SAN DIEGO – Praluent (alirocumab, Regeneron Pharmaceuticals Inc./Sanofi SA), a PCSK9 inhibitor that lowers cholesterol, invaded the American Diabetes Association (ADA) 77th Scientific Sessions.

The ADA, rather than the American Heart Association or the American College of Cardiology meetings, was the right place for the data because the two trials presented specifically tested Praluent in patients with diabetes mellitus (DM).

As part of Regeneron and Sanofi's ODYSSEY DM program, the duo tested Praluent in diabetic patients with hypercholesterolemia not adequately controlled by the maximum tolerated statin therapy who also had atherosclerotic cardiovascular disease (ASCVD) or other cardiovascular (CV) risk factor. One trial, ODYSSEY DM-Insulin, looked specifically at patients taking insulin at the start of the trial, while ODYSSEY DM-Dyslipidemia examined the drug's effect in diabetics with mixed dyslipidemia, defined as elevations in non-high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels that are often accompanied by low levels of HDL cholesterol.

In both trials, patients were given 75 mg of Praluent or a placebo injection once every two weeks. Patients in the Praluent group who had a low-density lipoprotein (LDL) cholesterol level of greater than or equal to 70 mg/dL at eight weeks were given a higher dose of 150 mg starting at week 12.

The ODYSSEY DM-Insulin trial enrolled patients with both type 1 and type 2 diabetes although ADA attendees only got to see the data from type 2 patients; the type 1 data will be presented at a later date. In the type 2 diabetes patients, Praluent lowered LDL by 49 percent compared to the placebo after 24 weeks of treatment with 80 percent of patients taking Praluent reaching the recommended target LDL levels on the lower dose of 75 mg.

In the ODYSSEY DM-Dyslipidemia trial, which only enrolled patients with type 2 diabetes, rather than measuring LDL levels, researchers looked at non-HDL, which includes triglyceride-rich very low-density lipoprotein (VLDL) that often increases as diabetics become insulin resistant and lose the positive effects from HDL.

"Non-HDL is a better measure of risk, particularly when TG levels are high," explained Kausik Ray, chair of the Department of Public Health and Primary Care at Imperial College London.

After 24 weeks of treatment, Praluent reduced non-HDL by 32.5 percent compared to standard of care used as the control. About one-third of the patients taking Praluent required up-titration to the higher dose.

"These data support use of alirocumab as a treatment option in people with diabetes mellitus at high cardiovascular risk," concluded Lawrence Leiter, associate scientist at the Li Ka Shing Knowledge Institute at St. Michael's Hospital in Toronto, about the two studies.

Diabetes drugs join the party

Not to be outdone by their cardiovascular brethren, a pair of presentations of diabetes drugs at Sunday's sessions also focused on cardiovascular risk.

The REMOVAL trial investigated if three years of treatment with metformin reduces heart disease in middle-age adults with type 1 diabetes who had three or more risk factors for cardiovascular disease. The 428 adults in the study from five different countries had been diagnosed with type 1 diabetes for an average for 33 years.

The multicenter international group, supported by funding from JDRF, used ultrasound to measure atherosclerosis in the carotid artery in patients with type 1 diabetes. Results of the study, which were simultaneously published in Lancet Diabetes and Endocrinology, were mixed with the primary endpoint of mean far-wall carotid artery intima-media thickness (cIMT) failing to achieve statistical significance with a 0.005 mm per year reduction for patients taking metformin compared to placebo (p-value=0.1664).

But when the group looked at maximal cIMT, one of the prespecified tertiary outcome that also measures focal thickening, the measurement was significantly reduced by 0.013 mm per year in the metformin group compared to placebo (p-value=0.0093).

"[Cardiovascular disease] benefit is suggestive but is by no means conclusive," Naveed Sattar, professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, concluded, pointing out that the patients in the study were relatively well-treated with statins and other cholesterol-lowering drugs, which may have reduced the metformin affect on mean cIMT.

Those presentations also offered an update on the LEADER trial that was presented at last year's ADA. The trial showed Victoza (liraglutide, Novo Nordisk A/S) reduced major cardiovascular events in patients with type 2 diabetes.

Researchers looked at various potential reasons why the glucagon-like peptide-1 (GLP-1) receptor agonist was able to reduce cardiovascular risk including Victoza's ability to improve glycemic control, body weight, blood pressure and lipid level, but none of the individual effects seemed to account for the cardiovascular benefit.

"In humans, we don't actually know what the mechanism is for liraglutide's benefit," concluded Richard Pratley, senior investigator at the Translational Research Institute for Metabolism and Diabetes and the medical director of the Florida Hospital Diabetes Institute.

Unlike Victoza, other GLP-1 receptor agonists – Lyxumia/Adlyxin (lixisenatide, Sanofi SA) and Bydureon (exenatide extended-release, Astrazeneca plc) – haven't shown a cardiovascular benefit.

"These drugs are not all the same; we only find out what they actually do when we study them," Steven Nissen, chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine at Cleveland Clinic's Sydell and Arnold Miller Family Heart & Vascular Institute, warned about assuming class effects.