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Cited by 315Lipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and LipoproteinsAcute Myocardial Infarction Research

Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

Open access
Ray, Kausik K, Colhoun, Helen M, Szarek, Michael, Baccara-Dinet, Marie, Bhatt, Deepak L, Bittner, Vera A, Budaj, Andrzej J, Diaz, Rafael +1695 more·2019·The Lancet Diabetes & Endocrinology
DOI 10.1016/s2213-8587(19)30158-5
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Abstract

Background After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes.Methods ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA 1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.Findings At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction p interaction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (p interaction=0·11).Interpretation After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes.Funding Sanofi and Regeneron Pharmaceuticals.

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Crossref · 10.1016/s2213-8587(19)30158-5

Cites

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Claims the paper makes

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  • Findingown data

    The hazard ratio for the primary endpoint comparing diabetes with prediabetes was 1.90 (95% CI 1.65-2.17, p<0.0001).

    “for those with diabetes versus those with prediabetes, the HR was 1•90 (1•65-2•17, p<0•0001; figure 1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Across the trial, alirocumab-treated patients had lower LDL cholesterol regardless of baseline glycaemic category.

    “Over the course of the trial, patients treated with alirocumab had lower LDL cholesterol concentrations, irrespective of baseline glycaemic category (figure 3).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Alirocumab produced a similar relative decrease in ischaemic cardiovascular events in patients with and without diabetes, compared with placebo.

    “The relative reduction in risk of ischaemic cardiovascular events with alirocumab compared with placebo was similar between those with and without diabetes.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the alirocumab group, relative risk reduction for the primary endpoint was similar in diabetes (HR 0.84, 95% CI 0.74-0.97), prediabetes (0.86, 0.74-1.00), and normoglycaemia (0.85, 0.70-1.03).

    “In the alirocumab group, the relative reduction in risk of the primary endpoint was similar among patients with diabetes (HR 0•84, 95% CI 0•74-0•97), prediabetes (0•86, 0•74-1•00), and normoglycaemia (0•85, 0•70-1•03).”
    Quote in the paperSubstantial claim
  • Findingown data

    Among alirocumab-treated patients, median month-4 LDL cholesterol was 0.80 mmol/L in diabetes, prediabetes, and normoglycaemia.

    “In patients treated with alirocumab, median LDL cholesterol concentrations at month 4 were 0•80 mmol/L (IQR 0•52-1•22) in those with diabetes, 0•80 mmol/L (0•54-1•27) in those with prediabetes, and 0•80 mmol/L (0•54-1•30) in those with normoglycaemia.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 35
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    Findingreasoning

    The number needed to treat was 43 for diabetes patients and 82 for those without diabetes.

    “resulting in a number needed to treat of 43 for people with diabetes and 82 for those without (figure 4, appendix).”
    Quote in the paperSubstantial claim

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

    Findingcitation

    The glycometabolic abnormality distribution in our trial resembled an earlier acute coronary syndrome study, with about 70% having diabetes or prediabetes.

    “The distribution of patients with glycometabolic abnormalities in our trial was similar to that in an earlier study of people with a previous acute coronary syndrome, 14 with about 70% of the cohort having diabetes or prediabetes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Norhammar, 2002, Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the placebo group, primary endpoint rates were 6.5 per 100 person-years for diabetes, 3.4 for prediabetes, and 3.1 for normoglycaemia.

    “In the placebo group, the rate of the primary endpoint was 6•5 per 100 person-years for patients with diabetes at baseline, 3•4 per 100 person-years for those with prediabetes, and 3•1 per 100 person-years for those with normoglycaemia.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    At randomisation, 5444 (28.8%) patients had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normoglycaemia.

    “diabetes (n=37 with type 1 diabetes), 8246 (43•6%) patients had prediabetes, and 5234 (27•7%) patients had normo glycaemia.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Baseline BMI, non-HDL cholesterol, and triglycerides were highest in diabetes and lowest in normoglycaemia, while HDL cholesterol showed the reverse pattern.

    “Baseline values of BMI, non-HDL cholesterol, and triglycerides were highest among patients with diabetes and lowest among those in the normoglycaemia group, with the opposite relation seen for HDL cholesterol concentrations.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    HbA1c and fasting glucose findings were similar in the prediabetes and normoglycaemia subgroups.

    “These findings were similar among patients with either prediabetes (HbA 1c : 5•92% with alirocumab vs 5•95% with placebo; fasting serum glucose 5•85 vs 5•85 mmol/L) or normoglycaemia (HbA 1c : 5•55% vs 5•56%; fasting serum glucose: 5•40 vs 5•40 mmol/L) at baseline (figure 5).”
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    Findingown data

    In the group without diabetes at baseline, 5955 participants (44.2%) could be followed for 3-5 years.

    “Of the patients without diabetes at baseline, 5955 (44•2%) were eligible for 3-5 years of follow-up (table).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Absolute risk reduction with alirocumab was larger in diabetes (2.3%, 95% CI 0.4-4.2) than prediabetes (1.2%, 0.0-2.4) or normoglycaemia (1.2%, -0.3-2.7), with p interaction=0.0019.

    “However, the substantially higher absolute risk among patients with diabetes resulted in a greater absolute risk reduction with alirocumab treatment (2•3%, 95% CI 0•4 to 4•2) compared with patients with prediabetes (1•2%, 0•0 to 2•4) or normoglycaemia (1•2%, -0•3 to 2•7; p interaction =0•0019 among the three glycaemic categories)”
    Quote in the paperSubstantial claim

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

    Findingcitation

    Abnormal glycometabolic status is common after acute coronary syndrome, with roughly one third having diabetes and a similar share having prediabetes.

