Indications
Tirzepatide is approved for use as an adjunct to diet and exercise to enhance glycemic control in adults with type 2 diabetes mellitus. Additionally, it is indicated for the chronic management of weight in adult patients who are obese or overweight, provided they have at least one weight-related comorbid condition, such as hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease. In Europe, tirzepatide can be administered either as a monotherapy or in combination with other antidiabetic medications. It is important to note that this drug has not been studied in individuals with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus.
Pharmacodynamics
Tirzepatide is a synthetic peptide known for its glucose-lowering capabilities. Its mechanism of action involves the stimulation of the first- and second-phase insulin secretion and a reduction in glucagon levels, all in a glucose-dependent manner. Furthermore, tirzepatide has been shown to delay gastric emptying, lower both fasting and postprandial glucose levels, decrease food intake, and reduce body weight in individuals with type 2 diabetes. The drug also increases insulin sensitivity. The conjugation of the peptide to a C20 fatty diacid moiety through a hydrophilic linker at the lysine residue at position 20 allows for high binding to albumin in the plasma, thereby prolonging its half-life.
Absorption
When administered subcutaneously at doses ranging from 1 to 5 mg, the maximum concentration (Cmax) of tirzepatide ranges from 108 to 397 ng/mL, with an average bioavailability of 80%. The time to reach maximum concentration (Tmax) varies between eight to 72 hours post-administration. Steady-state plasma concentrations are typically achieved after four weeks of once-weekly subcutaneous administration. Due to tirzepatide's effect on delaying gastric emptying, it may influence the absorption of other concurrently administered oral medications. Hence, caution is advised when using tirzepatide alongside other oral treatments.
Metabolism
Tirzepatide undergoes metabolism primarily through proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis. These metabolic pathways ensure the proper breakdown and elimination of the drug from the body.
Mechanism of Action
Tirzepatide functions by leveraging its dual agonistic properties at both the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, which play critical roles in glucose homeostasis. GLP-1 receptors, located throughout the body including pancreatic beta-cells and the gastrointestinal tract, are central to the regulation of glucose levels. They enhance insulin secretion in response to glucose, slow gastric emptying, decrease plasma glucagon concentrations, and promote weight loss through anorexigenic pathways in the brain. The mechanisms of GIP, primarily responsible for insulinotropic effects following food intake, complement those of GLP-1. Although the precise mechanism by which tirzepatide operates is not fully understood, its dual activation of GIP and GLP-1 receptors likely underlies its efficacy in managing glycemic levels and body weight. Research indicates that simultaneous GIP and GLP-1 receptor stimulation can significantly augment insulin responses and reduce glucagon secretion more effectively than activating each pathway individually. Tirzepatide exhibits high binding affinity for both GIP and GLP-1 receptors, demonstrating comparable binding to the GIP receptor as native GIP and slightly lower affinity for GLP-1R compared to native GLP-1. This interaction stimulates glucose-dependent insulin secretion via activation at either receptor. Nonetheless, the specific contributions of GIP receptor agonism within this mechanism necessitate further exploration, as current preclinical and clinical studies present inconsistent findings regarding its role in glycemic and weight management.
