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Cited by 597Diabetes Treatment and ManagementDiabetes Management and ResearchPharmacology and Obesity Treatment

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

Open access
Dahl, Dominik, Onishi, Yukiko, Norwood, Paul, Huh, Ruth, Bray, Ross, Patel, Hiren, Rodríguez, Ángel·2022·JAMA
DOI 10.1001/jama.2022.0078PMC PMC8826179
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Abstract

Importance: The effects of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, as an addition to insulin glargine for treatment of type 2 diabetes have not been described. Objective: To assess the efficacy and safety of tirzepatide added to insulin glargine in patients with type 2 diabetes with inadequate glycemic control. Design, Setting, and Participants: Randomized phase 3 clinical trial conducted at 45 medical research centers and hospitals in 8 countries (enrollment from August 30, 2019, to March 20, 2020; follow-up completed January 13, 2021) in 475 adults with type 2 diabetes and inadequate glycemic control while treated with once-daily insulin glargine with or without metformin. Interventions: Patients were randomized in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of 5-mg (n = 116), 10-mg (n = 119), or 15-mg (n = 120) tirzepatide or volume-matched placebo (n = 120) over 40 weeks. Tirzepatide was initiated at 2.5 mg/week and escalated by 2.5 mg every 4 weeks until the assigned dose was achieved. Main Outcomes and Measures: The primary end point was mean change from baseline in glycated hemoglobin A1c (HbA1c) at week 40. The 5 key secondary end points included mean change in body weight and percentage of patients achieving prespecified HbA1c levels. Results: Among 475 randomized participants (211 [44%] women; mean [SD] age, 60.6 [9.9] years; mean [SD] HbA1c, 8.31% [0.85%]), 451 (94.9%) completed the trial. Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group. At week 40, mean HbA1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001 for both). Mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]). Mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, -8.8 kg with 15-mg tirzepatide and 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001 for all). Higher percentages of patients treated with tirzepatide vs those treated with placebo had HbA1c less than 7% (85%-90% vs 34%; P < .001 for all). The most common treatment-emergent adverse events in the tirzepatide groups vs placebo group were diarrhea (12%-21% vs 10%) and nausea (13%-18% vs 3%). Conclusions and Relevance: Among patients with type 2 diabetes and inadequate glycemic control despite treatment with insulin glargine, the addition of subcutaneous tirzepatide, compared with placebo, to titrated insulin glargine resulted in statistically significant improvements in glycemic control after 40 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04039503.

Integrity signals

Registry

Crossref · 10.1001/jama.2022.0078

Cites

18 of 20 references verified0 citation errors · 2 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 29 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    At week 40, in the treatment regimen estimand, mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide vs 1.6 kg with placebo, a difference of -7.1 kg (95% CI, -8.7 to -5.4; P<.001).

    “At week 40, the mean body weight change from baseline was -5.4 kg with 5-mg tirzepatide, -7.5 kg with 10-mg tirzepatide, and -8.8 kg with 15-mg tirzepatide vs 1.6 kg with placebo (5 mg: difference, -7.1 kg [95% CI, -8.7 to -5.4]; 10 mg: difference, -9.1 kg [95% CI, -10.7 to -7.5]; 15 mg: difference, -10.5 kg [95% CI, -12.1 to -8.8]; P < .001for all; treatment-regimen estimand; Table 2; eFigure 3A”
    Quote in the paperNot a substantial claim
  • Findingown data

    At week 40, tirzepatide 15 mg reduced mean fasting serum glucose by -62.6 mg/dL vs -39.2 mg/dL with placebo, a difference of -23.4 mg/dL (95% CI, -31.0 to -15.8; P<.001; treatment-regimen estimand).

    “At week 40, tirzepatide significantly reduced mean fasting serum glucose by -58.2 mg/dL for the 5-mg dose, -64.0 mg/dL for the 10-mg dose, and -62.6 mg/dL for the 15-mg dose, compared with -39.2 mg/dL for placebo (5 mg: difference, -19.0 mg/dL [95% CI, -26.6 to -11.4]; P < .001; 10 mg: difference, -24.9 mg/dL [95% CI, -32.3 to -17.4]; P < .001;15 mg: difference, -23.4 mg/dL [95% CI, -31.0 to -15.8”
    Quote in the paperSubstantial claim
  • Findingown data

    At week 40, tirzepatide 5 mg reduced mean fasting serum glucose by -58.2 mg/dL vs -39.2 mg/dL with placebo, a difference of -19.0 mg/dL (95% CI, -26.6 to -11.4; P<.001; treatment-regimen estimand).

