Tirzepatide

Overview

Tirzepatide is a revolutionary once-weekly injectable medication developed by Eli Lilly that became the first dual GIP/GLP-1 receptor agonist approved by the FDA. It is approved as Mounjaro for type 2 diabetes (2022) and Zepbound for obesity (2023).

In clinical trials, tirzepatide demonstrated unprecedented weight loss efficacy, with participants losing an average of 20-25% of their body weight - significantly more than any previously approved medication.

Key Characteristics

• Origin: Synthetic 39 amino acid peptide
• Classification: Dual incretin receptor agonist (GIP + GLP-1)
• FDA Status: Approved (Mounjaro, Zepbound)
• Unique Feature: First-in-class dual agonist
• Dosing: Once weekly subcutaneous injection

The Dual Agonist Advantage

Unlike semaglutide (GLP-1 only), tirzepatide activates TWO incretin receptors:

| Receptor | Tirzepatide | Semaglutide | |----------|-------------|-------------| | GIP Receptor | Yes (primary) | No | | GLP-1 Receptor | Yes | Yes | | Weight Loss | ~20-25% | ~15-17% |

Mechanism

Primary Mechanisms

1. GIP Receptor Activation

Glucose-dependent Insulinotropic Polypeptide effects:

• Enhances insulin secretion (glucose-dependent)
• May improve beta cell function
• Affects adipose tissue metabolism
• Potential CNS appetite effects
• Complements GLP-1 actions

2. GLP-1 Receptor Activation

Glucagon-Like Peptide-1 effects:

• Stimulates insulin release
• Suppresses glucagon secretion
• Slows gastric emptying
• Reduces appetite centrally
• Promotes satiety

3. Synergistic Weight Loss

The combination produces superior effects:

• Greater appetite suppression than either alone
• Enhanced metabolic effects
• Improved body composition
• Potentially better preservation of lean mass
• More significant HbA1c reduction

4. Glucose Regulation

For diabetes:

• Glucose-dependent insulin release (safer)
• Reduced glucagon when blood sugar is high
• Improved insulin sensitivity
• Beta cell protection

Research

SURMOUNT Trials (Obesity)

SURMOUNT-1 Results

In non-diabetic obesity:

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

At highest dose:

• 1 in 3 participants lost ≥25% body weight
• Average loss of ~52 lbs (23.6 kg)
• Significant improvements in all cardiometabolic markers

SURMOUNT-2 Results

In diabetic obesity:

• Similar weight loss efficacy
• Significant HbA1c reduction
• Improved cardiovascular markers

SURPASS Trials (Diabetes)

Glycemic Control

Across SURPASS trials:

• HbA1c reductions of 1.9-2.4%
• Up to 95% of patients achieved HbA1c under 7%
• Superior to semaglutide 1 mg in head-to-head
• Meaningful fasting glucose improvements

Cardiovascular Effects

Emerging Data

2025-2026 research shows:

• Significant blood pressure reduction
• Improved lipid profiles
• Reduced inflammatory markers
• Cardiovascular outcome trials ongoing

Comparison to Semaglutide

| Outcome | Tirzepatide 15mg | Semaglutide 2.4mg | |---------|------------------|-------------------| | Weight Loss | ~21% | ~15-17% | | HbA1c Reduction | ~2.0-2.4% | ~1.5-1.8% | | GI Side Effects | Similar | Similar | | Dosing | Weekly | Weekly |

Dosing

FDA-Approved Protocols

Administration Notes

Gradual Titration is Critical

• Start at 2.5 mg - this is NOT a therapeutic dose
• Increase by 2.5 mg every 4 weeks
• Slower titration reduces GI side effects
• Can pause at any dose level
• Maximum approved: 15 mg weekly

Injection Technique

• Subcutaneous injection (abdomen, thigh, or upper arm)
• Rotate injection sites
• Can be given any time of day
• Does not need to be timed with meals
• Can change injection day if needed (3+ days from last dose)

If Dose Missed

• Take as soon as possible within 4 days
• If >4 days, skip and resume regular schedule
• Do not double doses

Pen Options

Available as single-dose pens:

• 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg
• KwikPen format (Mounjaro)
• Refrigerate before first use
• Room temperature okay for up to 21 days

Pharmacokinetics

Absorption

• Subcutaneous: Slow absorption from injection site
• Peak levels: 8-72 hours
• Bioavailability: ~80%

Distribution

• Highly bound to albumin (99%)
• Volume of distribution: ~10.3 L
• Explains long half-life

Metabolism

• Proteolytic cleavage (not CYP450)
• Metabolites inactive
• No significant drug interactions

Elimination

• Half-life: ~5 days
• Enables weekly dosing
• Eliminated primarily via urine
• Steady state: 4-5 weeks

Safety

Known Side Effects

Very Common (>10%)

• Nausea (most common, improves over time)
• Diarrhea
• Decreased appetite (therapeutic effect)
• Vomiting
• Constipation
• Dyspepsia

Common (1-10%)

• Abdominal pain
• Injection site reactions
• Fatigue
• Hypoglycemia (mainly with sulfonylureas)
• GERD/reflux
• Hair loss (associated with rapid weight loss)

Serious (Rare)

• Pancreatitis (discontinue if suspected)
• Gallbladder disease
• Severe GI symptoms
• Hypersensitivity reactions

Contraindications

Absolute:

• Personal or family history of medullary thyroid carcinoma (MTC)
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Hypersensitivity to tirzepatide

Relative/Use with Caution:

• History of pancreatitis
• Severe gastroparesis
• Severe GI disease
• Retinopathy (rapid glucose changes may worsen)
• Pregnancy/breastfeeding

Drug Interactions

Adjust timing with:

• Oral medications (slowed absorption due to delayed gastric emptying)
• Particularly important for birth control pills

Monitor closely with:

• Insulin (reduce dose to prevent hypoglycemia)
• Sulfonylureas (reduce dose to prevent hypoglycemia)

Managing Side Effects

Nausea Strategies

• Eat smaller meals
• Avoid high-fat foods
• Stay hydrated
• Ginger or peppermint may help
• Slower titration if severe

Constipation

• Increase fiber intake
• Adequate hydration
• Regular physical activity
• OTC remedies if needed

Hair Loss

• Related to rapid weight loss, not the drug directly
• Ensure adequate protein intake
• Consider biotin supplementation
• Usually temporary

Monitoring

Before Starting

• HbA1c and fasting glucose
• Renal function
• Lipid panel
• Thyroid function (TSH)
• Personal/family history of MTC

During Treatment

• Weight and BMI
• HbA1c (every 3-6 months)
• Blood pressure
• Symptoms of pancreatitis
• GI tolerability

If Diabetic

• Blood glucose monitoring
• Adjust other diabetes medications
• Watch for hypoglycemia

Regulatory

Current Status

| Region | Status | |--------|--------| | United States | FDA-approved (Mounjaro for T2DM, Zepbound for obesity) | | European Union | EMA-approved | | WADA | Not prohibited | | Insurance | Coverage varies; prior authorization often required |

Legal Considerations

• Prescription medication
• FDA-approved for specific indications
• Off-label use common for weight loss without diabetes
• Compounded versions exist (unregulated)
• Insurance may require documented obesity/diabetes

Clinical Outlook

Tirzepatide represents a major advancement:

• First dual GIP/GLP-1 agonist
• Best-in-class weight loss efficacy
• Strong diabetes control
• Cardiovascular outcome trials ongoing
• Oral formulation in development
• May expand to other indications (NASH, heart failure)

References