Efficacy and Safety of Alirocumab in Insulin-treated Diabetics with High Cardiovascular Risk

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. [1]

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. [2] 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. [2]

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. [5] 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. [6]

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)

Methods Inclusion Criteria:

–       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)

Exclusion Criteria:

–       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
Baseline Characteristics  

T2D T1D
Alirocumab

(n= 294)

Placebo

(n= 147)

Alirocumab

(n= 51)

Placebo

(n= 25)

Mean (SD) age, years 63.9 (8.9) 64.0 (9.4) 54.9 (10.1) 58.5 (7.8)
Age group, n (%)
  <65 years 143 (48.6) 73 (49.7) 42 (82.4) 19 (76.0)
  >65 to <75 years 126 (42.9 55 (37.4) 8 (15.7 6 (24.0)
  >75 years 25 (8.5) 19 (12.9) 1 (2.0) 0
Male, n (%) 161 (54.8) 78 (53.1) 29 (56.9) 17 (68.0)
Race, n (%)
  White 259 (88.1) 135 (91.8) 50 (98.0) 24 (96.0)
  Black 27 (9.2) 7 (4.8) 1 (2.0) 0
  Asian 7 (2.4) 3 (2.0) 0 0
  Other 1 (0.3) 2 (1.4) 0 1 (4.0)
Ethnicity, n (%)
  Hispanic 13 (4.4) 8 (5.4) 1 (2.0) 0
  Not Hispanic 280 (95.2) 138 (93.9) 50 (98.0) 25 (100)
  Unknown 1 (0.3) 1 (0.7) 0 0
Mean (SD) BMI, kg/m2 32.6 (4.8) 32.7 (5.5) 30.6 (6.3) 28.7 (4.8)
Mean (SD) HbA1c, % 7.5 (1.0) 7.5 (1.0) 7.8 (1.0) 7.7 (0.8)
ASCVD, n (%) 119 (40.5) 58 (39.5) 11 (21.6) 5 (20.0)
No ASCVD + additional CV risk factors, n (%) 175 (59.5) 89 (60.5) 40 (78.4) 20 (80.0)
Current smoker, n (%) 38 (12.9) 15 (10.2) 10 (19.6) 3 (12.0)
Mean (SD) calculated LDL cholesterol, mg/dL 110.8 (36.5) 109.6 (39.1) 126.4 (58.2) 110.2 (31.2)
Concomitant LLT, n (%)
  Any statin 222 (75.5) 113 (76.9) 36 (70.6) 16 (64.0)
  Statin

monotherapy

174 (59.2) 88 (59.9) 31 (60.8) 12 (48.0)
  Any other LLTs 78 (26.5) 33 (22.4) 7 (13.7) 7 (28.0)
Statin intolerancea 72 (24.5) 33 (22.4) 15 (29.4) 9 (36.0)
Concomitant antihyperglycemic drugs, n (%)
  Insulin 293 (99.7)b 146 (99.3)b 51 (100.0) 25 (100.0)
  Any other agent 202 (68.7) 110 (74.8) 8 (15.7) 1 (4.0)
Select information provided.

a Number of participants not currently taking statin who are statin-intolerant based on medical history, as reported by investigator.

b One participant in the alirocumab group and one participant in the placebo group were not receiving insulin at the time of randomization, and they remained without insulin treatment for the duration of the trial.

Results  

T2D Alirocumab

(n= 294)

Placebo

(n= 147)

Difference vs placebo, %

[95% CI], p value

Mean (SD) calculated LDL-C
  Baseline, mg/dL 110.3 (35.9) 109.5 (38.7)
  Week 24, mg/dL 55.1 (33.7) 107.3 (37.0)
% change from baseline to

week 24

−48.2 (1.6) 0.8 (2.2) −49.0 (2.7)

[−54.4 to −43.6], <.0001

Select information provided.
T1D Alirocumab

(n= 49)

Placebo

(n= 25)

Difference vs placebo, %

[95% CI], p value

Mean (SD) calculated LDL-C
  Baseline, mg/dL 122.5 (47.8) 110.2 (31.2)
  Week 24, mg/dL 55.9 (33.5) 101.8 (31.8)
% change from baseline to

week 24

−51.8 (3.7) −3.9 (5.3) −47.8 (6.5)

[−60.7 to −35.0], <.0001

Select information provided.
Adverse Events  

Treatment-emergent adverse events (TEAEs) for overall population (safety population)
% (n) of participantsa Alirocumab

(n = 344)

Placebo

(n = 170)

TEAEs
  Any TEAE 64.5 (222) 64.1 (109)
  Treatment-emergent serious adverse event 9.0 (31) 9.4 (16)
  TEAEs leading to death 0 0.6 (1)
  TEAEs leading to treatment discontinuation 4.9 (17) 2.4 (4)
Adverse events of special interest
  Allergic events requiring consultation with another physician 1.5 (5) 2.4 (4)
  Neurological events requiring additional

examination/procedures and/or consultation with a specialist

0.3 (1) 0.6 (1)
  Neurocognitive events 1.2 (4) 0
  Increase in alanine aminotransferase 0.6 (2) 0.6 (1)
TEAEs occurring in ≥2% of participants (in any group)
  Bronchitis 2.6 (9) 0.6 (1)
  Pneumonia 0.6 (2) 2.4 (4)
  Nasopharyngitis 4.9 (17) 5.3 (9)
  Upper respiratory tract infection 0.9 (3) 2.4 (4)
  Urinary tract infection 4.4 (15) 4.1 (7)
  Influenza 2.3 (8) 2.9 (5)
  Hyperglycemia 0.9 (3) 2.4 (4)
  Hypoglycemia 1.7 (6) 2.4 (4)
  Headache 2.9 (10) 2.4 (4)
  Dizziness 2.6 (9) 1.2 (2)
  Hypertension 2.9 (10) 2.9 (5)
  Cough 1.5 (5) 2.9 (5)
  Diarrhea 4.4 (15) 4.1 (7)
  Nausea 2.3 (8) 2.4 (4)
  Arthralgia 2.9 (10) 1.8 (3)
  Myalgia 4.4 (15) 1.8 (3)
  Musculoskeletal pain 1.2 (4) 2.4 (4)
  Pain in extremity 1.7 (6) 2.9 (5)
  Fatigue 2.0 (7) 1.8 (3)
  Peripheral edema 2.0 (7) 0.6 (1)
  Fall 2.0 (7) 1.8 (3)
a Subjects may be counted in more than one category

Select information provided

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. [7] Despite the positive evidence provided by the study, obtaining and utilizing alirocumab may prove to be difficult for patients needing additional lipid lowering therapy.

References

[1] 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.

[2] 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.

[3] 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.

[4] 9. Cardiovascular Disease and Risk Management. Diabetes Care. 2017;40(Suppl 1):S75-S87.

[5] Praluent® [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; September 2017.

[6] 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.

[7] Alirocumab. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  http://online.lexi.com.  Accessed October 30, 2017.

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