    “At week 40, tirzepatide significantly reduced mean fasting serum glucose by -58.2 mg/dL for the 5-mg dose, -64.0 mg/dL for the 10-mg dose, and -62.6 mg/dL for the 15-mg dose, compared with -39.2 mg/dL for placebo (5 mg: difference, -19.0 mg/dL [95% CI, -26.6 to -11.4]; P < .001; 10 mg: difference, -24.9 mg/dL [95% CI, -32.3 to -17.4]; P < .001;15 mg: difference, -23.4 mg/dL [95% CI, -31.0 to -15.8”
    Quote in the paperSubstantial claim
  • Findingown data

    At week 40, mean percent change from baseline in insulin glargine dose was 13.0% for 5-mg tirzepatide vs 75.0% for placebo, a difference of -35.4% (95% CI, -46.0% to -22.8%; P<.001).

    “At week 40, the mean percent change from baseline in insulin dose was 13.0% for 5-mg tirzepatide, 8.1% for 10-mg tirzepatide, -11.4% for 15-mg tirzepatide, and 75.0% for placebo (5 mg: difference, -35.4% [95% CI, -46.0% to -22.8%]; 10 mg: difference, -38.2% [95% CI, -48.3% to -26.1%]; 15 mg: difference, -49.3% [95% CI, -57.7% to -39.4%]; P < .001for all; Table 2; Figure 2F; eFigure 4 in Supplement”
    Quote in the paperSubstantial claim
  • Findingown data

    A significantly greater percentage of patients receiving tirzepatide vs placebo achieved the composite outcome of HbA1c less than 7.0% without body weight gain and without clinically significant documented hypoglycemia or severe hypoglycemia (78%-80% vs 12%; P<.001; efficacy estimand).

    “Similarly, a signifi- cantly greater percentage of patients receiving tirzepatide vs placebo achieved the 2 composite outcomes, HbA 1c less than 7.0% (78%-80% vs 12%) or less than or equal to 6.5% (67%- 78% vs 8%) without body weight gain and without clinically significant documented hypoglycemia or severe hypoglyce- mia (P < .001 for all; efficacy estimand; eTable 2 in Supple- ment 2).”
    Quote in the paperSubstantial claim
  • May combine two claims. 20
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Increasing basal insulin dose often improves glycemic control but can be associated with increased risk of hypoglycemia and weight gain, resulting in inadequate intensification of insulin dose in clinical practice.

    “Although increasing the basal insulin dose often improves glycemic control, it can also be associated with increased risk of hypoglycemia and weight gain, resulting in inadequate intensification of insulin dose in clinical practice.1”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [1] Swinnen, 2009, Insulin therapy for type 2 diabetes., Diabetes Care source

      The 'Titration and timing of basal insulin' section says dose titration can achieve glycemic targets, and 'When should insulin therapy be intensified?' says hypoglycemia can limit aggressive titration. The 'Weight gain' section associates insulin therapy with weight gain but finds no evidence of a dose–response relationship in studies of basal insulin initiation. The paper also notes prolonged uncontrolled hyperglycemia in practice, but does not establish that weight gain causes inadequate basal-dose intensification. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Glucose-dependent insulinotropic polypeptide facilitates postprandial lipid clearance.

    “It also suppresses glucagon secretion during hyperglycemia, signals glucagon secretion during hypoglycemia, facilitates postprandial lipid clearance, and promotes satiety.[8][9][10]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Baggio, 2021, Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease., Mol Metab source

      The GIP section (page not specified) says GIP promotes lipid accretion in fat cells, supporting a related role in lipid handling. It does not state that GIP facilitates clearance of circulating lipids after a meal; searches for postprandial lipid clearance and meal-related triglyceride clearance did not establish that more specific claim. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [9] Campbell, 2013, Pharmacology, physiology, and mechanisms of incretin hormone action., Cell Metab source
    • cites [10] Nauck, 2018, Incretin hormones: their role in health and disease., Diabetes Obes Metab source

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

    Premisecitation

    Glucose-dependent insulinotropic polypeptide signals glucagon secretion during hypoglycemia.

