Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test
Open accessAbstract
Context: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. Objective: This work aimed to evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. Methods: A 28-week double–blind, randomized, placebo-controlled trial of patients with type 2 diabetes treated with metformin was conducted at 2 clinical research centers in Germany. Interventions included tirzepatide 15 mg, semaglutide 1 mg, and placebo. Main outcome measures included glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2–mmol/L glucose (ISR7.2), β-cell glucose sensitivity (β-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. Results: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < .01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < .01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < .01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < .05), showing improved β-CGS. MMTT-derived β-CGS was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < .01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. Conclusion: These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.
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TL;DR
In a 28-week randomized trial in adults with type 2 diabetes on metformin, tirzepatide 15 mg improved fasting glucose and total mixed-meal tolerance test (MMTT) glucose AUC more than semaglutide 1 mg, with greater reductions in total insulin secretion rate and greater improvements in insulin sensitivity and glucagon suppression. Model-based meal-test analyses suggest these differences are driven mainly by greater fasting glucose lowering and improved β-cell responsiveness at fixed glucose levels.
Key findings
- At week 28, fasting glucose least squares mean was 81 mg/dL with tirzepatide, 90 mg/dL with semaglutide, and 128 mg/dL with placebo (both active treatments P < .001 vs placebo; tirzepatide vs semaglutide P < .01). Total MMTT glucose AUC0-240min was reduced significantly more with tirzepatide vs semaglutide (P < .01), while incremental glucose AUC did not differ significantly between treatments.
- Total postmeal insulin secretion rate (ISR) AUC0-240min decreased more with tirzepatide vs semaglutide (P < .01), alongside greater improvement in insulin sensitivity with tirzepatide (P < .01). Matsuda, Stumvoll, and oral glucose insulin sensitivity indices all improved vs placebo and more with tirzepatide vs semaglutide (P < .01), consistent with hyperinsulinemic euglycemic clamp-derived M values.
- ISR at 7.2 mmol/L increased significantly more with tirzepatide vs semaglutide (P < .05); hyperglycemic clamp-derived β-cell glucose sensitivity improved more with tirzepatide vs semaglutide (P < .01), but MMTT-derived β-cell glucose sensitivity increased without a significant between-treatment difference.
- Both treatments reduced fasting and total glucagon AUC; total glucagon AUC was reduced significantly more with tirzepatide vs semaglutide (P < .01). Estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. HbA1c change was −2.05% with tirzepatide, −1.64% with semaglutide, and +0.29% with placebo; body weight change was −11.2 kg, −6.9 kg, and 0.0 kg, respectively (P < .001 tirzepatide vs semaglutide for both).
Methods
- 28-week double-blind, randomized, placebo-controlled, parallel-arm mechanism-of-action trial at 2 clinical research sites in Germany (NCT03951753); N = 117 adults aged 20 to 74 years with type 2 diabetes, BMI 25 to 45, treated with stable metformin with or without 1 additional oral antihyperglycemic medication, randomized 3:3:2 to once-weekly subcutaneous tirzepatide 15 mg, semaglutide 1 mg, or placebo.
- Standardized MMTT provided 35% of daily energy requirements with fixed macronutrient contributions (15% protein, 45% carbohydrate, 40% fat); glucose, insulin, C-peptide, and glucagon were measured before and after meal ingestion. Model-derived ISR and β-cell function indices included ISR at 7.2 mmol/L, β-cell glucose sensitivity, rate sensitivity, and potentiation; insulin sensitivity was assessed by Matsuda, oral glucose insulin sensitivity, Stumvoll, and hyperinsulinemic euglycemic clamp M value; hepatic insulin-to-glucagon ratio was estimated.
- Analysis of covariance compared week 28 values or change from baseline across groups using baseline value as a covariate; analysis of variance compared baseline variables.
Limitations
- Stated: this was a mechanism-of-action study with a comparatively small sample size powered for hyperglycemic clamp-derived primary end points and not explicitly powered for the parameters evaluated here; the population was limited to participants with type 2 diabetes and modest hyperglycemia, so results may not extrapolate to other subsets; semaglutide 1 mg was the highest available dose at the time of study design, and it is unknown whether higher doses might perform differently.
- Stated: gastric emptying was not assessed, though prior evidence of short-lived tachyphylaxis makes it unlikely to affect the meal tolerance test results for either agent.
- Evident from the text: MMTT-derived β-cell glucose sensitivity did not significantly differ between tirzepatide and semaglutide while hyperglycemic clamp-derived β-cell glucose sensitivity did; the authors note the reason is unclear and may relate to the lower range of glucose stimulation achieved with the MMTT.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
15 of 35 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured
- Premisecitation§ Discussion · p. 7
The slope of the relationship between glucose and insulin secretion (β-CGS) is a major controller of postprandial glucose levels.
“The slope of the relationship between glucose and insulin secretion (ie, β -CGS) is a major controller of postprandial glu cose levels (23, 24).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [23] Mari, 2010, Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance, Diabetologia source
The Methods define β-cell glucose sensitivity as the slope of the insulin-secretion response to glucose. The Results and Discussion identify it as the largest contributor to glucose levels during an oral glucose tolerance test, but the paper assesses a glucose load rather than a meal and does not establish that the slope controls postprandial glucose levels generally. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [24] Ferrannini, 2005, β-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis, J Clin Endocrinol Metab source
- Premisecitation§ Abstract · p. 2
50% to 60% of participants treated with tirzepatide 15 mg achieved normoglycemia (glycated hemoglobin below 39 mmol/mol [5.7%]).
“Notably, 50% to 60% of partici pants treated with tirzepatide 15 mg achieved normoglycemia (glycated hemoglobin values below 39 mmol/mol [5.7%]) (13), as defined by the American Diabetes Association (14).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [13] 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] American Diabetes Association, 2022, Standards of Medical Care in Diabetes-2022 abridged for primary care providers, Clin Diabetes source
- Premisecitation§ Discussion · p. 7
Tirzepatide has dual actions through the GLP-1 and GIP receptors.
“Tirzepatide has dual actions through the GLP-1 and GIP re ceptors (30).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] 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
- Findingown data§ Model-derived Indices of β -Cell Function · p. 6
MMTT-derived ISR at a glucose of 7.2 mmol/L adjusted for potentiation markedly improved with both tirzepatide (P < .001) and semaglutide (P < .01) vs placebo.
“This measure markedly improved with both tirzepatide ( P < .001) and semaglutide ( P < .01) vs placebo”
Quote in the paperSubstantial claim - Findingown data§ Abstract · p. 2
Incremental glucose AUC did not differ significantly between tirzepatide and semaglutide.
“Incremental glucose AUC did not differ significantly between treatments”
Quote in the paperSubstantial claim
- Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 6
No significant differences were noted between the tirzepatide and semaglutide treatment groups in the average postmeal insulin-to-glucagon ratio.
“No significant dif ferences were noted between the tirzepatide and semaglutide treatment groups in the average postmeal insulin-to-glucagon ratio (see Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Discussion · p. 7
Changes in incremental glucose AUC0-240min did not differ significantly between treatments.
“while changes in incremental glucose AUC0-240min did not differ sig nificantly between treatments (see Table 2 and our previous report (13)).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] 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
- Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4
Total postmeal ISR AUC0-240min decreased after treatment with tirzepatide and semaglutide.
