Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands
Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins
ATC code: A10BX16
Tirzepatide is a long acting dual GIP and GLP-1 receptor agonist. Both receptors are present on the pancreatic α and β endocrine cells, brain, heart, vasculature, immune cells (leukocytes), gut and kidney. GIP receptors are also present on adipocytes.
Tirzepatide is highly selective to human GIP and GLP-1 receptors. Tirzepatide has high affinity to both the GIP and GLP-1 receptors. The activity of tirzepatide on the GIP receptor is similar to native GIP hormone. The activity of tirzepatide on the GLP-1 receptor is lower compared to native GLP-1 hormone.
Tirzepatide improves glycaemic control by lowering fasting and postprandial glucose concentrations in patients with type 2 diabetes through several mechanisms.
Tirzepatide increases pancreatic β-cell glucose sensitivity. It enhances first- and second-phase insulin secretion in a glucose dependent manner.
In a hyperglycaemic clamp study in patients with type 2 diabetes, tirzepatide was compared to placebo and the selective GLP-1 receptor agonist semaglutide 1 mg for insulin secretion. Tirzepatide 15 mg enhanced the first and second-phase insulin secretion rate by 466% and 302% from baseline, respectively. There was no change in first- and second-phase insulin secretion rate for placebo.
Tirzepatide improves insulin sensitivity.
Tirzepatide 15 mg improved whole body insulin sensitivity by 63%, as measured by M-value, a measure of glucose tissue uptake using hyperinsulinemic euglycaemic clamp. The M-value was unchanged for placebo.
Tirzepatide lowers body weight in patients with type 2 diabetes, which may contribute to improvement in insulin sensitivity. Reduced food intake with tirzepatide contributes to body weight loss. The body weight reduction is mostly due to reduced fat mass.
Tirzepatide reduced the fasting and postprandial glucagon concentrations in a glucose dependent manner. Tirzepatide 15 mg reduced fasting glucagon concentration by 28% and glucagon AUC after a mixed meal by 43%, compared with no change for placebo.
Tirzepatide delays gastric emptying which may slow post meal glucose absorption and can lead to a beneficial effect on postprandial glycaemia. Tirzepatide induced delay in gastric emptying diminishes over time.
The safety and efficacy of tirzepatide were evaluated in five global randomised, controlled, phase 3 studies (SURPASS 1-5) assessing glycaemic control as the primary objective. The studies involved 6 263 treated patients with type 2 diabetes (4 199 treated with tirzepatide). The secondary objectives included body weight, fasting serum glucose (FSG) and proportion of patients reaching target HbA1c. All five phase 3 studies assessed tirzepatide 5 mg, 10 mg and 15 mg. All patients treated with tirzepatide started with 2.5 mg for 4 weeks. Then the dose of tirzepatide was increased by 2.5 mg every 4 weeks until they reached their assigned dose.
Across all studies, treatment with tirzepatide demonstrated sustained, statistically significant and clinically meaningful reductions from baseline in HbA1c as the primary objective compared to either placebo or active control treatment (semaglutide, insulin degludec and insulin glargine) for up to 1 year. In 1 study these effects were sustained for up to 2 years. Statistically significant and clinically meaningful reductions from baseline in body weight were also demonstrated. Results from the phase 3 studies are presented below based on the on-treatment data without rescue therapy in the modified intent-to-treat (mITT) population consisting of all randomly assigned patients who were exposed to at least 1 dose of study treatment, excluding patients discontinuing study treatment due to inadvertent enrolment.
In a 40 week double blind placebo-controlled study, 478 patients with inadequate glycaemic control with diet and exercise, were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or placebo. Patients had a mean age of 54 years and 52% were men. At baseline the patients had a mean duration of diabetes of 5 years and the mean BMI was 32 kg/m².
