Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2)
Open accessAbstract
Context: In previous SURPASS studies tirzepatide reduced hemoglobin glycated A1c (HbA1c) and body weight and improved markers of insulin sensitivity and β-cell function to a greater extent than comparators. Objective: Explore changes in biomarkers of β-cell function and insulin sensitivity and in efficacy profiles in baseline biomarker quartile analyses with tirzepatide compared to semaglutide. Design: Post hoc analysis of SURPASS-2 phase 3 trial (participants randomly assigned to receive weekly subcutaneous tirzepatide or semaglutide for 40 weeks). Setting: Post hoc analysis of 128 sites in 8 countries. Participants: A total of 1879 participants with type 2 diabetes. Interventions: Once-weekly tirzepatide (5, 10, 15 mg) or semaglutide 1 mg. Main outcomes measures: Change in homeostatic model assessment indices for pancreatic β-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR), fasting glucagon, fasting C-peptide, and fasting insulin. Results: At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P < .05). There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P < .05). Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C–peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05). HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile. Conclusion: In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline β-cell function and insulin resistance, compared with semaglutide.
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Written from the paper’s full text.
TL;DR
In a post hoc analysis of SURPASS-2, tirzepatide improved fasting markers of β-cell function and insulin sensitivity more than semaglutide 1 mg in adults with type 2 diabetes on metformin. HbA1c and body weight reductions were greater with tirzepatide across baseline HOMA2-B and HOMA2-IR quartiles, with no significant treatment-by-quartile interaction.
Key findings
- At week 40, HOMA2-B increased by 96.9%–120.4% with tirzepatide 5, 10, and 15 mg vs 84.0% with semaglutide 1 mg (P < .05).
- HOMA2-IR decreased by 15.5%–24.0% with tirzepatide vs 5.1% with semaglutide, and fasting insulin changed by −8.9% to −20.9% with tirzepatide vs +0.6% with semaglutide (P < .05).
- Tirzepatide 10 and 15 mg reduced fasting C-peptide by 5.2%–6.0% and fasting glucagon by 53.0%–55.3%, compared with semaglutide’s C-peptide increase of 3.3% and glucagon reduction of 47.7% (P < .05).
- HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile; no significant interaction was detected between HOMA quartiles and treatment group.
Methods
- Post hoc analysis of SURPASS-2, a phase 3, international, multicenter, randomized, open-label, active-controlled 40-week trial at 128 sites in 8 countries; 1879 participants with type 2 diabetes and inadequate glycemic control on metformin were randomized 1:1:1:1 to weekly subcutaneous tirzepatide 5, 10, or 15 mg or semaglutide 1 mg.
- Fasting blood samples were collected at baseline and weeks 8, 16, 24, 40, and safety follow-up; HOMA2-B and HOMA2-IR were computed with the HOMA2 calculator, and fasting glucose, insulin, C-peptide, and glucose-adjusted glucagon were measured.
- Changes were analyzed using mixed models for repeated measures in the modified intention-to-treat efficacy estimand, including baseline HOMA2-B and HOMA2-IR quartile analyses; nominal P values were reported at a 2-sided α of 0.05 with no adjustment for multiple comparisons.
Limitations
- The paper states that this was an exploratory post hoc biomarker analysis; biomarkers were collected only under fasting conditions, limiting analyses to surrogate fasting markers of β-cell function and insulin sensitivity and excluding dynamic or postprandial responses.
- The paper states that additional studies are warranted to define mechanisms, and that the analysis does not account for social determinants of health that may affect glycemic and weight outcomes.
- Evident from the text: the parent trial was open-label, and this post hoc analysis did not conduct additional adverse-event analyses; statistical testing used nominal P values without multiple-comparison adjustment.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
23 of 43 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured
- Findingown data
HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-IR baseline quartile.
“HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-IR baseline quartile (Fig. 2B, Supplementary Table S1 (16)).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Frías JP, De Block C, Brown K, et al Supplementary data for “Tirzepatide improved markers of islet cell function and insulin sensitivity in people with T2D (SURPASS-2)”. Zenodo. Deposited 1 February 2024. https://zenodo.org/records/10606145. source
- Premisecitation
In the phase 2 study, tirzepatide improved markers of insulin sensitivity to a greater extent than placebo or dulaglutide.
“In the phase 2 study, tirzepatide improved markers of insulin sensitivity and β-cell function to a greater extent than placebo or dulaglutide (11).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] 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
- Premisecitation
In the phase 2 study, tirzepatide improved markers of β-cell function to a greater extent than placebo or dulaglutide.
“In the phase 2 study, tirzepatide improved markers of insulin sensitivity and β-cell function to a greater extent than placebo or dulaglutide (11).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] 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
- Findingown data
HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-B baseline quartile.
“HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-B baseline quartile (Fig. 2A, Supplementary Table S1 (16)).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Frías JP, De Block C, Brown K, et al Supplementary data for “Tirzepatide improved markers of islet cell function and insulin sensitivity in people with T2D (SURPASS-2)”. Zenodo. Deposited 1 February 2024. https://zenodo.org/records/10606145. source
- Premisecitation
Improvements in insulin sensitivity with tirzepatide were only partly attributable to weight loss.
“Improvements in insulin sensitivity were only partly attributable to weight loss.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] 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
- Premisecitation
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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [24] Lee, 2023, Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1), J Endocr Soc source
- Premisecitation
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.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [24] Lee, 2023, Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1), J Endocr Soc source
- Premisecitation
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).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] 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 ('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
- Interpretationcitation
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).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [10] 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 [11] 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 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
- Premisecitation
Recent studies indicate that agonism of the GIP receptor is important for maximal stimulation of insulin secretion from human pancreatic β cells.
