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Cited by 6,900Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsHeart Failure Treatment and Management

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Open access
Marso, Steven P., Bain, Stephen C., Consoli, Agostino, Eliaschewitz, Freddy G., Jódar, Esteban, Leiter, Lawrence A., Lingvay, Ildiko, Rosenstock, Julio +7 more·2016·New England Journal of Medicine
DOI 10.1056/nejmoa1607141
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Abstract

BACKGROUND: Establishing cardiovascular safety of new therapies for type 2 diabetes is important. Safety data are available for the subcutaneous form of the glucagon-like peptide-1 receptor agonist semaglutide but are needed for oral semaglutide. METHODS: We assessed cardiovascular outcomes of once-daily oral semaglutide in an event-driven, randomized, double-blind, placebo-controlled trial involving patients at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors only). The primary outcome in a time-to-event analysis was the first occurrence of a major adverse cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The trial was designed to rule out 80% excess cardiovascular risk as compared with placebo (noninferiority margin of 1.8 for the upper boundary of the 95% confidence interval for the hazard ratio for the primary outcome). RESULTS: A total of 3183 patients were randomly assigned to receive oral semaglutide or placebo. The mean age of the patients was 66 years; 2695 patients (84.7%) were 50 years of age or older and had cardiovascular or chronic kidney disease. The median time in the trial was 15.9 months. Major adverse cardiovascular events occurred in 61 of 1591 patients (3.8%) in the oral semaglutide group and 76 of 1592 (4.8%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.57 to 1.11; P<0.001 for noninferiority). Results for components of the primary outcome were as follows: death from cardiovascular causes, 15 of 1591 patients (0.9%) in the oral semaglutide group and 30 of 1592 (1.9%) in the placebo group (hazard ratio, 0.49; 95% CI, 0.27 to 0.92); nonfatal myocardial infarction, 37 of 1591 patients (2.3%) and 31 of 1592 (1.9%), respectively (hazard ratio, 1.18; 95% CI, 0.73 to 1.90); and nonfatal stroke, 12 of 1591 patients (0.8%) and 16 of 1592 (1.0%), respectively (hazard ratio, 0.74; 95% CI, 0.35 to 1.57). Death from any cause occurred in 23 of 1591 patients (1.4%) in the oral semaglutide group and 45 of 1592 (2.8%) in the placebo group (hazard ratio, 0.51; 95% CI, 0.31 to 0.84). Gastrointestinal adverse events leading to discontinuation of oral semaglutide or placebo were more common with oral semaglutide. CONCLUSIONS: In this trial involving patients with type 2 diabetes, the cardiovascular risk profile of oral semaglutide was not inferior to that of placebo. (Funded by Novo Nordisk; PIONEER 6 ClinicalTrials.gov number, NCT02692716.).

Integrity signals

Registry

Crossref · 10.1056/nejmoa1607141

Cites

16 of 16 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 9 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Recently, trials evaluating empagliflozin and liraglutide have shown improved cardiovascular outcomes in patients with type 2 diabetes who were at high risk for cardiovascular events.

    “Recently, trials evaluating a sodium-glucose cotransporter 2 inhibitor (empagliflozin) and a glucagon-like peptide 1 (GLP-1) analogue (liraglutide) have shown improved cardiovascular outcomes in patients with type 2 diabetes who were at high risk for cardiovascular events.2,3”
    Quote in the paperNot a substantial claim2 of 2 sources checked
  • Findingown data

    The number of patients who would need to be treated to prevent one event of the primary outcome over a period of 24 months was 45 on the basis of Kaplan-Meier estimates.

    “The number of patients who would need to be treated to prevent one event of the primary outcome over a period of 24 months was 45 on the basis of Kaplan-Meier estimates.8”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [8] source

      The “Only survival probabilities available” section explains how to calculate a time-specific number needed to treat from Kaplan–Meier estimates. It does not report an NNT of 45 at 24 months; the Discussion table gives 6.4 at two years for its lung-cancer example. Thus the source supports the method, but not the claimed result. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    To date, two antihyperglycemic agents have been shown to reduce the rate of cardiovascular events in patients with type 2 diabetes at high cardiovascular risk.