Table 2. SURPASS 1: Results at week 40:
| Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Placebo | ||
|---|---|---|---|---|---|
| mITT population (n) | 121 | 121 | 120 | 113 | |
| HbA1c (%) | Baseline (mean) | 7.97 | 7.88 | 7.88 | 8.08 |
| Change from baseline | -1.87## | -1.89## | -2.07## | +0.04 | |
| Difference from placebo [95% CI] | -1.91** [-2.18, -1.63] | -1.93** [-2.21, -1.65] | -2.11** [-2.39, -1.83] | - | |
| HbA1c (mmol/mol) | Baseline (mean) | 63.6 | 62.6 | 62.6 | 64.8 |
| Change from baseline | -20.4## | -20.7## | -22.7## | +0.4 | |
| Difference from placebo [95% CI] | -20.8** [-23.9, -17.8] | -21.1** [-24.1, -18.0] | -23.1** [-26.2, -20.0] | - | |
| Patients (%) achieving HbA1c | <7% | 86.8** | 91.5** | 87.9** | 19.6 |
| ≤6.5% | 81.8†† | 81.4†† | 86.2†† | 9.8 | |
| <5.7% | 33.9** | 30.5** | 51.7** | 0.9 | |
| FSG (mmol/L) | Baseline (mean) | 8.5 | 8.5 | 8.6 | 8.6 |
| Change from baseline | -2.4## | -2.6## | -2.7## | +0.7# | |
| Difference from placebo [95% CI] | -3.13** [-3.71, -2.56] | -3.26** [-3.84, -2.69] | -3.45** [-4.04, -2.86] | - | |
| FSG (mg/dL) | Baseline (mean) | 153.7 | 152.6 | 154.6 | 155.2 |
| Change from baseline | -43.6## | -45.9## | -49.3## | +12.9# | |
| Difference from placebo [95% CI] | -56.5** [-66.8, -46.1] | -58.8** [-69.2, -48.4] | -62.1** [-72.7, -51.5] | - | |
| Body weight (kg) | Baseline (mean) | 87.0 | 85.7 | 85.9 | 84.4 |
| Change from baseline | -7.0## | -7.8## | -9.5## | -0.7 | |
| Difference from placebo [95% CI] | -6.3** [-7.8, -4.7] | -7.1** [-8.6, -5.5] | -8.8** [-10.3, -7.2] | - | |
| Patients (%) achieving weight loss | ≥5% | 66.9†† | 78.0†† | 76.7†† | 14.3 |
| ≥10% | 30.6†† | 39.8†† | 47.4†† | 0.9 | |
| ≥15% | 13.2† | 17.0† | 26.7† | 0.0 | |
* p<0.05, **p<0.001 for superiority, adjusted for multiplicity.
† p<0.05, ††p<0.001 compared to placebo, not adjusted for multiplicity.
# p<0.05, ##p<0.001 compared to baseline, not adjusted for multiplicity.
Figure 1. Mean HbA1c (%) and mean body weight (kg) from baseline to week 40:
In a 40 week active-controlled open-label study, (double-blind with respect to tirzepatide dose assignment) 1 879 patients were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or semaglutide 1 mg once weekly, all in combination with metformin. Patients had a mean age of 57 years and 47% were men. At baseline the patients had a mean duration of diabetes of 9 years and the mean BMI was 34 kg/m².
Table 3. SURPASS 2: Results at week 40:
| Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Semaglutide 1 mg | ||
|---|---|---|---|---|---|
| mITT population (n) | 470 | 469 | 469 | 468 | |
| HbA1c (%) | Baseline (mean) | 8.33 | 8.31 | 8.25 | 8.24 |
| Change from baseline | -2.09## | -2.37## | -2.46## | -1.86## | |
| Difference from semaglutide [95% CI] | -0.23** [-0.36, -0.10] | -0.51** [-0.64, -0.38] | -0.60** [-0.73, -0.47] | - | |
| HbA1c (mmol/mol) | Baseline (mean) | 67.5 | 67.3 | 66.7 | 66.6 |
| Change from baseline | -22.8## | -25.9## | -26.9## | -20.3## | |
| Difference from semaglutide [95% CI] | -2.5** [-3.9, -1.1] | -5.6** [-7.0, -4.1] | -6.6** [-8.0, -5.1] | N/A | |
| Patients (%) achieving HbA1c | <7% | 85.5* | 88.9** | 92.2** | 81.1 |
| ≤6.5% | 74.0† | 82.1†† | 87.1†† | 66.2 | |
| <5.7% | 29.3†† | 44.7** | 50.9** | 19.7 | |
| FSG (mmol/L) | Baseline (mean) | 9.67 | 9.69 | 9.56 | 9.49 |
| Change from baseline | -3.11## | -3.42## | -3.52## | -2.70## | |
| Difference from semaglutide [95% CI] | -0.41† [-0.65, -0.16] | -0.72†† [-0.97, -0.48] | -0.82†† [-1.06, -0.57] | - | |
| FSG (mg/dL) | Baseline (mean) | 174.2 | 174.6 | 172.3 | 170.9 |
| Change from baseline | -56.0## | -61.6## | -63.4## | -48.6## | |
| Difference from semaglutide [95% CI] | -7.3† [-11.7, -3.0] | -13.0†† [-17.4, -8.6] | -14.7†† [-19.1, -10.3] | - | |
| Body weight (kg) | Baseline (mean) | 92.6 | 94.9 | 93.9 | 93.8 |
| Change from baseline | -7.8## | -10.3## | -12.4## | -6.2## | |
| Difference from semaglutide [95% CI] | -1.7** [-2.6, -0.7] | -4.1** [-5.0, -3.2] | -6.2** [-7.1, -5.3] | - | |
| Patients (%) achieving weight loss | ≥5% | 68.6† | 82.4†† | 86.2†† | 58.4 |
| ≥10% | 35.8†† | 52.9†† | 64.9†† | 25.3 | |
| ≥15% | 15.2† | 27.7†† | 39.9†† | 8.7 | |
* p<0.05, **p<0.001 for superiority, adjusted for multiplicity.