“Consistent with these clinical observations, recent studies indicate that agonism of the GIP receptor is important for maximal stimulation of insulin secretion from human pancreatic β cells (20, 21).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [20] Meier, 2003, Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia, Diabetologia source
The introductory text on p. 1 says GIP stimulates insulin secretion in healthy subjects, and the Discussion (p. 3) says this effect is most prominent during hyperglycaemia. The study itself examines glucagon secretion; it does not establish that GIP-receptor agonism is necessary for maximal insulin secretion from human pancreatic β cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [21] Christensen, 2011, Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans, Diabetes source
The Discussion (page unavailable) reports that GIP robustly potentiates glucose-induced insulin secretion during hyperglycemia, supporting a role in stimulating insulin secretion in humans. It does not establish that GIP-receptor agonism is necessary for maximal stimulation, and its findings are in healthy subjects under specific glycemic conditions. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Treatment with tirzepatide 10 or 15 mg significantly reduced proinsulin/C-peptide ratios, indicators of pancreatic β-cell stress, greater than dulaglutide.
“Furthermore, treatment with tirzepatide 10 or 15 mg significantly reduced proinsulin/C-peptide ratios, indicators of pancreatic β-cell stress, greater than dulaglutide (11).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] 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
- Findingown data
At week 40, tirzepatide 10 and 15 mg produced significant reductions in fasting C-peptide (5.2%-6.0%) compared with an increase of 3.3% with semaglutide 1 mg in participants with type 2 diabetes (P < .05).
“Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C–peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05).”
Quote in the paperSubstantial claim - Findingown data
HOMA2-B index significantly increased from baseline by 8 weeks in all cohorts.
“HOMA2-B index significantly increased from baseline by 8 weeks in all cohorts.”
Quote in the paperSubstantial claim - Findingown data
Greater reductions in HOMA2-IR (computed with insulin) were seen with all doses of tirzepatide, from 15.5% to 24.0% vs semaglutide (5.1%) (P < .05) at week 40.
“Greater reductions in HOMA2-IR (computed with insulin) were seen with all doses of tirzepatide, from 15.5% to 24.0% vs semaglutide (5.1%) (P < .05) at week 40 (Fig. 1E, Table 3).”
Quote in the paperSubstantial claim - Findingown data
Body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile.
“HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile.”
Quote in the paperNot a substantial claim - Findingown data
Significantly greater increases in HOMA2-B were observed with tirzepatide (5 mg, 10 mg, 15 mg) doses (96.9%-120.4%) vs semaglutide 1 mg (84.0%) (P < .05) at week 40.
“Significantly greater increases in HOMA2-B were observed with tirzepatide (5 mg, 10 mg, 15 mg) doses (96.9%-120.4%) vs semaglutide 1 mg (84.0%) (P < .05) at week 40 (Fig. 1C, Table 3).”
Quote in the paperSubstantial claim - Findingown data
At week 40, tirzepatide 5, 10, and 15 mg produced greater increases in HOMA2-B (96.9-120.4%) than semaglutide 1 mg (84.0%) in participants with type 2 diabetes (P < .05).
“At week 40, a greater increase in HOMA2-B was seen with tirzepatide (5, 10, 15 mg) doses (96.9-120.4%) than with semaglutide 1 mg (84.0%) (P < .05).”
Quote in the paperSubstantial claim - Findingown data
Greater and significant reductions in fasting C-peptide were seen with tirzepatide 10 and 15 mg (5.2%-6.0%) compared with the observed increase with semaglutide 1 mg (3.3%) (P < .05) at week 40.
“Greater and significant reductions in fasting C-peptide were seen with tirzepatide 10 and 15 mg (5.2%-6.0%) compared with the observed increase with semaglutide 1 mg (3.3%) (P < .05) at week 40 (Fig. 1B, Table 3).”
Quote in the paperSubstantial claim - Findingown data
At week 40, tirzepatide 5, 10, and 15 mg produced greater reductions in fasting insulin than semaglutide 1 mg in participants with type 2 diabetes.
“ETD vs semaglutide (95% CI) at week 40 | −9.5 (−17.1, −1.1)* | −15.1 (−22.3, −7.3)** | −21.4 (−28.0, −14.1)** |”
Quote in the paperSubstantial claim - Findingown data
At week 40, HbA1c reductions were greater with all tirzepatide doses than semaglutide 1 mg in the overall population.
“ETD vs semaglutide (95% CI) at week 40 | −0.23 (−0.36, −0.10)** | −0.51 (−0.64, −0.38)** | −0.60 (−0.73, −0.47)** |”
Quote in the paperSubstantial claim - Findingown data
HbA1c reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile.
“HbA1c and body weight reductions were greater with all tirzepatide doses than semaglutide within each HOMA2-B and HOMA2-IR baseline quartile.”
Quote in the paperSubstantial claim - Findingown data
Greater reductions in fasting insulin were seen with all doses of tirzepatide, from 8.9% to 20.9% vs an increase of 0.6% with semaglutide (P < .05) at week 40.
“Greater reductions in fasting insulin were seen with all doses of tirzepatide, from 8.9% to 20.9% vs an increase of 0.6% with semaglutide (P < .05) at week 40 (Fig. 1D, Table 3).”
