Structural determinants of dual incretin receptor agonism by tirzepatide

Sun, Bingfa; Willard, Francis S.; Feng, Dan; Alsina‐Fernandez, Jorge; Chen, Qi; Vieth, Michał; Ho, Joseph; Showalter, Aaron D.; Stutsman, Cynthia; Ding, Liyun; Suter, Todd M.; Dunbar, James D.; Carpenter, John W.; Mohammed, Faiz Ahmad; Aihara, Eitaro; Brown, Robert A.; Bueno, Ana B.; Emmerson, Paul J.; Moyers, Julie S.; Kobilka, Tong Sun; Coghlan, Matthew P.; Kobilka, Brian K.; Sloop, Kyle W.

doi:10.1073/pnas.2116506119

Cited by 59 publications

(33 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Overall tirzepatide seems to preferentially activate GIP receptors over GLP-1 receptors in isolated cell systems with high-grade expression of GIP and GLP-1 receptors. Structural prerequisites explaining receptor bifunctionality as well as the preferential binding to and activation of GIP relative to GLP-1 receptors have been extensively studied [25]. Concentrations of tirzepatide, GIP and GLP-1 leading to half maximal tracer displacement (binding affinity) and to half-maximal cAMP generation reported in Coskun et al 2018 [13] are displayed in Fig.…”

Section: Tirzepatide (Ly3298176): Pharmacologic Development Of a Unim...mentioning

confidence: 99%

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Nauck

D’Alessio

2022

Cardiovasc Diabetol

141

View full text Add to dashboard Cite

Tirzepatide is the first dual GIP/GLP-1 receptor co-agonist approved for the treatment of type 2 diabetes in the USA, Europe, and the UAE. Tirzepatide is an acylated peptide engineered to activate the GIP and GLP-1 receptors, key mediators of insulin secretion that are also expressed in regions of the brain that regulate food intake. Five clinical trials in type 2-diabetic subjects (SURPASS 1–5) have shown that tirzepatide at 5–15 mg per week reduces both HbA1c (1.24 to 2.58%) and body weight (5.4–11.7 kg) by amounts unprecedented for a single agent. A sizable proportion of patients (23.0 to 62.4%) reached an HbA1c of < 5.7% (which is the upper limit of the normal range indicating normoglycaemia), and 20.7 to 68.4% lost more than 10% of their baseline body weight. Tirzepatide was significantly more effective in reducing HbA1c and body weight than the selective GLP-1 RA semaglutide (1.0 mg per week), and titrated basal insulin. Adverse events related to tirzepatide were similar to what has been reported for selective GLP-1RA, mainly nausea, vomiting, diarrhoea, and constipation, that were more common at higher doses. Cardiovascular events have been adjudicated across the whole study program, and MACE-4 (nonfatal myocardial infarction, non-fatal stroke, cardiovascular death and hospital admission for angina) events tended to be reduced over up to a 2 year-period, albeit with low numbers of events. For none of the cardiovascular events analysed (MACE-4, or its components) was a hazard ratio > 1.0 vs. pooled comparators found in a meta-analysis covering the whole clinical trial program, and the upper bounds of the confidence intervals for MACE were < 1.3, fulfilling conventional definitions of cardiovascular safety. Tirzepatide was found to improve insulin sensitivity and insulin secretory responses to a greater extent than semaglutide, and this was associated with lower prandial insulin and glucagon concentrations. Both drugs caused similar reductions in appetite, although tirzepatide caused greater weight loss. While the clinical effects of tirzepatide have been very encouraging, important questions remain as to the mechanism of action. While GIP reduces food intake and body weight in rodents, these effects have not been demonstrated in humans. Moreover, it remains to be shown that GIPR agonism can improve insulin secretion in type 2 diabetic patients who have been noted in previous studies to be unresponsive to GIP. Certainly, the apparent advantage of tirzepatide, a dual incretin agonist, over GLP-1RA will spark renewed interest in the therapeutic potential of GIP in type 2 diabetes, obesity and related co-morbidities.

show abstract

Section: Tirzepatide (Ly3298176): Pharmacologic Development Of a Unim...mentioning

confidence: 99%

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Nauck

D’Alessio

2022

Cardiovasc Diabetol

141

View full text Add to dashboard Cite

show abstract

“…GLP-1 RA can not only bind to the GLP-1 receptor of the gastrointestinal tract and inhibit gastric emptying but also aggravate anorexia and/or satiety by activating central GLP-1 receptors, which are widely distributed in the brain ( Shah and Vella, 2014 ). Tirzepatide, a fatty acid-modified double intestinal insulinotropic receptor agonist, shows similar pharmacology to natural GIP on glucose-dependent insulinotropic polypeptide receptor (GIPR) but shows a preference for the cyclic adenosine monophosphate signal on GLP-1R ( Sun B. et al, 2022a ). Similar to GLP-1 RAs, compared with control, tirzepatide increases the risk of gastrointestinal adverse reactions, however, mainly due to add-on therapy.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of tirzepatide in patients with type 2 diabetes: A systematic review and meta-analysis

