What is Tirzepatide?

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What is Tirzepatide?​

Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1 receptor agonists. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for blood glucose management in adults with type 2 diabetes and for chronic weight management. It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH).

Glucagon-like peptide-1 (GLP-1) lowers blood glucose by several mechanisms, including stimulating insulin secretion and suppressing glucagon secretion during hyperglycemia. Glucose-dependent insulinotropic polypeptide (GIP) also stimulates insulin release during hyperglycemia, but it also stimulates glucagon release during hypoglycemia. Thus, a dual agonist for both GLP-1 and GIP receptors theoretically could enhance glycemic control while minimizing hypoglycemia in patients with type 2 diabetes. Tirzepatide is a dual agonist for both receptors. Researchers have examined its effects in two industry-sponsored randomized trials that involved patients with type 2 diabetes.

Research Example 1:​

In one trial, three doses of tirzepatide (given subcutaneously once weekly) were compared with placebo in 478 patients, most of whom were not taking other diabetes medications. During 40 weeks of treatment, all 3 doses lowered mean glycosylated hemoglobin (HbA1c) by about 2 percentage points (from a baseline of 7.9%) and reduced mean weight by 7 to 9 kg (from a baseline of 86 kg). Neither HbA1c level nor weight changed in the placebo group. Severe hypoglycemia did not occur.

Tirzepatide showed robust improvements in glycemic control and bodyweight, without increased risk of hypoglycemia. The safety profile was consistent with GLP-1 receptor agonists, indicating a potential monotherapy use of tirzepatide for type 2 diabetes treatment.

Research Example 2:​

In the other trial, three doses of tirzepatide were compared with the GLP-1 agonist semaglutide, injected weekly, in 1900 metformin-treated patients with type 2 diabetes (mean HbA1c, 8.3%; mean weight, 94 kg). At 40 weeks, mean reduction in HbA1c was significantly greater with tirzepatide (2.30% with the highest tirzepatide dose vs. 1.86% with semaglutide). Mean reduction in weight also was greater with tirzepatide (11.2 kg with the highest dose vs. 5.7 kg with semaglutide). Severe hypoglycemia was rare in all groups. See figures below from the study.



Figure 1. Effect of Once-Weekly Tirzepatide, as Compared with Semaglutide, on the Glycated Hemoglobin Level, Percentage of Patients Who Met Glycated Hemoglobin Level Targets, and Fasting Serum Glucose Levels.

Least-squares means (±SE) are presented, unless otherwise noted. Error bars indicate the standard error. Estimated treatment differences (ETDs) are least-squares means (95% confidence interval) at 40 weeks in the modified intention-to-treat population.

Panel A shows the change from baseline in the glycated hemoglobin level at 40 weeks, as assessed with the use of analysis of covariance with multiple imputation according to treatment for the missing glycated hemoglobin level at 40 weeks (treatment-regimen estimate).

Panel B shows the values for glycated hemoglobin levels over time, derived from a mixed-model repeated-measures analysis (efficacy estimate). Arrows indicate the times at which the maintenance doses of tirzepatide (5 mg, 10 mg, or 15 mg) and semaglutide 1 mg were achieved.

Panel C shows the percentage of patients who met glycated hemoglobin level targets of less than 7.0%, 6.5% or less, and less than 5.7% at 40 weeks (treatment-regimen estimate). The percentage was calculated with the use of Rubin’s rules by combining the percentages of patients who met the target in imputed data sets. The glycated hemoglobin levels of 6.5% or less and less than 5.7% (tirzepatide 5-mg group only) were not controlled for type 1 errors; thus, P values are not presented.

Panel D shows fasting serum glucose values over time, derived from mixed-model repeated-measures analysis (efficacy estimate). Arrows indicate the times at which the maintenance doses of tirzepatide (5 mg, 10 mg, or 15 mg) and semaglutide 1 mg were achieved.





Figure 2: Effect of Once-Weekly Tirzepatide, as Compared with Semaglutide, on Body Weight, the Percentage of Patients Who Met Weight-Loss Goals, and the Lipid Profile.

Least-squares means (±SE) are presented, unless otherwise noted. Error bars indicate the standard error.
Panel A shows the change from baseline in body weight at 40 weeks, as assessed with analysis of covariance with multiple imputation for treatment for missing weight at 40 weeks (treatment-regimen estimate). ETDs are least-squares means (95% confidence interval) at 40 weeks in the modified intention-to-treat population.
Panel B shows the change from baseline in body weight over time, derived from a mixed-model repeated-measures analysis (efficacy estimate). The percent changes from baseline values at 40 weeks are shown in parentheses. Arrows indicate the times at which the maintenance doses of tirzepatide (5 mg, 10 mg, or 15 mg) and semaglutide 1 mg were achieved.
Panel C shows the percentage of patients who had body-weight reductions of at least 5%, 10%, or 15% from baseline to week 40 (treatment-regimen estimate). The percentage was calculated with the use of Rubin’s rules by combining the percentages of patients who met the target in imputed data sets.
Panel D shows the percent change (±SE) from baseline in lipid levels at 40 weeks, as estimated with the use of log transformation. HDL denotes high-density lipoprotein, LDL low-density lipoprotein, and VLDL very-low-density lipoprotein.

Research Example 3:​

In the most recent study, participants taking tirzepatide lost up to 52 lb. (24 kg) in this 72-week phase 3 study 63% of participants taking tirzepatide 15 mg achieved at least 20% body weight reductions as a key secondary endpoint.

“Tirzepatide (5 mg, 10 mg, 15 mg) achieved superior weight loss compared to placebo at 72 weeks of treatment in topline results from Eli Lilly and Company's (NYSE: LLY) SURMOUNT-1 clinical trial, with participants losing up to 22.5% (52 lb. or 24 kg) of their body weight for the efficacy estimandi. This study enrolled 2,539 participants and was the first phase 3 global registration trial evaluating the efficacy and safety of tirzepatide in adults with obesity, or overweight with at least one comorbidity, who do not have diabetes. Tirzepatide met both co-primary endpoints of superior mean percent change in body weight from baseline and greater percentage of participants achieving body weight reductions of at least 5% compared to placebo for both estimates. The study also achieved all key secondary endpoints at 72 weeks.”

Results showed average body weight reductions of 15.0% (5 mg), 19.5% (10 mg), 20.9% (15 mg), 3.1% (placebo). The percentage of participants achieving body weight reductions of ≥5% was 85% (5 mg), 89% (10 mg), 91% (15 mg), 35% (placebo), and the [percentage of participants achieving body weight reductions of ≥20% was 30% (5 mg, not controlled for type 1 error), 50% (10 mg), 57% (15 mg), 3.1% (placebo)