Tirzepatide

Overview

Tirzepatide is a first-in-class dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist developed by Eli Lilly. Approved as Mounjaro for type 2 diabetes in 2022 and as Zepbound for chronic weight management in 2023, it represents a new paradigm in incretin-based therapy.

The SURMOUNT trials demonstrated unprecedented weight loss efficacy, with participants achieving up to 22.5% body weight reduction - approaching results previously only achievable through bariatric surgery.

Mechanism of Action

Tirzepatide uniquely engages two incretin pathways:

GIP Receptor Activation

• Enhances insulin secretion in a glucose-dependent manner
• May improve beta-cell function
• Affects adipose tissue metabolism
• Potential role in fat oxidation

GLP-1 Receptor Activation

• Glucose-dependent insulin secretion
• Glucagon suppression
• Delayed gastric emptying
• Central appetite suppression

Synergistic Effects

The dual agonism provides:

• Greater glycemic control than GLP-1 alone
• Enhanced weight loss (possibly via GIP's effects on adipose tissue)
• Potential cardiovascular benefits (under investigation in SURPASS-CVOT)

The molecule features a C20 fatty diacid moiety enabling once-weekly dosing through extended albumin binding.

Research Summary

SURMOUNT Program (Weight Management)

SURMOUNT-1 (n=2,539): Non-diabetic adults with obesity

• 5mg: 15.0% weight loss
• 10mg: 19.5% weight loss
• 15mg: 20.9% weight loss
• Placebo: 3.1% weight loss

SURMOUNT-2 (n=938): Adults with obesity and type 2 diabetes

• 10mg: 12.8% weight loss
• 15mg: 14.7% weight loss
• Placebo: 3.2% weight loss

SURMOUNT-3 (n=579): Intensive lifestyle intervention comparison

• 15mg: 26.6% weight loss with lifestyle intervention

SURPASS Program (Diabetes)

Head-to-Head vs Semaglutide (SURPASS-2)

Pharmacokinetics

Common Protocols

Note: The following represents FDA-approved dosing schedules. This is not medical advice.

Weight Management (Zepbound)

• Week 1-4: 2.5mg once weekly
• Week 5-8: 5mg once weekly
• Week 9-12: 7.5mg once weekly (optional intermediate)
• Week 13-16: 10mg once weekly
• Week 17-20: 12.5mg once weekly (optional intermediate)
• Week 21+: 15mg once weekly (maximum)

Diabetes (Mounjaro)

• Start: 2.5mg weekly for 4 weeks
• Increase by 2.5mg every 4 weeks
• Maximum: 15mg weekly

Dose adjustments should be individualized based on tolerability and response.

Administration

Injection Sites

• Abdomen
• Thigh
• Upper arm

Injection Guidelines

• Once weekly, same day each week
• Can be given any time of day, with or without meals
• Rotate injection sites
• If dose missed, take within 4 days; if >4 days, skip and resume schedule
• Pre-filled single-dose pens (KwikPen)
• Refrigerate unused pens at 2-8°C
• Can keep at room temperature (up to 30°C) for 21 days

Side Effects

Common (>5% incidence)

• Nausea (12-18%)
• Diarrhea (12-17%)
• Vomiting (5-9%)
• Constipation (6-7%)
• Abdominal pain (5-6%)
• Decreased appetite (5-9%)
• Dyspepsia (5-8%)

GI effects are dose-dependent and typically diminish over time.

Less Common (1-5%)

• Injection site reactions
• Fatigue
• Hypoglycemia (mainly with sulfonylureas/insulin)
• Hair loss
• GERD

Serious (Rare)

• Pancreatitis (0.2%)
• Gallbladder disease
• Hypersensitivity reactions
• Acute kidney injury

Warnings

• Thyroid C-cell tumor risk (rodent studies)
• Contraindicated with personal/family history of MTC or MEN2

Interactions

Contraindications

• Personal/family history of medullary thyroid carcinoma
• Multiple Endocrine Neoplasia syndrome type 2
• Known hypersensitivity to tirzepatide

Drug Interactions

• Insulin/sulfonylureas: Increased hypoglycemia risk; dose reduction may be needed
• Oral contraceptives: Recommend non-oral backup for 4 weeks after initiation and each dose increase
• Oral medications with narrow therapeutic index: Monitor levels due to delayed gastric emptying

Precautions

• History of pancreatitis
• Severe GI disease
• Diabetic retinopathy
• Renal impairment (no dose adjustment needed but monitor)

Community Insights

The following represents aggregated reports from online communities and should not be considered medical advice or verified claims.

Commonly Reported Experiences

• Often described as having stronger appetite suppression than semaglutide
• "Sulfur burps" reported more frequently than with GLP-1 only agonists
• Many report feeling "food neutral" rather than nauseous
• Energy levels often improved alongside weight loss
• Some report better blood sugar stability than with semaglutide

Practical Tips Shared

• Slow titration crucial - some stay at lower doses longer
• High-protein diet seems to help preserve muscle
• Fiber supplements may help with constipation
• Evening dosing reported to help some with nausea

Concerns Discussed

• Insurance coverage and cost remain major barriers
• Supply shortages have been an issue
• Long-term sustainability without medication unclear
• Some report "tolerance" requiring higher doses over time

References

1. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. [PMID: 35658024]

2. Garvey WT, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2). Lancet. 2023;402(10402):613-626. [PMID: 37385278]

3. Frías JP, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515. [PMID: 34170647]

4. Rosenstock J, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1). Lancet. 2021;398(10295):143-155. [PMID: 34186022]

5. FDA Label - Mounjaro (tirzepatide) injection. Reference ID: 5008851.

6. FDA Label - Zepbound (tirzepatide) injection. 2023.