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Cited by 48Diabetes Treatment and ManagementDiabetes Management and ResearchPancreatic function and diabetes

Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1).

Open access
Lee, Clare J, Mao, Huzhang, Thieu, Vivian T, Landó, Laura Fernández, Thomas, Melissa K·2023·Journal of the Endocrine Society
DOI 10.1210/jendso/bvad056PMC PMC10157777
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Abstract

Context: Tirzepatide is a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for treatment of type 2 diabetes (T2D). SURPASS-1, a phase 3 trial of tirzepatide monotherapy in people with early T2D, enables evaluating effects of tirzepatide on pancreatic beta-cell function and insulin sensitivity (IS) without other background antihyperglycemic medications. Objective: Explore changes in biomarkers of beta-cell function and IS with tirzepatide monotherapy. Design: Post hoc analyses of fasting biomarkers with analysis of variance and mixed model repeated measures. Setting: Forty-seven sites in 4 countries. Patients: Four hundred seventy-eight T2D participants. Intervention: Tirzepatide (5, 10, 15 mg), placebo. Main Outcome Measure(s): Analyze biomarkers of beta-cell function and IS at 40 weeks. Results: At 40 weeks, markers of beta-cell function improved with tirzepatide monotherapy vs placebo with reductions from baseline in fasting proinsulin levels (49-55% vs −0.6%) and in intact proinsulin/C-peptide ratios (47-49% vs −0.1%) (P < .001, all doses vs placebo). Increases from baseline in homeostatic model assessment for beta-cell function (computed with C-peptide) (77-92% vs −1.4%) and decreases in glucose-adjusted glucagon levels (37-44% vs +4.8%) were observed with tirzepatide vs placebo (P < .001, all doses vs placebo). IS improved as indicated by reductions from baseline in homeostatic model assessment for insulin resistance (9-23% vs +14.7%) and fasting insulin levels (2-12% vs +15%), and increases in total adiponectin (16-23% vs −0.2%) and insulin-like growth factor binding protein 2 (38-70% vs +4.1%) with tirzepatide vs placebo at 40 weeks (P ≤ .031, all doses vs placebo, except for fasting insulin levels with tirzepatide 10 mg). Conclusions: As monotherapy for early T2D, tirzepatide achieved significant improvements in biomarkers of both pancreatic beta-cell function and IS.

AI snapshot

Written from the paper’s full text.

TL;DR

In post hoc analyses of SURPASS-1, tirzepatide monotherapy improved fasting biomarkers of pancreatic beta-cell function and insulin sensitivity versus placebo in adults with early type 2 diabetes. These changes occurred alongside previously reported improvements in glycemic control and body weight.

Key findings

  • At 40 weeks, beta-cell markers improved with tirzepatide 5, 10, and 15 mg versus placebo: fasting proinsulin decreased 49–55% vs −0.6%, proinsulin/C-peptide ratio decreased 47–49% vs −0.1%, HOMA2-B increased 77–92% vs −1.4%, and glucose-adjusted glucagon decreased 37–44% vs +4.8% (P < .001, all doses vs placebo).
  • Insulin sensitivity markers improved with tirzepatide versus placebo: HOMA2-IR decreased 9–23% vs +14.7%, fasting insulin decreased 2–12% vs +15%, total adiponectin increased 16–23% vs −0.2%, and IGFBP-2 increased 38–70% vs +4.1% (P ≤ .031, all doses vs placebo, except fasting insulin with tirzepatide 10 mg).
  • The trial enrolled adults with early T2D; overall mean diabetes duration was 4.7 years, mean baseline HbA1c was 7.94%, and mean BMI was 31.9 kg/m².

Methods

  • Post hoc biomarker analyses of SURPASS-1, a 40-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 3 trial conducted at 47 sites in 4 countries; participants were randomized 1:1:1:1 to once-weekly tirzepatide 5, 10, or 15 mg or volume-matched placebo.
  • Modified intent-to-treat population: 478 randomized and treated, 475 analyzed (tirzepatide 5 mg n = 121; 10 mg n = 121; 15 mg n = 120; placebo n = 115). Fasting blood samples were collected at baseline and weeks 8, 16, 24, and 40.
  • Baseline measures used ANOVA; change and percent change from baseline used mixed model repeated measures, with log transformation for percent-change analyses except fasting serum glucose. No multiplicity adjustments were made; significance was two-sided alpha = .05.