    “Abnormal glycometabolic status is common in patients after an acute coronary syndrome, with about a third having diabetes and a similar proportion having prediabetes.14”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Norhammar, 2002, Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study, Lancet source

      Not checked in the free run.

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

    Findingown data

    Among placebo recipients, median month-4 LDL cholesterol was 2.25 mmol/L for diabetes, 2.25 for prediabetes, and 2.28 for normoglycaemia.

    “In patients given placebo, these values were 2•25 mmol/L (1•84-2•77) for those with diabetes, 2•25 mmol/L (1•86-2•77) for those with prediabetes, and 2•28 mmol/L (1•89-2•77) for those with normoglycaemia.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Follow-up had a median of 2.8 years; 8242 participants could be followed for 3-5 years.

    “Median follow-up duration was 2•8 years, with 8242 patients eligible for 3-5 years of follow-up (ie, randomly assigned at least 3 years before the common study end date of Nov 11, 2017).”
    Quote in the paperNot a substantial claim

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    Findingown data

    For SGLT2 inhibitors, 0.1% (n=26) were receiving them at baseline, rising to 1.5% (n=290) during the study.

    “For SGLT2 inhibitors, the corresponding numbers were 0•1% (n=26) at baseline, increasing to 1•5% (n=290) during the study.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Median follow-up was 2.8 years (IQR 2.3-3.4).

    “Median follow-up was 2•8 years (IQR 2•3-3•4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The number needed to treat for a median of 2.8 years to prevent one primary endpoint event was 43 for patients with diabetes and 82 for those without.

    “The corresponding number needed to treat for a median of 2•8 years to avoid one primary endpoint event was 43 for patients with diabetes at baseline versus 82 for patients without diabetes at baseline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With median follow-up of 2.8 years and 5955 (44.2%) patients without diabetes eligible for 3-5 years of follow-up, alirocumab did not adversely affect glycaemic measures or raise new-onset diabetes risk.

    “With a median follow-up of 2•8 years and with 5955 (44•2%) patients without diabetes eligible for 3-5 years of follow-up, alirocumab did not adversely affect measures of glycaemia or increase the risk of new-onset diabetes.”
    Quote in the paperSubstantial claim

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

    Findingown data

    At baseline, 0.2% (n=47) of the total study population were receiving a GLP-1 receptor agonist, rising to 0.9% (n=173) during the study.

    “At baseline, 0•2% (n=47) of the total study population were receiving a GLP-1 receptor agonist, which increased to 0•9% (n=173) during the study”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    In FOURIER, follow-up was relatively short and an excess new-onset diabetes risk among baseline normoglycaemia patients could not be ruled out.

    “However, the median and maximum durations of follow-up were fairly short and an excess risk of new-onset diabetes among patients with normoglycaemia at baseline was not excluded.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Statin therapy can raise diabetes risk in a dose-dependent manner.

    “Observations that statins increase the risk of new-onset diabetes 6,7 raise theoretical concerns”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Preiss, 2011, Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis, JAMA source

      Not checked in the free run.

    • cites [7] Sattar, 2010, Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials, Lancet source

      Not checked in the free run.

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

    Premisecitation

    In acute coronary syndromes, diabetes patients have among the highest reported recurrent cardiovascular event rates.

    “in acute coronary syndromes, patients with diabetes have some of the highest reported rates of recurrent cardiovascular events, 1,2”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Bonaca, 2018, Polyvascular disease, type 2 diabetes, and long-term vascular risk: a secondary analysis of the IMPROVE-IT trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

    • cites [2] Giugliano, 2018, Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), Circulation source

      Not checked in the free run.

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

    Study design and conductown data

    New-onset diabetes incidence in the prediabetes and normoglycaemia subgroups was specified in advance.

    “The incidence of new-onset diabetes among participants with prediabetes or normoglycaemia was prespecified; we also report post-hoc HRs for new-onset diabetes in these two subgroups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    After acute coronary syndrome, diabetes patients face particularly high recurrent ischaemic cardiovascular event risk and gain the greatest absolute benefit from a given degree of lipid lowering with high-intensity statins or statins plus ezetimibe.

    “After an acute coronary syndrome, patients with diabetes are at particularly high risk of recurrent ischaemic cardiovascular events, and also derive the greatest absolute benefit from a given degree of lipid lowering with high-intensity statins 15 or statins plus ezetimibe.2,16”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Ahmed, 2006, Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial, Eur Heart J source

      Not checked in the free run.

    • cites [2] Giugliano, 2018, Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), Circulation source

      Not checked in the free run.

    • cites [16] Cannon, 2015, Ezetimibe added to statin therapy after acute coronary syndromes, N Engl J Med source

      Not checked in the free run.

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

    Study design and conductown data

    Randomisation was performed centrally using an interactive voice-response or web-response system.

    “Randomisation was done centrally with an interactive voice-response or web-response system (appendix).”
    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 endpoint was analysed in the intention-to-treat population, which comprised every randomised patient and followed the treatment group to which they were assigned.

    “analysed in the intention-totreat population (defined as all randomly assigned patients analysed according to allocated treatment group).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A FOURIER analysis showed consistent relative risk reduction for cardiovascular events in patients with or without baseline diabetes and no rise in new-onset diabetes.

    “An analysis of a large cardiovascular outcomes trial (FOURIER) of the PCSK9 inhibitor evolocumab showed a consistent reduction in the relative risk of cardiovascular events in patients with or without diabetes at baseline and no increase in the risk of new-onset diabetes.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The 2017 American College of Endocrinology guidelines classify these patients as extreme risk and recommend aiming for LDL cholesterol below 1.42 mmol/L.

