Alirocumab and Cardiovascular Outcomes in Patients with Acute Coronary Syndrome (ACS) and Diabetes: Prespecified Analyses of ODYSSEY OUTCOMES

1. Alirocumab and Cardiovascular Outcomes
in Patients with Acute Coronary Syndrome
(ACS) and Diabetes: Prespecified Analyses
of ODYSSEY OUTCOMES
Kausik K. Ray, Helen M. Colhoun, Michael Szarek, Marie T. Baccara-Dinet, Deepak L. Bhatt,
Vera Bittner, Andrzej Budaj, Rafael Diaz, Shaun G. Goodman, Corinne Hanotin,
J. Wouter Jukema, Virginie Loizeau, Renato D. Lopes, Angèle Moryusef, Robert Pordy,
Arsen Ristic, Matthew T. Roe, José Tuñón, Harvey D. White, Andreas Zeiher,
Gregory G. Schwartz, Ph. Gabriel Steg
On behalf of the ODYSSEY OUTCOMES Investigators
American Diabetes Association 2018 (Orlando, FL)
ClinicalTrials.gov: NCT01663402

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Disclosures
The trial was funded by Sanofi and Regeneron Pharmaceuticals
• KR discloses the following relationships:
• Research grants: Amgen, Sanofi, Regeneron, MSD, Pfizer
• Consultancy: Amgen, Sanofi, Regeneron, MSD, Pfizer, Astra
Zeneca, Lilly, The Medicines Company, Kowa, IONIS, Takeda,
Novo Nordisk, Boehringer Ingelheim, Esperion, Cipla,
Algorithm, Abbvie, Resverlogix, Cerenis

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1. Ference BA, et al. NEJM 2016;375:2144-53. 2. Sabatine MS, et al. Lancet Diabetes Endocrinol 2017; 5: 941–50.
3. Colhoun HM, et al. Eur Heart J 2016;37:2981–2989.
ACS, acute coronary syndrome; CV, cardiovascular; PCSK9, proprotein convertase subtilisin/kexin type 9
• A majority of patients with ACS have a glucometabolic abnormality (prediabetes or
diabetes)
• ACS patients with diabetes are at higher risk for recurrent ischemic CV events than
ACS patients without diabetes, and derive greater absolute benefit from high-intensity
statin therapy or ezetimibe + statin
• Genetic loss of function in PCSK9 is associated with increased risk of new-onset
diabetes (NOD)1
• Evolocumab (FOURIER) in chronic atherosclerotic CV disease2 showed greater absolute
benefit in patients with diabetes than in those without diabetes. Neither FOURIER nor
the Phase 3a alirocumab program (4974 patients) showed an increased risk of NOD3
In this prespecified analysis from the ODYSSEY OUTCOMES trial, we compared the CV
efficacy and glucometabolic safety of alirocumab or placebo among people with
diabetes, prediabetes, or normoglycemia
Background and Goals

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Main inclusion criteria
• ACS: Myocardial infarction or unstable angina,
1−12 months prior to randomization
• High-intensity statin therapy or documented
statin intolerance
• Inadequate control of lipids: LDL-C ≥70 mg/dL
or non−HDL-C ≥100 mg/dL or apolipoprotein B
≥80 mg/dL
Treatment and endpoints
• Alirocumab 75 mg (starting dose) or 150 mg SC
every 2 weeks, blindly titrated to achieve LDL-C
25−50 mg/dL
• Alirocumab blindly down titrated if LDL-C <25
mg/dL, or switched to placebo if LDL-C <15
mg/dL, on two consecutive measurements
• Primary endpoint: time to first event of CHD
death, non-fatal MI, ischemic stroke, or unstable
angina
• Glycemic measures examined according to
baseline glucometabolic status and treatment
assignment
Glucometabolic status defined as
• Diabetes mellitus: Medical history of diabetes
type 1 or 2, A1c ≥6.5%, two values of fasting
serum glucose ≥126 mg/dL, or use of diabetes
medication
• Prediabetes: A1C ≥5.7% and <6.5% at baseline,
or two fasting glucose values >100 mg/dL but
no more than one ≥126 mg/dL
• Normoglycemia: None of the above
New-onset diabetesbased on any of the following:
• ≥2 A1c ≥6.5%
• ≥2 fasting glucose measurements ≥126 mg/dL
• Investigator-reported diabetes-related adverse
event
• Initiation of diabetes medication (confirmed as
NOD by a blinded external expert panel)
Study Overview