Limitations

  • Stated by the paper: the biomarker analysis was exploratory and post hoc, assessments were made under fasting conditions, and additional studies are warranted to further define mechanisms.
  • Stated by the paper: there were no adjustments for multiplicity.
  • Evident from the text: some dose-specific within-group percent changes were not significant (fasting insulin, HOMA2-IR, and fasting C-peptide with the 5 and 10 mg doses per the table note), and the findings rely on fasting biomarkers rather than direct clamp-based measures.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1210/jendso/bvad056

Cites

28 of 28 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

11 of 32 cited sources checked · 4 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    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].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [6] Heise, 2022, Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial, Lancet Diabetes Endocrinol source
    • cites [14] Thomas, 2021, Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes, J Clin Endocrinol Metab source

      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
  • Findingown data

    HOMA2-B indices rapidly increased at week 8 and reached a peak up to 103% at week 24 in a dose-dependent manner with tirzepatide treatment.

    “HOMA2-B indices rapidly increased at week 8 and reached the peak up to 103% at week 24 in a dose-dependent manner with tirzepatide treatment.”
    Quote in the paperSubstantial claim
  • Findingown data

    At 40 weeks, in participants with early type 2 diabetes, tirzepatide monotherapy (5, 10, or 15 mg) increased IGFBP-2 from baseline by 38-70%, compared with +4.1% for placebo (P < .001, all doses vs placebo).

    “At 40 weeks, percent increase from baseline of IGFBP-2 levels ranged from 38% to 70% with tirzepatide (P < .001, all doses) compared to 4.1% with placebo (P > .05) (Fig. 2D). Estimated treatment differences in percent change from baseline in IGFBP-2 levels were significant between tirzepatide and placebo at 40 weeks (P < .001, all tirzepatide doses vs placebo) (Table 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    At 40 weeks, in participants with early type 2 diabetes, tirzepatide monotherapy (5, 10, or 15 mg) increased HOMA2-B (computed with C-peptide) from baseline by 77-92%, compared with −1.4% for placebo (P < .001, all doses vs placebo).

    “Increases from baseline in homeostatic model assessment for beta-cell function (computed with C-peptide) (77-92% vs −1.4%) and decreases in glucose-adjusted glucagon levels (37-44% vs +4.8%) were observed with tirzepatide vs placebo (P < .001, all doses vs placebo).”
    • Also stated in: § Tirzepatide Improved Markers of Beta-cell Function · plain
      “At 40 weeks, HOMA2-B (computed with C-peptide) significantly increased with all tirzepatide doses, ranging from 80% to 92% (P < .001, all doses) and decreased with placebo by −1.4% (P > .05) (Fig. 1C).”
    Quote in the paperSubstantial claim
  • Findingown data

    At 40 weeks, in participants with early type 2 diabetes, tirzepatide monotherapy (5, 10, or 15 mg) reduced fasting proinsulin levels from baseline by 49-55%, compared with −0.6% for placebo (P < .001, all doses vs placebo).

    “At 40 weeks, markers of beta-cell function improved with tirzepatide monotherapy vs placebo with reductions from baseline in fasting proinsulin levels (49-55% vs −0.6%) and in intact proinsulin/C-peptide ratios (47-49% vs −0.1%) (P < .001, all doses vs placebo).”
    • Also stated in: § Tirzepatide Improved Markers of Beta-cell Function · plain
      “At 40 weeks, percent change from baseline of fasting proinsulin levels ranged from −55% to −49% with tirzepatide (P < .001, all doses) compared to −0.6% with placebo (P > .05) (Fig. 1A and Table 2).”
    Quote in the paperSubstantial claim
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Premisecitation

    In preclinical studies, tirzepatide improved insulin sensitivity in GLP-1 receptor null mice, demonstrating an important role of GIP receptor agonism in insulin sensitization, in addition to contributions of both GLP-1 and GIP receptor agonism to glucose-dependent insulin secretion.

