In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight.
A body-weight reduction of 5% or more has long been considered the threshold for clinically meaningful effect on the basis of improvement in metabolic health. It is remarkable that in this trial, the majority (89% to 91%) of participants receiving 10-mg or 15-mg doses of tirzepatide achieved this benchmark. Weight reductions of 10% or more, 15% or more, and 20% or more yield additional clinical benefits, may be required for improvement in certain weight-related complications, and are often more desired therapeutic goals in clinical practice. The majority of participants reached these three higher weight-loss targets (78–84%, 67–71%, and 50–57%, respectively), across the 10-mg and 15-mg dose groups.
Among patients without diabetes, administering tirzepatide 5 to 15 mg once weekly for managing obesity led to remarkable reductions in body weight, ranging from 16.5% to 22.4% over 72 weeks.
A 6-week phase 1 study of participants without T2D who had overweight or obesity found reduced activation in certain brain regions relevant to appetite regulation in response to high-fat/high-sugar food images among participants assigned to tirzepatide 10 mg as compared with placebo. Overall, preclinical and phase 1 data support that the primary mechanism for weight reduction by tirzepatide is regulation of appetite and decreases in food cravings and food intake, with increased lipid metabolism.
In people with obesity, tirzepatide did not impact metabolic adaptation but increased fat oxidation and decreased calorie intake by reducing overall appetite.
Tirzepatide and semaglutide decreased weight primarily through a reduction in fat mass. Nevertheless, the absolute changes in total and fat mass were greater with tirzepatide, suggesting that the added efficacy of tirzepatide may be achieved by utilizing body fat more effectively than semaglutide.
Tirzepatide administration for 72 weeks elicited significant weight reduction ranging from 5% to 20.9% across different trials in a dose-dependent manner. Moreover, tirzepatide exhibited favorable effects on glycemic control, with notable reductions in HbA1c levels ranging from 20.4 mmol/mol with the 5 mg dose to 28.2 mmol/mol with the 15 mg dose. Additionally, tirzepatide exerts a beneficial impact on lipid profile parameters, including reductions in total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels, while increasing high-density lipoprotein cholesterol concentrations.
Tirzepatide, a novel long-acting glucose-dependent insulinotropic polypeptide receptor (GIPR)/glucagon-like peptide 1 receptor (GLP-1R) agonist, has recently demonstrated greater clinical efficacy in reducing HbA1c, body weight, and serum triglyceride levels as compared with placebo or selective GLP-1R agonists. Consistent with this, we demonstrated tirzepatide stimulates lipolysis in human adipocytes while increasing expression and activation state of HSL, a key enzyme involved in the lipolytic breakdown of stored triglycerides.