Quote in the paperSubstantial claim - Findingown data
At week 40, tirzepatide 5, 10, and 15 mg produced greater reductions in HOMA2-IR (15.5%-24.0%) than semaglutide 1 mg (5.1%) in participants with type 2 diabetes (P < .05).
“There was a greater reduction in HOMA2-IR with all doses of tirzepatide (15.5%-24.0%) than with semaglutide 1 mg (5.1%) (P < .05).”
Quote in the paperSubstantial claim - Findingown data
At week 40, tirzepatide 10 and 15 mg produced greater reductions in fasting glucagon (53.0%-55.3%) than semaglutide 1 mg (47.7%) in participants with type 2 diabetes (P < .05).
“Tirzepatide 10 and 15 mg resulted in a significant reduction in both fasting C-peptide (5.2%-6.0%) and fasting glucagon (53.0%-55.3%) compared with an increase of C–peptide (3.3%) and a reduction of glucagon (47.7%) with semaglutide 1 mg (P < .05).”
Quote in the paperSubstantial claim - Findingown data
An initial increase in fasting insulin levels was seen at week 8 followed by decreases over time as higher doses of tirzepatide were achieved in dose escalation.
“An initial increase in fasting insulin levels was seen at week 8 followed by decreases over time as higher doses of tirzepatide were achieved in dose escalation.”
Quote in the paperNot a substantial claim - Findingown data
At week 40, body weight reductions were greater with all tirzepatide doses than semaglutide 1 mg in the overall population.
“ETD vs semaglutide (95% CI) at week 40 | −1.7 (−2.6, −0.7)** | −4.1 (−5.0, −3.2)** | −6.2 (−7.1, −5.3)** |”
Quote in the paperNot a substantial claim - Findingown data
In the overall population, fasting glucagon levels progressively decreased over time.
“In the overall population, fasting glucagon levels progressively decreased over time, and greater and significant reductions were seen with tirzepatide 10 and 15 mg (53.0 to 55.3%) than with semaglutide 1 mg (47.7%) (P < .05) at week 40 (Fig. 1A, Table 3).”
Quote in the paperNot a substantial claim - Findingown data
Body weight reductions were numerically greater across HOMA2-IR quartiles with all tirzepatide doses (range, 8.2%-13.5%) than with semaglutide (6.1%-7.1%).
“Body weight reductions were numerically greater across HOMA2-IR quartiles with all tirzepatide doses (range, 8.2%-13.5%) than with semaglutide (6.1%-7.1%) (Fig. 2D, Table 2).”
Quote in the paperNot a substantial claim - Findingown data
No significant differences were observed in baseline HbA1c between Q1 and Q4 in the HOMA2-IR quartiles.
“No significant differences were observed in baseline HbA1c between Q1 and Q4 in the HOMA2-IR quartiles (Table 2; P = .179).”
Quote in the paperNot a substantial claim - Findingown data
In this post hoc analysis, tirzepatide demonstrated significant and rapid improvement in hyperglucagonemia and related α-cell dysfunction, as indicated by reductions in fasting glucagon levels adjusted for fasting glucose ranging from 48.7% to 55.3%.
“In this post hoc analysis, tirzepatide demonstrated significant and rapid improvement in hyperglucagonemia and related α-cell dysfunction, as indicated by reductions in fasting glucagon levels adjusted for fasting glucose ranging from 48.7% to 55.3%.”
Quote in the paperSubstantial claim - Findingown data
Across all HOMA2-IR quartiles, weight reduction differences were not clearly noted within quartiles despite mean baseline weight differences.
“Across all HOMA2-IR quartiles, weight reduction differences were not clearly noted within quartiles despite mean baseline weight differences (Table 2; P < .001).”
Quote in the paperNot a substantial claim - Findingown data
Body weight reductions were numerically greater across HOMA2-B quartiles with all tirzepatide doses (range, 7.9%-14.1%) than with semaglutide (6.4%-7.2%).
“Body weight reductions were numerically greater across HOMA2-B quartiles with all tirzepatide doses (range, 7.9%-14.1%) than with semaglutide (6.4%-7.2%) (Fig. 2C, Table 1).”
Quote in the paperNot a substantial claim - Findingown data
The interaction between HOMA quartiles and treatment group was not significant for HOMA2-B or HOMA2-IR.
“The interaction between HOMA quartiles and treatment group was not significant for HOMA2-B or HOMA2-IR.”
- Also stated in: § Body Weight Changes Within HOMA2-B and HOMA2-IR Baseline Quartiles · plain
“No significant interactions were detected between HOMA quartiles and treatment group.”
Quote in the paperNot a substantial claim - Also stated in: § Body Weight Changes Within HOMA2-B and HOMA2-IR Baseline Quartiles · plain
- Findingown data
HbA1c reductions were similar across all HOMA2-IR quartiles.
“but were similar across all HOMA2-IR quartiles.”
Quote in the paperSubstantial claim - Findingown data
In exploratory linear correlation analyses, changes in HOMA2-B were moderately negatively correlated with changes in HbA1c in the SURPASS-2 study population at week 40.
“In exploratory linear correlation analyses, changes in HOMA2-B were moderately negatively correlated with changes in HbA1c in the SURPASS-2 study population at week 40 (data not shown)”
Quote in the paperNot a substantial claim - Premisecitation
In a phase 1 mechanistic study, tirzepatide treatment produced substantial improvements in insulin sensitivity.
