Results from two ODYSSEY studies indicate the favorable lipid lowering effects of Alirocumab, a PCSK9 inhibitor, in type 2 diabetes patients can potentially reduce the risk of cardiovascular disease.
Despite numerous current treatment agents to treat mixed dyslipidemia in patients with both T1DM and T2DM, many patients continue to have difficulty in controlling lipid levels. These patients with persistent lipid abnormalities have continued risk for cardiovascular mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein in upregulating the low-density lipoprotein receptors on the liver. Currently, there are two FDA approved PCSK9 Inhibitors; alirocumab and evolocumab. Alirocumab, a fully human monoclonal antibody, has shown a 60% reduction in LDL-C from baseline in the ODYSSEY LONG TERM. However, it was still unclear if the lipid lowering effect of this new class of medication is correlated with decreased risk of cardiovascular event and mortality. Previous evidence is also uncertain if this class alters glycemic control in diabetic patients.
The purpose of the ODYSSEY DM-Insulin Trial is to evaluate the efficacy and safety of alirocumab in insulin treated type 1 and type 2 diabetics with difficulty in reaching lipid goals and high cardiovascular risk. According to the rationale and design of the ODYSSEY DM-Insulin Trial, all participants were required to be on stable insulin therapy, have high risk or established cardiovascular disease and a baseline LDL-C ≥ 70 mg/dL on the maximum tolerable statin dose. A total of 517 participants were enrolled in the phase IIIb, double-blind, placebo controlled trial for 24 weeks. These participants were randomized in a 2:1 ratio with 75mg alirocumab subcutaneous injection every two weeks or a placebo. The alirocumab study group had an opportunity to titrate up to 150 mg of alirocumab in week 12 if their LDL-C was still ≥ 70 mg/dL at week 8. The primary outcome of interest was the percent change of LDL-C from baseline to week 24 between alirocumab and placebo. The results of the 441 participants with T2DM showed a 48.2% reduction in the primary outcome by the alirocumab study group and a 0.8% increase by the placebo study group (mean difference = 49%; p < 0.0001). The Common side effects experienced in the alirocumab study group were nasopharyngitis, myalgia, arthralgia and cough. However, researchers stated alirocumab was well tolerated. Results of the 76 participants with T1DM have not been released yet.
Another study, the ODYSSEY DM-DYSLIPIDEMIA sought to evaluate the efficacy and safety of alirocumab in type 2 diabetics with high cardiovascular risk and difficulty reaching lipid goals. This study was unique because alirocumab would be compared to usual care in lipid-lowering therapies and the primary outcome was interested in assessing the reduction of non-HDL-C from baseline to week 24 between the two study groups. According to the rationale and design of the ODYSSEY DM-DYSLIPIDEMIA trial, participants were required to have stable and controlled type 2 diabetes, have high risk or established cardiovascular disease and have uncontrolled mixed dyslipidemia on the maximum tolerable statin dose. In this phase 3b/4, open-label, parallel group study, 413 participants were randomized in a 2:1 ratio to receive 75mg alirocumab subcutaneous injection every two week or usual care lipid lowering therapies. Again, participants in the alirocumab study group were given an opportunity to titrate up to 150 mg of alirocumab in week 12 if LDL-C was still ≥ 70 mg/dL at week 8. The results showed alirocumab had a significant reduction of non-HDL-C compared to usual care therapies (37.3% vs 4.7%; p < 0.0001) and a significant difference in mean (32.5%; p < 0.0001). LDL-C, which was also an outcome of interest, was also found to have a significant reduction in the alirocumab study group (43.3% vs 0.3%; p < 0.0001). Common side effect experienced in the alirocumab study group were urinary tract infections, diarrhea and nasopharyngitis. Despite these side effects, researchers reported alirocumab was well tolerated.
In conclusion, the use of alirocumab improved the lipid levels of these participants. These studies also suggest an association with alirocumab reducing the risk of cardiovascular disease. However, more studies with clinical outcomes such as cardiovascular events are necessary to confirm these results. In addition, alirocumab was found to have no impact on glycemic control in patients with diabetes. This gives type 2 diabetic patients another safe and effective option in controlling dyslipidemia. However, health care providers and patients will need to consider the high cost of this medication.
- Many patients with diabetes still have difficulty achieving adequate lipid goals, despite current therapies.
- Alirocumab, in addition to maximum tolerable statin dose, has shown to improved lipid control without affecting glycemic control.
- Improved lipid control with alirocumab can potentially reduce the risk of cardiovascular disease in patients with type 2 diabetes.
American Diabetes Association. Medication That Inhibits PCSK9 Safely Reduces Cardiovascular Risk in Patients with Type 2 Diabetes. Press Release. Available at: http://www.diabetes.org/newsroom/press-releases/2017/leiter-henry-scientific-sessions-2017.html. Accessed June 15, 2017.
PRNewswire. Regeneron and Sanofi Announce Positive Results from First Dedicated Studies Evaluating Praluent® (alirocumab) in Individuals with Diabetes and Hypercholesterolemia. Press Release. Available at: http://www.prnewswire.com/news-releases/regeneron-and-sanofi-announce-positive-results-from-first-dedicated-studies-evaluating-praluent-alirocumab-in-individuals-with-diabetes-and-hypercholesterolemia-300472008.html. Accessed June 15, 2017.
Cariou B, Leiter LA, Müller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated patients with type 1 or 2 diabetes and high cardiovascular risk: Rational and design of the ODYSSEY DM-INSULIN trial. Diabetes Metab. 2017. Epub 2017/03/24. doi: 10.1016/j.diabet.2017.01.004
Müller-Wieland D, Leiter LA, Cariou B, et al. Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidemia at high cardiovascular risk. Cardiovascular Diabetology. 2017; 16(1):70 doi: 10.1186/s12933-017-0552-4
Joanna Martinez-Mendez, PharmD Candidate 2018, Lake Erie College of Osteopathic Medicine School of Pharmacy: FL Campus