    “In preclinical studies, tirzepatide improved insulin sensitivity in GLP-1 receptor null mice, thus demonstrating the important role of GIP receptor agonism in insulin sensitization [9] in addition to contributions of both GLP-1 and GIP receptor agonism to glucose-dependent insulin secretion [10].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [9] Samms, 2021, GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice, J Clin Invest source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [10] Coskun, 2018, LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept, Mol Metab source

      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

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Impaired insulin production from pancreatic beta cells and impaired insulin action both contribute to hyperglycemia in type 2 diabetes.

    “Impaired insulin production from pancreatic beta cells and impaired insulin action both contribute to hyperglycemia in T2D [8].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Czech, 2017, Insulin action and resistance in obesity and type 2 diabetes, Nat Med source

  • May combine two claims.

    Premisecitation

    In a phase 2b trial, only 21% of the variation in improvement in HOMA2-IR was directly attributable to weight loss with tirzepatide 15 mg and 13% with tirzepatide 10 mg in multiple linear regression analysis, suggesting that the observed insulin-sensitizing effects of tirzepatide were only partially attributable to weight loss.

    “In a phase 2b trial, only 21% of the variation in improvement HOMA2-IR was directly attributable to weight loss with tirzepatide 15 mg and 13% with tirzepatide 10 mg in multiple linear regression analysis, suggesting that the observed insulin-sensitizing effects of tirzepatide were only partially attributable to weight loss [14].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Thomas, 2021, Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes, J Clin Endocrinol Metab source

  • Classified as probably not a substantial claim.

    Premisecitation

    Elevated proinsulin levels and proinsulin/C-peptide ratios may lead to endoplasmic reticulum stress and failure of pancreatic beta cells.

    “Elevated proinsulin levels and proinsulin/C-peptide ratios may lead to endoplasmic reticulum stress and failure of pancreatic beta cells [16].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Laybutt, 2007, Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes, Diabetologia source

      The Discussion links ER stress to beta-cell apoptosis and describes a proinsulin folding mutation as one possible trigger. The paper does not say that elevated proinsulin levels or proinsulin/C-peptide ratios cause ER stress or beta-cell failure; its experiments instead examine lipid-induced stress. The cited passages have section labels but no page numbers in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [13] Brown, 2022, Tirzepatide improved markers of islet-cell function (fasting glucagon and HOMA2-B) and insulin sensitivity (fasting insulin and HOMA2-IR) compared with semaglutide in people with type 2 diabetes, Diabetes source
    • cites [14] Thomas, 2021, Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes, J Clin Endocrinol Metab source

      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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In people with obesity, fasting and postprandial glucagon levels are higher compared to those with normal body weight.

    “Similarly, in people with obesity, fasting and postprandial glucagon levels are higher compared to those with normal body weight [19].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Stern, 2019, Obesity dysregulates fasting-induced changes in glucagon secretion, J Endocrinol source

  • May combine two claims.

    Premisecitation

    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].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Thomas, 2021, Dual GIP and GLP-1 receptor agonist tirzepatide improves beta-cell function and insulin sensitivity in type 2 diabetes, J Clin Endocrinol Metab source

      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

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reduced levels of adiponectin have also been associated with metabolic syndrome, dyslipidemia, and cardiovascular disease.

    “Reduced levels of adiponectin have also been associated with metabolic syndrome, dyslipidemia, and cardiovascular disease [22].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Kadowaki, 2006, Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome, J Clin Invest source

  • May combine two claims.

    Premisecitation

    In human adipocytes, GIP receptors are present and functionally active.

    “In human adipocytes, GIP receptors are present and functionally active [23‐25].”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [23] Yip, 2000, GIP Biology and fat metabolism, Life Sci source

      The section on GIP effects on fat cells (page unavailable) reports GIP receptor expression and a response to GIP stimulation in rat adipocytes and a mouse adipocyte model. It does not establish that receptors are present and functionally active in human adipocytes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [24] Samms, 2020, How may GIP enhance the therapeutic efficacy of GLP-1?, Trends Endocrinol Metab source
    • cites [25] Weaver, 2008, Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model, Int J Obes (Lond) source

  • May combine two claims.

    Findingown data

    At 40 weeks, in participants with early type 2 diabetes, tirzepatide monotherapy reduced fasting insulin levels from baseline by 2-12%, compared with +15% for placebo; treatment differences vs placebo were significant for tirzepatide 5 and 15 mg (P ≤ .031) but not for 10 mg.