Tang

Zhang²,

Zeng³

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Purpose: A systematic review and meta-analysis was conducted to combine the data available from clinical trials and evaluate the clinical efficacy and safety of tirzepatide in people with type 2 diabetes (T2D).Methods: We systematically searched the MEDLINE, Embase, Cochrane Library, and clinical trials registries (https://clinicaltrials.gov) up to 25 March 2022 for randomized controlled trials (RCTs) that compared tirzepatide with placebo or active hypoglycemic drugs in subjects with T2D. Heterogeneity was judged by the I2 value and Cochran’s Q test. The randomized effects model was adopted to calculate risk ratios and weighted mean differences (WMDs). The primary outcome was the change from baseline in HbA1c levels. Secondary efficacy endpoints were fasting serum glucose (FSG), change of body weight, blood pressure, fasting lipid profiles, and safety indexes.Results: Six trials comprising 6,579 subjects (4,410 in the tirzepatide group and 2,054 in the control group) fulfilled the pre-specified criteria and were included in the study. Tirzepatide treatment resulted in reducing HbA1c (WMD: -1.07%; 95% confidence intervals [CIs]: −1.44, −0.56), FSG (WMD, −21.50 mg/dl; 95% CI: −34.44, −8.56), body weight (WMD: −7.99 kg; 95% CI −11.36, −4.62), and blood pressure and ameliorated fasting lipid profiles, without increasing hypoglycemia, either as monotherapy or an add-on therapy. Tirzepatide increased the risk of gastrointestinal adverse events mainly in add-on therapy but not in terms of pancreatitis or cholelithiasis. Furthermore, tirzepatide presented a dose–response effect on the reduction in HbA1c and body weight and increase in nausea and vomiting.Conclusion: In patients with type 2 diabetes, tirzepatide shows superior blood glucose control and weight loss performance, without an increased risk of hypoglycemia.Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO), identifier (CRD42022319442).

show abstract

“…The peptide sequence of tirzepatide contains two non-coded amino acid residues (Aib, α-amino isobutyric acid) at position 2 and 13, which are responsible for its long half-life and high affinity to albumin [32]. The C-terminus of the peptide is amidated (Figure 2) [33]. The molecular formula of tirzepatide is C 225 H 348 N 48 O 68 and the molecular weight is 4813.…”

Section: Structure and Activitymentioning

confidence: 99%

“…Tirzepatide has significantly better therapeutic efficacy than current drugs [20,41]. It is superior to semaglutide [33,42] and insulin degludec [33,43]. The main critical improvements are modification of residues in the peptide backbone to obtain GIP receptor-activating activity, prolongation of the C-terminus with a sequence of C-terminal of exenatide, and conjugation of the fatty acid side chain to prolong half-life (116.7 h) [30,44].…”

Section: Structure and Activitymentioning

confidence: 99%

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

Chavda¹,

et al. 2022

View full text Add to dashboard Cite

The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, and is referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known as a ‘twincretin’, is a ‘first-in-class’ and the only dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels and improve insulin sensitivity, as well as reducing body weight by more than 20% and improving lipid metabolism. This novel anti-diabetic drug is a synthetic peptide analog of the human GIP hormone with a C20 fatty-diacid portion attached which, via acylation technology, can bind to albumin in order to provide a dose of the drug, by means of subcutaneous injection, once a week, which is appropriate to its a half-life of about five days. Tirzepatide, developed by Eli Lilly, was approved, under the brand name Mounjaro, by the United States Food and Drug Administration in May 2022. This started the ‘twincretin’ era of enormously important and appealing dual therapeutic options for diabetes and obesity, as well as advanced management of closely related cardiometabolic settings, which constitute the leading cause of morbidity, disability, and mortality worldwide. Herein, we present the key characteristics of tirzepatide in terms of synthesis, structure, and activity, bearing in mind its advantages and shortcomings. Furthermore, we briefly trace the evolution of this kind of medical agent and discuss the development of clinical studies.

show abstract

Structural determinants of dual incretin receptor agonism by tirzepatide

Cited by 59 publications

References 56 publications

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction

Efficacy and safety of tirzepatide in patients with type 2 diabetes: A systematic review and meta-analysis

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review

Contact Info

Product

Resources

About