    “It also suppresses glucagon secretion during hyperglycemia, signals glucagon secretion during hypoglycemia, facilitates postprandial lipid clearance, and promotes satiety.[8][9][10]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Baggio, 2021, Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease., Mol Metab source
    • cites [9] Campbell, 2013, Pharmacology, physiology, and mechanisms of incretin hormone action., Cell Metab source
    • cites [10] Nauck, 2018, Incretin hormones: their role in health and disease., Diabetes Obes Metab source

  • May combine two claims.

    Premisecitation

    When added to basal insulin, selective GLP-1 receptor agonists have demonstrated improved glycemic control and body weight loss without increasing the risk of hypoglycemia and reducing insulin requirements.

    “When added to basal insulin, selective glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated improved glycemic control and body weight loss without increasing the risk of hypoglycemia and reducing insulin requirements.[2][3][4][5][6]”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [2] Pozzilli, 2017, Placebo-controlled, randomized trial of the addition of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide to titrated daily insulin glargine in patients with type 2 diabetes (AWARD-9)., Diabetes Obes Metab source
    • cites [3] Zinman, 2019, Efficacy, safety, and tolerability of oral semaglutide versus placebo added to insulin with or without metformin in patients with type 2 diabetes: the PIONEER 8 trial., Diabetes Care source

      The Introduction says GLP-1 receptor agonists added to insulin reduce HbA1c and body weight without increasing hypoglycemia, and the Conclusions report an insulin-sparing effect with oral semaglutide 7 and 14 mg. But PIONEER 8 studied basal, basal-bolus, and premixed insulin regimens; its reported reduction in total daily insulin dosage is not established specifically for the basal-insulin group. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [4] Rosenstock, 2020, Impact of a weekly glucagon-like peptide 1 receptor agonist, albiglutide, on glycemic control and on reducing prandial insulin use in type 2 diabetes inadequately controlled on multiple insulin therapy: a randomized trial., Diabetes Care source

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

    Premisecitation

    Glucose-dependent insulinotropic polypeptide suppresses glucagon secretion during hyperglycemia.

    “It also suppresses glucagon secretion during hyperglycemia, signals glucagon secretion during hypoglycemia, facilitates postprandial lipid clearance, and promotes satiety.[8][9][10]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Baggio, 2021, Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease., Mol Metab source
    • cites [9] Campbell, 2013, Pharmacology, physiology, and mechanisms of incretin hormone action., Cell Metab source
    • cites [10] Nauck, 2018, Incretin hormones: their role in health and disease., Diabetes Obes Metab source

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

    Premisecitation

    Glucose-dependent insulinotropic polypeptide promotes satiety.

    “It also suppresses glucagon secretion during hyperglycemia, signals glucagon secretion during hypoglycemia, facilitates postprandial lipid clearance, and promotes satiety.[8][9][10]”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Baggio, 2021, Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease., Mol Metab source

      The GIP section reports that activating hypothalamic GIP-receptor-expressing neurons may reduce food intake, consistent with findings from GIP-receptor agonists in mice with diet-induced obesity. This supports a possible appetite-related effect, but the paper does not establish the unqualified claim that GIP itself promotes satiety. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [9] Campbell, 2013, Pharmacology, physiology, and mechanisms of incretin hormone action., Cell Metab source
    • cites [10] Nauck, 2018, Incretin hormones: their role in health and disease., Diabetes Obes Metab source

  • The quote only partly states this claim.

    Findingown data

    At week 40, in the treatment regimen estimand, mean HbA1c change from baseline was -2.11% with 5-mg tirzepatide vs -0.86% with placebo, a difference of -1.24% (95% CI, -1.48% to -1.01%; P<.001).