    “with the 2017 American College of Endocrinology guidelines referring to these patients as an extreme-risk group in whom physicians should aim for LDL cholesterol concentrations below 1•42 mmol/L (55 mg/dL).3”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Jellinger, 2017, American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease, Endocr Pract source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Despite a median LDL cholesterol of 0.80 mmol/L on alirocumab, treatment had no effect on plasma glucose, HbA1c, or incident diabetes among 13,480 patients without baseline diabetes, including 5955 followed for 3-5 years.

    “Reassuringly, despite achieving a median LDL cholesterol concentration of 0•80 mmol/L with alirocumab, assigned treatment had no effect on plasma glucose concentrations, HbA 1c , or incident diabetes among 13 480 patients without diabetes at baseline, including 5955 patients followed up for 3-5 years.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    In a FOURIER subgroup of 6189 patients with baseline normoglycaemia, evolocumab was linked to higher new-onset diabetes risk (HR 1.60, 95% CI 1.13-2.28).

    “an increased risk of new-onset diabetes was seen among a subgroup of 6189 patients with normoglycaemia at baseline (hazard ratio [HR] 1•60, 95% CI 1•13-2•28).10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Sabatine, 2017, Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

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

    Study design and conductown data

    All participating institutions obtained ethics committee approval, and every participant gave informed consent.

    “Ethics committee approval was obtained at all participating institutions.All participants provided informed consent.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    In FOURIER, evolocumab versus placebo over a median 2.2 years in 16,533 patients without baseline diabetes did not increase new-onset diabetes risk.

    “Although there was no increased risk of new-onset diabetes with the PCSK9 inhibitor evolocumab compared with placebo over a median 2•2 years (maximum 3•75 years) of follow-up in 16 533 patients without diabetes at baseline”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Sabatine, 2017, Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

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    Study design and conductown data

    The academic statistician conducted the analyses in this report independently of the funders.

    “Analyses in the present report were performed independently of the funders by the academic statistician (MS); the funders contributed to data interpretation and provided input on the report.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Bococizumab versus placebo over about 1 year median exposure produced a small but significant fasting glucose increase without excess new-onset diabetes risk.

    “A small but significant increase in fasting glucose without excess risk of new-onset diabetes was reported with bococizumab compared with placebo over a median exposure of about 1 year.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Ridker, 2017, Cardiovascular efficacy and safety of bococizumab in high-risk patients, N Engl J Med source

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    Study design and conductnone given

    No formal power calculation was carried out for this prespecified analysis.

    “Formal power calculations were not done for this prespecified analysis, but statistical assumptions for the overall trial have been reported previously, 12”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    In acute coronary syndrome patients, reducing LDL cholesterol below 1.81 mmol/L with statins, or further to about 1.42 mmol/L with statins plus ezetimibe, lowers cardiovascular disease events.

    “In patients with acute coronary syndromes, lowering LDL cholesterol to below 1•81 mmol/L (70 mg/dL) with statins, or further to around 1•42 mmol/L (55 mg/dL) with statins plus ezetimibe, reduces cardiovascular disease events.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The study's results extend earlier evidence for intensive lipid lowering and ezetimibe in diabetes and acute coronary syndrome, and agree with recent guidelines that lowered LDL cholesterol targets.

    “Our findings build upon previous evidence supporting the use of intensive lipid-lowering therapy and ezetimibe in patients with diabetes and acute coronary syndrome, and are aligned with the recent updating of some clinical guidelines”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Jellinger, 2017, American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease, Endocr Pract source

      Not checked in the free run.

    • cites [17] 2002, Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report, Circulation source

      Not checked in the free run.

    • cites [18] Grundy, 2004, Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The event rate in baseline diabetes was twice that in patients without diabetes, so alirocumab's absolute risk reduction in diabetes was double that in patients without diabetes.

    “However, the event rate in patients with diabetes at baseline was two-times higher than that in patients without, such that the absolute risk reduction with alirocumab for patients with diabetes was double that achieved in patients without diabetes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    More data from large populations with longer observation are required to establish the glycometabolic safety of PCSK9 inhibition.

    “Further data in large populations over a longer observation period are needed to determine the glycometabolic safety of PCSK9 inhibition.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All components of the primary composite endpoint were adjudicated while group assignment was masked.

    “All components of the primary composite endpoint were adjudicated with group assignment masked.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Participants were assigned in a 1:1 ratio to receive either alirocumab 75 mg by subcutaneous injection every two weeks or matching placebo, with country as a stratification factor.

    “Patients were randomly assigned (1:1) to treatment with alirocumab 75 mg subcutaneously every 2 weeks or matching placebo, stratified by country.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The trial was double-blind; both patients and investigators were unaware of treatment allocation, including titration and substitution, and of lipid concentrations.

    “The trial had a double-blind design, with patients and investigators masked to treatment assignment, including titration and substitution, and to lipid concentrations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The ODYSSEY OUTCOMES trial was a randomised, double-blind, placebo-controlled study conducted at 1315 sites across 57 countries, comparing alirocumab with placebo in patients hospitalised for acute coronary syndrome 1-12 months before randomisation.

    “ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    An external diabetes expert committee, unaware of group assignment, confirmed diabetes diagnoses.

    “with a diabetes diagnosis confirmed by an external diabetes expert committee that was masked to group assignment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The trial is registered on ClinicalTrials.gov under identifier NCT01663402.

    “The ODYSSEY OUTCOMES trial is registered with ClinicalTrials.gov,number NCT01663402.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Individual components of the composite primary endpoint were not analysed for alirocumab effect because power was insufficient.

