AT EASD 2017

LISBON (FRONTLINE MEDICAL NEWS) Additional data released from the ODYSSEY DM clinical trials program show that the PCSK9 inhibitor alirocumab lowers lipid levels works just as well in patients with type 1 diabetes as it does in those with type 2 diabetes, plus it may have an edge over using older, add-on lipid-lowering therapies such as fibrates.

The findings were presented at the annual meeting of the European Association for the Study of Diabetes.

In one study involving 76 insulin-treated patients with T1DM, treatment with alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) reduced low-density lipoprotein cholesterol levels by a mean of 47.8% versus placebo from baseline to week 24 (P less than .0001), the primary endpoint of the study.

Furthermore, in a separate study involving 413 patients with T2DM with mixed hyperlipidemia, alirocumab decreased levels of non–high-density lipoprotein cholesterol (non-HDL-C) by 33.3% compared with fenofibrate (P less than .0001).

These new results from the ODYSSEY DM-INSULIN and ODYSSEY DM-DYSLIPIDEMIA trials, respectively, add to those already presented this year at the annual scientific sessions of the American Diabetes Association.

At the ADA meeting it was reported that, after 24 weeks, alirocumab therapy cut LDL-C by 49% more than placebo (P less than .0001) in insulin-treated patients with T2DM, and that non-HDL-C fell by 32.5% more compared with usual care (P less than .0001) in the lipid trial.

“We have studied two groups of high- to very-high cardiovascular risk patients with diabetes mellitus: those on insulin and those with mixed dyslipidemia in whom previously only secondary data were available,” said Stefano Del Prato, MD, who presented the lipid study. “These are dedicated studies in these specific populations,” he added.

In these high-risk diabetic populations, Dr. Del Prato, professor of endocrinology and metabolism and chief of the section of diabetes, University of Pisa, Italy, observed “alirocumab was superior in lipid-lowering efficacy compared to standard care, with no specific safety issues.”

Efficacy unaffected by co-administration with insulin use

Helen Colhoun, MD, AXA chair of medical informatics and life course epidemiology at the University of Edinburgh, presented the updated findings of the ODYSSEY DM-INSULIN study, which recruited 517 patients, the majority (n = 441) of whom had T2DM.

In the study, alirocumab, a monoclonal antibody that targets proprotein convertase subtilisin–kexin type 9 (PCSK9), was compared with placebo in patients with established atherosclerotic cardiovascular disease or other cardiovascular risk factors, and in whom LDL-C was 70 mg/dL (1.8 mmol/L) or higher.

The percentage change in LDL-C from baseline to week 24 was similarly reduced in T1DM and T2DM, Dr. Colhoun observed, and commensurate with data seen across the ODYSSEY phase III trials program. Of note, the majority of type 2 (80%) and type 1 (63%) patients did not need the dose of alirocumab to be increased and remained on the starting dose of 75 mg every 2 weeks.

“It is very pleasing to see no evidence of loss of efficacy of alirocumab among people with type 1 diabetes,” Dr. Colhoun said. Despite the “modest sample size, you can see the treatment effect is highly, clinically, and statistically significant.”

The results of the ODYSSEY DM-INSULIN trial, which were published online , Sept. 14, 2017, to coincide with their presentation at the meeting, also showed that the percentage change in LDL-C over time is “well sustained” and that 70% and 76% of patients with T1DM and T2DM, respectively, can achieve an LDL-C target of less than 70 mg/dL (1.8 mmol/L) and 79% and 71% can hit a non-HDL-C target of less than 100 mg/dL (2.6 mmol/L).

Other lipid parameters – including apolipoprotein (Apo) B, total cholesterol, Lp(a), and triglycerides – were also reduced to a greater extent in patients treated with alirocumab versus those given placebo. Dr. Colhoun drew attention to the reduction in Lp(a), which dropped by 23% in patients with T1DM and by 19% in patients with T2DM, as it is an important risk factor for peripheral vascular disease, and it is not affected by statin therapy.

“What this trial has told us is that coadministering alirocumab with insulin does not adversely affect its efficacy,” said Dr. Colhoun. “There’s absolutely no evidence of alirocumab altering HbA1c or fasting plasma glucose,” she added. There was also no affect on how patients were treated, either with insulin therapy or antihyperglycemic drugs.