“The total postmeal ISR AUC0-240min decreased after treatment with tirzepatide and semaglutide”
Quote in the paperSubstantial claim - Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4
No significant differences in basal ISR were observed between tirzepatide and semaglutide groups.
“nevertheless, no significant differences were observed between the tirzepa tide and semaglutide groups.”
Quote in the paperNot a substantial claim - Findingown data§ Model-derived Indices of β -Cell Function · p. 6
Rate sensitivity was not significantly affected by any treatment.
“Rate sensitivity was not significantly affected by any treat ment.”
Quote in the paperNot a substantial claim - Findingown data§ Insulin Sensitivity Indices · p. 6
The Matsuda, Stumvoll, and OGIS indices all reflected improvements in insulin sensitivity with both treatments compared to placebo.
“The Matsuda, Stumvoll, and OGIS indices all reflected improvements in insulin sensitivity with both treatments com pared to placebo.”
Quote in the paperSubstantial claim - Findingown data§ Abstract · p. 2
A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide.
“A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide ( P < .01)”
Quote in the paperSubstantial claim - Findingown data§ Discussion · p. 6
There were no significant changes in rate sensitivity comparing baseline to week 28 within treatments or in pairwise comparisons across treatments.
“There were no significant changes in rate sensitivity, compar ing baseline to week 28 within treatments or in pairwise com parisons across treatments (see Table 2).”
Quote in the paperNot a substantial claim - Findingown data§ Discussion · p. 6
The total postmeal ISR was lower with tirzepatide than with semaglutide.
“and the total postmeal ISR was lower with tirzepatide than with semaglu tide.”
Quote in the paperSubstantial claim - Findingown data§ Model-derived Indices of β -Cell Function · p. 6
The increase in MMTT-derived ISR at a glucose of 7.2 mmol/L adjusted for potentiation was significantly larger with tirzepatide vs semaglutide (P < .05).
“and the increase was sig nificantly larger with tirzepatide vs semaglutide ( P < .05) (see Table 2).”
- Also stated in: § Discussion · p. 6 · plain
“Increases in the ISR at a glucose of 7.2 mmol/L and in glucagon suppression were greater with tir zepatide than with semaglutide.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · p. 6 · plain
- Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 6
The decrease in total glucagon AUC0-240min was greater with tirzepatide than with semaglutide (P < .01).
“but to a greater degree with tirzepa tide vs semaglutide ( P < .01) (see Table 2).”
- Also stated in: § Discussion · p. 6 · plain
“and in glucagon suppression were greater with tir zepatide than with semaglutide.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · p. 6 · plain
- Findingown data§ Abstract · p. 2
The estimated hepatic insulin-to-glucagon ratio did not change substantially with either tirzepatide or semaglutide.
“The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: The hepatic insulin-to-glucagon ratio calculation uses population average assumptions for portal blood flow and glucagon kinetics.
- Findingown data§ Abstract · p. 2
ISR7.2 was significantly increased with tirzepatide vs semaglutide.
“ISR7.2 was significantly increased with tirzepatide vs semaglutide ( P < .05)”
Quote in the paperSubstantial claim- The authors state this as an assumption: The ISR-glucose relationship is approximately linear, as used in the model.
- The authors state this as an assumption: During the MMTT, potentiation phenomena modify the ISR-glucose relationship.
- Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 6
Total glucagon AUC0-240min significantly decreased with tirzepatide and semaglutide compared with placebo (both P < .001).
“Total glucagon AUC0-240min significantly decreased with tirzepatide and semaglutide compared with placebo (both P < .001)”
Quote in the paperNot a substantial claim - Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4
In adults with type 2 diabetes treated with metformin, tirzepatide 15 mg reduced fasting glucose from baseline to week 28 significantly more than semaglutide 1 mg.
“Fasting glucose concentrations significantly decreased from baseline to week 28 with tirzepatide (reduced to least squares mean of 81 mg/dL) and semaglutide (90 mg/dL) com pared with placebo (128 mg/dL) (both P < .001 vs placebo), and this reduction was significantly greater with tirzepatide compared with semaglutide ( P < .01).”
- Also stated in: § Abstract · p. 2 · plain
“Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide ( P < .01).”
Quote in the paperSubstantial claim - Also stated in: § Abstract · p. 2 · plain
- Findingown data§ Abstract · p. 2
Glucagon AUC was significantly reduced with tirzepatide vs semaglutide.
“with glucagon AUC significantly reduced with tirzepatide vs semaglutide ( P < .01).”
Quote in the paperSubstantial claim - Findingown data§ Model-derived Indices of β -Cell Function · p. 6
The improvement in hyperglycemic clamp-derived β-CGS was significantly greater with tirzepatide than with semaglutide (P < .01).
“In contrast, the improvement in β -CGS derived from the hyperglycemic clamp was significantly greater ( P < .01) with tirzepatide than with semaglutide (see Table 2; Fig. 2D).”
- Also stated in: § Discussion · p. 6 · plain
“The increase in hyperglycemic clamp -derived β -CGS was significantly greater with tirzepatide than with semaglutide”
Quote in the paperSubstantial claim - Also stated in: § Discussion · p. 6 · plain
- Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4
Tirzepatide and semaglutide both reduced total and incremental glucose AUC0-240min after the meal compared with placebo.
“Tirzepatide and semaglutide both reduced total and incremental glucose area under the curve from time 0 to 240 minutes (AUC0-240min) after the meal compared with pla cebo (see Table 2).”
Quote in the paperSubstantial claim - Findingown data§ Model-derived Indices of β -Cell Function · p. 6
The model-derived relationship between ISR and glucose concentration was shifted upward with tirzepatide and semaglutide.
“The model-derived relationship between the ISR and glucose concentration was shifted upward with tirzepatide and sema glutide (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data§ Model-derived Indices of β -Cell Function · p. 6
The improvement in ISR at a glucose of 5.3 mmol/L was significantly greater after treatment with tirzepatide vs semaglutide (P < .05).
“with a significantly greater improvement ( P < .05) seen after treatment with tirze patide vs semaglutide (see Table 2).”
Quote in the paperSubstantial claim - Findingown data§ Model-derived Indices of β -Cell Function · p. 6
ISR at a glucose of 5.3 mmol/L assessed in the baseline period before the hyperglycemic clamp was significantly increased (P < .001) with both tirzepatide and semaglutide compared with placebo.
“Similarly, the ISR at a glucose of 5.3 mmol/L as sessed in the baseline period before the hyperglycemic clamp was significantly increased ( P < .001) with both tirzepatide and semaglutide compared with placebo”
Quote in the paperSubstantial claim - Findingown data§ Abstract · p. 2
Insulin sensitivity improved more with tirzepatide than with semaglutide.
“in the context of greater improvement in insulin sensitivity with tirzepatide ( P < .01).”
Quote in the paperSubstantial claim - Findingown data§ Abstract · p. 2
In adults with type 2 diabetes, tirzepatide 15 mg reduced MMTT total glucose AUC significantly more than semaglutide 1 mg.
“Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide ( P < .01).”
- Also stated in: § Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4 · plain
“Total glucose AUC0-240min was reduced significantly more with tirzepatide vs semaglutide ( P < .01).”
Quote in the paperSubstantial claim - Also stated in: § Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4 · plain
- Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4
Incremental AUC0-240min reductions were similar between tirzepatide and semaglutide.