“A phase 1 mechanistic study demonstrated substantial improvements in β-cell function, insulin sensitivity, and glucagon secretion in response to treatment with tirzepatide, that in combination contributed to the observed glucose-lowering effects (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] 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
- Premisecitation
In a phase 1 mechanistic study, the improvements in β-cell function, insulin sensitivity, and glucagon secretion in combination contributed to the observed glucose-lowering effects of tirzepatide.
“A phase 1 mechanistic study demonstrated substantial improvements in β-cell function, insulin sensitivity, and glucagon secretion in response to treatment with tirzepatide, that in combination contributed to the observed glucose-lowering effects (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] 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
- Premisecitation
In a phase 1 mechanistic study, tirzepatide treatment produced substantial improvements in β-cell function.
“A phase 1 mechanistic study demonstrated substantial improvements in β-cell function, insulin sensitivity, and glucagon secretion in response to treatment with tirzepatide, that in combination contributed to the observed glucose-lowering effects (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] 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
- Premisecitation
In a phase 1 mechanistic study, tirzepatide treatment produced substantial improvements in glucagon secretion.
“A phase 1 mechanistic study demonstrated substantial improvements in β-cell function, insulin sensitivity, and glucagon secretion in response to treatment with tirzepatide, that in combination contributed to the observed glucose-lowering effects (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] 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
- Interpretationreasoning
Collectively these results support the hypothesis that GIP receptor agonism may confer additional insulin-sensitizing actions beyond the effects of activating the GLP-1R alone.
“Collectively these results support the hypothesis that GIP receptor agonism may confer additional insulin-sensitizing actions beyond the effects of activating the GLP-1R alone.”
Quote in the paperSubstantial claim - Premisecitation
In mechanistic studies in people with T2D treated for 28 weeks with tirzepatide dose escalated to 15 mg or semaglutide 1 mg, administration of tirzepatide resulted in significantly greater increases in total insulin secretion from pancreatic β cells in hyperglycemic clamp studies and in the disposition index than did semaglutide.
“Furthermore, in mechanistic studies in people with T2D treated for 28 weeks with tirzepatide dose escalated to 15 mg or semaglutide 1 mg, administration of tirzepatide resulted in significantly greater increases in total insulin secretion from pancreatic β cells in hyperglycemic clamp studies and in the disposition index than did semaglutide (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] 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
- Interpretationown data
These observations suggest dual agonism of both GLP-1 and GIP receptors has the potential to provide additional improvement in pancreatic β-cell function compared with selective agonism of GLP-1 receptors alone for some people with T2D.
“These observations suggest dual agonism of both GLP-1 and GIP receptors has the potential to provide additional improvement in pancreatic β-cell function compared with selective agonism of GLP-1 receptors alone for some people with T2D.”
Quote in the paperSubstantial claim - Interpretationcitation
These observations were consistent with observed greater numerical improvements in additional metabolic measures often associated with insulin resistance in people living with diabetes, including fasting triglyceride and high-density lipoprotein cholesterol levels as well as body mass indices, following treatment with tirzepatide compared with semaglutide.
“These observations were consistent with observed greater numerical improvements in additional metabolic measures often associated with insulin resistance in people living with diabetes, including fasting triglyceride and high-density lipoprotein cholesterol levels as well as body mass indices, following treatment with tirzepatide compared with semaglutide (6).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Frías, 2021, Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes, N Engl J Med source
- Interpretationown data
People with markers of diminished pancreatic β-cell function at baseline had the most glycemic improvement.
“People with markers of diminished pancreatic β-cell function at baseline had the most glycemic improvement.”
Quote in the paperSubstantial claim - Interpretationreasoning
The distinct efficacy profile of tirzepatide may be attributed to enhancements in both islet cell function and insulin sensitivity.
“The distinct efficacy profile of tirzepatide may be attributed to enhancements in both islet cell function and insulin sensitivity.”
Quote in the paperSubstantial claim - Premisecitation
In hyperinsulinemic euglycemic clamp studies, treatment of people with T2D with tirzepatide 15 mg for 26 weeks produced a large and significant increase in insulin sensitivity measured by M-value that was greater than that observed for treatment with semaglutide 1 mg.
“In hyperinsulinemic euglycemic clamp studies, treatment of people with T2D with tirzepatide 15 mg for 26 weeks produced a large and significant increase in insulin sensitivity measured by M-value that was greater than that observed for treatment with semaglutide 1 mg (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] 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
- Classified as probably not a substantial claim. 13
- May combine two claims. 20
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTirzepatide is a first-in-class, once-weekly, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for treatment of people with type 2 diabetes and obesity.
“Tirzepatide is a first-in-class, once-weekly, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist approved for treatment of people with T2D and obesity (1, 3, 4).”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [1] De Block, 2023, Tirzepatide for the treatment of adults with type 2 diabetes: an endocrine perspective, Diabetes Obes Metab source
The Abstract and Introduction describe tirzepatide as a GIP/GLP-1 receptor agonist given once weekly and approved in the United States for adults with type 2 diabetes. They say its use for obesity and chronic weight management was under investigation, not approved. The cited passages call it novel but do not establish the specific “first-in-class” designation. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [3] Jastreboff, 2022, Tirzepatide once weekly for the treatment of obesity, N Engl J Med source
- cites [4] U.S. Food and Drug Administration
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationIn the SURPASS phase 3 trials, tirzepatide (5, 10, and 15 mg) reduced body weight up to 12.9 kg, significantly more than placebo (SURPASS-1), semaglutide 1 mg (SURPASS-2), insulin degludec (SURPASS-3), insulin glargine (SURPASS-4), and placebo as an add on to insulin glargine (SURPASS-5).