    “The effect of alirocumab on individual components of the composite primary endpoint was not analysed due to insufficient power.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mendelian randomisation analyses show that genetically determined PCSK9 loss of function is associated with higher incident diabetes, while clinical trials of PCSK9 inhibitors show no such effect.

    “Mendelian randomisation analyses 8,20,21 have shown that genetically determined loss of function of PCSK9 is associated with an increased risk of incident diabetes, but clinical trials of PCSK9 inhibitors have shown no such effect.9”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [8] Ference, 2016, Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes, N Engl J Med source

      Not checked in the free run.

    • cites [20] Schmidt, 2017, PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study, Lancet Diabetes Endocrinol source

      Not checked in the free run.

    • cites [21] Lotta, 2016, Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis, JAMA source

      Not checked in the free run.

    • cites [9] Colhoun, 2016, No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY phase 3 studies, Eur Heart J source

      Not checked in the free run.

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

    Premisecitation

    Statins raise new-onset diabetes risk by 9% versus placebo and by an additional 12% when high-intensity statins are compared with moderate-intensity statins.

    “statins increase the risk of new-onset diabetes by 9% versus placebo, and by an additional 12% when comparing high-intensity statins with moderate-intensity statins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Sattar, 2010, Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials, Lancet source

      Not checked in the free run.

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

    Study design and conductnone given

    This study's LDL cholesterol values come from intention-to-treat analysis, and ODYSSEY OUTCOMES used a treat-to-target design.

    “the LDL cholesterol concentrations presented in our study are from the intention-to-treat analysis and ODYSSEY OUTCOMES used a treat-to-target design.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    GLP-1 receptor agonists and SGLT2 inhibitors benefit patients with chronic stable cardiovascular disease, but efficacy has not been shown after acute coronary syndrome.

    “GLP-1 receptor agonists and SGLT2 inhibitors have shown benefit in patients with chronic stable cardiovascular disease, but efficacy has not been shown in the post-acute coronary syndrome setting.27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Pfeffer, 2016, Lixisenatide in type 2 diabetes and acute coronary syndrome, N Engl J Med

      Not checked in the free run.

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

    Premisecitation

    Current evidence suggests that newer diabetes treatments and lipid lowering have complementary benefits.

    “the evidence to date suggests that the benefits of newer diabetes treatments and lipid lowering are complementary.26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Verma, 2018, Liraglutide reduces cardiovascular events and mortality in type 2 diabetes mellitus independently of baseline low-density lipoprotein cholesterol levels and statin use, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In FOURIER, the relative risk reduction for the primary endpoint among patients with diabetes was 17%, similar to the 16% relative reduction in four-point MACE in ODYSSEY OUTCOMES.

    “The relative risk reduction for the primary endpoint of five-point major adverse cardiovascular events in FOURIER among those with diabetes at baseline was 17%, similar to the 16% relative reduction in the risk of four-point major adverse cardiovascular events in ODYSSEY OUTCOMES.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Sabatine, 2017, Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At 3 years, 17.1% of patients with diabetes in FOURIER's placebo group had a primary endpoint event, reduced absolutely by 2.7% with evolocumab.

    “At 3 years, the proportion of individuals with diabetes in the placebo group who had experienced a primary endpoint event was 17•1% in FOURIER, and was reduced in absolute terms by 2•7% with evolocumab.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Sabatine, 2017, Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

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

    Premisecitation

    Patients with prediabetes have been reported to have worse cardiovascular outcomes than those with normoglycaemia.

    “patients with prediabetes have been reported to have worse cardiovascular outcomes than those with normoglycaemia”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Stranders, 2004, Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus, Arch Intern Med source

      Not checked in the free run.

    • cites [23] Bhadriraju, 2006, Association between blood glucose and long-term mortality in patients with acute coronary syndromes in the OPUS-TIMI 16 trial, Am J Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The FOURIER trial suggested a possible higher new-onset diabetes risk with evolocumab in normoglycaemic patients but not in prediabetic patients, with few events and wide confidence intervals.

    “Findings from an analysis of the FOURIER cardiovascular outcomes trial 10 with the PCSK9 inhibitor evolocumab suggested a possible increased risk of new-onset diabetes among patients with normoglycaemia at baseline, but not among those with prediabetes at baseline, albeit with a small number of events and wide CIs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Sabatine, 2017, Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

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

    Study design and conductreasoning

    It is uncertain whether greater use of GLP-1 receptor agonists or SGLT2 inhibitors would change the magnitude of alirocumab's benefit in patients with acute coronary syndrome and diabetes.

    “It is uncertain whether greater use of these classes of drugs would affect the magnitude of the observed benefit of alirocumab treatment in patients with acute coronary syndrome and diabetes”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In recent acute coronary syndrome, diabetes marks a large subgroup (about one third) at substantially greater risk who gain more from targeting LDL cholesterol to 0.65-1.30 mmol/L.

    “The findings of our study suggest that, among patients with a recent acute coronary syndrome, the presence of diabetes highlights a large subgroup (about a third) with substantially enhanced risk and who derive greater benefits from targeting even lower LDL cholesterol concentrations of 0•65-1•30 mmol/L.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    This trial had longer follow-up than FOURIER and used a masked diabetes endpoint adjudication committee to identify new-onset diabetes cases.

    “Our trial had longer follow-up than FOURIER to assess safety and efficacy and a masked diabetes endpoint adjudication committee to determine cases of new-onset diabetes.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Although these results are reassuring, the long-term glycaemic effects of PCSK9 inhibitors beyond 5 years remain unknown.

    “although the present results are reassuring, the long-term effects (ie, beyond 5 years) of PCSK9 inhibitors on glycaemic status are still unknown.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: New-onset diabetes with statins was only confirmed many years after regulatory approval through meta-analyses of multiple trials.