“Incremental AUC0-240min reductions were similar”
Quote in the paperSubstantial claim - Findingown data§ Insulin Sensitivity Indices · p. 6
Greater improvements in insulin sensitivity were observed after treatment with tirzepatide vs semaglutide (P < .01).
“Greater improvements in insulin sensitivity were observed after treatment with tirzepatide vs semaglutide ( P < .01).”
- Also stated in: § Discussion · p. 6 · plain
“Improvements in insulin sen sitivity indices were greater with tirzepatide than with semaglutide”
Quote in the paperSubstantial claim - Also stated in: § Discussion · p. 6 · plain
- Premisecitation§ Discussion · p. 6
First-phase ISR improved more with tirzepatide compared to semaglutide in this study.
“While first-phase ISR improved more with tirzepa tide compared to semaglutide in this study (13)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] 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§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4
Lower fasting glucose achieved with tirzepatide was an important contributor to the total glucose AUC0-240min reduction.
“indicating that the lower fasting glucose achieved with tirzepatide was an important contributor to the total glucose AUC0-240min re duction.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion · p. 9
Superior control of hyperglucagonemia likely contributes to the greater improvement in fasting glucose levels with tirzepatide.
“Superior control of hyperglucagonemia likely contributes to the greater improvement in fasting glucose levels with tirzepatide.”
Quote in the paperSubstantial claim- Rests on an assumption: Glucagon is an important determinant of hepatic glucose output and therefore fasting glucose concentrations.
- Interpretationreasoning§ Abstract · p. 2
The greater total glucose AUC reduction with tirzepatide vs semaglutide was mainly attributable to greater suppression of fasting glucose.
“therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion · p. 7
At the low glucose concentrations achieved during the MMTT, the contribution of β-cell glucose responsiveness may be modest compared with the significance of improved insulin sensitivity and reduced glucagon concentrations.
“at the low glucose concentrations achieved during the MMTT, the contribution of β -cell glucose responsiveness may be modest compared with the significance of improved insulin sensitivity and reduced glucagon concen trations.”
Quote in the paperSubstantial claim - Interpretationown data§ Insulin Sensitivity Indices · p. 6
The changes in MMTT-derived insulin sensitivity indices were consistent with the improvements in insulin sensitivity observed from hyperinsulinemic euglycemic clamp-derived M values.
“These changes were consistent with the improve ments in insulin sensitivity observed from the hyperinsuline mic euglycemic clamp-derived M values (see Fig. 3A).”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Discussion · p. 9
Results from the present evaluations emphasize the role of tirzepatide in the control of fasting glucose concentration.
“Results from the present evaluations emphasize the role of tirzepatide in the control of fasting glucose concentra tion.”
Quote in the paperSubstantial claim- Rests on an assumption: Fasting glucose level sets the starting point for a meal-induced glucose excursion.
- Interpretationown data§ Discussion · p. 7
These differences reflect the greater improvement in insulin sensitivity with tirzepatide.
“These differ ences reflect the greater improvement in insulin sensitivity with tirzepatide.”
Quote in the paperSubstantial claim - Interpretationcitation§ Discussion · p. 7
The balanced action reflected in the estimated hepatic insulin-to-glucagon ratio suggests that, through intra-islet effects, improvements in β-cell responses may contribute to the overall improvement of glucagon control, beyond direct actions on α cells.
“As noted earlier, the balanced action reflected in the es timated hepatic insulin-to-glucagon ratio suggests that, through intra-islet effects, improvements in β -cell responses may contribute to the overall improvement of glucagon con trol, beyond direct actions on α cells (33).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Nauck, 2021, The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update, Diabetes Obes Metab source
- Premisecitation§ Discussion · p. 7
We have previously shown in the evaluated data set a greater suppression of glucagon with tirzepatide vs semaglutide.
“We have previously shown in the evaluated data set a greater suppression of glucagon with tir zepatide vs semaglutide (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] 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§ Discussion · p. 7
A contribution of this effect to the greater improvement in fasting and postchallenge glucose control with tirzepatide is suggested but not definitively demonstrated.
“A contribution of this effect to the greater improvement in fasting and postchal lenge glucose control with tirzepatide is suggested but not de finitively demonstrated”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion · p. 7
The greater reduction in fasting glucose with tirzepatide is likely a result of greater hepatic sensitivity to this insulin exposure, perhaps augmented by differential insulin secretion responses to glucose increments above the fasting concentration.
“The greater reduction in fasting glucose with tirzepatide is therefore likely a result of greater hepatic sensitivity to this insulin exposure, perhaps augmented by differential insulin secretion responses to glu cose increments above the fasting concentration.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion · p. 8
It is unlikely that gastric emptying is affecting the meal tolerance test results for either agent.
“Therefore, it is unlikely that gastric emptying is affecting the meal tolerance test results for either agent.”
Quote in the paperNot a substantial claim - Interpretationcitation§ Discussion · p. 9
Treatment effects on model-derived parameters of β-cell function evaluated here are consistent with improvements in β-cell function with tirzepatide vs semaglutide previously reported from the hyperglycemic clamp.
“In conclusion, the treatment effects on model-derived pa rameters of β -cell function evaluated here are consistent with the improvements in β -cell function with tirzepatide vs semaglutide previously reported from the hyperglycemic clamp.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] 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§ Discussion · p. 9
Greater improvement in β-cell responsiveness for tirzepatide compared with semaglutide is evident by the MMTT- and hyperglycemic clamp-derived ISRs at fixed glucose levels and by the hyperglycemic clamp-derived β-CGS.
“Greater improvement in β -cell responsiveness for tirzepa tide compared with semaglutide is evident by the MMTT- and hyperglycemic clamp -derived ISRs at fixed glucose levels and by the hyperglycemic clamp -derived β -CGS.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract · p. 2
The increase in ISR7.2 with tirzepatide vs semaglutide shows improved β-cell glucose sensitivity (β-CGS).
“ISR7.2 was significantly increased with tirzepatide vs semaglutide ( P < .05), showing improved β -CGS.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The ISR-glucose relationship is approximately linear, as used in the model.
- The authors state this as an assumption: During the MMTT, potentiation phenomena modify the ISR-glucose relationship.
- Interpretationown data§ Discussion · p. 9
Improvements in hepatic insulin sensitivity and whole-body insulin sensitivity further contribute to fasting and postprandial glycemic control achieved with tirzepatide.
“Improvements in hepatic insulin sensitivity and whole-body insulin sensitivity further contribute to fasting and postpran dial glycemic control achieved with tirzepatide.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion · p. 7
The overall improvement in glucose control with tirzepatide compared with semaglutide appears mainly due to the greater reduction in fasting glucose levels, which sets the starting point for a meal-induced excursion.
“Therefore, the overall improvement in glucose control with tirzepatide compared with semaglutide appears to be mainly due to the greater reduction in fasting glucose lev els, which sets the starting point for a meal-induced excursion.”
Quote in the paperSubstantial claim- Rests on an assumption: Fasting glucose level sets the starting point for a meal-induced glucose excursion.
- May combine two claims. 34
- Classified as probably not a substantial claim. 20
May combine two claims.
Premisecitation§ Abstract · p. 2In phase 3 trials in patients with type 2 diabetes, tirzepatide reduced glycated hemoglobin by 20.8 to 28.4 mmol/mol (1.9% to 2.6%) and body weight by 5.6% to 13.9%.
