Kayla Peltier, Mercer University College of Pharmacy
In 2015, the Centers for Disease Control and Prevention (CDC) estimates that 23.0 million Americans were living with diabetes and 7.2 million of Americans had undiagnosed diabetes. 
Diabetes is a risk factor for atherosclerotic cardiovascular disease (ASCVD), and the National Lipid Association (NLA) guidelines classify patients with diabetes as high-to-very-high-risk for developing ASCVD.  Due to the concern, the most current lipid guidelines from the American College of Cardiology (AHA)/American Heart Association (AHA) and the American Diabetes Association (ADA) standards of care recommend that patients aged 40 to 75 years with diabetes be started on moderate-intensity statin therapy for primary prevention of ASCVD. [3,4] The NLA guidelines recommend that diabetic patients receive either moderate- or high-intensity statin therapy, regardless of patient age. 
Alirocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin kexin type 9 (PCSK9) and is indicated for the treatment of heterozygous familial hypercholesterolemia or clinical ASCVD in addition to lifestyle modifications and maximally tolerated statin therapy in adults who require additional LDL-C lowering.  Concerns have been raised about the safety and efficacy of PCSK9 inhibitors in addition to the use of insulin therapy in diabetic patients. Therefore, this study aimed to investigate the efficacy and safety of alirocumab in patients with diabetes mellitus. 
|Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN randomized trial|
|Design||Phase IIIb, randomized, double-blind, placebo-controlled, parallel-group multicenter trial; N= 517|
|Objective||To investigate the efficacy and safety of alirocumab in subjects with type 2 (T2D) or type 1 (T1D)|
|Study Groups||Alirocumab (T2D n= 294; T1D n= 51)
Placebo (T2D n= 147; T1D n= 25)
– Age 18 years and older
– Type 1 or type 2 diabetics with a diagnosis >1 year prior to screening
– Documented history of ASCVD (including established coronary heart disease [CHD], documented peripheral arterial disease [PAD], or ischemic stroke) and/or at least one additional cardiovascular risk factor
– Poorly controlled low-density lipoprotein cholesterol (LDL-C; >70 mg/dL) despite a stable maximally tolerated statin therapy with or without other lipid-lowering therapy (LLT)
– Plan to initiate a new LLT or modify the dose of current LLT during the course of the study
– Not on a stable LLT dose for at least 4 weeks prior to screening
– Use of nutraceuticals or over-the-counter products that can affect lipid levels
– Use of red yeast rice products within 4 weeks of screening
– Use of systemic corticosteroids (unless as replacement therapy for pituitary/adrenal disease)
– Use of continuous hormone replacement therapy unless stable for at least 6 weeks prior to screening
– Myocardial infarction (MI), unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), carotid surgery or stenting, stroke, transient ischemic attack (TIA), endovascular procedure, or surgical intervention for peripheral vascular disease within 3 months prior to screening
– HIV positive
– BMI > 45 kg/m2
After a three week screening period, subjects were randomized (2:1) to receive either alirocumab or placebo for a 24 week study period, followed by an eight week safety observation period. Subjects received diabetes treatment dictated by local/regional standards of care, and were on a stable glucose and lipid management diet. Alirocumab or placebo was administered via prefilled pen devices as 1 mL subcutaneously every two weeks. Alirocumab was initiated at 75 mg every two weeks, and the dose was increased to 150 mg every two weeks at week 12 if LDL-C at week 8 was >70 mg/dL.
|Duration||35 weeks (3 week screening period, 24 week treatment period, and 8 week safety observation period)|
|Primary Outcome Measure||Least squares (LS) mean (standard error [SE]) percentage change in calculated LDL-C levels from baseline to week 24|
|Study Author Conclusions||Treatment with alirocumab significantly reduced LDL cholesterol levels in subjects with insulin-treated diabetes (T2D or T1D), and the treatment was generally well tolerated.|
This study provided positive efficacy and safety data for the use of alirocumab in diabetic patients with hypercholesterolemia at risk of developing ASCVD. However, alirocumab was compared to placebo and patients were not given a standardized regimen for additional lipid lowering therapy (e.g. statins, non-statin therapy, diet, and lifestyle modification). Furthermore, Lexicomp® reports that 1 mL (one dose) of alirocumab costs $672.00.  Despite the positive evidence provided by the study, obtaining and utilizing alirocumab may prove to be difficult for patients needing additional lipid lowering therapy.
 Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Atlanta, GA: Centers for Disease Control and Prevention, U.S. Dept of Health and Human Services; 2017.
 Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1–full report. J Clin Lipidol. 2015;9(2):129-69.
 Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45.
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 Praluent® [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; September 2017.
 Leiter LA, Cariou B, Müller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN randomized trial. Diabetes Obes Metab. 2017;1–12. doi: 10.1111/dom.13114.
 Alirocumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed October 30, 2017.