  • May combine two claims.

    Premisecitation

    FOURIER used a fixed evolocumab dose, and its reported LDL cholesterol values came from patients who stayed on treatment, had follow-up laboratory measurements, and had no background statin change.

    “FOURIER used a fixed dose of evolocumab and the LDL cholesterol concen trations described are for patients who remained on treatment, had follow-up laboratory measurements, and had no change in background statin treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Sabatine, 2017, Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

57 of 57

  • The paper relies on this without support.

    A lower number needed to treat implies more favourable cost-effectiveness for alirocumab.

    “Accordingly, patients with diabetes and acute coronary syndrome are a group in whom the costeffectiveness of alirocumab treatment is more favourable.”

  • The paper relies on this without support.

    The glycaemic safety of alirocumab can be generalized to PCSK9 inhibitors as a class.

    “The present findings provide greater reassurance about the glycaemic safety of PCSK9 inhibitors as a class.”

  • The paper relies on this without support.

    About 70% of patients in clinical trials of established atherosclerosis have a glycometabolic abnormality at randomisation.

    “in clinical trials that enrol patients with established atherosclerosis, about 70% already have a glycometabolic abnormality at randomisation (prediabetes or diabetes).”

  • The paper relies on this without support.

    New-onset diabetes with statins was only confirmed many years after regulatory approval through meta-analyses of multiple trials.

    “new-onset diabetes with statins was only confirmed many years after regulatory approval through meta-analyses of multiple trials.”
4 of 4

