Tirzepatide — Research, Dosing & Price Guide

Tirzepatide is a first-in-class dual GLP-1/GIP receptor agonist that has redefined the treatment landscape for type 2 diabetes and obesity. FDA-approved as Mounjaro (diabetes, 2022) and Zepbound (obesity, 2023), tirzepatide produces the most dramatic weight loss ever seen in a pharmaceutical — up to 22.5% in the SURMOUNT-1 trial. Its dual incretin mechanism activates both GLP-1 and GIP receptors, producing superior metabolic effects compared to GLP-1-only agonists like semaglutide. Tirzepatide has also shown groundbreaking results in obstructive sleep apnea, heart failure with preserved ejection fraction, and MASH.

Tirzepatide is a 39-amino acid synthetic peptide based on the GIP (glucose-dependent insulinotropic polypeptide) sequence, engineered with GLP-1R agonist activity — making it a 'twincretin' that activates both major incretin receptors. The molecule has approximately 5:1 GIP:GLP-1 receptor affinity, with a C20 fatty diacid acyl chain enabling albumin binding for a ~5-day half-life and once-weekly dosing. GLP-1R activation provides well-established metabolic effects: appetite suppression via hypothalamic satiety centers, glucose-dependent insulin secretion, glucagon suppression, and delayed gastric emptying. The GIP receptor component is what makes tirzepatide unique. GIP receptor agonism was previously thought to be obesogenic (since GIP promotes fat storage postprandially), but tirzepatide's pharmacological GIP activation produces paradoxically beneficial metabolic effects. At pharmacological doses, GIPR activation appears to enhance central appetite suppression (potentially through GIP receptors in the hypothalamus and brainstem), improve insulin sensitivity in adipose tissue (promoting healthy fat storage over ectopic deposition), enhance lipid metabolism, and increase energy expenditure. GIPR agonism may also explain tirzepatide's lower nausea rates compared to semaglutide at equivalent weight loss — GIP appears to have anti-emetic properties that partially counteract GLP-1-induced nausea. The combined receptor activation produces a synergistic effect on beta-cell function. Tirzepatide improved insulin sensitivity (via the Matsuda index) and beta-cell function (via the disposition index) to a greater degree than semaglutide, suggesting direct GIPR-mediated beta-cell trophic effects. In SURPASS-2, 86% of tirzepatide patients achieved HbA1c <7% vs. 79% for semaglutide 1 mg. The weight loss mechanism involves both reduced caloric intake (appetite suppression, reduced food reward) and metabolic components (improved fat oxidation, enhanced energy expenditure). Brain imaging studies show tirzepatide reduces neural responses to food cues in reward-processing regions.

• SURMOUNT-1 (2022, NEJM, n=2,539): 15 mg tirzepatide produced 22.5% body weight loss vs. 2.4% placebo at 72 weeks — the largest weight loss from any drug in a major trial
• SURPASS-2 (2021, NEJM): Head-to-head vs. semaglutide 1 mg — tirzepatide 15 mg produced 2.4 kg greater weight loss and superior HbA1c reduction
• SURMOUNT-2 (2023, Lancet): In T2D patients with obesity, 15 mg tirzepatide produced 14.7% weight loss with robust glycemic improvement
• SURMOUNT-MMO (ongoing): Cardiovascular outcomes trial expected to provide MACE data by 2027
• SURMOUNT-OSA (2024, NEJM): Tirzepatide reduced AHI (apnea-hypopnea index) by 51–63%, with 40–50% of patients achieving effective resolution of obstructive sleep apnea
• SYNERGY-NASH (2024): Tirzepatide produced MASH resolution in up to 74% of patients (vs. 13% placebo) with fibrosis improvement in 30% — dramatically superior to any existing treatment
• SUMMIT trial (2024, NEJM): Tirzepatide improved heart failure composite endpoint in HFpEF patients with obesity
• 36.2% of participants in SURMOUNT-1 lost ≥25% of body weight, approaching bariatric surgery-level results
• Post-hoc analyses show improvements in blood pressure, triglycerides, liver enzymes, inflammatory markers, and quality of life