† p<0.05, ††p<0.001 compared to semaglutide 1 mg, not adjusted for multiplicity.
# p<0.05, ##p<0.001 compared to baseline, not adjusted for multiplicity
Figure 2. Mean HbA1c (%) and mean body weight (kg) from baseline to week 40:
In a 52 week active-controlled open-label study, 1 444 patients were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or insulin degludec, all in combination with metformin with or without a SGLT2i. 32% of patients were using SGLT2i at baseline. At baseline the patients had a mean duration of diabetes of 8 years, a mean BMI of 34 kg/m², a mean age of 57 years and 56% were men.
Patients treated with insulin degludec started at a dose of 10 U/day which was adjusted using an algorithm for a target fasting blood glucose of <5 mmol/L. The mean dose of insulin degludec at week 52 was 49 units/day.
Table 4. SURPASS 3: Results at week 52:
| Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Titrated insulin degludec | ||
|---|---|---|---|---|---|
| mITT population (n) | 358 | 360 | 358 | 359 | |
| HbA1c (%) | Baseline (mean) | 8.17 | 8.19 | 8.21 | 8.13 |
| Change from baseline | -1.93## | -2.20## | -2.37## | -1.34## | |
| Difference from insulin degludec [95% CI] | -0.59** [-0.73, -0.45] | -0.86** [-1.00, -0.72] | -1.04** [-1.17, -0.90] | - | |
| HbA1c (mmol/mol) | Baseline (mean) | 65.8 | 66.0 | 66.3 | 65.4 |
| Change from baseline | -21.1## | -24.0## | -26.0## | -14.6## | |
| Difference from insulin degludec [95% CI] | -6.4** [-7.9, -4.9] | -9.4** [-10.9, -7.9] | -11.3** [-12.8, -9.8] | - | |
| Patients (%) achieving HbA1c | <7% | 82.4** | 89.7** | 92.6** | 61.3 |
| ≤6.5% | 71.4†† | 80.3†† | 85.3†† | 44.4 | |
| <5.7% | 25.8†† | 38.6†† | 48.4†† | 5.4 | |
| FSG (mmol/L) | Baseline (mean) | 9.54 | 9.48 | 9.35 | 9.24 |
| Change from baseline | -2.68## | -3.04## | -3.29## | -3.09## | |
| Difference from insulin degludec [95% CI] | 0.41† [0.14, 0.69] | 0.05 [-0.24, 0.33] | -0.20 [-0.48, 0.08] | - | |
| FSG (mg/dL) | Baseline (mean) | 171.8 | 170.7 | 168.4 | 166.4 |
| Change from baseline | -48.2## | -54.8## | -59.2## | -55.7## | |
| Difference from insulin degludec [95% CI] | 7.5† [2.4, 12.5] | 0.8 [-4.3, 5.9] | -3.6 [-8.7, 1.5] | - | |
| Body weight (kg) | Baseline (mean) | 94.5 | 94.3 | 94.9 | 94.2 |
| Change from baseline | -7.5## | -10.7## | -12.9## | +2.3## | |
| Difference from insulin degludec [95% CI] | -9.8** [-10.8, -8.8] | -13.0** [-14.0, -11.9] | -15.2** [-16.2, -14.2] | - | |
| Patients (%) achieving weight loss | ≥5% | 66.0†† | 83.7†† | 87.8†† | 6.3 |
| ≥10% | 37.4†† | 55.7†† | 69.4†† | 2.9 | |
| ≥15% | 12.5†† | 28.3†† | 42.5†† | 0.0 | |
* p<0.05, **p<0.001 for superiority, adjusted for multiplicity.