    “At 40 weeks, reductions in percent change from baseline of fasting insulin ranged from 2% to 12% with tirzepatide (P > .05 tirzepatide 5 and 10 mg; P = .034, tirzepatide 15 mg) compared to increases of 15% with placebo (P = .034) (Fig. 2A). Estimated treatment differences in percent change from baseline in fasting insulin levels were significant between tirzepatide 5 and 15 mg vs placebo at 40”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 40 weeks, in participants with early type 2 diabetes, tirzepatide monotherapy (5, 10, or 15 mg) reduced HOMA2-IR (computed with insulin) from baseline by 9-23%, compared with +14.7% for placebo; treatment differences vs placebo were significant for all doses (P ≤ .006).

    “At 40 weeks, percent change from baseline of HOMA2-IR (computed with insulin) reductions with tirzepatide ranged from 9% to 23% (P < .001, tirzepatide 15 mg only) compared to a 14.7% increase with placebo (P = .028) (Fig. 2B and Table 2). Estimated treatment differences in percent change from baseline in HOMA2-IR (computed with insulin) were significant between tirzepatide and placebo at 40 weeks”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 40 weeks, in participants with early type 2 diabetes, tirzepatide monotherapy (5, 10, or 15 mg) increased total adiponectin from baseline by 16-23%, compared with −0.2% for placebo; treatment differences vs placebo were significant (P ≤ .028).

    “At 40 weeks, percent increase from baseline of total adiponectin levels ranged from 16% to 23% with tirzepatide (P ≤ .001, all doses) compared to a decrease of .2% with placebo (P > .05) (Fig. 2C and Table 2). Estimated treatment differences in percent change from baseline in total adiponectin levels were significant between tirzepatide and placebo at 40 weeks (P ≤ .028, all tirzepatide doses vs”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All participants provided signed informed consent and protocols were approved by local ethical review boards.

    “All participants provided signed informed consent and protocols were approved by local ethical review boards.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The SURPASS-1 trial was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki.

    “The SURPASS-1 trial was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    There were no adjustments for multiplicity.

    “There were no adjustments for multiplicity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Participants who discontinued study drug due to inadvertent enrollment were excluded, and data collected after study drug discontinuation or rescue drug initiation were excluded from analysis.

    “Participants who discontinued study drug due to inadvertent enrollment were excluded. Data collected after study drug discontinuation or rescue drug initiation were excluded from analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In a recently published mechanism of action study, once-weekly tirzepatide at the 15 mg dose added to background metformin demonstrated significant improvements in glycemic control through concurrent improvements in beta-cell function and insulin sensitivity and by reductions in glucagon secretion.

    “In a recently published mechanism of action study, once-weekly tirzepatide at the 15 mg dose added to background metformin demonstrated significant improvements in glycemic control through concurrent improvements in beta-cell function and insulin sensitivity and by reductions in glucagon secretion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Heise, 2022, Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial, Lancet Diabetes Endocrinol source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The SURPASS-1 trial was a 40-week, multicenter, randomized, double-blind, placebo-controlled, parallel group trial.

    “Briefly, participants in this 40-week, multicenter, randomized, double-blind, placebo-controlled, parallel group trial were randomly assigned (1:1:1:1) to receive once a week tirzepatide (5, 10, or 15 mg) or volume-matched placebo in a single-dose pen.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Rosenstock, 2021, Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial, Lancet source
    • cites [11] Lee

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Adiponectin is exclusively produced in adipocytes, and adiponectin levels are lower in type 2 diabetes and obesity compared to the healthy state.

    “Adiponectin is exclusively produced in adipocytes, and adiponectin levels are lower in T2D and obesity compared to the healthy state [20, 21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Yamauchi, 2001, The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity, Nat Med source
    • cites [21] Arita, 1999, Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity, Biochem Biophys Res Commun source

  • May combine two claims.

    Premisecitation

    In SURPASS-2 on background metformin therapy, tirzepatide treatment resulted in greater reductions in HOMA2-IR and improvements in HOMA2-B than active comparator semaglutide 1 mg in conjunction with substantial improvements in HbA1c and body weight.