“In phase 3 trials in patients with T2D, tirzepatide reduced glycated hemoglobin by 20.8 to 28.4 mmol/mol (1.9% to 2.6%) and reduced body weight by 5.6% to 13.9% (8-12).”
Quote in the paperNot a substantial claim1 of 5 sources checked- 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] Ludvik, 2021, Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial, Lancet source
- cites [10] 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] Frías, 2021, Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes, N Engl J Med source
- cites [12] 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
The Primary Outcome and Key Secondary Outcomes sections report HbA1c reductions of 2.11%–2.40% and weight loss of 5.4–8.8 kg across tirzepatide doses at week 40. This trial supports reductions within the cited ranges, but it does not establish the full ranges across phase 3 trials, particularly the 13.9% weight-loss endpoint. Page numbers are not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Premisecitation§ Discussion · p. 7GLP-1 and GIP both contribute to incretin responses, and GIP receptors are important for the incretin action of tirzepatide.
“GLP-1 and GIP both contribute to incretin re sponses (31), and GIP receptors are important for the incretin action of tirzepatide (32).”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ Discussion · p. 7Based on observations of GIP effects to augment adipose tissue glucose uptake and the contribution of adipose tissue action to the insulin-sensitizing effect of tirzepatide, it is possible that the GIP component of the mechanism of action of tirzepatide may contribute through these actions to improvements in insulin sensitivity.
“Based on observa tions of GIP effects to augment adipose tissue glucose uptake (34) and the contribution of adipose tissue action to the insulin-sensitizing effect of tirzepatide (5), it is possible that the GIP component of the mechanism of action of tirzepa tide may contribute through these actions to improvements in insulin sensitivity.”
Quote in the paperNot a substantial claim2 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 7GLP-1 and GIP both modulate glucagon release but with differential effects according to glycemic status.
“GLP-1 and GIP both modulate glucagon release but with differential effects according to gly cemic status (26-28)”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [26] El, 2021, GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells, Sci Adv source
- cites [27] Mathiesen, 2019, The effects of dual GLP-1/GIP receptor agonism on glucagon secretion-a review, Int J Mol Sci source
- cites [28] Muller, 2017, The new biology and pharmacology of glucagon, Physiol Rev source
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ Discussion · p. 7The 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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Lee, 2023, Tirzepatide as monotherapy improved markers of beta-cell function and insulin sensitivity in type 2 diabetes (SURPASS-1), J Endocr Soc source
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
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussion · p. 7The effect of tirzepatide on gastric emptying has been previously evaluated and found to be short-lived due to tachyphylaxis.
“The effect of tirzepatide on gastric emptying has been previously eval uated and found to be short-lived due to tachyphylaxis (35).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [35] Urva, 2020, The novel dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide transiently delays gastric emptying similarly to selective long-acting GLP-1 receptor agonists, Diabetes Obes Metab source
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ Abstract · p. 2Postprandial insulin excursions drive glucose disposal through actions in muscle and adipose tissue, and GIP enhances insulin sensitivity and glucose disposal in adipose tissue.
“Postprandial excursions of insulin drive glucose dis posal through actions in muscle and adipose tissue, along with effects of postprandial excursions in GIP, to enhance insulin sensitivity and augment glucose disposal in adipose tissue (2-5).”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [2] Ceperuelo-Mallafré, 2014, Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance, J Clin Endocrinol Metab source
The section “GIP improves insulin sensitivity in human adipocytes” reports increased insulin-induced glucose uptake after 24 hours of GIP exposure in cultured adipocytes, with a similar result in myocytes. The Discussion cautions that these in-vitro findings are difficult to reconcile with postprandial GIP action and that little is known about its effects in human adipose tissue in vivo. Thus, the paper supports the cellular effect but not the claim that postprandial GIP excursions augment adipose glucose disposal. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [3] Mohammad, 2011, Gastric inhibitory peptide controls adipose insulin sensitivity via activation of cAMP-response element-binding protein and p110β isoform of phosphatidylinositol 3-kinase, J Biol Chem source
The ‘GIP Potentiates Insulin Action in Adipocytes’ section reports that GIP increased insulin-stimulated glucose uptake in adipocytes, supporting the adipose-tissue part of the claim. The Discussion connects this effect to nutrient disposal after meals. Our copy does not establish the claim about postprandial insulin driving glucose disposal through muscle, and the paper’s own experiments used adipocytes rather than postprandial measurements. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [4] Conte, 2012, Multiorgan insulin sensitivity in lean and obese subjects, Diabetes Care source
The Conclusions (page unavailable) describe insulin concentrations simulating postprandial conditions and report insulin-stimulated muscle glucose uptake and suppression of adipose-tissue lipolysis. The Results (page unavailable) also report increased glucose disposal with insulin infusion. The paper does not establish adipose-tissue glucose disposal or the claimed effects of GIP; a search for GIP found no relevant passage. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [5] Samms, 2021, GIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice, J Clin Invest source
The Introduction describes GIP release after food intake and its effects on adipose metabolism. The Results report insulin-stimulated glucose disposal in muscle and adipose tissue, while the Discussion links GIP receptor agonism to improved insulin sensitivity and adipose glucose disposal in obese mice. The paper does not establish that normal postprandial GIP excursions themselves produce those adipose effects; its experiments used tirzepatide and a long-acting GIP receptor agonist. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
Findingown data§ Discussion · p. 6In this mechanism-of-action trial, tirzepatide improved handling of a meal challenge, showing reductions in fasting glucose and glucose excursions that were accompanied by reductions in fasting and total insulin and C-peptide excursions.
“In this mechanism-of-action trial, tirzepatide improved hand ling of a meal challenge, showing reductions in fasting glucose and glucose excursions that were accompanied by reductions in fasting and total insulin and C-peptide excursions.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Model-derived Indices of β -Cell Function · p. 6MMTT-derived β-CGS slope improved from baseline with semaglutide and tirzepatide but did not significantly differ between these treatment arms.
“When derived from the MMTT, the slope of this relationship (ie, β -CGS) was improved from baseline with semaglutide and tirzepatide but did not significantly differ be tween these treatment arms (see Table 2; Fig. 2C).”
- Also stated in: § Discussion · p. 7 · plain
“Glucose sensitivity assessed from the modeled relationship of glucose and insulin secretion from the MMTT was improved from baseline with both tirze patide and semaglutide but was not significantly different be tween these treatments.”
- Also stated in: § Discussion · p. 9 · plain
“MMTT-derived β -CGS was increased in both treatment groups but not signifi cantly different between tirzepatide and semaglutide.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · p. 7 · plain
May combine two claims.
Findingown data§ Abstract · p. 2MMTT-derived β-CGS was increased but not significantly different between tirzepatide and semaglutide.
“MMTT-derived β -CGS was increased but not significantly different between treatments.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: The ISR-glucose relationship is approximately linear, as used in the model.
- The authors state this as an assumption: During the MMTT, potentiation phenomena modify the ISR-glucose relationship.
May combine two claims.
Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4Both tirzepatide 15 mg and semaglutide 1 mg significantly decreased fasting glucose from baseline to week 28 compared with placebo.
“Fasting glucose concentrations significantly decreased from baseline to week 28 with tirzepatide (reduced to least squares mean of 81 mg/dL) and semaglutide (90 mg/dL) com pared with placebo (128 mg/dL) (both P < .001 vs placebo)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4Fasting glucagon concentrations decreased with both tirzepatide and semaglutide, with a lower concentration achieved with tirzepatide vs semaglutide; however, no significant difference in the change from baseline was observed between these treatments.
