Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes

Frías, Juan P.; Davies, Melanie J.; Rosenstock, Julio; Manghi, Federico C. Pèrez; Landó, Laura Fernández; Bergman, Brandon; Liu, Bing; Cui, Xuewei; Brown, Katelyn

doi:10.1056/nejmoa2107519

Cited by 973 publications

(1,169 citation statements)

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“…Of note is that tirzepatide was reported to cause biased signaling at GLP-1R in favor of cAMP response over β-arrestin recruitment 35 . The combined activation of GIPR and GLP-1R by tirzepatide not only improved both glucose-dependent insulin secretion and glucose tolerance in mice 38 , but also showed significantly better efficacy than semaglutide and dulaglutide with regard to glucose control and weight loss 15,16 .…”

Section: Resultsmentioning

confidence: 95%

“…Both GIP and GLP-1 are released upon nutrient ingestion to promote insulin secretion by pancreatic β-cells. However, they have opposed effects on circulating GCG levels 7,15 . GIPR activation also has different roles in lipid metabolism from that of GLP-1 44 .…”

Section: Discussionmentioning

confidence: 99%

“…GIPR activation also has different roles in lipid metabolism from that of GLP-1 44 . Maintenance of GCG action might be a key to the superior therapeutic efficacy of tirzepatide 15,16,45 . Structurally, the binding of tirzepatide to GIPR reshaped the ECL1 conformation relative to that of GIP, but made no change in the GLP-1R structure.…”

Section: Discussionmentioning

confidence: 99%

“…1a). Tirzepatide is an investigational once-weekly GIPR/GLP-1R dualagonist 14 with a profound therapeutic superiority in reducing blood glucose and body weight beyond several approved drugs such as semaglutide 15 and dulaglutide 16 in multiple head-to-head clinical trials. Peptide 20, a GIPR/GLP-1R/GCGR triagonist (currently in phase 1 clinical trial) 17 with balanced potency at the three receptors, is evolved from a GLP-1R/GCGR dualagonist 18 through iterative sequence refinement and modification (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for the therapeutic advantage of dual and triple agonists at the human GIP, GLP-1 or GCG receptors

Zhao

Zhou

Cong

et al. 2021

Preprint

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Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dualagonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their superior efficacies over monoagonist such as semaglutide, we determined cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility and therapeutic supremacy of tirzepatide and peptide 20.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural basis for the therapeutic advantage of dual and triple agonists at the human GIP, GLP-1 or GCG receptors

Zhao

Zhou

Cong

et al. 2021

Preprint

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“…[9]. Für Tirzepatid, einen dualen GLP-1-und GIP-Rezeptor-Agonisten, zeigten sich bereits bemerkenswerte Gewichtsreduktionseffekte bei Patienten mit Typ-2-Diabetes in der SURPASS-2-Studie [10].…”

Section: Kommentarunclassified

Therapie der Adipositas mit Semaglutid

Blüher

Nitschmann

2021

Internist

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Your article is protected by copyright and all rights are held exclusively by Springer Medizin Verlag GmbH, ein Teil von Springer Nature. This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".

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Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes

Dahl

Onishi

Norwood³

et al. 2022

JAMA

320

437

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The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described. OBJECTIVE To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control.DESIGN, SETTING, AND PARTICIPANTS Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020 follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin.INTERVENTIONS Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. MAIN OUTCOMES AND MEASURESThe primary end point was mean change from baseline in glycated hemoglobin A 1c (HbA 1c ) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA 1c levels. RESULTS Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA 1c , 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA 1c change from baseline was −2.40% with 10-mg tirzepatide and −2.34% with 15-mg tirzepatide vs −0.86% with placebo (10 mg: difference vs placebo, −1.53% [97.5% CI, −1.80% to −1.27%]; 15 mg: difference vs placebo, −1.47% [97.5% CI, −1.75% to −1.20%]; P < .001 for both). Mean HbA 1c change from baseline was −2.11% with 5-mg tirzepatide (difference vs placebo, −1.24% [95% CI, −1.48% to −1.01%]; P < .001]). Mean body weight change from baseline was −5.4 kg with 5-mg tirzepatide, −7.5 kg with 10-mg tirzepatide, −8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, −7.1 kg [95% CI, −8.7 to −5.4]; 10 mg: difference, −9.1 kg [95% CI, −10.7 to −7.5]; 15 mg: difference, −10.5 kg [95% CI, −12.1 to −8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA 1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%).CONCLUSIONS AND RELEVANCE Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks.

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Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes

Cited by 973 publications

References 23 publications

Structural basis for the therapeutic advantage of dual and triple agonists at the human GIP, GLP-1 or GCG receptors

Structural basis for the therapeutic advantage of dual and triple agonists at the human GIP, GLP-1 or GCG receptors

Therapie der Adipositas mit Semaglutid

Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes

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