Marlene Busko

September 19, 2017

LISBON, PORTUGAL — In patients with atherosclerotic cardiovascular disease and blood lipid levels that were inadequately controlled with a statin, the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) did not worsen diabetes or increase the odds of developing diabetes within 2 years, in a prespecified analysis of the FOURIER study.

Compared with placebo, evolocumab reduced the risk of the primary composite outcome of cardiovascular death, myocardial infarction (MI), stroke, hospital admission for unstable angina, or coronary revascularization during follow-up by 17% in the patients with diabetes and by 13% in patients without diabetes, according to these latest data, reported at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting last week.

"What we've shown here is that evolocumab results in additional cardiovascular benefit [and] is a good treatment option in patients with diabetes who can't achieve target," second author Lawrence A Leiter, MD, University of Toronto, Ontario, told Medscape Medical News.

Importantly, "as typically used, as an add-on to statin, evolocumab was not associated with an increased risk for diabetes."

The new analysis, with lead author Marc S Sabatine, MD, Harvard Medical School, Boston, Massachusetts, was simultaneously published in Lancet Diabetes and Endocrinology.

The takeaway message is that for diabetic patients, as for other patients with atherosclerotic disease, "the lower the LDL cholesterol, the better," and "there is no apparent sign for any increased signal of safety, especially with diabetes induction for prediabetic patients," assigned commenter Alberico L Catapano, PhD, University of Milan, Italy, told Medscape Medical News.

Similarly, in an accompanying editorial, Luca A Lotta, MD, PhD, and Prof Simon J Griffin from the University of Cambridge, United Kingdom, write: "These data from FOURIER suggest that evolocumab is an effective and safe option for patients with diabetes and atherosclerotic disease."

But cost and access remain issues, they stress.

Does Evolocumab Increase Risk of Diabetes?

Dr Sabatine and colleagues aimed to determine the safety and efficacy of evolocumab in patients with and without diabetes in the large FOURIER trial.

As reported previously in March, FOURIER randomized 27,564 patients who were 40 to 85 years old and had established cardiovascular disease (prior MI or stroke or symptomatic peripheral arterial disease) and LDL cholesterol > 1.8 mmol or non-HDL cholesterol > 2.6 mmol/L to receive either placebo injections or evolocumab injections (140 mg every 2 weeks or 420 mg once a month, depending on patient preference).

A total of 40% of the patients in FOURIER had diabetes (defined as HbA1c > 6.5% or fasting plasma glucose > 126 mg/dL), which was mainly diagnosed by patient history (91%) and less often by baseline blood tests or review of records (9%).

Among the 60% of patients without diabetes, 38% of patients had prediabetes (HbA1c 5.7%–6.4% or fasting plasma glucose 100 to 125 mg/dL) and 22% of patients had normal blood glucose levels.

The patients, whether with or without diabetes, had similar baseline characteristics, with a mean age of 63, and about a quarter were female

Patients with diabetes had had it for a median of 5.7 years and 25% were taking insulin.

During a median 2.2-years of follow-up, the risk of cardiovascular death, MI, stroke, hospital admission for unstable angina, or coronary revascularization was lower in patients taking evolocumab, including patients with diabetes (HR, 0.83; = .0008) and patients without diabetes (HR, 0.87; = .0052).

For the triple end point of risk of cardiovascular death, MI, and stroke, the HRs were 0.82 (= .0021) for those with diabetes taking evolocumab and 0.78 (= .0002) for those without diabetes, compared with the placebo groups.

Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR, 1.05), including in those with prediabetes (HR, 1.00).

HbA1c and fasting plasma glucose levels were similar in patients receiving evolocumab or placebo.

"These results reassure us that PCSK9 inhibition is unlikely to have a major effect on diabetes risk," say Drs Lotta and Griffin in their editorial.

Among patients with diabetes at baseline, 79% of patients in the evolocumab group and in the placebo group had adverse events. Similarly, among patients without diabetes at baseline, 77%% of patients in each group had adverse events. Evolocumab did not affect body weight.

Cost and Access Remain Issues

Dr Sabatine and colleagues suggest that use of evolocumab in patients with atherosclerotic CVD and diabetes might be "particularly attractive from a cost-effectiveness standpoint."

"The number needed to treat with evolocumab over 3 years to prevent one primary-end-point event was 62 in patients without diabetes, but only 37 in patients with diabetes," they write.

"If PCSK9 inhibitors or other emerging therapies have few adverse effects, including a minimal effect on diabetes risk, such findings [as those in the current study] might influence prescribing decisions," according to the editorialists.

However, cost remains a big issue, and use of these agents varies widely in different geographic areas, they note.

Dr Leiter agreed that "cost and access remain issues with PCSK9 inhibitors, which vary somewhat geographically."

In North America, the indication for use of PCSK9 inhibitors "is limited to people with either the genetic familial hypercholesterolemia or known cardiovascular disease."

So people with diabetes without known heart disease are not eligible for PCSK9 inhibitors in North America, whereas the European indication is "much broader and includes all at-risk patients with elevated LDL levels or mixed dyslipidemia," Dr Leiter noted.

But even within Europe, access and coverage vary widely.

In England, for example, it is very difficult to get PCSK9 inhibitors reimbursed, whereas in Italy or the Netherlands, "reimbursement is much larger in terms of patient population being treated," according to Dr Catapano.

"In view of their high costs, access to PCSK9 inhibitors is likely to remain limited for the vast majority of the half a billion people with type 2 diabetes worldwide for the foreseeable future," Drs Lotta and Griffin conclude in their editorial.

More Insight to Come from ODYSSEY Outcomes Trial

The ongoing study with a different PCSK9 inhibitor, alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals), ODYSSEY Outcomes, in "a somewhat different patient population, taking patients post–acute coronary syndrome," will have results likely next spring, Dr Leiter said.

"It will have 18,000 patients and about a quarter have diabetes, so we're going to get a lot more data on the value of PCSK9 inhibitors."

The study was funded by Amgen. Dr Sabatine reports research grant support (through Brigham and Women's Hospital) from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, Intarcia, Janssen Research and Development, the Medicines Company, MedImmune, Merck, Novartis, Poxel, Pfizer, Roche Diagnostics, and Takeda and honoraria for consulting from Alnylam, Amgen, AstraZeneca, Cubist, CVS Caremark, Esperion, Intarcia, Ionis, Janssen Research and Development, the Medicines Company, MedImmune, Merck, and MyoKardia. Dr Leiter has received research grant support (through St Michael's Hospital) from Amgen, Eli Lilly, Merck, Pfizer, Regeneron/Sanofi, and the Medicines Company and personal fees for consulting and providing continuing medical education (CME) on behalf of Amgen, Eli Lilly, Esperion, Kowa, Merck, Regeneron/Sanofi, and the Medicines Company. Disclosures for the coauthors are listed in the paper. Griffin receives an honorarium and reimbursement of travel expenses from Eli Lilly associated with membership of an independent data monitoring committee for a randomized cardiovascular-end-point trial of a glucose-lowering drug. He received honoraria from Janssen for speaking at an educational meeting in 2015 and from AstraZeneca for speaking at an educational meeting in 2017. Lotta declares no relevant financial relationships.   

Lancet Diabetes Endocrinol. Published online September 14, 2017. Abstract, Editorial

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