“Fasting glucagon concentrations decreased with both tirzepatide and semaglutide, with a lower concentration achieved with tirzepatide vs semaglutide; how ever, no significant difference in the change from baseline was observed between these treatments.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Abstract · p. 2Both tirzepatide and semaglutide reduced fasting glucagon and total glucagon AUC.
“Both treatments reduced fasting glucagon and total glucagon AUC”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Discussion · p. 7This proportionality of glucagon with insulin was not different between treatments, arguing against a differential α-cell effect when comparing effects of tirzepatide and semaglutide.
“This proportionality of glucagon with insulin was not different be tween treatments, arguing against a differential α -cell effect when comparing effects of tirzepatide and semaglutide.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Model-derived Indices of β -Cell Function · p. 6A decrease in the potentiation ratio at 120 minutes was observed with tirzepatide, which was significantly different (P < .01) vs semaglutide and placebo.
“A decrease in the potentiation ratio at 120 minutes was observed with tirzepatide, which was significantly differ ent ( P < .01) vs semaglutide and placebo (see Table 2).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Discussion · p. 7In the present analyses, we did not find marked differences in the estimated hepatic insulin-to-glucagon ratio, which accounts for dynamic aspects of glucagon action at the liver, suggesting that the changes in glucagon response were proportional to the changes in insulin response.
“In the present analyses we did not find marked differ ences in the estimated hepatic insulin -to -glucagon ratio, which accounts for dynamic aspects of glucagon action at the liver, suggesting that the changes in glucagon response were proportional to the changes in insulin response.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Metabolic Responses Assessed With the Mixed-Meal Tolerance Test · p. 4Basal ISR was reduced with both tirzepatide and semaglutide, but a significant reduction vs placebo was only seen with tirzepatide when comparing change from baseline to week 28.
“Accordingly, the basal ISR was reduced with both treatments, but a significant reduc tion vs placebo was only seen with tirzepatide when compar ing change from baseline to week 28 ( P < .05)”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Discussion · p. 6Reductions in fasting glucose and glucose AUC0-240min were greater with tirzepatide than with semaglutide.
“Reductions in fasting glucose and glucose AUC0-240min were greater with tirzepatide than with semaglutide.”
- Also stated in: § Discussion · p. 7 · plain
“Fasting and total glucose AUC0-240min during the MMTT decreased more with tirzepatide than with semaglutide”
Quote in the paperSubstantial claim- Also stated in: § Discussion · p. 7 · plain
May combine two claims.
Findingcitation§ Discussion · p. 7The reduction in total MMTT ISR was greater with tirzepatide than with semaglutide, concordant with the observations for total and incremental insulin AUC0-240min.
“The reduc tion in the total MMTT ISR was greater with tirzepatide than with semaglutide, concordant with the observations for total and incremental insulin AUC0-240min (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] 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
May combine two claims.
Findingown data§ Discussion · p. 6Both treatments improved glucose-stimulated insulin secretion (β-CGS and standardized ISR at a glucose level of 7.2 mmol/L), glucagon suppression, and insulin sensitivity.
“Both treatments improved glucose-stimulated insulin se cretion ( β -CGS and standardized ISR at a glucose level of 7.2 mmol/L), glucagon suppression, and insulin sensitivity.”
Quote in the paperSubstantial claimMay combine two claims.
Findingcitation§ Discussion · p. 7During the hyperglycemic clamp, glucose sensitivity increased more with tirzepatide than with semaglutide, consistent with the treatment effect on previously reported classic insulin secretion response indices from the hyperglycemic clamp.
“During the hyperglycemic clamp, glucose sensitivity increased more with tirzepatide than with semaglu tide, consistent with the treatment effect on the previously re ported classic insulin secretion response indices from the hyperglycemic clamp (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] 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
May combine two claims.
Findingown data§ Discussion · p. 6The basal ISR was reduced with both treatments, achieving statistical significance vs placebo in the tirzepatide group.
“The basal ISR was reduced with both treatments, achieving statistical significance vs placebo in the tirzepatide group”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Model-derived Indices of β -Cell Function · p. 6The baseline values of MMTT-derived ISR at a glucose of 7.2 mmol/L adjusted for potentiation were affected by the presence of 3 outlier values below 1 in the data set.
“The baseline val ues of MMTT-derived ISR at a glucose of 7.2 mmol/L ad justed for potentiation were affected by the presence of 3 outlier values below 1 in the data set.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisecitation§ Abstract · p. 2GLP-1 and GIP contribute to meal-stimulated insulin secretion via GLP-1 and GIP receptors located on pancreatic β cells.
“These hormones contribute to meal-stimulated insulin secre tion via GLP-1 and GIP receptors located on the pancreatic β cell (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Nauck, 2019, GIP and GLP-1: stepsiblings rather than monozygotic twins within the incretin family, Diabetes source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Abstract · p. 2Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist approved in the United States for treatment of type 2 diabetes and obesity.
“More recently, tirzepatide, a once -weekly GIP/GLP-1 receptor agonist (RA), was approved in the United States for treatment of T2D and obesity (7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Eli Lilly and Company, 2022
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisecitation§ Abstract · p. 2In a prior clinical study, tirzepatide 15 mg showed significantly greater improvement than semaglutide 1 mg in hyperinsulinemic euglycemic clamp-derived insulin sensitivity and in insulin secretion responses assessed using the hyperglycemic clamp.
“This study demonstrated a significantly greater improvement with tirzepatide than with semaglutide in hyperinsulinemic euglycemic clamp -derived insulin sensitivity and in insulin secretion responses assessed using the hyperglycemic clamp (13).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] 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.
Study design and conductnone given§ Study Design and Participants · p. 3Treatment effects on MMTT- and hyperglycemic clamp-derived parameters of insulin secretion and sensitivity were prespecified end points.
“Treatment effects on MMTT- and hyperglycemic clamp -derived parameters of insulin secretion and sensitivity were prespecified end points.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ Discussion · p. 6The greater improvements in insulin sensitivity indices with tirzepatide reflect improved glycemic control achieved with reduced insulin secretion requirements.
“Improvements in insulin sen sitivity indices were greater with tirzepatide than with semaglutide, reflecting improved glycemic control achieved with reduced insulin secretion requirements.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data§ Study Design and Participants · p. 3The trial was a randomized, double-blind, parallel-arm, mechanism-of-action clinical trial run at 2 clinical research sites in Germany.
“Briefly, this was a randomized, doubleblind, parallel-arm, mechanism-of-action clinical trial run at 2 clinical research sites in Germany (ClinicalTrials.gov identi fier: NCT03951753).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Discussion · p. 6Rate sensitivity is a marker of early ISR, modestly correlated with first-phase ISR.
“Rate sensitivity is a marker of early ISR, modestly correlated with first-phase ISR (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Mari, 2008, Beta-cell function assessment from modelling of oral tests: an effective approach, Diabetes Obes Metab source
Classified as probably not a substantial claim.
Study design and conductnone given§ Statistical Analyses · p. 4Data from all randomly assigned patients receiving at least one dose of study drug were included in statistical analysis.
“Data from all randomly assigned patients receiving at least one dose of study drug were included in statistical analysis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning§ Discussion · p. 6The lack of corollary differences in rate sensitivity may be due to the considerable variability of this parameter.