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Ray, K. K., Colhoun, H. M., Szarek, M., Baccara-Dinet, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Lopes, R. D., Moryusef, A., Murin, J., Pordy, R., Ristic, A. D., Roe, M. T., Tuñón, J., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P. G., Schwartz, G. G., Steg, P. G., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J.-F., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Lopes, R. D., Gotcheva, N. N., Prieto, J.-C., Yong, H., López-Jaramillo, P., Pećin, I., Reiner, Z., Ostadal, P., Viigimaa, M., Nieminen, M. S., Chumburidze, V., Marx, N., Danchin, N., Liberopoulos, E., Montenegro Valdovinos, P. C., Tse, H.-F., Kiss, R. G., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H. S., Kim, S.-H., Erglis, A., Laucevicius, A., Kedev, S., Yusoff, K., Ramos López, G. A., Alings, M., Halvorsen, S., Correa Flores, R. M., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tuñón, J., de Silva, H. A., Hagström, E., Landmesser, U., Chiang, C.-E., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Vogel, R., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J.-L., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. J. G., Tricoci, P., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M. C., Brennan, J. M., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C. N., Hlatky, M. A., Jordan, J. D., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H. G., Patel, C. B., Bernardez-Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Schuyler Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Trotter, C., Van Diepen, S., Wilson, M. D., Yan, A. T., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Hominal, M. A., Montaña, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, O., Codutti, O. R., Jure, H. O., Bono, J. O., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. D., Colombo, H. R., Liberman, A., Fuentealba, V., Luciardi, H. L., Waisman, G. D., Berli, M. A., Garcia Duran, R. O., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Hii, C. L., Shaw, J., Arstall, M. A., Horowitz, J., Ninio, D., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. G., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Delle-Karth, G., Frey, B., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. C., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Kulić, M., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Nigro Maia, L., Rech, R., Rossi, P. R., Cerqueira, M. J. A., Duda, N., Kalil, R., Kormann, A., Abrantes, J. A. M., Pimentel Filho, P., Soggia, A. P., de Santos, M. O., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Manenti, E. R. F., Precoma, D. B., Moura Jorge, J. C., de B Silva, P. G., Silveira, J. A., Saporito, W., Marin-Neto, J. A., Feitosa, G. S., Ritt, L. E. F., de Souza, J. A., Costa, F., Souza, W. K., Reis, H. J., Machado, L., Ayoub, J. C. A., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Gospodinov, M., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Lutchmedial, S., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Huynh, T., Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yañez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zhong, Y., Zheng, Y., Li, X., Peng, D., Zhao, S., Li, Y., Liu, X., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Xiang, M., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Sanchez Vallejo, G., Luna Botia, D. C., Botero Lopez, R., Molina De Salazar, D. I., Cadena Bonfanti, A. J., Cotes Aroca, C., Diego Higuera, J., Blanquicett, M., Barrera Silva, S. I., Garcia Lozada, H. J., Coronel Arroyo, J. A., Accini Mendoza, J. L., Fernandez Ruiz, R. L., Quintero Ossa, A. M., Manzur Jatin, F. G., Sotomayor Herazo, A., Castellanos Parada, J., Suarez Arambula, R., Urina Triana, M. A., Fernandez Trujillo, A. M., Strozzi, M., Car, S., Jerić, M., Miličić, D., Benčić, M. L., Pintarić, H., Prvulović, Đ., Šikić, J., Peršić, V., Mileta, D., Štambuk, K., Babić, Z., Tomulic, V., Lukenda, J., Mejic-Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Velicka, Z., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Poulsen, S. H., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bøttcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Betton Johansen, P., Hald, F., Johansen, P., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P. M., Lomholdt, J. D., Klausen, I. C., Nielsen, P. K., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopõld, Ü., Märtsin, K., Jurgenson, T., Kristjan, A., Helsinki, J. K., Vikman, S., Huikuri, H., Airaksinen, J., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Machecourt, J., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefèvre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Edward, K., Rauch-Kröhnert, U., Stratmann, M., Appel, K.-F., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Vöhringer, H. F., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Werner, C., Marx, N., Gielen, S., Nuding, S., Winkelmann, B., Behrens, S., Sydow, K., Karakas, M., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Böcker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., Weißbrodt, M., Schaeufele, T., Weil, J., Völler, H., Waltenberger, J., Natour, M., Schmitt, S., Müller-Wieland, D., Steiner, S., Heidenreich, L., Offers, E., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Chachalis, G., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Fausto Ovando, S. R., Arango Benecke, J. L., Rodriguez De