    “Mean HbA 1c change from baseline was -2.11% with 5-mg tirzepatide (difference vs placebo, -1.24% [95% CI, -1.48% to -1.01%]; P < .001]).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At week 40, in the treatment regimen estimand, mean HbA1c change from baseline was -2.34% with 15-mg tirzepatide vs -0.86% with placebo, a difference of -1.47% (97.5% CI, -1.75% to -1.20%; P<.001).

    “At week 40, mean HbA 1c change from baseline was -2.40% with 10-mg tirzepatide and -2.34% with 15-mg tirzepatide vs -0.86% with placebo (10 mg: difference vs placebo, -1.53% [97.5% CI, -1.80% to -1.27%]; 15 mg: difference vs placebo, -1.47% [97.5% CI, -1.75% to -1.20%]; P < .001for both).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group.

    “Treatment was prematurely discontinued by 10% of participants in the 5-mg tirzepatide group, 12% in the 10-mg tirzepatide group, 18% in the 15-mg tirzepatide group, and 3% in the placebo group.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    No deaths occurred during the study.

    “No deaths occurred during the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The most frequent treatment-emergent adverse event in the tirzepatide groups were gastrointestinal, including diarrhea (12%-21% vs 10% in the placebo group), nausea (13%-18% vs 2.5% in the placebo group), vomiting (7%-13% vs 2.5% in the placebo group), and decreased appetite (7%-14% vs 1.7% in the placebo group).

    “The most fre-quent treatment-emergent adverse event in the tirzepatide groups were gastrointestinal, including diarrhea (12%-21% vs 10% in the placebo group), nausea (13%-18% vs 2.5% in the placebo group), vomiting (7%-13% vs 2.5% in the placebo group), and decreased appetite (7%-14% vs 1.7% in the placebo group) (Table 3).”
    • Also stated in: § Discussion · plain
      “The most commonly reported treatment-emergent adverse events for patients receiving tirzepatide were gastrointestinal in nature and decreased over time, especially after reaching maintenance doses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At week 40, mean change in systolic and diastolic blood pressure was -6.1 to -12.6 mm Hg and -2.0 to -4.5 mm Hg for tirzepatide groups.

    “At week 40, mean change in systolic and diastolic blood pressure was -6.1 to -12.6 mm Hg and -2.0 to -4.5 mm Hg for tirzepatide”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Rates of premature treatment discontinuation due to adverse events were 6.0% (7/116) in the 5-mg tirzepatide group, 8.4% (10/119) in the 10-mg tirzepatide group, 10.8% (13/120) in the 15-mg tirzepatide group, and 2.5% (3/120) in the placebo group.

    “Rates of premature treatment discontinuation due to adverse events were 6.0% (7/116) in the 5-mg tirzepatide group, 8.4% (10/119) in the 10-mg tirzepatide group, 10.8% (13/120) in the 15-mg tirzepatide group, and 2.5% (3/120) in the placebo group (Table 3).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    At week 40, mean change in systolic and diastolic blood pressure was -1.7 mm Hg and -2.1 mm Hg for the placebo group.

    “-1.7 mm Hg and -2.1 mm Hg for the placebo group (eTable 7 in Supplement 2).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Investigators, site staff, clinical monitors, external independent adjudication committee members, sponsors, and patients remained blinded to treatment assignments until study completion.

    “Investigators, site staff, clinical monitors, external independent adjudication committee members, sponsors, and patients remained blinded to the treatment assignments until study completion.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Patients were randomized in a 1:1:1:1 ratio to receive 5 mg, 10 mg, or 15 mg tirzepatide or volume-matched placebo using a computer-generated random sequence via an interactive web response system and stratified by country, baseline HbA1c, and baseline metformin use.

    “Patients were randomized in a 1:1:1:1 ratio to receive 5 mg, 10 mg, or 15 mg of tirzepatide or volume-matched placebo (Figure 1) with a blocking schema (block size of 4) by a computer-generated random sequence using an interactive web response system and stratified based on country, baseline HbA 1c (≤8.0% or >8.0%[≤64 mmol/mol or >64 mmol/mol]), and baseline metformin use.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Glucose-dependent insulinotropic polypeptide is the primary incretin hormone responsible for meal-stimulated insulin secretion in healthy individuals.