“we did not ob serve corollary differences in rate sensitivity, perhaps due to the considerable variability of this parameter.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data§ Model-derived Indices of β -Cell Function · p. 6For MMTT-derived ISR at a glucose of 7.2 mmol/L adjusted for potentiation, statistical analyses are presented excluding the relevant individuals to better represent the data set; parallel results were obtained using the whole data set.
“For this parameter, stat istical analyses are presented in Table 2 excluding the relevant individuals to provide results that better represent the data set; parallel results were obtained using the whole data set.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationreasoning§ Discussion · p. 7It is reasonable to presume that both actions contribute to the augmented glucose-stimulated insulin secretion observed at elevated glucose concentrations seen with tirzepatide vs semaglutide, although this was not definitively evaluated in the present study.
“Therefore, it is reasonable to presume that both actions contribute to the augmented glucose-stimulated insulin secretion observed at elevated glu cose concentrations seen with tirzepatide vs semaglutide, al though this was not definitively evaluated in the present study.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ Discussion · p. 8The study population was limited to participants with T2D and modest hyperglycemia; thus, the results cannot necessarily be extrapolated to other subsets of individuals with this disease.
“The study population was limited to par ticipants with T2D and modest hyperglycemia; thus, the results cannot necessarily be extrapolated to other subsets of individuals with this disease.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ Discussion · p. 7The MMTT-derived indices of insulin sensitivity currently presented are consistent with the greater effect of tirzepatide on the hyperinsulinemic euglycemic clamp-derived M values, demonstrating the importance of this effect under physiologic circumstances.
“The MMTT-derived indices of insulin sensi tivity currently presented are consistent with the greater effect of tirzepatide on the hyperinsulinemic euglycemic clamp -de rived M values, demonstrating the importance of this effect under physiologic circumstances.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ Abstract · p. 2The greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.
“These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductnone given§ Discussion · p. 8The trial was a mechanism-of-action study, with a comparatively small sample size powered for hyperglycemic clamp-derived primary end points and not explicitly powered for the parameters evaluated here.
“The trial was a mechanism-of-action study, with a comparatively small sample size powered for hyperglycemic clamp -derived primary end points and not explicitly powered for the param eters evaluated here.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductown data§ Study Design and Participants · p. 3Participants (N = 117) were randomly assigned (3:3:2) to receive tirzepatide 15 mg, semaglutide 1 mg, or placebo.
“Participants (N = 117) were randomly assigned (3:3:2) to receive a onceweekly subcutaneous injection of tirzepatide 15 mg, semaglu tide 1 mg, or placebo.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ Discussion · p. 7The current observations highlight the importance of fasting glucose control in the overall improvement of glucose control and indicate a key differentiator between the efficacy of tirzepatide and semaglutide.
“The current observations highlight the importance of fast ing glucose control in the overall improvement of glucose con trol and indicate a key differentiator between the efficacy of tirzepatide and semaglutide.”
Quote in the paperSubstantial claim- Rests on an assumption: Fasting glucose level sets the starting point for a meal-induced glucose excursion.
Classified as probably not a substantial claim. May combine two claims.
Interpretationreasoning§ Discussion · p. 7The reason for the inconsistency between MMTT- and clamp-derived observations is not clear but may relate to the lower range of glucose stimulation achieved with the MMTT.
“The reason for this inconsistency between MMTT- and clamp-derived observations is not clear but may relate to the lower range of glucose stimulation achieved with the MMTT.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationcitation§ Discussion · p. 7GLP-1's effects to suppress glucagon could be contributing to the observed glucagon suppression directly, and both GIP and GLP-1 could be contributing to suppression indirectly via improved insulin secretion responses.
“GLP-1 ' s effects to suppress glucagon could be contributing to the observed glucagon suppression directly (29), and both GIP and GLP-1 could be contributing to suppression indirectly via improved insulin secretion re sponses.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Bagger, 2021, Glucagonostatic potency of GLP-1 in patients with type 2 diabetes, patients with type 1 diabetes, and healthy control subjects, Diabetes source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationreasoning§ Discussion · p. 7While combined GIPR and GLP-1R agonism is expected to produce β-cell function improvement, reduction of glucose levels and alleviation of glucose toxicity on the β-cell and parallel effects on insulin sensitivity may have contributed.
“While combined GIPR and GLP-1R agon ism is expected to produce β -cell function improvement, re duction of glucose levels and alleviation of glucose toxicity on the β -cell and parallel effects on insulin sensitivity may have contributed.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ Discussion · p. 7In aggregate, these observations suggest a greater β-cell glucose responsiveness with tirzepatide that is more readily demonstrated at higher glucose concentrations.
“In ag gregate, these observations suggest a greater β -cell glucose responsiveness with tirzepatide that is more readily demon strated at higher glucose concentrations.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ Discussion · p. 7We did not assess gastric emptying in this study.
“We did not assess gastric emptying in this study.”
Quote in the paperNot a substantial claim
The authors state this as an assumption.
The ISR-glucose relationship is approximately linear, as used in the model.
“The first component represents the dependence of the ISR on ab solute glucose concentration at any time point during the MMTT, by means of an approximately linear function relat ing the ISR to glucose.”
The authors state this as an assumption.
During the MMTT, potentiation phenomena modify the ISR-glucose relationship.
“During the MMTT, the ISR-glucose relationship is modified by potenti ation phenomena, which augment the ISR for a given glucose level at the end of the MMTT compared with the beginning.”
The authors state this as an assumption.
A linear relationship between ISR and glucose can be used to adjust basal ISR to a reference glucose of 5.3 mmol/L.
“assuming a linear relationship between the ISR and glucose using the clamp glu cose sensitivity as the slope.”
The authors state this as an assumption.
The hepatic insulin-to-glucagon ratio calculation uses population average assumptions for portal blood flow and glucagon kinetics.
“adjusted for population average assumptions for portal blood flow and glucagon kinetics (17).”
The paper relies on this without support.
Glucagon is an important determinant of hepatic glucose output and therefore fasting glucose concentrations.
“Glucagon is an important deter minant of hepatic glucose output and, therefore, fasting glu cose concentrations.”
The paper relies on this without support.
Fasting glucose level sets the starting point for a meal-induced glucose excursion.
“which sets the starting point for a meal-induced excursion.”
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 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 [20]
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.
Clamp and MMTT reference glucose levels are reversed
MinorThe discussion assigns 7.2 mmol/L to the hyperglycemic clamp and 5.3 mmol/L to the MMTT, respectively. The methods assign them the other way around.
“for both the hypergly cemic clamp and the MMTT, the ISRs at fixed glucose concen trations of 7.2 mmol/L and 5.3 mmol/L, respectively, improved more with tirzepatide than with semaglutide.”