• Mounjaro (T2D): Start 2.5 mg SC weekly for 4 weeks → 5 mg for ≥4 weeks → can increase by 2.5 mg increments every 4 weeks; max 15 mg weekly
• Zepbound (obesity): Same escalation schedule: 2.5 mg → 5 mg → 7.5 mg → 10 mg → 12.5 mg → 15 mg; each step held for ≥4 weeks
• Inject subcutaneously in abdomen, thigh, or upper arm once weekly on the same day each week
• No food timing restrictions for injection
• Slow dose escalation is essential — GI side effects are the primary tolerability concern
• If dose escalation is not tolerated, remain at current dose for an additional 4 weeks before retrying
• If a dose is missed, administer within 4 days; if >4 days, skip and resume schedule
• No established cycling protocol — used continuously for chronic disease management
• Single-use autoinjector pen; no reconstitution required (unlike compounded peptides)

Known Side Effects

• Nausea (24–33% across SURMOUNT trials, usually mild-to-moderate and transient during escalation — notably lower than semaglutide at comparable weight loss)
• Diarrhea (17–23%), constipation (11–17%), and vomiting (7–12%)
• Decreased appetite — intended pharmacological effect
• Injection site reactions in ~3–7% of users
• Gallbladder events (cholelithiasis, cholecystitis): 0.6–1.7%, higher with rapid weight loss
• Pancreatitis: rare (<0.2%) but requires monitoring for severe abdominal pain
• Hair thinning (telogen effluvium) reported in a subset of patients undergoing rapid weight loss
• Muscle mass loss: approximately 25–40% of total weight lost is lean mass — resistance training is strongly recommended

Safety Profile

Tirzepatide is FDA-approved with a comprehensive safety database from the SURPASS and SURMOUNT clinical programs involving over 20,000 patients. The safety profile is broadly consistent with the GLP-1 receptor agonist class, with GI side effects as the primary tolerability concern. Notably, tirzepatide appears to have lower nausea rates than semaglutide at equivalent weight loss levels, possibly due to the anti-emetic effect of GIPR activation. The boxed warning for thyroid C-cell tumors applies (rodent data; no human cases established). Contraindicated in personal/family history of medullary thyroid carcinoma or MEN2. Pancreatitis monitoring is standard. The SURMOUNT-MMO cardiovascular outcomes trial is ongoing — interim safety data has not raised cardiovascular concerns, and the SUMMIT HFpEF data is encouraging. Rapid weight loss increases gallstone risk; patients should be counseled about symptoms. Weight regain after discontinuation is a concern (SURMOUNT-4 showed ~14% weight regain in 36 weeks after stopping), supporting long-term use. Drug interactions are minimal. Not for use during pregnancy (Category X for animals).

Week 1–4 (2.5 mg): The introductory dose produces mild appetite changes. You may notice slightly reduced hunger and earlier satiety at meals. GI side effects (mild nausea after large meals) are possible but often minimal at this dose. Weight loss of 1–3 lbs. Week 5–8 (5 mg): Appetite suppression becomes clearly noticeable. Food noise diminishes — the mental preoccupation with food that many people with obesity experience begins to quiet. Portions naturally decrease. Weight loss of 3–5% from baseline. Week 9–16 (7.5–10 mg): Weight loss accelerates significantly. Weekly losses of 1.5–2.5 lbs are common. Cravings for high-calorie foods diminish markedly. Blood glucose and HbA1c improve substantially in diabetic patients. Clothes begin fitting differently. Week 17–24 (10–15 mg): Approaching full therapeutic dose. Weight loss of 10–15% from baseline. Metabolic markers (blood pressure, triglycerides, liver enzymes, CRP) show meaningful improvement. Sleep apnea symptoms may improve. Energy levels and physical function improve despite caloric deficit. Week 24–72 (maintenance at max tolerated dose): Continued weight loss reaching 18–22% at 52–72 weeks at the 15 mg dose. Body composition transformation is visually dramatic. Metabolic health markers normalize. Quality of life measures improve significantly. Weight loss typically plateaus around 60–72 weeks.

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