† p<0.05, ††p<0.001 compared to insulin degludec, not adjusted for multiplicity.
# p<0.05, ##p<0.001 compared to baseline, not adjusted for multiplicity
Figure 3. Mean HbA1c (%) and mean body weight (kg) from baseline to week 52:
In an active-controlled open-label study of up to 104 weeks (primary endpoint at 52 weeks), 2 002 patients with type 2 diabetes and increased cardiovascular risk were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or insulin glargine once daily on a background of metformin (95%) and/or sulphonylureas (54%) and/or SGLT2i (25%). At baseline the patients had a mean duration of diabetes of 12 years, a mean BMI of 33 kg/m², a mean age of 64 years and 63% were men. Patient treated with insulin glargine started at a dose of 10 U/day which was adjusted using an algorithm with a fasting blood glucose target of <5.6 mmol/L. The mean dose of insulin glargine at week 52 was 44 units/day.
Table 5. SURPASS 4: Results at week 52:
| Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Titrated insulin glargine | ||
|---|---|---|---|---|---|
| mITT population (n) | 328 | 326 | 337 | 998 | |
| 52 weeks | |||||
| HbA1c (%) | Baseline (mean) | 8.52 | 8.60 | 8.52 | 8.51 |
| Change from baseline | -2.24## | -2.43## | -2.58## | -1.44## | |
| Difference from insulin glargine [95% CI] | -0.80** [-0.92, -0.68] | -0.99** [-1.11, -0.87] | -1.14** [-1.26, -1.02] | - | |
| HbA1c (mmol/mol) | Baseline (mean) | 69.6 | 70.5 | 69.6 | 69.5 |
| Change from baseline | -24.5## | -26.6## | -28.2## | -15.7## | |
| Difference from insulin glargine [95% CI] | -8.8** [-10.1, -7.4] | -10.9** [-12.3, -9.6] | -12.5** [-13.8, -11.2] | - | |
| Patients (%) achieving HbA1c | <7% | 81.0** | 88.2** | 90.7** | 50.7 |
| ≤6.5% | 66.0†† | 76.0†† | 81.1†† | 31.7 | |
| <5.7% | 23.0†† | 32.7†† | 43.1†† | 3.4 | |
| FSG (mmol/L) | Baseline (mean) | 9.57 | 9.75 | 9.67 | 9.37 |
| Change from baseline | -2.80## | -3.06## | -3.29## | -2.84## | |
| Difference from insulin glargine [95% CI] | 0.04 [-0.22, 0.30] | -0.21 [-0.48, 0.05] | -0.44†† [-0.71, -0.18] | - | |
| FSG (mg/dL) | Baseline (mean) | 172.3 | 175.7 | 174.2 | 168.7 |
| Change from baseline | -50.4## | -54.9## | -59.3## | -51.4## | |
| Difference from insulin glargine [95% CI] | 1.0 [-3.7, 5.7] | -3.6 [-8.2, 1.1] | -8.0†† [-12.6, -3.4] | - | |
| Body weight (kg) | Baseline (mean) | 90.3 | 90.7 | 90.0 | 90.3 |
| Change from baseline | -7.1## | -9.5## | -11.7## | +1.9## | |
| Difference from insulin glargine [95% CI] | -9.0** [-9.8, -8.3] | -11.4** [-12.1, -10.6] | -13.5** [-14.3, -12.8] | - | |
| Patients (%) achieving weight loss | ≥5% | 62.9†† | 77.6†† | 85.3†† | 8.0 |
| ≥10% | 35.9†† | 53.0†† | 65.6†† | 1.5 | |
| ≥15% | 13.8†† | 24.0†† | 36.5†† | 0.5 | |
* p<0.05, **p<0.001 for superiority, adjusted for multiplicity.
† p<0.05, ††p<0.001 compared to insulin glargine, not adjusted for multiplicity.
