Tirzepatide Research & Studies

Tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, promoted significant body weight reduction in the phase 3 clinical trials. We conducted a preclinical study and a phase 1 clinical trial (NCT04081337) to understand potential mechanisms mediating tirzepatide-induced weight loss in mice and people with obesity. In calorie-restricted, obese mice, chronic treatment with tirzepatide reduced the drop in energy expenditure that occurred in vehicle-treated and pair-fed mice, indicating that tirzepatide attenuated metabolic adaptation. Respiratory exchange ratio also decreased in tirzepatide-treated mice, indicating increased fat oxidation. In the clinical trial, tirzepatide appeared to have no impact on metabolic adaptation but led to increased fat oxidation and reductions in appetite and calorie intake during an ad libitum test meal (vs. placebo). This is the first study to provide insights into the mechanisms of action of tirzepatide on weight loss with respect to calorie intake, energy expenditure, and macronutrient utilization.

Obesity is a chronic disease with significant global health repercussions. GLP-1 receptor agonists (GLP-1RAs) and dual GIP/GLP-1 receptor agonists (GIP/GLP-1RAs) are now established as evidence-based options for long-term obesity management. This review compares semaglutide and tirzepatide aims to support precise, equitable, and durable care for people with the disease of obesity.

Obesity increases the risk of heart failure with preserved ejection fraction. Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, causes considerable weight loss, but data are lacking with respect to its effects on cardiovascular outcomes.

Obesity is a chronic disease and causal precursor to myriad other conditions, including type 2 diabetes. In an earlier analysis of the SURMOUNT-1 trial, tirzepatide was shown to provide substantial and sustained reductions in body weight in persons with obesity over a 72-week period. Here, we report the 3-year safety outcomes with tirzepatide and its efficacy in reducing weight and delaying progression to type 2 diabetes in persons with both obesity and prediabetes.

Tirzepatide, a dual incretin agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, has favorable effects on glycemic control and body weight. The effects on cardiovascular outcomes are uncertain.

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease associated with liver-related complications and death. The efficacy and safety of tirzepatide, an agonist of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, in patients with MASH and moderate or severe fibrosis is unclear.

Although tirzepatide and semaglutide were shown to reduce weight in randomized clinical trials, data from head-to-head comparisons in populations with overweight or obesity are not yet available.

Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment.

Tirzepatide is a dual glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved by the US Food and Drug Administration in May 2022 for patients with type 2 diabetes mellitus (T2DM).

The worldwide prevalence of obesity has been increasing progressively over the past few decades and is predicted to continue to rise in coming years. Unfortunately, this epidemic is also affecting increasing rates of children and adolescents, posing a serious global health concern. Increased adiposity is associated with various comorbidities and increased mortality risk. Conversely, weight loss and chronic weight management are associated with improvements in overall morbidity and mortality. The pathophysiology of obesity is multifactorial with complex interactions between genetic and environmental factors. The foundation of most weight loss plans is lifestyle modification including dietary change and exercise. However, lifestyle modification alone is often insufficient to achieve clinically meaningful weight loss due to physiological mechanisms that limit weight reduction and promote weight regain. Therefore, research has focused on adjunctive pharmacotherapy to enable patients to achieve greater weight loss and improved chronic weight maintenance compared to lifestyle modification alone. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin hormone analogs that have proven effective for the management of type 2 diabetes mellitus as well as obesity and overweight. Tirzepatide is a novel "twincretin" that functions as a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA. Tirzepatide was recently approved by the Food and Drug Administration for the management of type 2 diabetes. Similar to previously approved GLP-1RAs, weight loss is a common side effect of tirzepatide which prompted research focused on its use as a primary weight loss therapy. Although this drug has not yet been approved as an antiobesity medication, there are several phase 3 clinical trials that have demonstrated superior weight loss efficacy compared with previously approved medications. This review article will discuss the discovery and mechanism of tirzepatide, as well as the completed and ongoing trials that may lead to its approval as an adjunctive pharmacotherapy for weight loss.

Tirzepatide (Mounjaro™) is a single molecule that combines dual agonism of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Native GIP and GLP-1 are incretin hormones that stimulate insulin secretion and decrease glucagon secretion. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, supresses appetite and improves satiety. Eli Lilly is developing tirzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovascular disorders in T2DM, heart failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortality/morbidity in obesity. In May 2022, tirzepatide received its first approval in the USA to improve glycaemic control in adults with T2DM, as an adjunct to diet and exercise. Tirzepatide is in phase III development for heart failure, obesity and cardiovascular disorders in T2DM, and in phase II development for non-alcoholic steatohepatitis. This article summarizes the milestones in the development of tirzepatide leading to this first approval for T2DM.

Tirzepatide is a new molecule capable of controlling glucose blood levels by combining the dual agonism of Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) receptors. GIP and GLP1 are incretin hormones: they are released in the intestine in response to nutrient intake and stimulate pancreatic beta cell activity secreting insulin. GIP and GLP1 also have other metabolic functions. GLP1, in particular, reduces food intake and delays gastric emptying. Moreover, Tirzepatide has been shown to improve blood pressure and to reduce Low-Density Lipoprotein (LDL) cholesterol and triglycerides. Tirzepatide efficacy and safety were assessed in a phase III SURPASS 1-5 clinical trial program. Recently, the Food and Drug Administration approved Tirzepatide subcutaneous injections as monotherapy or combination therapy, with diet and physical exercise, to achieve better glycemic blood levels in patients with diabetes. Other clinical trials are currently underway to evaluate its use in other diseases. The scientific interest toward this novel, first-in-class medication is rapidly increasing. In this comprehensive and systematic review, we summarize the main results of the clinical trials investigating Tirzepatide and the currently available meta-analyses, emphasizing novel insights into its adoption in clinical practice for diabetes and its future potential applications in cardiovascular medicine.

Obesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known.

Tirzepatide is a novel, once weekly, dual GIP/GLP-1 receptor agonist and is under development for the treatment of type 2 diabetes (T2D) and obesity. Its association with cardiovascular outcomes requires evaluation. This pre-specified cardiovascular meta-analysis included all seven randomized controlled trials with a duration of at least 26 weeks from the tirzepatide T2D clinical development program, SURPASS. The pre-specified primary objective of this meta-analysis was the comparison of the time to first occurrence of confirmed four-component major adverse cardiovascular events (MACE-4; cardiovascular death, myocardial infarction, stroke and hospitalized unstable angina) between pooled tirzepatide groups and control groups. A stratified Cox proportional hazards model, with treatment as a fixed effect and trial-level cardiovascular risk as the stratification factor, was used for the estimation of hazard ratios (HRs) and confidence intervals (CIs) comparing tirzepatide to control. Data from 4,887 participants treated with tirzepatide and 2,328 control participants were analyzed. Overall, 142 participants, 109 from the trial with high cardiovascular risk and 33 from the six trials with lower cardiovascular risk, had at least one MACE-4 event. The HRs comparing tirzepatide versus controls were 0.80 (95% CI, 0.57-1.11) for MACE-4; 0.90 (95% CI, 0.50-1.61) for cardiovascular death; and 0.80 (95% CI, 0.51-1.25) for all-cause death. No evidence of effect modifications was observed for any subgroups, although the evidence was stronger for participants with high cardiovascular risk. Tirzepatide did not increase the risk of major cardiovascular events in participants with T2D versus controls.

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over β-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal β-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.