Tirzepatide

Tirzepatide is an imbalanced dual agonist that primarily activates GIP receptors with secondary GLP-1R agonism. GIP receptor activation on pancreatic beta cells enhances glucose-dependent insulin secretion and may improve beta-cell function. GIP also acts on adipocytes to promote lipid storage and improve insulin sensitivity, and on hypothalamic neurons to modulate appetite. GLP-1R activation provides complementary appetite suppression, delayed gastric emptying, and glucose-dependent insulin secretion. The dual pathway engagement is hypothesized to produce additive or synergistic effects on metabolism beyond what either receptor alone achieves. A C-20 fatty diacid moiety extends the half-life to approximately 5 days, enabling weekly dosing.

The SURPASS program (5 Phase 3 trials in T2D) demonstrated HbA1c reductions of up to 2.46% and weight loss of up to 12.4 kg. SURPASS-2 showed superiority over semaglutide 1 mg for both HbA1c and weight endpoints. SURMOUNT-1 (n=2,539, obesity without T2D) showed mean weight loss of 15.0% (5 mg), 19.5% (10 mg), and 20.9% (15 mg) vs 3.1% placebo at 72 weeks. Over one-third of participants on the 15 mg dose lost 25% or more of body weight. SURMOUNT-2 (obesity with T2D) showed up to 14.7% weight loss. SURMOUNT-OSA demonstrated significant reduction in obstructive sleep apnea severity. A cardiovascular outcomes trial (SURPASS-CVOT) is ongoing. Limitations include the lack of completed cardiovascular outcomes data and comparisons against semaglutide 1 mg rather than the 2.4 mg weight management dose.

Mounjaro (tirzepatide 2.5, 5, 7.5, 10, 12.5, 15 mg injection) was FDA-approved in May 2022 for T2D. Zepbound (tirzepatide 2.5, 5, 7.5, 10, 12.5, 15 mg injection) was approved in November 2023 for chronic weight management in adults with obesity (BMI 30 or above) or overweight (BMI 27 or above) with at least one weight-related comorbidity. Manufactured by Eli Lilly and Company. Like semaglutide, tirzepatide products have experienced supply constraints. Cardiovascular outcomes trial data are pending.

Monitor HbA1c, fasting glucose, and body weight regularly. Titrate slowly: start at 2.5 mg weekly for 4 weeks, then 5 mg, with further increases in 2.5 mg increments at minimum 4-week intervals. Assess GI tolerability at each dose level before escalating. Monitor for signs and symptoms of pancreatitis (persistent severe abdominal pain). Thyroid monitoring per GLP-1RA class guidance. Monitor for gallbladder-related events, especially with rapid weight loss. Heart rate monitoring, as modest increases are observed.

These are general considerations for clinical awareness and do not constitute prescriptive monitoring recommendations for any individual patient.

Store refrigerated at 2 to 8 degrees C in original carton to protect from light. May be stored at room temperature (up to 30 degrees C) for up to 21 days if needed. Do not freeze. Discard if frozen. Each single-dose pen is for one-time use only. The pen should be inspected visually for particulate matter and discoloration prior to administration.

1. 1

   RCT

   Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1)

   Jastreboff AM, Aronne LJ, Ahmad NN, et al. (2022). New England Journal of Medicine

   Key findings: Phase 3 RCT in 2,539 adults with obesity. Mean weight reductions of 15.0% (5 mg), 19.5% (10 mg), and 20.9% (15 mg) vs 3.1% placebo at 72 weeks. Over one-third of participants receiving 15 mg lost 25% or more of body weight.

   Limitations: 72-week duration. Predominantly White participants. Lifestyle intervention in all arms.

   View source
2. 2

   RCT

   Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2)

   Frias JP, Davies MJ, Rosenstock J, et al. (2021). New England Journal of Medicine

   Key findings: Head-to-head comparison in 1,879 patients with T2D. All tirzepatide doses (5, 10, 15 mg) were noninferior and superior to semaglutide 1 mg for HbA1c reduction (up to 2.46% vs 1.86%). Weight loss was significantly greater with tirzepatide (up to 11.2 kg vs 5.7 kg).

   Limitations: Compared against semaglutide 1 mg, not the higher 2.4 mg dose. Open-label design.

   View source
3. 3

   FDA label

   MOUNJARO (tirzepatide) injection Prescribing Information

   Eli Lilly and Company. (2024). FDA

   Key findings: Full prescribing information including boxed warning for thyroid C-cell tumors, indications, dosing (2.5 mg titration to 5, 10, or 15 mg weekly), contraindications, and clinical pharmacology.

   Limitations: Label information; not primary research.

   View source
4. 4

   RCT

   Tirzepatide versus Insulin Glargine in Type 2 Diabetes (SURPASS-4)

   Del Prato S, Kahn SE, Pavo I, et al. (2021). Lancet

   Key findings: 52-week trial in 2,002 T2D patients with high CV risk. All tirzepatide doses were superior to insulin glargine for HbA1c reduction with weight loss rather than weight gain.

   Limitations: Open-label. Insulin glargine titrated to fasting glucose target; some may argue dosing was conservative.

   View source
5. 5

   RCT

   Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity (SURMOUNT-OSA)

   Malhotra A, Grunstein RR, Fietze I, et al. (2024). New England Journal of Medicine

   Key findings: Tirzepatide significantly reduced AHI (apnea-hypopnea index) in adults with moderate-to-severe obstructive sleep apnea and obesity, with some patients achieving remission of OSA.

   Limitations: 52-week duration. PAP therapy use varied between groups.

   View source