“In the SURPASS phase 3 trials, tirzepatide (5, 10, and 15 mg) reduced glycated hemoglobin A1c (HbA1c) up to 2.6% and reduced body weight up to 12.9 kg, significantly more than placebo (SURPASS-1), semaglutide 1 mg (SURPASS-2), insulin degludec (SURPASS-3), insulin glargine (SURPASS-4), and placebo as an add on to insulin glargine (SURPASS-5) (5-9).”
Quote in the paperNot a substantial claim1 of 5 sources checked- cites [5] 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 [6] Frías, 2021, Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes, N Engl J Med source
- cites [7] Ludvik, 2021, Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial, Lancet source
- cites [8] Del Prato, 2021, Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial, Lancet source
- cites [9] Dahl, 2022, Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial, JAMA source
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable, 1 not checked. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn the SURPASS phase 3 trials, tirzepatide (5, 10, and 15 mg) reduced HbA1c up to 2.6%, significantly more than placebo (SURPASS-1), semaglutide 1 mg (SURPASS-2), insulin degludec (SURPASS-3), insulin glargine (SURPASS-4), and placebo as an add on to insulin glargine (SURPASS-5).
“In the SURPASS phase 3 trials, tirzepatide (5, 10, and 15 mg) reduced glycated hemoglobin A1c (HbA1c) up to 2.6% and reduced body weight up to 12.9 kg, significantly more than placebo (SURPASS-1), semaglutide 1 mg (SURPASS-2), insulin degludec (SURPASS-3), insulin glargine (SURPASS-4), and placebo as an add on to insulin glargine (SURPASS-5) (5-9).”
Quote in the paperSubstantial claim1 of 5 sources checked- cites [5] 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 [6] Frías, 2021, Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes, N Engl J Med source
- cites [7] Ludvik, 2021, Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial, Lancet source
- cites [8] Del Prato, 2021, Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial, Lancet source
- cites [9] Dahl, 2022, Effect of subcutaneous tirzepatide vs placebo added to titrated insulin glargine on glycemic control in patients with type 2 diabetes: the SURPASS-5 randomized clinical trial, JAMA 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
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationType 2 diabetes results from multiple pathophysiological mechanisms, including defects in insulin secretion, insulin resistance, decreased incretin effect, increased glucagon secretion, and adiposity.
“Type 2 diabetes (T2D) results from multiple pathophysiological mechanisms, including defects in insulin secretion, insulin resistance, decreased incretin effect, increased glucagon secretion, and adiposity (1, 2).”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationThe analysis also does not account for social determinants of health, which may impact the glycemic and weight outcomes in this population.
“The analysis also does not account for social determinants of health, which may impact the glycemic and weight outcomes in this population (25).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Hill-Briggs, 2020, Social determinants of health and diabetes: a scientific review, Diabetes Care source
Classified as probably not a substantial claim.
PremisecitationRecent epidemiologic studies have combined analyses of genetic markers, clinical traits, and circulating biomarkers to propose that people living with T2D can be stratified into consistent phenotypic subtypes or clusters.
“Recent epidemiologic studies have combined analyses of genetic markers, clinical traits, and circulating biomarkers to propose that people living with T2D can be stratified into consistent phenotypic subtypes or clusters (17).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Deutsch, 2022, Phenotypic and genetic classification of diabetes, Diabetologia source
May combine two claims.
PremisecitationIn 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.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [24] Lee, 2023, Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1), J Endocr Soc source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationIn several independent cohorts, subgroups have been identified that were either characterized by lower pancreatic β-cell function as described by lower HOMA2-B indices or distinct subgroups characterized by higher insulin resistance as described by higher HOMA2-IR indices.
“In several independent cohorts, subgroups have been identified that were either characterized by lower pancreatic β-cell function as described by lower HOMA2-B indices or distinct subgroups characterized by higher insulin resistance as described by higher HOMA2-IR indices (17-19).”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [17] Deutsch, 2022, Phenotypic and genetic classification of diabetes, Diabetologia source
- cites [18] Ahlqvist, 2018, Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables, Lancet Diabetes Endocrinol source
- cites [19] Mahajan, 2018, Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes, Nat Genet source
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataThe reduction was significantly greater for tirzepatide 10 mg and 15 mg across all quartiles and for tirzepatide 5 mg in Q2 and Q3 (P < .05) within HOMA2-B quartiles.
“The reduction was significantly greater for tirzepatide 10 mg and 15 mg across all quartiles and for tirzepatide 5 mg in Q2 and Q3 (P < .05).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAcross HOMA2-B quartiles, the extent of HbA1c reductions was related to baseline HbA1c and largest in participants within Q1.
“Across HOMA2-B quartiles, the extent of HbA1c reductions was related to baseline HbA1c and largest in participants within Q1 (Fig. 2A, Table 1).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataFasting C-peptide levels initially increased at lower doses of tirzepatide in the initial stages of dose escalation and subsequently decreased over time.
“Fasting C-peptide levels initially increased at lower doses of tirzepatide in the initial stages of dose escalation and subsequently decreased over time.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataImprovement in HbA1c and weight loss were consistent and significantly higher with tirzepatide regardless of baseline β-cell function and insulin resistance biomarkers.