Leon, E. R., Yan, B. P., Siu, D. C., Turi, T., Merkely, B., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Édes, I., Müller, G., Horvath, I., Kapin, T., Szigeti, Z., Faluközy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N. R., Regella, R., Premchand, R. K., Mahajan, A., Pawar, S., Abhyanakar, A. D., Kerkar, P., Govinda, R. A., Oomman, A., Sinha, D., Patil, S. N., Kahali, D., Sawhney, J., Joshi, A. B., Chaudhary, S., Harkut, P., Guha, S., Porwal, S., Jujjuru, S., Pothineni, R. B., Monteiro, M. R., Khan, A., Iyengar, S. S., Grewal, J. S., Chopda, M., Fulwani, M. C., Patange, A., Sachin, P., Chopra, V. K., Goyal, N. K., Shinde, R., Manakshe, G. V., Patki, N., Sethi, S., Munusamy, V., Karna, S., Thanvi, S., Adhyapak, S., Patil, C., Pandurangi, U., Mathur, R., Gupta, J., Kalashetti, S., Bhagwat, A., Raghuraman, B., Yerra, S. K., Bhansali, P., Borse, R., Rahul, P., Das, S., Kumar, V., Abdullakutty, J., Saathe, S., Palimkar, P., Sathe, S., Atar, S., Shechter, M., Mosseri, M., Arbel, Y., Ehud, C., Ofer, H., Lotan, C., Rosenschein, U., Katz, A., Henkin, Y., Francis, A., Klutstein, M., Nikolsky, E., Zukermann, R., Turgeman, Y., Halabi, M., Marmor, A., Kornowski, R., Jonas, M., Amir, O., Hasin, Y., Rozenman, Y., Fuchs, S., Zvi, V., Hussein, O., Gavish, D., Vered, Z., Caraco, Y., Elias, M., Tov, N., Wolfovitz, E., Lishner, M., Elias, N., Piovaccari, G., De Pellegrin, A., Garbelotto, R., Guardigli, G., Marco, V., Licciardello, G., Auguadro, C., Scalise, F., Cuccia, C., Salvioni, A., Musumeci, G., Senni, M., Calabrò, P., Novo, S., Faggiano, P., Metra, M., De Cesare, N. B., Berti, S., Cavallini, C., Puccioni, E., Galvani, M., Tespili, M., Piatti, P., Palvarini, M., De Luca, G., Violini, R., De Leo, A., Olivari, Z., Perrone Filardi, P., Ferratini, M., Racca, V., Dai, K., Shimatani, Y., Kamiya, H., Ando, K., Takeda, Y., Morino, Y., Hata, Y., Kimura, K., Kishi, K., Michishita, I., Uehara, H., Higashikata, T., Hirayama, A., Hirooka, K., Doi, Y., Sakagami, S., Taguchi, S., Koike, A., Fujinaga, H., Koba, S., Kozuma, K., Kawasaki, T., Ono, Y., Shimizu, M., Katsuda, Y., Wada, A., Shinke, T., Kimura, T., Ako, J., Fujii, K., Takahashi, T., Sakamoto, T., Nakao, K., Furukawa, Y., Sugino, H., Tamura, R., Mano, T., Uematsu, M., Utsu, N., Ito, K., Haraguchi, T., Sato, K., Ueda, Y., Nishibe, A., Fujimoto, K., Masutani, M., Yoon, J. H., Kim, H.-L., Park, H. S., Chae, I.-H., Kim, M. H., Jeong, M. H., Rha, S., Kim, C., Kim, H.-S., Kim, H. 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M., Zwart, P., Monraats, P., Van Kesteren, H., Karalis, I., Jukema, J., Verdel, G. J., Brueren, B. R., Troquay, R. P., Viergever, E. P., Al-Windy, N. Y., Bartels, G. L., Cornel, J. H., Hermans, W. R., Herrman, J. P., Bos, R. J., Groutars, R. G., Van Der Zwaan, C. C., Kaplan, R., Lionarons, R., Ronner, E., Groenemeijer, B. E., Bronzwaer, P. N., Liem, A. A., Rensing, B. J., Bokern, M. J., Nijmeijer, R., Hersbach, F. M., Willems, F. F., Gosselink, A. T., Rasoul, S., Elliott, J., Wilkins, G., Fisher, R., Scott, D., Hart, H., Stewart, R., Harding, S., Ternouth, I., Fisher, N., Wilson, S., Aitken, D., Anscombe, R., Davidson, L., Tomala, T., Nygård, O., Sparby, J. A., Andersen, K., Gullestad, L., Jortveit, J., Munk, P. S., Singsaas, E. G., Hurtig, U., Calderon Ticona, J. R., Durand Velasquez, J. R., Negron Miguel, S. A., Sanabria Perez, E. S., Carrion Chambilla, J. M., Chavez Ayala, C. A., Castillo Leon, R. P., Vargas Gonzales, R. J., Hernandez Zuniga, J. D., Camacho Cosavalente, L. 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R., Ilic, S., Putnikovic Tosic, B., Stankovic, A., Arandjelovic, A., Radovanovic, S., Todic, B., Balinovac, J., Dincic, D. V., Seferovic, P., Karadzic, A., Dodic, S., Dimkovic, S., Jakimov, T., Poh, K.-K., Ong, H. Y., Tang I-Shing, J., Micko, K., Nociar, J., Pella, D., Fulop, P., Hranai, M., Palka, J., Mazur, J., Majercák, I., Dzupina, A., Fazekas, F., Gonsorcik, J., Bugan, V., Selecky, J., Kamensky, G., Strbova, J., Smik, R., Dukat, A., Žuran, I., Poklukar, J., Černič Šuligoj, N., Cevc, M., Cyster, H. P., Ranjith, N., Corbett, C., Bayat, J., Makotoko, E. M., du Toit Theron, H., Kapp, I. E., de V Basson, M. M., Lottering, H., Van Aswegen, D., Van Zyl, L. J., Sebastian, P. J., Pillay, T., Saaiman, J. A., Commerford, P. J., Cassimjee, S., Riaz, G., Ebrahim, I. O., Sarvan, M., Mynhardt, J. H., Reuter, H., Moodley, R., Vida, M., Cequier Fillat, A. R., Bodí Peris, V., Fuentes Jimenez, F., Marín, F., Cruz Fernández, J. M., Hidalgo Urbano, R. 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H., Kuo, J.-Y., Huang, T.-Y., Fang, C.-Y., Kaewsuwanna, P., Soonfuang, W., Jintapakorn, W., Sukonthasarn, A., Wongpraparut, N., Sastravaha, K., Sansanayudh, N., Kehasukcharoen, W., Piyayotai, D., Chotnoparatpat, P., Camsari, A., Kultursay, H., Mutlu, B., Ersanli, M., Demirtas, M., Kirma, C., Ural, E., Koldas, L., Karpenko, O., Prokhorov, A., Vakaluyk, I., Myshanych, H., Reshotko, D., Batushkin, V., Rudenko, L., Kovalskyi, I., Kushnir, M., Tseluyko, V., Mostovoy, Y., Stanislavchuk, M., Kyiak, Y., Karpenko, Y., Malynovsky, Y., Klantsa, A., Kutniy, O., Amosova, E., Tashchuk, V., Leshchuk, O., Rishko, M., Kopytsya, M., Yagensky, A., Vatutin, M., Bagriy, A., Barna, O. M., Ushakov, O., Dzyak, G., Goloborodko, B., Rudenko, A., Zheleznyy, V., Trevelyan, J., Zaman, A., Lee, K., Moriarty, A., Aggarwal, R. K., Clifford, P., Wong, Y.-K., Iqbal, S. M., Subkovas, E., Braganza, D., Sarkar, D., Storey, R., Griffiths, H., McClure, S., Muthusamy, R., Smith, S., Kurian, J., Levy, T., Barr, C., Kadr, H., Gerber, R., Simaitis, A., Soran, H., Mathur, A., Brodison, A., Ayaz, M., Cheema, M., Oliver, R., Thackray, S., Mudawi, T., Rahman, G., Sultan, A., Sharman, D., Sprigings, D., Butler, R., Wilkinson, P., Lip, G. Y., Halcox, J., Gallagher, S., Ossei-Gerning, N., Vardi, G., Baldari, D., Brabham, D., Treasure II, C., Dahl, C., Palmer, B., Wiseman, A., Khan, A., Puri, S., Mohart, A. 