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Baseline Characteristics*
Normoglycemia
(n=5234)
Prediabetes
(n=8246)
Diabetes
(n=5444)
Age (years) 56 (50, 63) 59 (52, 65) 59 (53, 66)
Female sex 20.6% 23.6% 31.9%
BMI, kg/m2, median (Q1,
Q3)
27 (25, 30) 28 (25, 31) 29 (26, 33)
NSTEMI/STEMI/UA 47.4/36.8/15.8% 47.6/36.1/16.3% 51.1/30.3/18.6%
Laboratory values, median (Q1, Q3)
LDL-C, mg/dL 86 (74, 104) 88 (74, 104) 85 (71, 104)
Non−HDL-C, mg/dL 112 (97, 134) 115 (100, 136) 117 (101, 140)
HDL-C, mg/dL 44 (38, 52) 43 (37, 51) 41 (35, 48)
Triglycerides, mg/dL 117 (87, 164) 127 (93, 177) 147 (106, 205)
A1c, % 5.4 (5.3, 5.5) 5.9 (5.7, 6.0) 7.0 (6.5, 8.2)
Fasting glucose, mg/dL 93.7 (88.3, 99.1) 100.9 (93.7, 108.1) 133.3 (111.7, 169.4)
*Alirocumab and placebo groups balanced through randomization in each glucometabolic category
BMI, body mass index

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Median percent change from baseline presented below each bar
*Intention-to-treat analysis
LDL-C Non-HDL-C HDL-C Triglyceride
0
40
80
120
160
200
Median(Q1,Q3),mg/dL
DiabetesPrediabetesNormoglycemia
Alirocumab
-65%-64%-64%
0%+1%+1%
-54%-54%-54%
0%0%+1%
+7%+8%+8% +3%+3%+3%
-16%-15%-14%
-2%+1%0%
Placebo
Alirocumab
Placebo
Alirocumab Placebo
Alirocumab
Placebo
Lipids at 16 Weeks After Randomization*

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Median (Q1, Q3) follow-up: 2.8 (2.3, 3.4) years
*P<0.0001 for comparison of hazard in people with diabetes vs that in people with normoglycemia or prediabetes
MACE CHD Death Non-Fatal MI Ischemic Stroke UA
0
3
6
9
12
15
18
Incidence(%)
Normoglycemia Prediabetes Diabetes
16.4%
9.2%
8.5%
11.2%
6.3%6.0%
3.8%
1.9%1.6%
2.7%
1.3%1.0% 0.9%0.5%0.6%
HR=1.90, p<0.0001
HR=2.09, p<0.0001
*
*
*
*
Incidence of CV Events in Placebo Group
was Greater in Patients With vs Without
Diabetes