“Improvement in HbA1c and weight loss were consistent and significantly higher with tirzepatide regardless of baseline β-cell function and insulin resistance biomarkers.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe reduction was significantly greater for tirzepatide 10 and 15 mg in each quartile and for tirzepatide 5 mg in Q3 (P < .05) within HOMA2-B quartiles.
“The reduction was significantly greater for tirzepatide 10 and 15 mg in each quartile and for tirzepatide 5 mg in Q3 (P < .05).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe reduction was significantly greater for tirzepatide 10 mg and 15 mg across all quartiles and for tirzepatide 5 mg in Q3 and Q4 (P < .05) within HOMA2-IR quartiles.
“The reduction was significantly greater for tirzepatide 10 mg and 15 mg across all quartiles and for tirzepatide 5 mg in Q3 and Q4 (P < .05).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningWeight reductions were related to baseline weight across HOMA2-B quartiles and the largest reduction was seen in Q4 (quartile with higher β-cell function).
“Weight reductions were related to baseline weight across HOMA2-B quartiles and the largest reduction was seen in Q4 (quartile with higher β-cell function).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe reduction was significantly greater for tirzepatide 10 and 15 mg across all quartiles and for tirzepatide 5 mg in Q1 and Q2 (P < .05) within HOMA2-IR quartiles.
“The reduction was significantly greater for tirzepatide 10 and 15 mg across all quartiles and for tirzepatide 5 mg in Q1 and Q2 (P < .05).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo adjustment for multiple comparisons was performed.
“No adjustment for multiple comparisons was performed.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIn this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline β-cell function and insulin resistance, compared with semaglutide.
“In this post hoc analysis, improvements in HbA1c and weight loss were consistent and significantly higher with tirzepatide, regardless of baseline β-cell function and insulin resistance, compared with semaglutide.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataSignificant differences across HOMA2-B baseline quartiles were observed in weight, BMI, HbA1c, fasting serum glucose, and mean duration of diabetes.
“Baseline characteristics were comparable across HOMA2-B baseline quartiles for some characteristics, but significant differences were observed in weight, body mass index (BMI), HbA1c, fasting serum glucose, and mean duration of diabetes (Table 1).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataSignificant differences across HOMA2-IR baseline quartiles were observed in age, weight, BMI, fasting serum glucose, and duration of diabetes.
“HOMA2-IR baseline quartiles were also comparable for some characteristics except for age, weight, BMI, fasting serum glucose, and duration of diabetes (Table 2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe use of each treatment (tirzepatide 5 mg, 10 mg, 15 mg; semaglutide 1 mg) was equal across HOMA2-B and HOMA2-IR baseline quartiles.
“The use of each treatment (tirzepatide 5 mg, 10 mg, 15 mg; semaglutide 1 mg) was equal across HOMA2-B and HOMA2-IR baseline quartiles.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe study is registered with ClinicalTrials.gov (NCT03987919).
“This study is registered with ClinicalTrials.gov (NCT03987919).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIt is well recognized that hyperglucagonemia is characteristic in T2D, promoting hepatic glucose output and exacerbating hyperglycemia.
“It is well recognized that hyperglucagonemia is characteristic in T2D, promoting hepatic glucose output and exacerbating hyperglycemia (22, 23).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [22] Baron, 1987, Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics, Diabetes source
- cites [23] Shah, 2000, Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus1, J Clin Endocrinol Metab
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataImprovements in pancreatic β-cell function in response to treatment were associated with, and may have contributed to, reductions in hyperglycemia.
“suggesting that improvements in pancreatic β-cell function in response to treatment were associated with, and may have contributed to, reductions in hyperglycemia.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenLimitations of this study include the exploratory nature of the post hoc biomarker analysis.
“Limitations of this study include the exploratory nature of the post hoc biomarker analysis.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThese improvements were maintained regardless of the baseline pancreatic β-cell function and insulin sensitivity, and the degree of HbA1c and body weight reduction was comparable across HOMA2-B and HOMA2-IR quartiles.
“These improvements were maintained regardless of the baseline pancreatic β-cell function and insulin sensitivity, and the degree of HbA1c and body weight reduction was comparable across HOMA2-B and HOMA2-IR quartiles.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenFindings are consistent with findings of in vitro, preclinical, mechanistic, and other randomized clinical trials assessing changes in β-cell function and insulin sensitivity with tirzepatide.
“Findings are consistent with findings of in vitro, preclinical, mechanistic, and other randomized clinical trials assessing changes in β-cell function and insulin sensitivity with tirzepatide.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIn the SURPASS-2 trial, tirzepatide 5 mg, 10 mg, and 15 mg demonstrated significant and clinically relevant enhancements in markers of pancreatic β-cell function and insulin sensitivity in conjunction with improved glycemic control and body weight reduction.
“In the SURPASS-2 trial, tirzepatide 5 mg, 10 mg, and 15 mg demonstrated significant and clinically relevant enhancements in markers of pancreatic β-cell function and insulin sensitivity in conjunction with improved glycemic control and body weight reduction.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataBiomarkers in this phase 3 study were collected only under fasting conditions, limiting the analysis to surrogate fasting markers of β-cell function and insulin sensitivity that were not able to incorporate dynamic or postprandial responses.
