continuous therapy
- Stopping drug: essentially complete weight regain within 12 months
- These are chronic therapies, not short-term interventions
- Analogous to antihypertensives: treat, don’t cure