# p<0.05, ##p<0.001 compared to baseline, not adjusted for multiplicity.
Figure 4. Mean HbA1c (%) and mean body weight (kg) from baseline to week 52:
In a 40 week double-blind placebo-controlled study, 475 patients with inadequate glycaemic control using insulin glargine with or without metformin were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or placebo. Insulin glargine doses were adjusted utilizing an algorithm with a fasting blood glucose target of <5.6 mmol/L. At baseline the patients had a mean duration of diabetes of 13 years, a mean BMI of 33 kg/m², a mean age of 61 years and 56% were men. The overall estimated median dose of insulin glargine at baseline was 34 units/day. The median dose of insulin glargine at week 40 was 38, 36, 29 and 59 units/day for tirzepatide 5 mg, 10 mg, 15 mg and placebo respectively.
Table 6. SURPASS 5: Results at week 40:
| Tirzepatide 5 mg | Tirzepatide 10 mg | Tirzepatide 15 mg | Placebo | ||
|---|---|---|---|---|---|
| mITT population (n) | 116 | 118 | 118 | 119 | |
| HbA1c (%) | Baseline (mean) | 8.29 | 8.34 | 8.22 | 8.39 |
| Change from baseline | -2.23## | -2.59## | -2.59## | -0.93## | |
| Difference from placebo [95% CI] | -1.30** [-1.52, -1.07] | -1.66** [-1.88, -1.43] | -1.65** [-1.88, -1.43] | - | |
| HbA1c (mmol/mol) | Baseline (mean) | 67.1 | 67.7 | 66.4 | 68.2 |
| Change from baseline | -24.4## | -28.3## | -28.3## | -10.2## | |
| Difference from placebo [95% CI] | -14.2** [-16.6, -11.7] | -18.1** [-20.6, -15.7] | -18.1** [-20.5, -15.6] | - | |
| Patients (%) achieving HbA1c | <7% | 93.0** | 97.4** | 94.0** | 33.9 |
| ≤6.5% | 80.0†† | 94.7†† | 92.3†† | 17.0 | |
| <5.7% | 26.1†† | 47.8†† | 62.4†† | 2.5 | |
| FSG (mmol/L) | Baseline (mean) | 9.00 | 9.04 | 8.91 | 9.13 |
| Change from baseline | -3.41## | -3.77## | -3.76## | -2.16## | |
| Difference from placebo [95% CI] | -1.25** [-1.64, -0.86] | -1.61** [-2.00, -1.22] | -1.60** [-1.99, -1.20] | - | |
| FSG (mg/dL) | Baseline (mean) | 162.2 | 162.9 | 160.4 | 164.4 |
| Change from baseline | -61.4## | -67.9## | -67.7## | -38.9## | |
| Difference from placebo [95% CI] | -22.5** [-29.5, -15.4] | -29.0** [-36.0, -22.0] | -28.8** [-35.9, -21.6] | - | |
| Body weight (kg) | Baseline (mean) | 95.5 | 95.4 | 96.2 | 94.1 |
| Change from baseline | -6.2## | -8.2## | -10.9## | +1.7# | |
| Difference from placebo [95% CI] | -7.8** [-9.4, -6.3] | -9.9** [-11.5, -8.3] | -12.6** [-14.2, -11.0] | - | |
| Patients (%) achieving weight loss | ≥5% | 53.9†† | 64.6†† | 84.6†† | 5.9 |
| ≥10% | 22.6†† | 46.9†† | 51.3†† | 0.9 | |
| ≥15% | 7.0† | 26.6^† | 31.6†† | 0.0 | |
* p<0.05, **p<0.001 for superiority, adjusted for multiplicity.
† p<0.05, ††p<0.001 compared to placebo, not adjusted for multiplicity.
# p<0.05, ##p<0.001 compared to baseline, not adjusted for multiplicity.
Figure 5. Mean HbA1c (%) and mean body weight (kg) from baseline to week 40:
Cardiovascular (CV) risk was assessed via a meta-analysis of patients with at least one adjudication confirmed major adverse cardiac event (MACE). The composite endpoint of MACE-4 included CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina.
In a primary meta-analysis of phase 2 and 3 registration studies, a total of 116 patients (tirzepatide: 60 [n = 4 410]; all comparators: 56 [n = 2 169]) experienced at least one adjudication confirmed MACE-4: The results showed that tirzepatide was not associated with excess risk for CV events compared with pooled comparators (HR: 0.81; CI: 0.52 to 1.26).
