Medication That Inhibits PCSK9 Safely Reduces Cardiovascular Risk in Patients with Type 2 Diabetes

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Michelle Kirkwood
press@diabetes.org
703-299-2053

San Diego, California
June 11, 2017

Results of two ODYSSEY studies with alirocumab

The medication alirocumab, a PCSK9 inhibitor, reduces LDL cholesterol levels as well as non-high-density lipoprotein cholesterol (non-HDL-C) in patients with type 2 diabetes, according to two ODYSSEY DIABETES (DM) presentations today at the “Inhibition of PCSK9 in Dyslipidemia Patients with Diabetes” symposium at the American Diabetes Association’s 77th Scientific Sessions® at the San Diego Convention Center. 

People with diabetes are more prone to have abnormal cholesterol levels, which can result in increased risk for cardiovascular disease (CVD). Cholesterol levels in the blood are modulated by the liver. Receptors on the liver bind cholesterol and allow it to be broken down. PCSK-9 is a protein that is known to reduce the activity of these receptors. Alirocumab is an approved monoclonal antibody that prevents PCSK-9 protein from impairing the liver’s receptors. This allows more cholesterol to be broken down by the liver, therefore lowering cholesterol levels. ODYSSEY is a large study program with alirocumab and includes numerous research trials utilizing the medication.

ODYSSEY DM-Insulin Trial

The ODYSSEY-DM Insulin Trial is an international Phase 3, randomized, double-blind, placebo-controlled, study conducted at 108 centers across the U.S. and Europe. The trial enrolled insulin treated patients with type 1 diabetes (T1D) and patients with type 2 diabetes (T2D) and who also had a high cardiovascular risk and  hypercholesterolemia (high levels of “bad” cholesterol) not adequately controlled by the maximum tolerated statin therapy. 

This analysis outlines the study results of the patients with T2D. The trial enrolled a total of 441 adults with T2D who had low-density lipoprotein cholesterol (LDL-C) levels at screening of ≥70mg/dL (1.81mmol/L). The patients were either taking the maximum tolerated cholesterol-lowering drug dose (called statins) or were unable to tolerate any statin. Additionally, the patients had atherosclerotic cardiovascular disease (ASCVD) or at least one other cardiovascular risk factor.

The patients were randomly assigned to receive either an injection of 75 mg of alirocumab (N=294) or a placebo (N=147) injection once every two weeks. The patients in the alirocumab group who had an LDL-C level of ≥70mg/dL at eight weeks received a blinded dose increase to 150mg at week 12 (a blinded dose indicates that the clinician and the patient were unaware if medication or placebo was administered). Primary endpoints of the trial were the difference between treatment arms in percentage change of calculated LDL-C from baseline to week 24, and adverse events. 

The results indicate that at 24-weeks, alirocumab significantly reduced LDL-C by 49 percent compared to the placebo and also improved other lipid parameters¹. Further, 80 percent of patients reached the recommended target LDL-C levels with the alirocumab dose of 75 mg. Researchers concluded that the co-administration of alirocumab and insulin was safe and the incidence of adverse events was generally similar between alirocumab and placebo. Additionally, alirocumab was generally well-tolerated and did not affect glucose control.

While this was the first dedicated trial of a PCSK9 inhibitor in patients with T2D, the results are comparable to what was previously seen in the ODYSSEY program. This study also evaluated the effect of alirocumab on some newer lipid parameters that will enable researchers to better understand the effect of alirocumab on atherogenic diabetic dyslipidemia (ADD). (ADD is characterized by high serum triglycerides, elevated LDL levels, low HDL levels and postprandial lipemia, with insulin resistance being the primary cause of ADD).

“People with diabetes are at high cardiovascular risk, and dyslipidemia is a major risk factor for macrovascular complications,” said Lawrence Leiter, MD, associate scientist at Li Ka Shing Knowledge Institute at St. Michael’s Hospital in Toronto, and professor in the departments of medicine and nutritional sciences at the University of Toronto. “Despite the current standard of care for lipid lowering therapy, many individuals with diabetes have persistent lipid abnormalities resulting in increased residual cardiovascular risk. For people with diabetes, cardiovascular risk increases with advanced duration of diabetes, particularly in insulin-treated patients. The results of the ODYSSEY DM-Insulin study provide valuable information on the efficacy and safety of alirocumab in this high cardiovascular risk group and will help guide clinical decision-making beyond statin therapy.”

Additional results on the efficacy and safety of alirocumab in patients with T1D will be extracted and reported at a later date.

Alirocumab Versus Usual Care in Diabetes with Mixed Dyslipidemia – ODYSSEY DM – DYSLIPIDEMIA Study

This international trial, “Efficacy and Safety of Alirocumab Versus Usual Care on Top of Maximally Tolerated Statin Therapy in Patients With Type 2 Diabetes and Mixed Dyslipidemia (ODYSSEY DM-Dyslipidemia),” was a randomized, open-label, parallel group study. The study focused on evaluating the efficacy and safety of alirocumab versus standard care (either no additional lipid lowering therapy or ezetimibe, fenofibrates, omega-3 fatty acids, nicotinic acid ) in patients with type 2 diabetes and mixed dyslipidemia who were at  high cardiovascular risk (established atherosclerotic CVD (ASCVD) or at least one other cardiovascular risk factor)  with non-high-density lipoprotein cholesterol (non-HDL- C) not adequately controlled with the maximum tolerated dosage of statin therapy. Mixed dyslipidemia was defined as elevations in non-HDL cholesterol and triglyceride levels that are often accompanied by low levels of HDL cholesterol.

