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Mounjaro ® (tirzepatide) injection
2.5 mg/5 mg/7.5 mg/10 mg/12.5 mg/15 mg
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What is Mounjaro® (tirzepatide) and how does its mechanism of action improve glycemic control in people with type 2 diabetes?
Tirzepatide is a long-acting GIP and GLP-1 receptor agonist for T2D that improves glycemic control by enhancing insulin secretion and sensitivity, improving beta-cell function, reducing glucagon, delaying gastric emptying, and decreasing food intake.
See important safety information, including boxed warning, in the attached prescribing information.
Content Overview
What Is the Mechanism of Action of Tirzepatide in Type 2 Diabetes?
- Enhanced Insulin Secretion with Tirzepatide
- Increased Insulin Sensitivity with Tirzepatide
- Beta-Cell Function with Tirzepatide
- Reduced Glucagon Concentrations with Tirzepatide
- Delayed Gastric Emptying with Tirzepatide
- Decreased Food Intake and Appetite with Tirzepatide
- Tirzepatide Molecular Description and Structure
- Tirzepatide Preclinical Studies on GIP and GLP-1 Receptor Activity
- How Does Tirzepatide Affect the Hypoglycemia Response in Type 2 Diabetes?
What Is the Mechanism of Action of Tirzepatide in Type 2 Diabetes?
Dual GIP and GLP-1 Receptor Agonism
Tirzepatide is a long-acting glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Tirzepatide is indicated for the treatment of adults and pediatric patients 10 years of age and older with type 2 diabetes (T2D) as an adjunct to diet and exercise.1
Tirzepatide lowers fasting and postprandial glucose concentration in patients with T2D. Tirzepatide improves glycemic control by
- enhancing the first- and second-phase insulin secretion
- increasing insulin sensitivity
- improving beta-cell function
- reducing fasting and postprandial glucagon concentrations
- transiently delaying gastric emptying, and
- decreasing food intake.1-3
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Enhanced Insulin Secretion with Tirzepatide
Tirzepatide increased first- and second-phase insulin secretion responses assessed by hyperglycemic clamp.2 As presented in Mean Insulin Concentration Over Time During Hyperglycemic Clamp, in a hyperglycemic clamp study, the first-phase insulin secretion rate (0-8 minutes) and second-phase insulin secretion rate (20-120 minutes) were increased with tirzepatide 15 mg treatment compared with placebo and semaglutide 1 mg; thus affecting the total insulin secretion rate.2
Figure 1 description: During the hyperglycemic clamp procedure, the first-phase insulin secretion rate (0-8 minutes) and second-phase insulin secretion rate (20-120 minutes) were increased with tirzepatide 15 mg treatment compared with placebo and semaglutide 1 mg.
Data are group averages. The red arrow indicates administration of a 5 g intravenous arginine bolus at 120 minutes.
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Increased Insulin Sensitivity with Tirzepatide
In a hyperinsulinemic euglycemic clamp study, tirzepatide 15 mg showed a relative increase of 63% from baseline in insulin sensitivity at 28 weeks as assessed by the clamp-derived M-value and in the context of a weight loss of 11.2 kg. In the same study, semaglutide 1 mg showed a relative increase of 35% from baseline in insulin sensitivity, along with a weight loss of 6.9 kg.2
The mechanism of action for the tirzepatide’s effect on improved insulin sensitivity is not clearly defined; however, in a phase 2b study, many markers of insulin sensitivity changed including
- homeostatic model assessment of insulin resistance (HOMA2-IR)
- fasting insulin
- adiponectin
- insulin-like growth factor binding protein (IGFBP) 1, and
- IGFBP-2.3
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Beta-Cell Function with Tirzepatide
Tirzepatide 15 mg showed an approximate 6-fold increase from baseline at 28 weeks in the clamp disposition index (cDI), a measure of beta-cell function. This was due to changes in both insulin secretion and insulin sensitivity. Tirzepatide's effect on beta-cell function differed from that of both semaglutide 1 mg and placebo.2