An additional analysis was conducted specifically for the SURPASS-4 study that enrolled patients with established CV disease. A total of 109 patients (tirzepatide: 47 [n = 995]; insulin glargine: 62 [n = 1 000]) experienced at least one adjudication confirmed MACE-4: The results showed that tirzepatide was not associated with excess risk for CV events compared with insulin glargine (HR: 0.74; CI: 0.51 to 1.08).
In the placebo-controlled phase 3 studies, treatment with tirzepatide resulted in a mean decrease in systolic and diastolic blood pressure of 6 to 9 mmHg and 3 to 4 mmHg, respectively. There was a mean decrease in systolic and diastolic blood pressure of 2 mmHg each in placebo treated patients.
Treatment with tirzepatide resulted in significant reductions from baseline in FSG (changes from baseline to primary end point were -2.4 mmol/L to -3.8 mmol/L). Significant reductions from baseline in FSG could be observed as early as 2 weeks. Further improvement in FSG was seen through to 42 weeks then was sustained through the longest study duration of 104 weeks.
Treatment with tirzepatide resulted in significant reductions in mean 2 hour post prandial glucose (mean of 3 main meals of the day) from baseline (changes from baseline to primary end point were -3.35 mmol/L to -4.85 mmol/L).
Across SURPASS 1-5 trials, tirzepatide 5 mg, 10 mg and 15 mg resulted in reduction in serum triglyceride of 15-19%, 18-27% and 21-25% respectively.
In the 40 week trial versus semaglutide 1 mg, tirzepatide 5 mg, 10 mg and 15 mg resulted in 19%, 24% and 25% reduction in serum triglycerides levels respectively compared to 12% reduction with semaglutide 1 mg.
In the 4 studies where tirzepatide was not combined with basal insulin, 93.6% to 100% of patients who achieved a normal glycaemia of HbA1c <5.7% (≤39 mmol/mol), at the primary endpoint visit with tirzepatide treatment did so without clinically significant hypoglycaemia. In Study SURPASS-5, 85.9% of patients treated with tirzepatide who reached HbA1c <5.7% (≤39 mmol/mol) did so without clinically significant hypoglycaemia.
The efficacy of tirzepatide was not impacted by age, gender, race, ethnicity, region, or by baseline BMI, HbA1c, diabetes duration and level of renal function impairment.
The European Medicines Agency has deferred the obligation to submit the results of studies with Mounjaro in one or more subsets of the paediatric population for the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
Tirzepatide is a 39-amino acid peptide with a C20 fatty diacid moiety that enables albumin binding and prolongs half-life.
Maximum concentration of tirzepatide is reached 8 to 72 hours post dose. Steady state exposure is achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose proportional manner.
Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm.
Absolute bioavailability of subcutaneous tirzepatide was 80%.
The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration in patients with type 2 diabetes is approximately 10.3 L. Tirzepatide is highly bound to plasma albumin (99%).
Tirzepatide is metabolised by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety and amide hydrolysis.
The apparent population mean clearance of tirzepatide is 0.06 L/h with an elimination half-life of approximately 5 days, enabling once weekly administration.
Tirzepatide is eliminated by metabolism. The primary excretion routes of tirzepatide metabolites are via urine and faeces. Intact tirzepatide is not observed in urine or faeces.
Age, gender, race, ethnicity or body weight, do not have a clinically relevant effect on the pharmacokinetics (PK) of tirzepatide.
Renal impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function and no clinically relevant differences were observed. This was also shown for patients with both type 2 diabetes mellitus and renal impairment based on data from clinical studies.
Hepatic impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function and no clinically relevant differences were observed.
Tirzepatide has not been studied in paediatric patients.
Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat-dose toxicity or genotoxicity.
A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.12, 0.36, and 1.02-fold the maximum recommended human dose (MRHD) based on AUC) administered by subcutaneous injection twice weekly. Tirzepatide caused an increase in thyroid C-cell tumours (adenomas and carcinomas) at all doses compared to controls. The human relevance of these findings is unknown.
In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly did not produce increased incidences of thyroid C-cell hyperplasia or neoplasia at any dose.
Animal studies with tirzepatide did not indicate direct harmful effects with respect to fertility.
In animal reproduction studies, tirzepatide caused foetal growth reductions and foetal abnormalities at exposures below the MRHD based on AUC. An increased incidence of external, visceral, and skeletal malformations and visceral and skeletal developmental variations were observed in rats. Foetal growth reductions were observed in rats and rabbits. All developmental effects occurred at maternally toxic doses.
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