    “Glucose-dependent insulinotropic polypeptide is the primary incretin hormone responsible for mealstimulated insulin secretion in healthy individuals.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Gasbjerg, 2019, Separate and combined glucometabolic effects of endogenous glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 in healthy individuals., Diabetes source

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

    Study design and conductnone given

    All cases of suspected pancreatitis and major adverse cardiovascular events were adjudicated by an independent clinical end point committee in a blinded manner.

    “All cases of suspected pancreatitis and major adverse cardiovascular events were adjudicated by an independent clinical end point committee in a blinded manner (eAppendix in Supplement 2).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The primary objective tested the 10-mg and 15-mg tirzepatide doses in parallel, controlled for multiplicity, and were accompanied by 2-sided 97.5% CIs; statistical significance was defined as P < .025.

    “The primary objective tested the 10-mg and 15-mg tirzepatide doses in parallel, controlled for multiplicity, and were accompanied by 2-sided 97.5% CIs; statistical significance was defined as P < .025.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tirzepatide has shown statistically significant reductions in HbA1c and body weight compared with insulin glargine when added to oral glucose-lowering medications.

    “Tirzepatide is a novel, once-weekly dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist that is administered via subcutaneous injection and has shown statistically significant reductions in hemoglobin A 1c (HbA 1c ) and body weight compared with the GLP-1 receptor agonist semaglutide (1 mg), 11 insulin degludec, 12 and insulin glargine 13 when added to oral glucose-lower”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] 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

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

    Premisecitation

    Although treatment guidelines generally recommend using GLP-1 receptor agonists prior to basal insulin in most cases, the treatment sequence may vary because the latter is still widely used as the first injectable therapy in clinical practice due to cost, reimbursement issues, and prescribing habits.

    “Although treatment guidelines generally recommend using GLP-1 receptor agonists prior to basal insulin in most cases, the treatment sequence may vary because the latter is still widely used as the first injectable therapy in clinical practice due to cost, reimbursement issues, and prescribing habits.16”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Yu, 2017, Characteristics associated with the choice of first injectable therapy among US patients with type 2 diabetes., Clin Ther source

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

    Study design and conductreasoning

    Due to the global nature of the study and the countries participating in it, the percentage of participants identifying as certain racial or ethnic groups was low.

    “Sixth, due to the global nature of the study and the countries participating in it, the percentage of participants identifying as certain racial or ethnic groups was low.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Tirzepatide has shown statistically significant reductions in HbA1c and body weight compared with insulin degludec when added to oral glucose-lowering medications.

    “Tirzepatide is a novel, once-weekly dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist that is administered via subcutaneous injection and has shown statistically significant reductions in hemoglobin A 1c (HbA 1c ) and body weight compared with the GLP-1 receptor agonist semaglutide (1 mg), 11 insulin degludec, 12 and insulin glargine 13 when added to oral glucose-lower”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] 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

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

    Premisecitation

    Tirzepatide has shown statistically significant reductions in HbA1c and body weight compared with semaglutide (1 mg) when added to oral glucose-lowering medications.

    “Tirzepatide is a novel, once-weekly dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist that is administered via subcutaneous injection and has shown statistically significant reductions in hemoglobin A 1c (HbA 1c ) and body weight compared with the GLP-1 receptor agonist semaglutide (1 mg), 11 insulin degludec, 12 and insulin glargine 13 when added to oral glucose-lower”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Frías, 2021, Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes., N Engl J Med source

  • May combine two claims.

    Study design and conductnone given

    The lack of adjustment of insulin dose for the first 4 weeks of treatment may have initially favored patients receiving tirzepatide, although this was compensated during the remainder of the 40-week treatment period.

    “Second, the lack of adjustment of insulin dose for the first 4 weeks of treatment may have initially favored patients receiving tirzepatide, although this was compensated during the remainder of the 40-week treatment period.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The patients enrolled in this study were treated with insulin glargine with or without metformin, and therefore the observations may not be directly extrapolated to other regimens using different oral antihyperglycemic medications.

