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Cited by 345Diabetes Treatment and ManagementDiabetes Management and ResearchPancreatic function and diabetes

Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes

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Thomas, Melissa K, Nikooienejad, Amir, Bray, Ross, Cui, Xuewei, Wilson, Jonathan, Duffin, Kevin, Milicevic, Zvonko, Haupt, Axel +1 more·2021·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgaa863PMC PMC7823251
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Abstract

Context: Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Objective: Explore mechanisms of glucose control by tirzepatide. Design: Post hoc analyses of fasting biomarkers and multiple linear regression analysis. Setting: Forty-seven sites in 4 countries. Patients or other Participants: Three hundred and sixteen subjects with type 2 diabetes. Interventions: Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Main Outcome Measures: Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Results: Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. Conclusions: Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.

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  • This finding is consistent with studies that demonstrated greater reductions in fasting and postprandial glucagon levels with tirzepatide treatment compared with selective GLP-1 receptor agonists in adults with T2D.

    “This finding is consistent with studies that demonstrated greater reductions in fasting and postprandial glucagon levels with tirzepatide treatment compared with selective GLP-1 receptor agonists in adults with T2D (10, 11).”

    From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [11]

    The Discussion reports greater reductions in fasting glucagon with tirzepatide than with dulaglutide in adults with T2D, and the Results identify significant differences for the 10- and 15-mg doses. The Methods state that glucagon was measured in fasting samples; this paper does not support the claim about postprandial glucagon. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • In a previous analysis of tirzepatide vs the selective GLP-1R agonist dulaglutide 1.5 mg, percent change from baseline in HOMA2-B (computed with fasting C-peptide) increases ranged from 93% to 163% for tirzepatide 5-mg, 10-mg, and 15-mg doses vs 72% with dulaglutide 1.5 mg (P < .05).

    “In a previous analysis of tirzepatide vs the selective GLP-1R agonist dulaglutide 1.5 mg, percent change from baseline in HOMA2-B (computed with fasting C-peptide) increases ranged from 93% to 163% for tirzepatide 5-mg, 10-mg, and 15-mg doses vs 72% with dulaglutide 1.5 mg (P < .05) (11).”

    From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [11]

    The Results section ('Tirzepatide improved markers of beta-cell function'; page not provided) reports the stated fasting C-peptide HOMA2-B increases: 93%–163% for tirzepatide 5, 10, and 15 mg, and 72% for dulaglutide. The Trial design section confirms the dulaglutide dose was 1.5 mg. However, the reported P < .001 values test increases within treatment groups; the paper reports a significant comparison with dulaglutide only for absolute HOMA2-B changes at tirzepatide 10 and 15 mg, not a P < .05 comparison of the stated percentage increases across all three doses. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • These findings are consistent with a 26-week, randomized, double-blind phase 2b clinical trial of tirzepatide with metformin background in most participants that showed improved beta-cell function with reductions in fasting proinsulin, intact proinsulin/C-peptide ratios, and dose-dependent increases in HOMA2-B indices compared with dulaglutide 1.5 mg.

    “These findings are consistent with a 26-week, randomized, double-blind phase 2b clinical trial of tirzepatide with metformin background in most participants that showed improved beta-cell function with reductions in fasting proinsulin, intact proinsulin/C-peptide ratios, and dose-dependent increases in HOMA2-B indices compared with dulaglutide 1.5 mg [14].”

    From Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1). (2023) · cites this paper as [14]

    Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • HOMA2-B improvements have also been observed with tirzepatide treatment combined with metformin in independent studies.

    “HOMA2-B improvements have also been observed with tirzepatide treatment combined with metformin in independent studies [13, 14].”

    From Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1). (2023) · cites this paper as [14]

    The Results section reports significant HOMA2-B increases with tirzepatide. The Discussion says more than 80% of participants received concomitant metformin, but the reported HOMA2-B results are for the treatment groups overall, not specifically for participants taking tirzepatide with metformin. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • This finding is consistent with studies that demonstrated greater reductions in glucagon levels with tirzepatide treatment compared with selective GLP-1 receptor agonists in adults with type 2 diabetes and background metformin therapy.

    “This finding is consistent with studies that demonstrated greater reductions in glucagon levels with tirzepatide treatment compared with selective GLP-1 receptor agonists in adults with T2D and background metformin therapy [6, 14].”

    From Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1). (2023) · cites this paper as [14]

    The Results (Tirzepatide improved markers of beta-cell function; page unavailable) report significantly greater reductions in glucose-adjusted glucagon with tirzepatide 10 and 15 mg than with dulaglutide, a selective GLP-1 receptor agonist. But the trial-design section says adults with type 2 diabetes were eligible with or without stable metformin therapy; the reported glucagon comparison is not specific to participants receiving background metformin. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Thomas, M. K., Nikooienejad, A., Bray, R., Cui, X., Wilson, J., Duffin, K., Milicevic, Z., Haupt, A., & Robins, D. A.
Affiliations
  • Eli Lilly (United States) (US)
  • Eli Lilly and Company, Vienna, Austria
Corresponding author
Thomas, Melissa K
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2020-11-24
Volume
106
Issue
2
Pages
388-396
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgaa863
PMC
PMC7823251
OpenAlex
W3108676144
Cited by
345
References
51
Citations by year
2026: 62 · 2025: 91 · 2024: 64 · 2023: 57 · 2022: 46 · 2021: 22 · 2020: 3
FWCI
24.13
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, public-domain)
  • DRYAD (public-domain)
Funders
Eli Lilly and Company
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
tirzepatide, dulaglutide, type 2 diabetes, GIP/GLP-1 receptor agonist, beta-cell function, insulin sensitivity, insulin resistance, weight loss, HOMA-IR, proinsulin/insulin ratio, adiponectin, IGFBP-1, IGFBP-2, glycemic control, GLP-1 receptor agonists
MeSH terms
Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide, Adolescent, Adult, Aged, Blood Glucose, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Gastric Inhibitory Polypeptide, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Middle Aged, Prognosis, Biomarkers, Clinical Trials, Phase II as Topic, Insulin-Secreting Cells, Young Adult

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