    “To date, two antihyperglycemic agents have been shown to reduce the rate of cardiovascular events in patients with type 2 diabetes at high cardiovascular risk.2,3”
    Quote in the paperSubstantial claim2 of 2 sources checked
  • Findingown data

    Retinopathy complications occurred more frequently with semaglutide than with placebo (50 [3.0%] vs 29 [1.8%]; hazard ratio, 1.76; 95% CI, 1.11 to 2.78; P = 0.02).

    “Retinopathy complications § 50 (3.0)1.49 29 (1.8) 0.86 1.76 (1.11-2.78)0.02”
    • Also stated in: § Discussion · plain
      “there was an unexpected higher rate of retinopathy complications (vitreous hemorrhage, blindness, or the need for treatment with an intravitreal agent or photocoagulation) in the semaglutide group.”
    Quote in the paperSubstantial claim
  • Findingown data

    Similar risk reductions for the primary outcome and its components were observed for both doses of semaglutide.

    “Similar risk reductions for the primary outcome and its components were observed for both doses of semaglutide (Fig. S4 in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 14
  • The quote only partly states this claim. 3

  • May combine two claims.

    Findingcitation

    Acute pancreatitis occurred in 9 patients in the semaglutide group and 12 in the placebo group; all events were mild according to the revised Atlanta criteria.

    “Acute pancreatitis occurred in 9 patients in the semaglutide group and in 12 in the placebo group; all events were mild, according to the revised Atlanta criteria.7”
    Quote in the paperNot a substantial claim1 of 1 sources checked

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

    Premisecitation

    An association between rapid glucose lowering and worsening of retinopathy has been reported in patients with type 1 diabetes.

    “An association between rapid glucose lowering and worsening of retinopathy has been reported in patients with type 1 diabetes.9,10”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] source
    • cites [10] source

  • May combine two claims.

    Findingown data

    The primary composite outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P<0.001 for noninferiority; P=0.02 for superiority).

    “The composite primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and 146 of 1649 (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority; P = 0.02 for superiority) (Fig. 1A).”
    • Also stated in: § RESULTS · plain
      “The primary outcome occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.58 to 0.95; P<0.001 for noninferiority).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the majority of patients, antibody formation was transient (only 4 patients tested positive during follow-up) and antibody titers were generally low.

    “In the majority of patients, antibody formation was transient -only 4 patients tested positive during follow-up -and antibody titers were generally low.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    At week 104, semaglutide 0.5 mg lowered mean systolic blood pressure by 1.3 mm Hg compared with placebo (P = 0.10).

    “the mean systolic blood pressure in the semaglutide group, as compared with the placebo group, was 1.3 mm Hg lower in the group receiving 0.5 mg (P = 0.10)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Antibodies against semaglutide were detected in 30 patients treated with semaglutide, with the greatest number (14) testing positive at week 44.

    “Antibodies against semaglutide were detected in 30 patients treated with semaglutide, with the greatest number of patients (14) testing positive at week 44.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At week 104, among patients receiving semaglutide, the mean body weight decreased from 92.1 kg at baseline to 88.5 kg in the 0.5 mg group and to 87.2 kg in the 1.0 mg group, for changes of -3.6 kg and -4.9 kg, respectively; in the placebo group, the mean body weight decreased to 91.4 kg and 91.6 kg, for changes of -0.7 kg and -0.5 kg, respectively.

    “At week 104, among patients receiving semaglutide, the mean body weight decreased from 92.1 kg at baseline to 88.5 kg in the group receiving 0.5 mg and to 87.2 kg in the group receiving 1.0 mg, for changes of -3.6 kg and -4.9 kg, respectively; in the placebo group, the mean body weight decreased to 91.4 kg and 91.6 kg, for changes of -0.7 kg and -0.5 kg, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nonfatal myocardial infarction occurred less frequently with semaglutide than with placebo, but the difference was not significant (47 [2.9%] vs 64 [3.9%]; hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P = 0.12).

    “a nonsignificant (26%) decrease in nonfatal myocardial infarction”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    At baseline, 2735 of the 3297 patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both.

    “At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The risk of cardiovascular death was similar in the two groups, with deaths reported in 44 patients (2.7%) in the semaglutide group and 46 patients (2.8%) in the placebo group (hazard ratio, 0.98; 95% CI, 0.65 to 1.48; P=0.92).