    “First, the patients enrolled in this study were treated with insulin glargine with or without metformin, and therefore the observations may not be directly extrapolated to other regimens using different oral antihyperglycemic medications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The effects of tirzepatide on glycemic control, body weight, lipid levels, and blood pressure on a background of titrated basal insulin in this trial were consistent with previously reported studies of tirzepatide and further validate its effectiveness across different patient populations differing in the duration of the disease, background glucose-lowering therapies, or comorbidities.

    “The effects of tirzepatide on glycemic control, body weight, lipid levels, and blood pressure on a background of titrated basal insulin in this trial were consistent with previously reported studies of tirzepatide [11][12][13][14] and further validate its effectiveness across different patient populations differing in the duration of the disease, background glucose-lowering therapies, or comorbidi”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11][12][13][14]

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

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

    Study design and conductnone given

    Strengths of the study include the randomized, double-blind, placebo-controlled design and titration of background basal insulin using a treat-to-target algorithm.

    “Strengths of the study include the randomized, doubleblind, placebo-controlled design and titration of background basal insulin using a treat-to-target algorithm.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tirzepatide was associated with reductions in blood pressure and improvements in lipid profile.

    “Additionally, tirzepatide was associated with reductions in blood pressure and improvements in lipid profile.[11][12][13][14]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] Frías, 2021, Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes., N Engl J Med source
    • cites [12] 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 [13] 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

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

    Premisenone given

    Tirzepatide is a novel, once-weekly dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist administered via subcutaneous injection.

    “Tirzepatide is a novel, once-weekly dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist that is administered via subcutaneous injection and has shown statistically significant reductions in hemoglobin A 1c (HbA 1c ) and body weight compared with the GLP-1 receptor agonist semaglutide (1 mg), 11 insulin degludec, 12 and insulin glargine 13 when added to oral glucose-lower”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Study design and conductnone given

    Although gastrointestinal adverse events and their severity are typically self-reported in most clinical trials, this approach has limitations.

    “Fourth, although gastrointestinal adverse events and their severity are typically self-reported in most clinical trials, this approach has limitations.”
    Quote in the paperNot a substantial claim
31 of 31

  • The paper relies on this without support.

    This is the first trial to assess the efficacy and adverse event profile of a dual GIP/GLP-1 receptor agonist in combination with a basal insulin regimen.

    “To the authors' knowledge, this is the first trial to assess the efficacy and adverse event profile of a dual glucosedependent insulinotropic polypeptide/GLP-1 receptor agonist in combination with a basal insulin regimen.”
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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?

  • In a Phase 2 study of subjects with obesity and T2D, 36 weeks of retatrutide treatment reduced body weight by approximately 16.9%, compared with approximately 2% for dulaglutide and approximately 3% for placebo.

    “In a back-to-back published Phase 2 study comprising of subjects with obesity and T2D, 36 weeks of retatrutide treatment reduced body weight by ~16.9%, compared to ~2% or ~3% with dulaglutide or placebo, respectively;”

    From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [166]

    The Abstract (page not provided) identifies this as a phase 3 trial of tirzepatide versus placebo added to insulin glargine over 40 weeks, not a 36-week phase 2 retatrutide trial with a dulaglutide comparator. Its reported weight changes are −5.4 to −8.8 kg with tirzepatide and +1.6 kg with placebo, not the percentages attributed in the claim. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In the same Phase 2 study, retatrutide lowered HbA1c levels by approximately 2%, compared with approximately 1.4% for dulaglutide and approximately 0.01% for placebo at the 24-week time point.

    “furthermore, the triagonist lowered HbA1c levels by ~2%, compared to ~1.4% or ~0.01% with dulaglutide or placebo, respectively, at the 24 week time point166.”

    From Transforming obesity: The advancement of multi-receptor drugs (2024) · cites this paper as [166]

    The Primary Outcome section reports a different trial: tirzepatide versus placebo added to insulin glargine, with HbA1c changes measured at week 40. It gives changes of −2.40% and −2.34% for two tirzepatide doses versus −0.86% for placebo, not the claimed week-24 retatrutide, dulaglutide, and placebo results. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In individuals intensified to insulin therapy, combination therapy with a GLP-1 RA or dual GIP and GLP-1 RA has hypoglycemia benefits compared with insulin alone.