“The hyperglycemic clamp -derived ISR at a glucose of 5.3 mmol/L is conceptually similar to the ISR at 7.2 mmol/L derived from the MMTT”
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How to measure insulin sensitivity
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Self-citationThe New Biology and Pharmacology of Glucagon
Müller, T. D., Finan, B., Clemmensen, C., DiMarchi, R. D., & Tschöp, M. H. (2017) · Physiological Reviews · doi:10.1152/physrev.00025.2016 · Cited by 419 · see citing works
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Self-citationGIPR agonism mediates weight-independent insulin sensitization by tirzepatide in obese mice
Samms, R. J., Christe, M. E., Collins, K. A. L., Pirro, V., Droz, B. A., Holland, A. K., Friedrich, J. L., Wojnicki, S., Konkol, D. L., Cosgrove, R., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci146353 · Cited by 256 · see citing works
Assessing Insulin Secretion by Modeling in Multiple-Meal Tests
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Self-citationMeasuring and estimating insulin resistance in clinical and research settings
Gastaldelli, A. (2022) · Obesity · doi:10.1002/oby.23503 · Cited by 244 · see citing works
Standards of Medical Care in Diabetes—2021 Abridged for Primary Care Providers
American Diabetes Association (2020) · Clinical Diabetes · doi:10.2337/cd21-as01 · Cited by 216 · see citing works
Urva, S., Coskun, T., Loghin, C., Cui, X., Beebe, E., O'Farrell, L., Briere, D. A., Benson, C., Nauck, M. A., & Haupt, A. (2020) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.14110 · Cited by 143 · see citing works
Self-citationGIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells
El, K., Gray, S. M., Capozzi, M. E., Knuth, E. R., Jin, E., Svendsen, B., Clifford, A., Brown, J. L., Encisco, S. E., Chazotte, B. M., et al. (2021) · Science Advances · doi:10.1126/sciadv.abf1948 · Cited by 132 · see citing works
Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists
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Self-citationThe incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets
El, K., Douros, J. D., Willard, F. S., Novikoff, A., Sargsyan, A., Perez-Tilve, D., Wainscott, D. B., Yang, B., Chen, A., Wothe, D., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00811-0 · Cited by 118 · see citing works
Disruption of GIP/GIPR axis in human adipose tissue is linked to obesity and insulin resistance
Ceperuelo-Mallafré, V., Duran, X., Pachón, G., Roche, K., Garrido-Sánchez, L., Vilarrasa, N., Tinahones, F. J., Vicente, V., Pujol, J., Vendrell, J., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-3350 · Cited by 112 · see citing works
β‐cell function assessment from modelling of oral tests: an effective approach
Mari, A., & Ferrannini, E. (2008) · Diabetes, Obesity and Metabolism · doi:10.1111/j.1463-1326.2008.00946.x · Cited by 112 · see citing works
Self-citationMultiorgan insulin sensitivity in lean and obese subjects
Conte, C., Fabbrini, E., Kars, M., Mittendorfer, B., Patterson, B. W., & Klein, S. (2012) · Diabetes Care · doi:10.2337/dc11-1951 · Cited by 99 · see citing works
The effects of dual GLP-1/GIP receptor agonism on glucagon secretion-A Review
Mathiesen, D. S., Bagger, J. I., Bergmann, N. C., Lund, A., Christensen, M. B., Vilsbøll, T., & Knop, F. K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20174092 · Cited by 80 · see citing works
Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
Ferrannini, E., Muscelli, E., Frascerra, S., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75754 · Cited by 75 · see citing works
GIP and GLP-1: stepsiblings rather than monozygotic twins within the incretin family
Nauck, M. A., & Meier, J. J. (2019) · Diabetes · doi:10.2337/dbi19-0005 · Cited by 65 · see citing works
Mohammad, S., Ramos, L. S., Buck, J., Levin, L. R., Rubino, F., & McGraw, T. E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.289009 · Cited by 59 · see citing works
Lee, C. J., Mao, H., Thieu, V. T., Landó, L. F., & Thomas, M. K. (2023) · Journal of the Endocrine Society · doi:10.1210/jendso/bvad056 · Cited by 48 · see citing works
Self-citationGIP-induced vasodilation in human adipose tissue involves capillary recruitment
Asmar, M., Asmar, A., Simonsen, L., Dela, F., Holst, J. J., & Bülow, J. (2019) · Endocrine Connections · doi:10.1530/ec-19-0144 · Cited by 37 · see citing works
Incretin therapy for diabetes mellitus type 2
Holst, J. J. (2019) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000516 · Cited by 28 · see citing works
Bagger, J. I., Grøndahl, M. F. G., Lund, A., Holst, J. J., Vilsbøll, T., & Knop, F. K. (2021) · Diabetes · doi:10.2337/db20-0998 · Cited by 27 · see citing works
Urva, S., Nauck, M. A., Coşkun, T., Cui, X., Haupt, A., Benson, C., & Loghin, C. (2019) · Diabetes · doi:10.2337/db19-58-or · Cited by 2 · see citing works
Self-citationLEE, C., MAO, H., THIEU, V., & THOMAS, M. K. (2022) · Diabetes · doi:10.2337/db22-715-p
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Horn, D. B., Linetzky, B., Davies, M. J., Laffin, L. J., Wang, H., Murphy, M. A., Zimner-Rapuch, S., Lau, E., Arad, A. D., & Lee, C. J. (2026) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2025.6112 · Cited by 50 · see citing works
Billings, L. K., Hsia, S. H., Bays, H. E., et al. (2025) · The Lancet · doi:10.1016/s0140-6736(25)02155-5 · Cited by 41 · see citing works
Self-citationRochira, V., Greco, C., Boni, S., Costantino, F., Valentina, L. D., Zanni, E., Itani, L., & Ghoch, M. E. (2024) · Diseases · doi:10.3390/diseases12090204 · Cited by 34 · see citing works
“…on the following bases: (i) 14 because the participants were on medications other than TZP that might interfere with body weight and BC [20,21,34–45]; (ii) two due to the short duration of the TZP treatment [46,47]; (iii) one because it had an open-label lead-in period [48]; and (iv) five for…”
BackgroundMedical nutrition therapy for the management of type 2 diabetes mellitus
Barrea, L., Verde, L., Colao, A., Mandarino, L. J., & Muscogiuri, G. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-025-01161-5 · Cited by 25 · see citing works
Zhang, Y., Xie, Y., Xia, S., Ge, X., Li, J., Liu, F., Jia, F., Wang, S., Zhou, Q., Gao, M., et al. (2025) · Advanced Science · doi:10.1002/advs.202411980 · Cited by 22 · see citing works
Mather, K. J., Mari, A., Weerakkody, G. J., Heise, T., DeVries, J. H., Urva, S., Coşkun, T., Miličević, Z., Haupt, A., & Thomas, M. K. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16159 · Cited by 20 · see citing works
“19,23,24 The strengths of this study include the use of the hyperinsulinemic euglycemic clamp to assess insulin sensitivity, the supportive evidence provided by the MMTT-derived Matsuda index and the double-blind, randomized trial design.”
Self-citationBajaj, H. S., Welch, M., Shah, P., Luna, E., Jaouimaa, F.-Z., Liu, B., Liu, R., Chen, Y., Patel, H., & Bartee, A. (2026) · The Lancet · doi:10.1016/s0140-6736(26)00967-0 · Cited by 23 · see citing works
Mari, A., Stefański, A., van Raalte, D. H., Ma, X., LaBell, E. S., Fan, L., Lee, C. J., Thomas, M. K., Bunck, M. C. M., & Ferrannini, E. (2025) · Diabetes Care · doi:10.2337/dc25-0763 · Cited by 15 · see citing works
“Results show that 72-week treatment with tirzepatide was associated with improved OGTT-assessed insulin sensitivity and β -cell function across all investigated doses of tirzepatide (5, 10, and 15 mg) in participants with either baseline prediabetes or normoglycemia.”