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(., Vidovich, M., Knutson, T., Friedman, D., Chaleff, F., Loussararian, A., Rozeman, P., Kimmelstiel, C., Kuvin, J., Silver, K., Foster, M., Tonnessen, G., Espinoza, A., Amlani, M., Wali, A., Malozzi, C., Jong, G. T., Massey, C., Wattanakit, K., O'Donnell, P. J., Singal, D., Jaffrani, N., Banuru, S., Fisher, D., Xenakis, M., Perlmutter, N., Bhagwat, R., Strader, J., Blonder, R., Akyea-Djamson, A., Labroo, A., Lee, K., Marais, H. J., Claxton, E., Weiss, R., Kathryn, R., Berk, M., Rossi, P., Joshi, P., Khera, A., Khaira, A. S., Kumkumian, G., Lupovitch, S., Purow, J., Welka, S., Hoffman, D., Fischer, S., Soroka, E., Eagerton, D., Pancholy, S., Ray, M., Erenrich, N., Farrar, M., Pollock, S., French, W. J., Diamantis, S., Guy, D., Gimple, L., Neustel, M., Schwartz, S., Pereira, E., Albert, S., Spriggs, D., Strain, J., Mittal, S., Vo, A., Chane, M., Hall, J., Vijay, N., Lotun, K., Lester, F. M., Nahhas, A., Pope, T., Nager, P., Vohra, R., Sharma, M., Bashir, R., Ahmed, H., Berlowitz, M., Fishberg, R., Barrucco, R., Yang, E., Radin, M., Sporn, D., Stapleton, D., Eisenberg, S., Landzberg, J., Mcgough, M., Turk, S., Schwartz, M., Sundram, P. S., Jain, D., Zainea, M., Bayron, C., Karlsberg, R., Dohad, S., Lui, H., Keen, W., Westerhausen, D., Khurana, S., Agarwal, H., Birchem, J., Penny, W., Chang, M., Murphy, S., Henry, J., Schifferdecker, B., Gilbert, J. M., Chalavarya, G., Eaton, C., Schmedtje, J. F., Christenson, S., Dotani, I., Denham, D., Macdonell, A., Gibson, P., Rahman, A., Al Joundi, T., Assi, N., Conrad, G., Kotha, P., Love, M., Giesler, G., Rubenstein, H., Gamil, D., Akright, L., Krawczyk, J., Cobler, J., Wells, T., Welker, J., Foster, R., Gilmore, R., Anderson, J., Jacoby, D., Harris, B., Gardner, G., Dandillaya, R., Vora, K., Kostis, J., Hunter, J., Laxson, D., Ball, E., Wells, T., Vora, K., Ball, E., Welker, J., Lopes, R., Egydio, F., Kawakami, A., Oliveira, J., Wozniak, J., Matthews, A., Ratky, C., Valiris, J., Berdan, L., Hepditch, A., Quintero, K., Rorick, T., Westbrook, M., Pascual, A., Rovito, C., Bezault, M., Drouet, E., Simon, T., White, H. D., Alsweiler, C., Luyten, A., Butters, J., Griffith, L., Shaw, M., Grunberg, L., Islam, S., Brégeault, M.-F., Bougon, N., Faustino, D., Fontecave, S., Murphy, J., Verrier, M., Agnetti, V., Andersen, D., Badreddine, E., Bekkouche, M., Bouancheau, C., Brigui, I., Brocklehurst, M., Cianciarulo, J., Devaul, D., Domokos, S., Gache, C., Gobillot, C., Guillou, S., Healy, J., Heath, M., Jaiwal, G., Javierre, C., Labeirie, J., Monier, M., Morales, U., Mrabti, A., Mthombeni, B., Okan, B., Smith, L., Sheller, J., Sopena, S., Pellan, V., Benbernou, F., Bengrait, N., Lamoureux, M., Kralova, K., Scemama, M., Bejuit, R., Coulange, A., Berthou, C., Repincay, J., Lorenzato, C., Etienne, A., Gouet, V., Lecorps, G., Loizeau, V., Normand, M., Ourliac, A., Rondel, C., Adamo, A., Beltran, P., Barraud, P., Dubois-Gache, H., Halle, B., Metwally, L., Mourgues, M., Sotty, M., Vincendet, M., Cotruta, R., Chengyue, Z., Fournie-Lloret, D., Morrello, C., Perthuis, A., Picault, P., Zobouyan, I., Colhoun, H. M., Dempsey, M. A., & McClanahan, M. A.
Affiliations
  • Sanofi (France) (FR)
  • University of Belgrade (RS)
  • University Hospital Bratislava (SK)
  • Hospital Universitario Fundación Jiménez Díaz (ES)
  • Imperial College London (GB)
  • Regeneron (United States) (US)
  • St. Michael's Hospital (CA)
  • University of Colorado Anschutz (US)
  • Duke University (US)
  • Instituto Cardiovascular de Rosario (AR)
  • State University of New York (US)
  • Inserm (FR)
  • Leiden University Medical Center (NL)
  • Sanofi (United States) (US)
  • Goethe University Frankfurt (DE)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Grochowski Hospital (PL)
  • Auckland City Hospital (NZ)
  • University of Edinburgh (GB)
ORCID
Venue
The Lancet Diabetes & Endocrinology
Publisher
Elsevier BV
Published
2019-08
Volume
7
Issue
8
Pages
618-628
ISSN
2213-8587 (ISSN-L)
DOI
10.1016/s2213-8587(19)30158-5
OpenAlex
W2954453953
Semantic Scholar
6851894f6f592c79864ce1ea2ac6dd961bea7d69
Cited by
315
References
30
Citations by year
2026: 17 · 2025: 34 · 2024: 46 · 2023: 54 · 2022: 37 · 2021: 50 · 2020: 62 · 2019: 15
FWCI
39.18
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Diabetes & Endocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • Lanzhou University Institutional Repository (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • HAL (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Hispana (submittedVersion, cc-by-nc-nd)
  • Institutional Repositories DataBase (IRDB) (submittedVersion)
  • Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Lirias (submittedVersion)
  • Biblos-e Archivo (Universidad Autónoma de Madrid) (submittedVersion, public-domain)
  • Griffith Research Online (submittedVersion, other-oa)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • American Heart Association
  • Boston Scientific Corporation
  • Abbott Laboratories
  • Janssen Pharmaceuticals
  • Amgen
  • Bristol-Myers Squibb
  • Servier
  • Cleveland Clinic
  • CSL Behring
  • Mayo Clinic
  • Boehringer Ingelheim
  • NIHR Imperial Biomedical Research Centre
  • Astellas Pharma US
  • Actavis
  • AstraZeneca
  • Bayer
  • Bayer HealthCare
  • Regeneron Pharmaceuticals
  • Daiichi-Sankyo
  • Merck Sharp and Dohme
  • Eli Lilly and Company
  • Portola Pharmaceuticals
  • Pfizer
  • Seventh Framework Programme
  • Hartstichting
  • Novo Nordisk
  • Ferring Pharmaceuticals
  • Biotronik
  • Merck
  • National Lipid Association
  • Novartis
  • Roche
  • Amarin Corporation
  • Medicines Company
  • Genentech
  • Gilead UK and Ireland Corporate Contributions
  • GlaxoSmithKline
  • MyoKardia
  • Arrien Pharmaceuticals
  • Regado Biosciences
  • Flatiron Health
  • Duke Clinical Research Institute
  • Icahn School of Medicine at Mount Sinai
  • Sanofi
  • American College of Cardiology Foundation
  • St. Jude Medical
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
Keywords
alirocumab, PCSK9 inhibitors, acute coronary syndrome, diabetes mellitus, LDL cholesterol lowering, cardiovascular outcomes, new-onset diabetes, glycemic control, ODYSSEY OUTCOMES trial
MeSH terms
Aged, Cardiovascular Diseases, Female, Humans, Male, Middle Aged, Diabetes Complications, Antibodies, Monoclonal, Humanized

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