“Biomarkers in this phase 3 study were collected only under fasting conditions, limiting the analysis to surrogate fasting markers of β-cell function and insulin sensitivity that were not able to incorporate dynamic or postprandial responses.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIn this post hoc analysis of the SURPASS 2 trial, treatment with tirzepatide at doses of 5 mg, 10 mg, and 15 mg significantly improved biomarkers of β-cell function and insulin sensitivity as well as glycemic control and body weight loss compared with the selective GLP-1 receptor agonist, semaglutide 1 mg, in people with T2D on concomitant metformin.
“In this post hoc analysis of the SURPASS 2 trial, treatment with tirzepatide at doses of 5 mg, 10 mg, and 15 mg significantly improved biomarkers of β-cell function and insulin sensitivity as well as glycemic control and body weight loss compared with the selective GLP-1 receptor agonist, semaglutide 1 mg, in people with T2D on concomitant metformin.”
Quote in the paperSubstantial claim
The paper relies on this without support.
β-cell dysfunction and impaired insulin resistance are interrelated in the pathogenesis of diabetes and result in inadequate glucose homeostasis.
“β-cell dysfunction and impaired insulin resistance are interrelated in the pathogenesis of diabetes and result in inadequate glucose homeostasis.”
The paper relies on this without support.
Concordant changes in markers of pancreatic β-cell function and insulin resistance were also observed in the SURPASS-1 and SURPASS-2 trials.
“Concordant changes in markers of pancreatic β-cell function and insulin resistance were also observed in the SURPASS-1 and SURPASS-2 trials.”
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?
HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-B baseline quartile.
“HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-B baseline quartile (Fig. 2A, Supplementary Table S1 (16)).”
From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [16]
HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-IR baseline quartile.
“HbA1c reductions were numerically greater with all tirzepatide doses than with semaglutide within each HOMA2-IR baseline quartile (Fig. 2B, Supplementary Table S1 (16)).”
From Tirzepatide Improved Markers of Islet Cell Function and Insulin Sensitivity in People With T2D (SURPASS-2) (2024) · cites this paper as [16]
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.
HOMA2-IR is incorrectly defined as β-cell function
MinorThe Table 2 note defines HOMA2-IR as an assessment of β-cell function, while the methods define it as an assessment of insulin resistance.
“HOMA2-IR, homeostasis model assessment for beta cell function (calculated with insulin)”
“Homeostatic model assessment (HOMA2) indices for pancreatic β-cell function (HOMA2-B) and for insulin resistance (HOMA2-IR)”
Discussion misstates baseline HbA1c in the highest HOMA2-B quartile
MinorThe discussion gives Q4 baseline HbA1c as 8.3%, but Table 1 reports 7.6% for Q4. The 8.3% figure is the overall mean, altering the stated comparison between Q1 and Q4.
“the difference in mean HbA1c at baseline between Q1 and Q4 (9.1% and 8.3%, respectively)”
“| HbA1c, % | 9.1 (1.01) | 8.4 (0.90) | 8.0 (0.82) | 7.6 (0.76) | 8.3 (1.03) | <.001 |”
C-peptide reduction is not significant for every tirzepatide dose
MinorThe discussion claims a significantly greater C-peptide reduction with each dose, but Table 3 shows no significance marker for the 5-mg comparison and its 95% confidence interval includes zero.
“Significantly greater reductions in HOMA2-IR, fasting insulin, and C-peptide concentrations were seen with each tirzepatide dose compared with semaglutide at week 40 in SURPASS-2.”
“| ETD vs semaglutide (95% CI) at week 40 | −6.6 (−12.9, 0.1) | −8.3 (−14.4, −1.6)* | −9.0 (−15.1, −2.4)* | |”
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Tirzepatide Once Weekly for the Treatment of Obesity
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Self-citationCorrect Homeostasis Model Assessment (HOMA) Evaluation Uses the Computer Program
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Flagged first, then by citations
4 of the 27 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Novel GLP-1-based Medications for Type 2 Diabetes and Obesity
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History of glucagon-like peptide-1 receptor agonists
Darwish, R., Abu-Sharia, G., & Butler, A. E. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.108045 · Cited by 24 · see citing works
Innovative Molecules and Delivery Technologies Enabling the Future of GLP-1-based Therapies
Xu, Y., Drucker, D. J., Traverso, G., & Beloqui, A. (2025) · Endocrine Reviews · doi:10.1210/endrev/bnaf027 · Cited by 9 · see citing works
Rosenstock, J., Robins, D. A., Duffin, K. L., Wilson, J. M., Lin, Y., Banerjee, H., Eyde, S., KAZDA, C. M., Кониг, М., & Mather, K. J. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70022 · Cited by 9 · see citing works
Vilsbøll, T., Malecki, M. T., Sharma, P., Thieu, V. T., Chivukula, K. K., & Kiljanski, J. I. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16592 · Cited by 9 · see citing works
“…cell secretory function, insulin sensitivity and inhibition of glucagon secretion are more pronounced with tirzepatide than with the GLP-1 RA, semaglutide 1 mg. 10,11 It also remains unclear as to what extent the greater weight loss (WL) seen with tirze-patide drives improved glycaemic control.”
Hamamoto, Y., Oura, T., & Hirase, T. (2025) · Diabetes Therapy · doi:10.1007/s13300-025-01704-z · Cited by 7 · see citing works
“[9].”
InfluentialInsulin resistance prediction from wearables and routine blood biomarkers
Metwally, A. A., Heydari, A. A., McDuff, D., Solot, A., Esmaeilpour, Z., Faranesh, A. Z., Zhou, M., Narayanswamy, G., Xu, M. A., Liu, X., et al. (2026) · Nature · doi:10.1038/s41586-026-10179-2 · Cited by 11 · see citing works
“Studies have shown that incretin-hormone agonists, such as GLP1 and GIP, act as sensitizers and improve IR 16,17 .”