    “Similarly, in SURPASS-2 on background metformin therapy, tirzepatide treatment resulted in greater reductions in HOMA2-IR and improvements in HOMA2-B than active comparator semaglutide 1 mg in conjunction with substantial improvements in HbA1c and body weight [2, 13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Frias, 2021, Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes, N Engl J Med source
    • cites [13] Brown, 2022, Tirzepatide improved markers of islet-cell function (fasting glucagon and HOMA2-B) and insulin sensitivity (fasting insulin and HOMA2-IR) compared with semaglutide in people with type 2 diabetes, Diabetes source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Participants were randomly assigned (1:1:1:1) to receive once weekly tirzepatide (5, 10, or 15 mg) or volume-matched placebo.

    “Briefly, participants in this 40-week, multicenter, randomized, double-blind, placebo-controlled, parallel group trial were randomly assigned (1:1:1:1) to receive once a week tirzepatide (5, 10, or 15 mg) or volume-matched placebo in a single-dose pen.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Assignment to treatment group was determined by a computer-generated random sequence using the Eli Lilly and Company interactive web-response system.

    “Assignment to treatment group was determined by a computer-generated random sequence using the Eli Lilly and Company interactive web-response system.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    This study is registered with ClinicalTrials.gov (NCT03954834).

    “This study is registered with ClinicalTrials.gov (NCT03954834).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hyperglucagonemia is a hallmark in type 2 diabetes, promoting hepatic glucose output and exacerbating hyperglycemia.

    “Hyperglucagonemia is a hallmark in T2D, promoting hepatic glucose output and exacerbating hyperglycemia [17, 18].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Baron, 1987, Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics, Diabetes source
    • cites [18] Shah, 2000, Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus, J Clin Endocrinol Metab source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The analyses were performed on the modified intent-to-treat population, comprised of all randomly assigned participants with at least 1 dose of study drug exposure.

    “All analyses were performed on the modified intent-to-treat population, comprised of all randomly assigned participants with at least 1 dose of study drug exposure.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    IGFBP-2 is a member of the insulin and IGF signaling pathway, and IGFBP-2 levels in humans are inversely associated with BMI, fat mass, insulin levels, and fatty liver index.

    “IGFBP-2 is a member of the insulin and IGF signaling pathway, and IGFBP-2 levels in humans are inversely associated with BMI, fat mass, insulin levels, and fatty liver index [26‐30].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [26] Wittenbecher, 2019, Insulin-like growth factor binding protein 2 (IGFBP-2) and the risk of developing type 2 diabetes, Diabetes source
    • cites [27] Ballerini, 2004, Differential impact of simple childhood obesity on the components of the growth hormone-insulin-like growth factor (IGF)-IGF binding proteins axis, J Pediatr Endocrinol Metab source
    • cites [28] Allen, 2003, Lifestyle determinants of serum insulin-like growth-factor-I (IGF-I), C-peptide and hormone binding protein levels in British women, Cancer Causes Control source
    • cites [29] Street, 2013, Interactions among pro-inflammatory cytokines, IGF system and thyroid function in pre-pubertal obese subjects, J Biol Regul Homeost Agents
    • cites [30] Counts, 1992, The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins, J Clin Endocrinol Metab source
26 of 26

  • The paper relies on this without support.

    The fasting biomarkers measured (HOMA2-B, HOMA2-IR, proinsulin, proinsulin/C-peptide ratio, glucose-adjusted glucagon, adiponectin, and IGFBP-2) validly reflect pancreatic beta-cell function and insulin sensitivity.

    “Explore changes in biomarkers of beta-cell function and IS with tirzepatide monotherapy.”
    “Tirzepatide monotherapy at doses of 5, 10, and 15 mg in the SURPASS-1 trial demonstrated significant and clinically relevant enhancements in markers of pancreatic beta-cell function and insulin sensitivity in conjunction with improved glycemic control and body weight reduction.”

  • The paper relies on this without support.

    Fasting insulin levels reflect insulin production from pancreatic beta cells in the context of changes in metabolic demand and insulin sensitivity.

    “We measured fasting insulin levels as a reflection of insulin production from pancreatic beta cells in the context of changes in metabolic demand and insulin sensitivity.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The improvement in β-cell glucose responsiveness may be more important earlier in the course of therapy, before stable glucose control has been achieved and before additional improvements in insulin sensitivity are observed in conjunction with progressive weight loss over time.