Self-citationA Contemporary Rationale for Agonism of the GIP Receptor in the Treatment of Obesity
Samms, R. J., & Sloop, K. W. (2025) · Diabetes · doi:10.2337/dbi24-0026 · Cited by 19 · see citing works
Liu, Z., Chen, Y., Su, Y., PENG, Y., Xu, F. L., Yao, B., Liang, H., Lin, B., & Xu, W. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05844-0 · Cited by 9 · see citing works
Fat, muscle, and anti-obesity medications in cardiovascular disease prevention
Khan, M. S., Dawood, M. H., Handelsman, Y., Anker, S. D., Coats, A. J. S., Green, J. B., & Butler, J. (2026) · European Heart Journal · doi:10.1093/eurheartj/ehag201 · Cited by 9 · see citing works
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Abusedera, O., Sherif, J., Smida, M., & Fredericks, S. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14248734 · Cited by 5 · see citing works
“Tirzepatide appears to improve beta-cell function more significantly than semaglutide, likely due to its dual receptor function [31,38,39].”
Utzschneider, K. M., Tripputi, M., Butera, N. M., Mari, A., Rosin, S. P., Banerji, M. A., Bergenstal, R. M., Brown, N. M., Carlson, A. L., DeFronzo, R. A., et al. (2025) · Diabetes Care · doi:10.2337/dc24-2419 · Cited by 4 · see citing works
Self-citationTirzepatide in Treating Metabolic Disorders
Wei, S., & Xu, S. (2024) · International Journal of Drug Discovery and Pharmacology · doi:10.53941/ijddp.2024.100023 · Cited by 3 · see citing works
Opalska, L., Muciek, A., Mocarska, M., Orłowska, A., Strakowska, K., Maryńczak, A., Mencel, J., & Nitschke, N. (2024) · Quality in Sport · doi:10.12775/qs.2024.35.56425 · Cited by 2 · see citing works
“Both tirzepatide and semaglutide also reduce postprandial glucose and glucagon levels, but tirzepatide leads to a more significant reduction in meal-related insulin secretion compared to semaglutide [8].”
Hudanich, M., Smith, S. N., Marino, A., & Riskin, S. I. (2025) · Cureus · doi:10.7759/cureus.93104 · Cited by 1 · see citing works
“In the randomized controlled trial by Mather et al., researchers examined 117 adults 20-74 years of age, all diagnosed with type II diabetes mellitus (T2DM), with a BMI between 25 and 45 kg/m 2 over the course of a 28-week trial [9].”
InfluentialChan, Z. H., Omar, A. S., Gill, K., Volucke, G., Azhar, M. M., Haleem, S. M., Sia, J. E., Rahman, O. U., Ahmad, M., Shahid, N., et al. (2026) · Cardiology in Review · doi:10.1097/crd.0000000000001209 · Cited by 1 · see citing works
Kang, M., Ren, H., Zhen, Y., Liu, L., Xu, Q., Ma, Y., Zhang, L., Jia, H., Chen, Q., Jiang, Y., et al. (2026) · Archives of Pharmacal Research · doi:10.1007/s12272-026-01610-3 · Cited by 1 · see citing works
Nguyen, T., Hong, L., & Iso, T. (2026) · Cardiorenal Medicine · doi:10.1159/000552517 · Cited by 1 · see citing works
Clinical impact of tirzepatide on patients with chronic obstructive pulmonary disease
Wu, J.-Y., Lin, Y.-M., Hsu, W., Liu, T.-H., Tsai, Y., Huang, P., Chuang, M., & Lai, C. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1838392 · Cited by 1 · see citing works
“While both drug classes improve glycemic control and promote weight loss, tirzepatide has demonstrated superior efficacy (Moiz et al., 2025; Mather et al., 2024; Yao et al., 2024), suggesting that its dual mechanism may offer additional clinical benefits.”
Curto, R., Giglione, C., Cannarella, R., Berisha, H., Hattab, R., Condorelli, R. A., Vignera, S. L., Calogero, A. E., & Magni, P. (2026) · Pharmacological Research · doi:10.1016/j.phrs.2026.108278 · Cited by 1 · see citing works
Gao, S., & Borner, T. (2026) · Appetite · doi:10.1016/j.appet.2026.108723 · Cited by 1 · see citing works
Takiyama, T., Kitsunai, H., Maruyama, F., Kitao, N., Wakabayashi, Y., Ito, M., Kurihara, H., Yamamoto, K., Takeuchi, J., Nanbu, T., et al. (2026) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2026.109391 · Cited by 1 · see citing works
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
Self-citationUmińska, J. M., Ratajczak, J. M., Niezgoda, P., Gajda, R., Szarpak, Ł., Kubica, J., & Navarese, E. P. (2026) · Obesities · doi:10.3390/obesities6030038
GLP-1 therapies for obesity: mechanisms, outcomes, and regulatory challenges
Emos, D. D. O., González, J. D. J. M., Diani, L. M., Pinhel, M. A. D. S., Watanabe, L. M., Leca, A. V., Brandao, C. F. C., Nonino, C. B., & Noronha, N. Y. (2026) · Academia Drug Development and Pharmacotherapy · doi:10.20935/acaddrug8360
The systems medicine view of semaglutide: from clinical trials to molecular mechanisms
Vitorino, R. M. P. (2026) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2026.2695172
Sun, Y., Xie, C., Huang, W., Bound, M. J., Grivell, J., Jones, K. L., Horowitz, M., Macdonald, I. A., Rayner, C. K., & Wu, T. (2026) · Diabetes · doi:10.2337/db26-0267
Prakash, S., Dhama, N., & Kumar, A. (2026) · Journal of Pharmaceutical Innovation · doi:10.1007/s12247-026-10999-9
Quantitative insights into tirzepatide and semaglutide using longitudinal systems modeling
Yang, B., Cabrera, O., Mather, K. J., & Sherman, A. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag383
Self-citationMahmoud, 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
“The model-derived parameters, comprising the insulin secretion rate at a fixed glucose concentration of 7.2 mmol/L and β -cell glucose sensitivity, improved with tirzepatide, as did insulin sensitivity and the estimated hepatic insulin-to-glucagon ratio [18].”
Influential
- Authors
- Mather, K. J., Mari, A., Heise, T., DeVries, J. H., Hua, M., Urva, S., Coskun, T., Haupt, A., Heine, R. J., Pratt, E., Thomas, M. K., & Milicevic, Z.
- Affiliations
- Eli Lilly (United States) (US)
- National Research Council (IT)
- Profil Institute for Metabolic Research (DE)
- Lilly Research Laboratories, Eli Lilly and Company , Indianapolis, IN 46285 ,
- Corresponding author
- Mather, Kieren J
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2024-05-26
- Volume
- 109
- Issue
- 12
- Pages
- 3046-3054
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W4399032763
- Cited by
- 32
- References
- 34
- Citations by year
- 2026: 17 · 2025: 12 · 2024: 3
- FWCI
- 9.16
- Type
- journal article
- Language
- en
- Open access
- green
- pure.amsterdamumc.nl
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- tirzepatide, semaglutide, type 2 diabetes, mixed meal tolerance test, beta-cell function, insulin secretion rate, insulin sensitivity, glucagon suppression
- MeSH terms
- Glucagon-Like Peptide-2 Receptor, Glycemic Control, Tirzepatide, Semaglutide, Adult, Aged
About these checks
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 2026-10-29.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-29.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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