    “In individuals who are intensified to insulin therapy, combination therapy with a GLP-1 RA or a dual GIP and GLP-1 RA has been shown to have greater efficacy and durability of glycemic treatment effects, as well as weight and hypoglycemia benefits, than treatment intensification with insulin alone (89,131).”

    From 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025 (2025) · cites this paper as [131]

    The paper's safety results (section labeled “Downloaded From,” page not provided) do not show a hypoglycemia benefit from adding tirzepatide to insulin glargine. Hypoglycemia incidence was 14.2%–19.3% in the combination groups versus 12.5% with insulin glargine plus placebo; all three severe episodes occurred in the tirzepatide groups. (LLM, conf=0.87)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • SURPASS studies have shown that tirzepatide reduced HbA1c and fasting glucose levels more than titrated insulin degludec, insulin glargine or 1 mg once a week semaglutide independently of baseline HbA1c levels.

    “Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS) studies have shown that tirzepatide reduced HbA1c and fasting glucose levels more than the titrated insulin degludec, insulin glargine or 1 mg once a week semaglutide independently of the baseline levels of HbA1c.”

    From The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update. (2024) · cites this paper as [55]

    The Introduction reports greater HbA1c reductions with tirzepatide than with semaglutide 1 mg, insulin degludec, or insulin glargine. The Key Secondary Outcomes and Additional Secondary and Exploratory End Points sections report fasting-glucose reductions and no significant difference in HbA1c response between baseline-HbA1c subgroups, but those analyses compare tirzepatide with placebo added to insulin glargine—not with the three named drugs. Page numbers were unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • About 11% of those with T2DM did not respond even to the highest dose of tirzepatide.

    “However, about 11% of those with T2DM did not respond even to the highest dose of tirzepatide [53-55].”

    From The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update. (2024) · cites this paper as [55]

    The Key Secondary Outcomes section reports that 85%–90% of tirzepatide-treated participants reached an HbA1c target at week 40, so some did not reach that target. But the paper does not identify about 11% of the highest-dose group as nonresponders. Its 10.8% figure for the 15-mg group refers instead to discontinuation due to adverse events (Table 3); neither missing a target nor discontinuing treatment establishes no response. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

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

  • Severe hypoglycemia percentage does not match the group count

    Minor

    In the 10-mg tirzepatide group, 2 of 119 patients is 1.68%, which rounds to 1.7% at the table's precision, not 1.6%.

    Reported 1.6 · recomputed 1.680672

1 of 1

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Authors
Dahl, D., Onishi, Y., Norwood, P., Huh, R., Bray, R., Patel, H., & Rodríguez, Á.
Affiliations
  • Gemeinschaftspraxis für Innere Medizin und Diabetologie, Hamburg, Germany
  • The Institute of Medical Science, Asahi Life Foundation (JP)
  • Valley Endocrine and Research, Fresno, California
  • Eli Lilly (United States) (US)
  • Lilly Spain, Alcobendas, Madrid, Spain
Corresponding author
Rodríguez, Ángel
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2022-02-08
Volume
327
Issue
6
Pages
534
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2022.0078
PMC
PMC8826179
OpenAlex
W4210940103
Cited by
597
References
17
Citations by year
2026: 105 · 2025: 153 · 2024: 151 · 2023: 124 · 2022: 64
FWCI
91.12
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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 › Pharmacology › Pharmacology and Obesity Treatment
Keywords
tirzepatide, insulin glargine, type 2 diabetes, glycemic control, HbA1c, GIP/GLP-1 receptor agonist, combination therapy, metformin, body weight, adverse events, drug safety, treatment discontinuation, inadequate glycemic control, dose escalation, hypoglycemia, nausea, vomiting
MeSH terms
Insulin Glargine, Glycemic Control, Tirzepatide, Blood Glucose, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Double-Blind Method, Drug Therapy, Combination, Female, Gastric Inhibitory Polypeptide, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Injections, Subcutaneous, Male, Metformin, Middle Aged, Weight Loss

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 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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