Overall safety findings were “reassuring” and anti-drug antibodies were rare (2.1%) and did not affect the lipid-lowering effects of alirocumab.

Alirocumab beats fenofibrate as add-on lipid-lowering therapy

Presenting the ODYSSEY DM-DYSLIPIDEMIA data, which involved patients with T2DM, Dr. Del Prato observed that alirocumab was “generally well tolerated” and did not affect HbA1c or fasting plasma glucose levels.

He presented new data from a prespecified analysis that looked at the subgroup of 72 patients who were randomized into an alirocumab (n = 48) or fenofibrate (n = 24) as usual care arm. Dr. Del Prato reminded the audience that the choice of usual treatment was decided by the study investigators prior to randomizing patients, and that other usual care treatments included in the study were ezetimibe, omega-3 fatty acids, nicotinic acid, or no lipid-lowering therapy.

As in the insulin study, the majority (63.6%) of patients treated with alirocumab remained on the starting dose of 75 mg every 2 weeks and did not need up-titration.

Changes in the percentage of non-HDL-C from baseline over time were greater in the alirocumab group than in the usual care group, both in the overall population and in the fenofibrate subanalysis.

Higher percentages of patients treated with alirocumab achieved non-HDL-C compared with those given usual care (66.9% vs. 17.7% in overall population, 65.2% vs. 10.1% in fenofibrate sub-analysis) and LDL-C (70.8% vs. 16.3% and 71.9% vs. 17.5%, respectively) goals at week 24.

Alirocumab also significantly reduced levels of Apo B, total cholesterol, and Lp(a) versus the overall usual care group and also versus the fenofibrate usual care group, Dr. Del Prato said.

Taking the two studies together, he concluded: “These data support alirocumab as a treatment option in people with diabetes mellitus and hypercholesterolemia despite maximally tolerated statins,” Dr. Del Prato said.

Will the lipid-benefits translate into improved cardiovascular outcomes?

The question now is whether the lipid-lowering effects of alirocumab in patients with diabetes will translate into improved cardiovascular outcomes in patients with diabetes.

The results of the ODYSSEY OUTCOMES trial, which is evaluating cardiovascular outcomes during treatment with alirocumab after an acute coronary syndrome, are expected next year. While the trial is not being conducted specifically in patients with diabetes, it is expected that there will be subpopulations of T1DM and T2DM patients included.

Cardiovascular outcomes data on the PCSK9 inhibitor, evolocumab (Repatha, Amgen) in the FOURIER trial were published in March ( N Engl J Med 2017;376:1713-22 ) and provide some evidence that a reduction in major cardiovascular events may be possible with these agents.

Providing independent comment on the study, Angelo Avogaro, MD, of the University of Padova, Italy, said that the additional LDL-C lowering effect of alirocumab on top of statins could theoretically halve the projected 10-year risk of cardiovascular disease using data from the two ODYSSEY studies and the UKPDS Risk Engine . Using a baseline 10-year cardiovascular risk of around 26%-28%, this could be reduced to 11%-13%, he suggested.

Of note, Dr. Avogaro said, was that, at baseline, not all patients were on high intensity statins, the majority received moderate doses, with a good number of patients taking none or who were intolerant to statins included. “This, I like,” he observed.

A reassuring point was that there was no signal of having a detrimental effect on neurocognitive dysfunction, Dr. Avogaro observed, which concurs with recent data published on evolocumab ( N Engl J Med 2017; 377:633-43 ).

Nevertheless, longer-follow-up is needed to examine adverse effects, “especially in those insulin-treated patients experiencing severe hypoglycemic reactions.”

The ODYSSEY DM studies were funded by Sanofi and Regeneron Pharmaceuticals.

Dr. Colhoun has received research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Pfizer, Regeneron Pharmaceuticals, Roche Pharmaceuticals, and Sanofi. She has also been a consultant for Eli Lilly, Regeneron Pharmaceuticals, and Sanofi.

Dr. Del Prato has received research funding from AstraZeneca, Boehringer Ingelheim, Novartis, Merck Sharpe & Dohme, and Novo Nordisk. He is a consultant for or has received honoraria from the preceding companies, as well as from Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Laboratoires Servier, Sanofi-Aventis, and Takeda Pharmaceuticals.

Dr. Angelo Avogaro was the independent commentator selected by the EASD Scientific Committee. He disclosed receiving honoraria from Amgen and Sanofi.