    “The improvement in β -cell glucose responsiveness may be more important earlier in the course of therapy, before stable glucose control has been achieved and before additional improvements in insulin sensitivity are observed in conjunc­ tion with progressive weight loss over time (25).”

    From Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test (2024) · cites this paper as [25]

    The Discussion (page unavailable) reports rapid improvement in a marker of β-cell function and says early glycemic improvement preceded substantial weight loss. The Results section on insulin sensitivity (page unavailable) describes a pattern consistent with increasing insulin sensitivity over time. The paper does not establish that β-cell glucose responsiveness is more important before glucose control stabilizes, or that later sensitivity gains occur in conjunction with weight loss. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • In the same paper, the authors also reported reductions in HOMA2-IR and fasting insulin levels and increases in total adiponectin and IGF-binding protein 2 levels with tirzepatide vs placebo at week 40.

    “In the same paper, the authors also reported reductions in HOMA2-IR and fasting insulin levels and increases in total adiponectin and IGF-binding protein 2 levels with tirzepatide vs placebo at week 40.”

    From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [24]

  • In a recently published post hoc analysis of markers of β-cell function, in SURPASS-1, tirzepatide, as monotherapy, improved islet cell function, as demonstrated by greater reductions in hyperglucagonemia.

    “In a recently published post hoc analysis of markers of β-cell function, in SURPASS-1, tirzepatide, as monotherapy, improved islet cell function, as demonstrated by greater reductions in hyperglucagonemia (24).”

    From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [24]

  • These findings are also consistent with observations seen in the post hoc analysis by Lee et al, of the SURPASS-1 study, demonstrating tirzepatide monotherapy vs placebo achieved significant improvements in biomarkers of both pancreatic β-cell function and insulin sensitivity in people with T2D.

    “These findings are also consistent with observations seen in the post hoc analysis by Lee et al (24), of the SURPASS-1 study, demonstrating tirzepatide monotherapy vs placebo achieved significant improvements in biomarkers of both pancreatic β-cell function and insulin sensitivity in people with T2D.”

    From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [24]

  • The observation that HOMA2-B decreased with tirzepatide treatment and decreased further with withdrawal is in contrast to previously reported post hoc studies of tirzepatide in adults with type 2 diabetes and obesity, where a significant increase in HOMA2-B with tirzepatide treatment was observed.

    “This observation is in contrast to previously reported post hoc studies of tirzepatide in adults with type 2 diabetes and obesity, where a significant increase in HOMA2-B with tirzepatide treatment was observed.”

    From Cardiometabolic Parameter Change by Weight Regain on Tirzepatide Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial (2026) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Adiponectin baseline units differ between tables

    Minor

    Table 1 reports adiponectin in mg/mL, while Table 2 reports nearly identical baseline values in ug/mL-a thousandfold difference in units.

  • Week-12 biomarker comparison lacks a listed collection time

    Minor

    The methods list biomarker blood draws at weeks 8, 16, 24, and 40, but the results report a fasting-proinsulin treatment difference by week 12.

  • Abstract HOMA2-B range does not match Table 2

    Minor

    The abstract gives a lower bound of 77% for the week-40 HOMA2-B increase, but Table 2's three dose-group values range from 79.6% to 91.8%.

3 of 3

Cites

Flagged first, then by citations

3 of the 31 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. University of Oxford

Cited by

Sorted by citations

Related

Authors
Lee, C. J., Mao, H., Thieu, V. T., Landó, L. F., & Thomas, M. K.
Affiliations
Eli Lilly (United States) (US)
Corresponding author
Lee, Clare J
ORCID
Venue
Journal of the Endocrine Society
Publisher
The Endocrine Society
Published
2023-03-06
Volume
7
Issue
5
Pages
bvad056-bvad056
ISSN
2472-1972 (ISSN-L)
DOI
10.1210/jendso/bvad056
PMC
PMC10157777
OpenAlex
W4366769762
Cited by
48
References
31
Citations by year
2026: 11 · 2025: 15 · 2024: 17 · 2023: 4
FWCI
8.25
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the Endocrine Society (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
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, type 2 diabetes, early type 2 diabetes, monotherapy, beta-cell function, insulin sensitivity, proinsulin, C-peptide

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-14.

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