The study enrolled 413 people with type 2 diabetes from 110 centers from the U.S., Europe, South America, the Middle East, Australia and the U.K. The trial consisted of a 24-week treatment period, and a safety follow-up period of eight weeks. Patients were randomly assigned to receive either 75 mg of alirocumab (administered via an auto-injector every two weeks for 24 weeks); or standard care in a 2:1 ratio. Patients who were randomized to be in the alirocumab group, but who did not achieve adequate reduction in non HDL-cholesterol at 12 weeks follow-up, had their alirocumab dosage increased to 150 mg in a blinded manner (meaning the clinician and the patient were both unaware if the medication administered was alirocumab or placebo). Primary endpoint of the trial was the difference between treatment arms in percentage change of non-HDL-C from baseline to week 24.

After 24 weeks of treatment, data indicates that alirocumab significantly reduced the non-high-density lipoprotein cholesterol (non-HDL-C) by 32.5 percent compared to usual care. Non-HDL-C is considered to be a better predictor of cardiovascular risk than LDL-C levels, particularly in this patient population with type 2 diabetes with mixed dyslipidemia. Additionally, patients who received alirocumab had improvement in other lipid parameters  compared to the patients in the usual care group, and the majority of patients in the alirocumab group reached the recommended lipid levels on the 75 mg dose. The number of adverse events was generally similar between the two treatment arms. Further, alirocumab was generally well tolerated and did not affect glucose control.

“Cardiovascular disease is a significant cause of morbidity and mortality in people with type 2 diabetes,” said lead investigator Robert R. Henry, MD, professor of medicine in the division of endocrinology & metabolism at the University of California, San Diego, and chief of the endocrinology, metabolism & diabetes section and the Center for Metabolic Research at the VA Medical Center in San Diego. “Mixed dyslipidemia is commonly present in these patients and further increases their cardiovascular risk. The ODYSSEY-DM-DYSLIPIDEMA study is the first trial that directly compares a PCSK9 Inhibitor with usual care in patients with T2DM diabetes who have lipid disturbances. The results of our study will assist clinicians in the management of mixed dyslipidemia, which is a persistent challenge in clinical practice, for patients with type 2 diabetes.”

To speak with Dr. Leiter or Dr. Henry, please contact the Association’s media relations team on-site at the San Diego Convention Center on June 9 -13, by phone at 619-525-6250 or by email at press@diabetes.org.

The American Diabetes Association’s 77th Scientific Sessions, to be held June 9-13, 2017, at the San Diego Convention Center, is the world’s largest scientific meeting focused on diabetes research, prevention and care. During the five-day meeting, health care professionals have exclusive access to more than 2,500 original research presentations, participate in provocative and engaging exchanges with leading diabetes experts, and can earn Continuing Medical Education (CME) or Continuing Education (CE) credits for educational sessions. The program is grouped into eight interest areas: Acute and Chronic Complications; Behavioral Medicine, Clinical Nutrition, Education and Exercise; Clinical Diabetes/Therapeutics; Epidemiology/Genetics; Immunology/Transplantation; Insulin Action/Molecular Metabolism; Integrated Physiology/Obesity; and Islet Biology/Insulin Secretion. Brenda Montgomery, RN, MSHS, CDE²,  President of Health Care and Education, will deliver her address on Saturday, June 10, and Alvin C. Powers, MD, President of Medicine and Science, will present his address on Sunday, June 11. Eight abstracts were selected by the Scientific Sessions Meeting Planning Committee to be presented on Tuesday, June 13, in the President’s Oral Session. These abstracts represent important research being conducted in the field of diabetes today. In total, the 2017 Scientific Sessions includes 378 abstracts in 49 oral sessions; 2,152 poster presentations including 50 moderated poster discussions; and 360 published-only abstracts. Join the Scientific Sessions conversation on Twitter, #2017ADA.

About the American Diabetes Association

More than 29 million Americans have diabetes, and every 23 seconds another person is diagnosed with diabetes. The American Diabetes Association (Association) is the global authority on diabetes and since 1940 has been committed to its mission to prevent and cure diabetes and to improve the lives of all people affected by diabetes. To tackle this global public health crisis, the Association drives discovery in research to treat, manage and prevent all types of diabetes, as well as to search for cures; raises voice to the urgency of the diabetes epidemic; and provides support and advocacy for people living with diabetes, those at risk of developing diabetes and the health care professionals who serve them. For more information, please call the American Diabetes Association at 1-800-DIABETESS (1-800-342-2383) or visit diabetes.org. Information from both of these sources is available in English and Spanish. Find us on Facebook (American Diabetes Association), Twitter (@AmDiabetesAssn) and Instagram (@AmDiabetesAssn)

1 Parameters such as low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), total cholesterol (Total -C), lipoprotein a (Lp[a]), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), triglyceride rich lipoproteins (TGRLs), apolipoprotein A-1 (Apo A-1), apolipoprotein C-III (Apo C-III), lipid subfractions by nuclear magnetic resonance (NMR) spectroscopy (i.e. LDL-C particle size and LDL, very low-density lipoprotein [VLDL], HDL, and intermediate-density lipoprotein [IDL] particle number).

2 Disclosures for Brenda Montgomery. Employer: AstraZeneca Pharmaceuticals. Montgomery's role as President, Health Care & Education of the American Diabetes Association (Association) is a voluntary position to which she was elected by the members of the Association in 2015. She continues to recuse herself from any and all discussions, decisions or votes that have or could be perceived as having a conflict of interest with her employer.