Tirzepatide has additionally shown changes in homeostatic model assessment (HOMA) 2-B, an indirect assessment of beta-cell health calculated with either fasting insulin or fasting C-peptide, indicating changes in beta-cell function in adults with T2D treated with tirzepatide 5 mg, 10 mg, and 15 mg. These changes in beta-cell function with tirzepatide differed from those with the GLP-1 receptor agonist dulaglutide 1.5 mg and placebo.3
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Reduced Glucagon Concentrations with Tirzepatide
Tirzepatide reduces fasting and postprandial glucagon levels in a glucose-dependent manner. Tirzepatide 15 mg reduced fasting glucagon concentration by 28% and glucagon area under the curve (AUC) after a mixed meal by 43%, compared with no change for placebo after 28 weeks of treatment.2,4
Reduced glucagon secretion with tirzepatide was observed during mixed meal tolerance testing. Fasting and meal-stimulated glucagon concentrations were lower with tirzepatide 15 mg compared with placebo (p<.0001 for both).2
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Delayed Gastric Emptying with Tirzepatide
Tirzepatide delays gastric emptying. The delay is largest after the first dose and this effect diminishes over time. Tirzepatide slows postmeal glucose absorption, reducing postprandial glucose.1
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Decreased Food Intake and Appetite with Tirzepatide
Tirzepatide decreases food intake.4
In a phase 1 study in adults with T2D, treatment with tirzepatide 15 mg was associated with a change in body weight after 28 weeks compared with placebo and semaglutide 1 mg. This was largely driven by changes in
- fat mass,
- appetite, and
- energy intake.5
During this study,
- body composition was assessed by whole body densitometry to estimate the amount of fat mass
- appetite was assessed using a fasting visual analog scale assessing hunger, satiety, fullness and prospective food consumption, and
- energy intake was assessed using buffet-style lunch and measuring grams of consumed macronutrients.5,6
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Tirzepatide Molecular Description and Structure
Tirzepatide is an amino acid sequence with a C20 fatty diacid that enables albumin binding and prolongs the half-life. Tirzepatide selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1.1 Preclinical studies support that it binds at the GLP-1 receptor with lower affinity than endogenous GLP-1; however, it binds at the GIP receptor with equal affinity to endogenous GIP.7,8
Tirzepatide is based on the GIP sequence and contains
- aminoisobutyric acid, Aib) in positions 2 and 13
- a C-terminal amide, and
- Lys residue at position 20 that is attached to a 1,20-eicosanedioic acid via a linker (Tirzepatide Chemical Structure).1,8
The molecular weight of tirzepatide is 4813.53 Da, and the empirical formula is C225H348N48O68. The elimination half-life is approximately 5 days, enabling once-weekly dosing.1
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Tirzepatide Preclinical Studies on GIP and GLP-1 Receptor Activity
The contribution of agonism at the GLP-1 and GIP receptors by tirzepatide was evaluated in preclinical studies in isolated human pancreatic cells and animal models.7-9
In isolated human islets, GLP-1 receptor antagonism alone led to variable results between donors and did not significantly reduce tirzepatide-stimulated insulin secretion. However, antagonizing the GIP receptor consistently reduced insulin secretion across all 8 sets of human islets.9 When both GIP and GLP-1 receptors were antagonized, the insulinotropic effect was similar to that of GIP receptor antagonism (Effect of Tirzepatide on Insulin Secretion During GLP-1 and GIP Receptor Antagonism in Isolated Human Islets).9
Tirzepatide showed activity at both the GIP and GLP-1 receptors in isolated human islets; however, the relative effect at each receptor varied between donors.9
Figure 2 description: In isolated human islets, glucagon-like peptide-1 (GLP-1) receptor antagonism alone led to variable results between donors and did not meaningfully alter tirzepatide-stimulated insulin secretion. However, antagonizing the glucose-dependent insulinotropic polypeptide (GIP) receptor was associated with lower insulin secretion across all 8 sets of human islets. When both receptors were antagonized, the insulinotropic effect was similar to that of GIP receptor antagonism.