8. Median (Q1, Q3) follow-up: 2.8 (2.3, 3.4) years
Relative risk reduction
Treatment  baseline glucometabolic status: Pinteraction = 0.98
Absolute risk reduction
Pinteraction = 0.0019
0.75 0.85 1.0
Alirocumab
n/N (%)
903/9462 (9.5)
HR (95% CI)
Overall
Diabetes
Prediabetes
Placebo
n/N (%)
0.85 (0.78, 0.93)
0.84 (0.74, 0.97)
0.86 (0.74, 1.00)
0.85 (0.70, 1.03)
Subgroup
Normoglycemia
1052/9462 (11.1)
380/2693 (14.1) 452/2751 (16.4)
331/4130 (8.0) 380/4116 (9.2)
192/2639 (7.3) 220/2595 (8.5)
Alirocumab
Better
Placebo
Better
MACE Incidence
0%1.6%3.2%
ARR (95% CI)
1.6% (0.7%, 2.4%)
2.3% (0.4%, 4.2%)
1.2% (0%, 2.4%)
1.2% (-0.3%, 2.7%)
Alirocumab
Better
Placebo
Better
x
0.75 0.85 1.0
Alirocumab
n/N (%)
903/9462 (9.5)
HR (95% CI)
Overall
Diabetes
Prediabetes
Placebo
n/N (%)
0.85 (0.78, 0.93)
0.84 (0.74, 0.97)
0.86 (0.74, 1.00)
0.85 (0.70, 1.03)
Subgroup
Normoglycemia
1052/9462 (11.1)
380/2693 (14.1) 452/2751 (16.4)
331/4130 (8.0) 380/4116 (9.2)
192/2639 (7.3) 220/2595 (8.5)
Alirocumab
Better
Placebo
Better
MACE Incidence
0%1.6%3.2%
ARR (95% CI)
1.6% (0.7%, 2.4%)
2.3% (0.4%, 4.2%)
1.2% (0%, 2.4%)
1.2% (-0.3%, 2.7%)
Alirocumab
Better
Placebo
Better
Relative and Absolute Risk Reduction with
Alirocumab By Glucometabolic Status

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Analysis method for A1c and fasting glucose: repeated-measures mixed effects model; random
effects = slope, intercept; fixed effects = treatment, baseline value, and time. Only post-
randomization values prior to initiation of diabetes medication were included in the analysis.
*Without diabetes = prediabetes or normoglycemia.
Post-randomization A1c,Fasting Glucose,
and New-onset Diabetes by Baseline
Glucometabolic Status
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
0
5.5
5.6
5.7
5.8
5.9
6.0
Mean(95%CI)HbA1c,%
p=0.0008
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HbA1c
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
Mean(95%CI)FastingGlucose,mmol/L
p=0.84
All Patients
Without Diabetes
Normoglycemia
Prediabetes
Fasting Glucose
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
3
6
9
12
15
18
0
Incidence(95%CI),%
New Onset Diabetes
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HR (95% CI) =
1.00 (0.89-1.11)
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
0
5.5
5.6
5.7
5.8
5.9
6.0
Mean(95%CI)HbA1c,%
p=0.0008
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HbA1c
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
Mean(95%CI)FastingGlucose,mmol/L
p=0.84
All Patients
Without Diabetes
Normoglycemia
Prediabetes
Fasting Glucose
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
3
6
9
12
15
18
0
Incidence(95%CI),%
New Onset Diabetes
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HR (95% CI) =
1.00 (0.89-1.11)
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
0
5.5
5.6
5.7
5.8
5.9
6.0
Mean(95%CI)HbA1c,%
p=0.0008
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HbA1c
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
0
5.3
5.4
5.5
5.6
5.7
5.8
5.9
Mean(95%CI)FastingGlucose,mmol/L
p=0.84
All Patients
Without Diabetes
Normoglycemia
Prediabetes
Fasting Glucose
Alirocumab Placebo Alirocumab Placebo Alirocumab Placebo
3
6
9
12
15
18
0
Incidence(95%CI),%
New Onset Diabetes
All Patients
Without Diabetes
Normoglycemia
Prediabetes
HR (95% CI) =
1.00 (0.89-1.11)

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Conclusions
Among people with diabetes at baseline:
• Risk of recurrent ischemic events after ACS is high, despite intensive
statin treatment
• Using alirocumab to target LDL-C levels of 25−50 mg/dL:
• Produces a similar relative risk reduction to those without diabetes
• Produces a greater absolute risk reduction compared to those
without diabetes
Among people without diabetes at baseline, over the duration of this
study:
• No evidence of increased fasting serum glucose or A1c with alirocumab,
compared with placebo
• No overall increase in new-onset diabetes with alirocumab, compared
with placebo