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

ODYSSEY OUTCOMES Committees and Investigators

Research output: Contribution to journalArticle

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 HbA1c 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 pinteraction=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 (pinteraction=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.

Original languageEnglish (US)
Pages (from-to)618-628
Number of pages11
JournalThe Lancet Diabetes and Endocrinology
Volume7
Issue number8
DOIs
StatePublished - Aug 2019

Fingerprint

Acute Coronary Syndrome
Randomized Controlled Trials
Prediabetic State
LDL Cholesterol
Placebos
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Unstable Angina
Random Allocation
Incidence
alirocumab
Myocardial Infarction
Anticholesteremic Agents
Numbers Needed To Treat
Therapeutics
Type 2 Diabetes Mellitus
Lipoproteins
Medical Records
Coronary Disease
Fasting
Stroke

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

@article{fe74301b97774586a6c859ab5f530ff4,
title = "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",
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 HbA1c 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 pinteraction=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 (pinteraction=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.",
author = "{ODYSSEY OUTCOMES Committees and Investigators} and Ray, {Kausik K.} and Colhoun, {Helen M.} and Michael Szarek and Marie Baccara-Dinet and Bhatt, {Deepak L.} and Bittner, {Vera A.} and Budaj, {Andrzej J.} and Rafael Diaz and Goodman, {Shaun G.} and Corinne Hanotin and Harrington, {Robert A.} and Jukema, {J. Wouter} and Virginie Loizeau and Lopes, {Renato D.} and Ang{\`e}le Moryusef and Jan Murin and Robert Pordy and Ristic, {Arsen D.} and Roe, {Matthew T.} and Jos{\'e} Tu{\~n}{\'o}n and White, {Harvey D.} and Zeiher, {Andreas M.} and Schwartz, {Gregory G.} and Steg, {Philippe Gabriel} and Schwartz, {Gregory G.} and Steg, {Ph Gabriel} and Bhatt, {Deepak L.} and Bittner, {Vera A.} and Goodman, {Shaun G.} and Harrington, {Robert A.} and Jukema, {J. Wouter} and White, {Harvey D.} and Zeiher, {Andreas M.} and Pierluigi Tricoci and Roe, {Matthew T.} and Mahaffey, {Kenneth W.} and Edelberg, {Jay M.} and Guillaume Lecorps and Sasiela, {William J.} and Tamby, {Jean Fran{\cc}ois} and Aylward, {Philip E.} and Heinz Drexel and Peter Sinnaeve and Mirza Dilic and Lopes, {Renato D.} and Gotcheva, {Nina N.} and Prieto, {Juan Carlos} and Huo Yong and Patricio L{\'o}pez-Jaramillo and Ivan Pećin",
year = "2019",
month = "8",
doi = "10.1016/S2213-8587(19)30158-5",
language = "English (US)",
volume = "7",
pages = "618--628",
journal = "The Lancet Diabetes and Endocrinology",
issn = "2213-8587",
publisher = "Elsevier BV",
number = "8",

}

TY - JOUR

T1 - Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes

T2 - a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial

AU - ODYSSEY OUTCOMES Committees and Investigators

AU - Ray, Kausik K.

AU - Colhoun, Helen M.

AU - Szarek, Michael

AU - Baccara-Dinet, Marie

AU - Bhatt, Deepak L.

AU - Bittner, Vera A.

AU - Budaj, Andrzej J.

AU - Diaz, Rafael

AU - Goodman, Shaun G.

AU - Hanotin, Corinne

AU - Harrington, Robert A.

AU - Jukema, J. Wouter

AU - Loizeau, Virginie

AU - Lopes, Renato D.

AU - Moryusef, Angèle

AU - Murin, Jan

AU - Pordy, Robert

AU - Ristic, Arsen D.

AU - Roe, Matthew T.

AU - Tuñón, José

AU - White, Harvey D.

AU - Zeiher, Andreas M.

AU - Schwartz, Gregory G.

AU - Steg, Philippe Gabriel

AU - Schwartz, Gregory G.

AU - Steg, Ph Gabriel

AU - Bhatt, Deepak L.

AU - Bittner, Vera A.

AU - Goodman, Shaun G.

AU - Harrington, Robert A.

AU - Jukema, J. Wouter

AU - White, Harvey D.

AU - Zeiher, Andreas M.

AU - Tricoci, Pierluigi

AU - Roe, Matthew T.

AU - Mahaffey, Kenneth W.

AU - Edelberg, Jay M.

AU - Lecorps, Guillaume

AU - Sasiela, William J.

AU - Tamby, Jean François

AU - Aylward, Philip E.

AU - Drexel, Heinz

AU - Sinnaeve, Peter

AU - Dilic, Mirza

AU - Lopes, Renato D.

AU - Gotcheva, Nina N.

AU - Prieto, Juan Carlos

AU - Yong, Huo

AU - López-Jaramillo, Patricio

AU - Pećin, Ivan

PY - 2019/8

Y1 - 2019/8

N2 - 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 HbA1c 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 pinteraction=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 (pinteraction=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.

AB - 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 HbA1c 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 pinteraction=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 (pinteraction=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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U2 - 10.1016/S2213-8587(19)30158-5

DO - 10.1016/S2213-8587(19)30158-5

M3 - Article

C2 - 31272931

AN - SCOPUS:85068931122

VL - 7

SP - 618

EP - 628

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

SN - 2213-8587

IS - 8

ER -