Abbreviations: Ant = antagonist; AUC = area under the curve; GIP = glucose-dependent insulinotropic polypeptide; GIPR = glucose-dependent insulinotropic polypeptide receptor; GLP-1= glucagon-like peptide-1; GLP-1R = glucagon-like peptide-1 receptor.
In animal studies, blood sugar values were lower following tirzepatide administartion in the absence of GLP-1 receptor. In obese insulin-resistant mice lacking the GLP-1 receptor, tirzepatide also resulted in a change in glycemic control. This indicates that tirzepatide, acting through the GIP receptor, is sufficient for glycemic control.7
A long-acting, selective GIP receptor agonist was associated with decreased hyperglycemia when given to mice lacking the GLP-1 receptor in a glucose challenge test.7
Blood sugar values were also lower following tirzepatide administration in the absence of GIP receptor as shown in GIP receptor null mice.8
Taken together, these findings suggest that tirzepatide, acting through the GLP-1 and GIP receptors, contributes to glycemic control. These preclinical observations are not currently possible to confirm in humans given the available pharmacological tools.7
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How Does Tirzepatide Affect the Hypoglycemia Response in Type 2 Diabetes?
Tirzepatide reduces fasting and postprandial glucagon levels in adults with T2D, and its effects on the counter-regulatory response to hypoglycemia was investigated.2,10
In a hypoglycemic clamp study in patients with T2D, response of glucagon to hypoglycemia was maintained with tirzepatide 15 mg and did not differ compared with placebo as presented in Mean Changes in Glucagon During Induced Hypoglycemia.10
In addition, response of other counter-regulatory hormones, including growth hormone and adrenaline, did not differ between treatments, while increases in cortisol and noradrenaline responses were attenuated with tirzepatide 15 mg compared with placebo. During hypoglycemia, insulin secretion was reduced to a greater extent with tirzepatide 15 mg compared with placebo.10
Figure 2 description: During the hypoglycemic clamp procedure, mean changes in glucagon did not differ in patients with type 2 diabetes treated with tirzepatide 15 mg compared with those receiving placebo.
Abbreviations: LSM = least squares mean; PBO = placebo; TZP = tirzepatide.
a At nadir, n=32 for placebo. Data were analyzed using a linear mixed-effects model with treatment, treatment period, and treatment sequence as fixed effects and patient as a random effect, using a restricted maximum likelihood method.
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Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Mounjaro [package insert]. Indianapolis, IN: Eli Lilly and Company; 2026.
2Heise T, Mari A, DeVries JH, et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. 2022;10(6):418-429. https://doi.org/10.1016/S2213-8587(22)00085-7
3Thomas MK, Nikooienejad A, Bray R, et al. Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes. J Clin Endocrinol Metab. 2021;106(2):388-396. https://doi.org/10.1210/clinem/dgaa863
4Data on file, Eli Lilly and Company and/or one of its subsidiaries.
5Heise T, DeVries JH, Urva S, et al. Tirzepatide reduces appetite, energy intake, and fat mass in people with type 2 diabetes. Diabetes Care. 2023;46(5):998-1004. https://doi.org/10.2337/dc22-1710
6Heise T, DeVries JH, Urva S, et al. Tirzepatide reduces appetite, energy intake, and fat mass in people with T2D. Abstract presented at: American Diabetes Association; June 3-7, 2022; New Orleans, United States.
7Samms RJ, Christe ME, Collins KAL, et al. GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice. J Clin Invest. 2021;131(12):e146353. https://doi.org/10.1172/JCI146353
8Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3-14. https://doi.org/10.1016/j.molmet.2018.09.009
9El K, Douros JD, Willard FS, et al. The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab. 2023;5(6):945-954. https://doi.org/10.1038/s42255-023-00811-0
10Pieber TR, Svehlikova E, Urva S, et al. Effect of tirzepatide on the counter-regulatory response to hypoglycemia during a hypoglycemic clamp in people with type 2 diabetes. Abstract presented at: 83rd Scientific Session of the American Diabetes Association; June 23-26, 2023; San Diego, CA, USA.
Date of Last Review: July 16, 2026