Reis‐Barbosa, P. H., Águila, M. B., & Mandarim‐de‐Lacerda, C. A. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15937 · Cited by 4 · see citing works
Updated Review of HOMA-IR (Homeostatic Model Assessment for Insulin Resistance)
Ambalavanan, J. (2025) · Evidence to Action Official Journal of MDCalc · doi:10.65357/001c.154184 · Cited by 4 · see citing works
Strategies to Address the Metabolic Burden of Psychotropic Medications
Anthamatten, A., & Henry-Okafor, Q. (2025) · The Journal for Nurse Practitioners · doi:10.1016/j.nurpra.2025.105346 · Cited by 3 · see citing works
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Glucagon suppression under GLP-1RA therapy: hidden trade-offs for muscle and resilience
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“In mechanistic substudies, tirzepatide produced sub - stantial reductions in fasting and postprandial glucagon concentrations, in some cases exceeding those observed with semaglutide [ 9 , 10 ].”
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“Tirzepatide enhances β -cell function via dual GIP and GLP-1 receptor stimulation—promoting glucose-dependent insulin secretion, lowering the proinsulin/C-peptide ratio, and increasing homeostatic model assessment 2 of β -cell function (HOMA2-https β ) [6,20].”
Tirzepatide: The Most Effective Drug Therapy for Prevention of Type 2 Diabetes
Mikhail, N. (2025) · Clinical Endocrinology and Metabolism · doi:10.31579/2834-8761/073
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“The SURPASS‐2 trial demonstrated HbA1c reductions up to 2.3% (25 mmol/mol) and weight loss over 11 kg with tirzepatide, exceeding outcomes with semaglutide 1 mg [25].”
InfluentialBhaduri, G., BHATTACHARYYA, S., Mukherjee, S., & Gokalani, R. A. (2026) · Acta Diabetologica · doi:10.1007/s00592-025-02636-7
Tirzepatide improves pancreatic β-cell function in mice and patients with type 2 diabetesPreprint
Li, Z., Guo, J., Cheng, Y., Zhang, T., Luo, X., Zhang, S., Ren, Q., Wu, Z., Chen, N., & Li, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.13.704343
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Tirzepatide Versus Intensified Conventional Care After 2 Years of Treatment in Early Type 2 Diabetes
Prato, S. D., Heine, R. J., Manghi, F. P., Hsia, S. H., Valderas, E. G., Zeytinoglu, M., Razzoli, E., Kiljanski, J. I., Sharma, P., Knights, A. W., et al. (2026) · Annals of Internal Medicine · doi:10.7326/annals-25-05602
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“…derived from SURPASS-2 suggested that differences between tirzepatide and semaglutide may extend beyond conventional glycemic endpoints to markers of islet-cell function, insulin sensitivity, composite metabolic target attainment, and durability of combined glycemic and weight benefit [7–10].”
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“…with significant improvements in markers of beta-cell function and insulin sensitivity in people with type 2 diabetes, as demonstrated by greater increases in HOMA2-β and reductions in HOMA2-IR, fasting C-peptide, glucagon, and insulin levels compared with semaglutide and placebo [20, 21].”
Exploring on the Hyperinsulinism Management in Women with Polycystic Ovary Syndrome
de Medeiros, S. F., Yamamoto, M. M. W., Jacomeli, J., Soares, J. M., Maciel, G. A. R., & Baracat, E. C. (2026) · Journal of Gynecology and Obstetrics · doi:10.11648/j.jgo.20261403.12
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Mahmoud, R., Yousif, A. A. Z., Osman, A. F. M., Omer, E. O. E., Talaat, A. I. A., Mohamed, O., Akasha, S. A. M., Saleh, E., & Osman, H. M. M. (2026) · Cureus · doi:10.7759/cureus.116733
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- Authors
- Frias, J. P., De Block, C., Brown, K., Wang, H., Thomas, M. K., Zeytinoglu, M., & Maldonado, J. M.
- Affiliations
- Velocity Clinical Research , Los Angeles, CA 90057 , USA
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp , 2650 Edegem, Belgium
- Eli Lilly (United States) (US)
- TechData Service , King of Prussia, PA 19406 , USA
- Lilly Research Laboratories, Eli Lilly and Company , San Juan 00918 , Puerto Rico
- Corresponding author
- Maldonado, Juan M
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2024-01-22
- Volume
- 109
- Issue
- 7
- Pages
- 1745-1753
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC11180500
- OpenAlex
- W4391091645
- Semantic Scholar
- 59a3370e3f7f4292f53c5bebdf663dd0dcc4703d
- Cited by
- 31
- References
- 27
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 2
- FWCI
- 8.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Clinical Endocrinology & Metabolism (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, semaglutide, beta-cell function, insulin sensitivity, insulin resistance, HOMA2-B, HOMA2-IR, fasting C-peptide, HbA1c, weight loss, GLP-1 receptor agonists, GIP/GLP-1 dual agonist
- MeSH terms
- Glucagon-Like Peptide-2 Receptor, Tirzepatide, Semaglutide, Adult, Aged, Blood Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Glucagon-Like Peptides, Female, Gastric Inhibitory Polypeptide, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Islets of Langerhans, Male, Middle Aged, Biomarkers, Treatment Outcome, Insulin-Secreting Cells
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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.
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