    “The risk of cardiovascular death was similar in the two groups, with deaths reported in 44 patients (2.7%) in the semaglutide group and 46 (2.8%) in the placebo group (hazard ratio, 0.98; 95% CI, 0.65 to 1.48; P = 0.92) (Fig. 1D).”
    • Also stated in: § RESULTS · plain
      “Rates of death from cardiovascular causes were similar in the two groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mean body weight in the semaglutide group, as compared with the placebo group, was 2.9 kg lower in the 0.5 mg group and 4.3 kg lower in the 1.0 mg group (P<0.001 for both comparisons).

    “Thus, the mean body weight in the semaglutide group, as compared with the placebo group, was 2.9 kg lower in the group receiving 0.5 mg and 4.3 kg lower in the group receiving 1.0 mg (P<0.001 for both comparisons) (Fig. 2B, and Table S10 in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Nonfatal myocardial infarction occurred in 47 patients (2.9%) in the semaglutide group and 64 patients (3.9%) in the placebo group, a difference that was not significant (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P=0.12).

    “Nonfatal myocardial infarction occurred in 47 patients (2.9%) in the semaglutide group and 64 (3.9%) in the placebo group, a difference that was not significant (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P = 0.12) (Fig. 1B).”
    • Also stated in: § RESULTS · plain
      “Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74; 95% CI, 0.51 to 1.08; P = 0.12)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The rates of malignant neoplasms were similar in the two groups, but were higher in the semaglutide group receiving 1.0 mg and lower in the group receiving 0.5 mg than in the placebo groups.

    “The rates of malignant neoplasms, which were similar in the two groups, were higher in the semaglutide group receiving 1.0 mg and lower in the group receiving 0.5 mg than in the placebo groups”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Although the overall number of retinopathy events was low, there was an unexpected higher rate of retinopathy complications in the semaglutide group.

    “Although the overall number of retinopathy events was low, there was an unexpected higher rate of retinopathy complications (vitreous hemorrhage, blindness, or the need for treatment with an intravitreal agent or photocoagulation) in the semaglutide group.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    At week 104, semaglutide 0.5 mg increased mean pulse rate by 2.0 bpm compared with placebo (P<0.001).

    “the mean pulse rate in the semaglutide group, as compared with the placebo group, was 2.0 bpm higher in the group receiving 0.5 mg”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Nonfatal stroke occurred less frequently with semaglutide than with placebo (27 [1.6%] vs 44 [2.7%]; hazard ratio, 0.61; 95% CI, 0.38 to 0.99; P = 0.04).

    “a significant (39%) decrease in the rate of nonfatal stroke”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During the trial, significantly more patients in the placebo group than in the semaglutide group received additional antihyperglycemic agents, including insulin, which was initiated more than twice as frequently in the placebo group.

    “During the trial, significantly more patients in the placebo group than in the semaglutide group received additional antihyperglycemic agents, including insulin, which was initiated more than twice as frequently in the placebo group (Table S7B in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At week 104, among patients receiving semaglutide, the mean glycated hemoglobin level decreased from 8.7% at baseline to 7.6% in the 0.5 mg group and to 7.3% in the 1.0 mg group, for changes of -1.1% and -1.4%, respectively; in the placebo group, the mean level decreased to 8.3% in the two dose groups, for a reduction of 0.4% in each group.

    “At week 104, among patients receiving semaglutide, the mean glycated hemoglobin level decreased from 8.7% at baseline to 7.6% in the group receiving 0.5 mg and to 7.3% in the group receiving 1.0 mg, for changes of -1.1% and -1.4%, respectively; in the placebo group, the mean level decreased to 8.3% in the two dose groups, for a reduction of 0.4% in each group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The mean glycated hemoglobin level in the semaglutide group, as compared with the placebo group, was 0.7 percentage points lower in the 0.5 mg group and 1.0 percentage point lower in the 1.0 mg group (P<0.001 for both comparisons).

    “Thus, the mean glycated hemoglobin level in the semaglutide group, as compared with the placebo group, was 0.7 percentage points lower in the group receiving 0.5 mg and 1.0 percentage point lower in the group receiving 1.0 mg (estimated treatment difference) (P<0.001 for both comparisons) (Fig. 2A, and Table S10 in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The majority of gastrointestinal events were mild or moderate in severity and occurred during the first 30 weeks.

