Background

The PCSK9 inhibitor alirocumab reduces LDL-c levels and non-HDL-C in patients with type 2 diabetes (T2D), according to two ODYSSEY DIABETES (DM) presentations at the ‘Inhibition of PCSK9 in Dyslipidemia Patients with Diabetes’ symposium at the American Diabetes Association’s 77th Scientific Sessions in San Diego.

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 T2D and who also had a high CV risk and hypercholesterolemia 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 LDL-C levels at screening of ≥70mg/dL (1.81mmol/L). The patients were either taking the maximum tolerated statin dose or were unable to tolerate any statin. Additionally, the patients had atherosclerotic CV disease (ASCVD) or at least one other CV 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. 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% compared to the placebo and also improved other lipid parameters. Further, 80% 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: high serum triglycerides, elevated LDL levels, low HDL levels and postprandial lipemia, with insulin resistance being the primary cause of ADD).

The 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 T2D and mixed dyslipidemia who were at high CV risk (established atherosclerotic CVD (ASCVD) or at least one other CV risk factor) with non-HDL- C not adequately controlled with the maximum tolerated dosage of statin therapy. Mixed dyslipidemia was defined as elevations in non-HDL-c and triglyceride levels that are often accompanied by low levels of HDL-c.

The study enrolled 413 people with T2D 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. 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 non-HDL-C by 32.5% compared to usual care. Non-HDL-C is considered to be a better predictor of CV risk than LDL-C levels, particularly in this patient population with T2D 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.

Source: press release ADA, June 11, 2017