    “The majority of gastrointestinal events were mild or moderate in severity and occurred during the first 30 weeks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    More patients in the semaglutide group discontinued treatment because of adverse events, mainly gastrointestinal.

    “Fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The rate of malignant neoplasms was similar in the pooled semaglutide group and the pooled placebo group, although the highest rate was observed with the semaglutide dose of 1.0 mg.

    “The rate of malignant neoplasms was similar in the pooled semaglutide group and the pooled placebo group, although the highest rate was observed with the semaglutide dose of 1.0 mg.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Clinically meaningful and sustained weight loss and a reduction in systolic blood pressure occurred in the semaglutide group versus the placebo group over 2 years.

    “Clinically meaningful and sustained weight loss and a reduction in systolic blood pressure occurred in the semaglutide group versus the placebo group over 2 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The treatment effect of semaglutide and the accrual of more events than estimated resulted in a significantly lower risk of the primary outcome among patients in the semaglutide group.

    “However, the treatment effect of semaglutide and the accrual of more events than estimated resulted in a significantly lower risk of the primary outcome among patients in the semaglutide group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The rate of pancreatic cancer was lower with semaglutide, and no medullary thyroid carcinomas were reported in this trial.

    “The rate of pancreatic cancer -an event of interest for this drug class -was lower with semaglutide, and no medullary thyroid carcinomas were reported in this trial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Semaglutide was associated with significant and sustained reductions in glycated hemoglobin levels, as compared with placebo, with similar rates of hypoglycemia.

    “Semaglutide was associated with significant and sustained reductions in glycated hemoglobin levels, as compared with placebo, with similar rates of hypoglycemia.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    P values other than that for the primary hypothesis have not been adjusted for multiplicity.

    “P values other than that for the primary hypothesis have not been adjusted for multiplicity and have been calculated to test for null hypotheses of no difference.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The trial was randomized, double-blind, placebo-controlled, parallel-group.

    “We performed a randomized, double-blind, placebo-controlled, parallel-group trial at 230 sites in 20 countries.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The lower risk of the primary outcome was principally driven by a significant 39% decrease in the rate of nonfatal stroke and a nonsignificant 26% decrease in nonfatal myocardial infarction, with no significant difference in the rate of cardiovascular death.

    “This lower risk was principally driven by a significant (39%) decrease in the rate of nonfatal stroke and a nonsignificant (26%) decrease in nonfatal myocardial infarction, with no significant difference in the rate of cardiovascular death.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    An independent data and safety monitoring committee performed ongoing surveillance and had access to all the data in an unblinded fashion.

    “An independent data and safety monitoring committee performed ongoing surveillance and had access to all the data in an unblinded fashion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The risk reduction for the primary outcome was seen despite an increase in pulse rate, which is a class effect for GLP-1-receptor agonists.

    “The risk reduction for the primary outcome was seen despite an increase in pulse rate, a class effect for GLP-1-receptor agonists.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The increase in pulse rate observed with semaglutide is a class effect of GLP-1 receptor agonists.

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

    Study design and conductown data

    The mean percentage of time during which patients received semaglutide was 86.5% (87.7% for 0.5 mg and 85.3% for 1.0 mg), and the mean percentage during which patients received placebo was 89.5% (89.4% for 0.5 mg and 89.6% for 1.0 mg).

    “The mean percentage of time during which patients received semaglutide was 86.5% (87.7% among those receiving 0.5 mg and 85.3% among those receiving 1.0 mg), and the mean percentage during which patients received placebo was 89.5% (89.4% among those receiving 0.5 mg and 89.6% among those receiving 1.0 mg).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Testing for superiority for the primary outcome was not prespecified or adjusted for multiplicity.

    “Testing for superiority for the primary outcome was not prespecified or adjusted for multiplicity.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Vital status was known for 99.6% of the patients by the end of the trial.

    “Vital status was known for 99.6% of the patients by the end of the trial (Figs.S1A and S1B in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Randomization was stratified according to cardiovascular disease status, insulin treatment, and estimated glomerular filtration rate at screening.

    “The randomization of patients was stratified according to cardiovascular disease status (established cardiovascular or chronic kidney disease or cardiovascular risk factors only), insulin treatment (none, basal insulin only, or premixed insulin), and estimated glomerular filtration rate (≤30 ml or >30 ml per minute per 1.73 m 2 of body-surface area) at screening.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All results were analyzed on an intention-to-treat basis that included the full analysis set, with the exception of adverse events leading to premature discontinuation, which were included in the as-treated safety analysis.

    “All results were analyzed on an intention-to-treat basis that included the full analysis set (i.e., all patients who underwent randomization according to the planned treatment), with the exception of adverse events leading to premature discontinuation, which were included in the as-treated safety analysis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Semaglutide is a GLP-1 analogue with an extended half-life of approximately 1 week, permitting once-weekly subcutaneous administration.

    “Semaglutide, a GLP-1 analogue with an extended half-life of approximately 1 week (which permits once-weekly subcutaneous administration), 4”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

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

    Study design and conductown data

    Rates of premature treatment discontinuation were similar across groups (20% overall).

    “Rates of premature treatment discontinuation were similar across groups (20% overall) (Table S5 in the Supplementary Appendix).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Semaglutide-treated patients had a lower risk of new or worsening nephropathy, according to differences in macroalbuminuria, but a higher risk of diabetic retinopathy complications than did those receiving placebo.

    “Semaglutide-treated patients had a lower risk of new or worsening nephropathy, according to differences in macroalbuminuria, but a higher risk of diabetic retinopathy complications than did those receiving placebo.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Each outcome, except for peripheral revascularization, was adjudicated in a blinded fashion by an external, independent event-adjudication committee.

    “Each outcome, except for peripheral revascularization, was adjudicated in a blinded fashion by an external, independent event-adjudication committee.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    In this trial, the risk reduction of the primary outcome was driven by a significant decrease in the rate of nonfatal stroke and a nonsignificant decrease in the rate of nonfatal myocardial infarction, with no difference in cardiovascular death.

    “In this trial, the risk reduction of the primary outcome was driven by a significant decrease in the rate of nonfatal stroke and a nonsignificant decrease in the rate of nonfatal myocardial infarction, with no difference in cardiovascular death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Patients were followed for a relatively short duration (2.1 years) and were at high cardiovascular risk.

    “Patients were followed for a relatively short duration (2.1 years) and were at high cardiovascular risk.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    The beneficial effect of semaglutide on cardiovascular outcomes may relate to modification of the progression of atherosclerosis.

    “The beneficial effect of semaglutide on cardiovascular outcomes may relate to modification of the progression of atherosclerosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The trial was not powered to show superiority, so such testing was not prespecified.

    “It was not powered to show superiority, so such testing was not prespecified.”
    Quote in the paperSubstantial claim
44 of 44

  • The paper relies on this without support.

    The cardiovascular effects of semaglutide in type 2 diabetes are unknown.

    “The cardiovascular effects of semaglutide, a glucagon-like peptide 1 analogue with an extended half-life of approximately 1 week, in type 2 diabetes are unknown.”

  • The paper relies on this without support.

    Semaglutide is currently in development but not yet approved for the treatment of type 2 diabetes.

    “is currently in development but not yet approved for the treatment of type 2 diabetes.”

  • The paper relies on this without support.

    The increase in pulse rate observed with semaglutide is a class effect of GLP-1 receptor agonists.

    “a class effect for GLP-1-receptor agonists.”
3 of 3

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?

  • Major cardiovascular trials in patients with T2DM, including the LEADER, SUSTAIN-6, HARMONY Outcomes and REWIND trials, have collectively demonstrated a significant reduction in cardiovascular death with GLP-1RA therapy, ranging from 12% to 26%.

    “Major cardiovascular trials in patients with T2DM, including the LEADER, SUSTAIN-6, HARMONY Outcomes and REWIND trials, 22 -25 have collectively demonstrated a significant reduction in cardiovascular death with GLP-1RA therapy, ranging from 12% to 26%.”

    From <scp>Glucagon‐like peptide‐1 receptor agonists</scp> improve biomarkers of inflammation and oxidative stress: A systematic review and meta‐analysis of randomised controlled trials (2021) · cites this paper as [23]

    The Cardiovascular Outcomes section reports that SUSTAIN-6 found a significant reduction in the composite cardiovascular outcome, but cardiovascular death was similar with semaglutide and placebo (hazard ratio 0.98; P = 0.92). Thus, this trial does not support the claim that it demonstrated a significant 12%–26% reduction in cardiovascular death. (LLM, conf=0.93)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Serious adverse events varied from 7% to 25.2% across studies.

    “Serious adverse events varied from 7% to 25.2%”

    From Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review (2024) · cites this paper as [26]

    The adverse-event table reproduced in the Discussion reports serious adverse events in 33.6% to 39.9% of this trial’s groups, not 7% to 25.2%. Its 25.2% figure refers to severe adverse events, a separately defined category; the paper does not report a range across studies. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • In the SUSTAIN program, 83 patients (1.4%) treated with semaglutide developed a gallbladder event, compared with 39 patients (1.9%) in the placebo group.

    “In the SUSTAIN program, 83 patients (1.4%) treated with semaglutide developed a gallbladder event, compared with 39 patients (1.9%) in the placebo group”

    From Safety of Semaglutide (2021) · cites this paper as [28]

    The Safety section reports 58 patients with gallbladder disorders in the semaglutide group and 61 in the placebo group, not 83 and 39. The Patients section also describes this trial rather than a pooled SUSTAIN-program analysis; page numbers were not supplied in our copy. (LLM, conf=0.90)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Compared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g creatinine, doubling of serum creatinine, ESKD, or death from ESKD) by 39%.

    “Specifically, compared with placebo, empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to UACR >300 mg/g creatinine, doubling of serum creatinine, ESKD, or death from ESKD) by 39%”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [98]

    The Results section reports a reduction in new or worsening nephropathy with semaglutide, not empagliflozin, versus placebo (hazard ratio 0.64, corresponding to 36% rather than 39%). The Discussion attributes the 39% reduction to nonfatal stroke, not nephropathy. The Other Outcomes section also defines a different nephropathy composite from the one claimed; page numbers are unavailable in our copy. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Canagliflozin reduced the risk of reduction in eGFR, ESKD, or death from ESKD by 40%.

    “and the risk of reduction in eGFR, ESKD, or death from ESKD by 40%”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [98]

    The Results (section “A Primary Outcome”; page unavailable) report a lower risk of new or worsening nephropathy with semaglutide, not a 40% reduction in the stated kidney-disease composite with canagliflozin. The paper reports a hazard ratio of 0.64 for its different nephropathy outcome. (LLM, conf=0.85)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

Cites

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Authors
Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A., Lingvay, I., Rosenstock, J., Seufert, J., Warren, M. L., Woo, V., Hansen, O., Holst, A. G., Pettersson, J., & Vilsbøll, T.
Affiliations
  • St. Michael's Hospital (CA)
  • University of Copenhagen (DK)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2016-11-10
Volume
375
Issue
19
Pages
1834-1844
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1607141
OpenAlex
W2519510391
Semantic Scholar
883e9785193db22caecc913601d42f080b3b93be
Cited by
6,900
References
15
Citations by year
2026: 914 · 2025: 985 · 2024: 845 · 2023: 631 · 2022: 607 · 2021: 641 · 2020: 676 · 2019: 597 · 2018: 535 · 2017: 404 · 2016: 57 · 2015: 1 · 2014: 2 · 2013: 2
FWCI
532.92
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • ABACUS. Repositorio de Producción Científica (Universidad Europea) (submittedVersion, other-oa)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Amgen
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Sanofi
  • Intarcia Therapeutics
  • MannKind Corporation
  • Medicines Company
  • Mylan
  • Novo Nordisk
  • Novo Nordisk Fonden (NNF15OC0016230, NNF12OC1015904, NNF16OC0020224)
  • Servier
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
semaglutide, oral semaglutide, type 2 diabetes, cardiovascular safety, major adverse cardiovascular events, GLP-1 receptor agonists, myocardial infarction, stroke, cardiovascular mortality, non-inferiority, high cardiovascular risk, chronic kidney disease, older adults, cardiovascular risk stratification, cardiovascular risk factors
MeSH terms
Semaglutide, Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Diabetic Retinopathy, Glucagon-Like Peptides, Female, Gastrointestinal Diseases, Glycated Hemoglobin, Humans, Male, Middle Aged, Glucagon-Like Peptide 1, Kaplan-Meier Estimate

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 2026-10-16.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-16.

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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