'Double Whammy': Where do PCSK9 Inhibitors Fit for Diabetes/ACS?

Marlene Busko

July 12, 2019

Newly published results indicate that the injectable PCSK9 inhibitor alirocumab (Praluent, Sanofi/Regeneron) was more cost-effective in patients with a recent acute coronary syndrome (ACS) and uncontrolled 'bad' low-density lipoprotein cholesterol (LDL-C) (despite statins) if they also had diabetes.

The findings, from a prespecified analysis of the ODYSSEY OUTCOMES trial, were published online July 1 in the Lancet Diabetes & Endocrinology by lead author Kausik K. Ray, MD, MBChB, Imperial College, London, UK.

When results of the analysis were first reported by Ray at the American Diabetes Association (ADA) 2018 Scientific Sessions, the cost of the injectable drug was a major concern, as a year's supply was $14,000 at that time in the United States.

However, alirocumab and a competitor PCSK9 inhibitor evolocumab (Repatha, Amgen) both cost about $5800 a year now, which by back of the envelope estimates still means an annual cost of around $125,000 to prevent one event over 2 years.

And although expensive, the cost is covered by insurance for certain appropriate candidates, explained Amit Khera, MD, director, Preventive Cardiology Program, UT Southwestern Medical Center, Dallas, Texas, who was not involved in the study.

So finding the groups of patients who will benefit most from these pricy drugs is key, he told Medscape Medical News.

The current results "remind us that patients with diabetes who have ACS" are a high-risk group who have a "double whammy," which makes some of them appropriate candidates for more aggressive LDL-C lowering with PCSK9 inhibitors, added Khera, who is also president of the American Society of Preventive Cardiology.

Statins First, Then Ezetimibe? Or PSCK9 Inhibitors in a Select Few

Frederick J. Raal, PhD, and Farzahna Mohamed, MB, Division of Endocrinology and Metabolism, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa, also agree that this study supports aggressive LDL-C lowering with a PCSK9 inhibitor in patients with both ACS and diabetes.

In an accompanying editorial they write: "The analysis suggests that while we await the results of outcomes studies with...newer agents [such as fibrates, icosapent ethyl, bempedoic acid, and angiopoietin-like 3 inhibitors], we should aim to reduce LDL-C aggressively in people with diabetes, since their absolute cardiovascular (CV) risk is high and there does not seem to be a threshold below which LDL-C lowering is not associated with further CV benefit."

First-line therapy remains a high-intensity statin, with the addition of ezetimibe if necessary, they continue.

After that, "a PCSK9 inhibitor should be considered in patients who are intolerant to statins, those who do not achieve optimal LDL-C concentrations with existing therapy, or in those with progressive atherosclerosis despite this therapy."

Khera agrees that "the take-home [from this study] is we definitely should be aggressive in targeting" low LDL-C in patients with ACS and diabetes and uncontrolled LDL-C.

If such patients are already on a maximal intensity statin and their LDL-C is still above their target level, he said, then this study supports starting additional lipid-lowering therapy.

Although US guidelines recommend giving ezetimibe next, after a statin, the guidelines were written when PCSK9 drugs were more expensive, injectable lipid-lowering therapy was new, and there weren't much data, he explained. 

Still, for most patients, starting ezetimibe first would be reasonable.

But, "You know you're going to get a very modest reduction with ezetimibe — only 20% — and some patients' won't ever achieve a reasonable LDL goal," Khera observed.

"So the higher the LDL-C is, like in those with familial hypercholesterolemia, maybe the more it is reasonable to start with a PCSK9 inhibitor first?" he posited. "They are very unlikely to have sufficient LDL-C lowering with ezetimibe alone. In my opinion, it would be reasonable to start PCSK9 inhibitors first after the statin to not prolong the time it takes to get the LDL-C down."

"This would apply to a small subset of individuals and is outside the guidelines," Khera acknowledged.

He added that, in his opinion, guidelines generally focus on the majority of individuals for whom ezetimibe would be sufficient.

Diabetes Doubles Risk of CV Events

In ODYSSEY OUTCOMES, almost 19,000 patients who had had an ACS within the past year and were on maximal-intensity statins and optimal medical therapy were randomized to an alirocumab injection of 75 mg every 2 weeks, increased to 150 mg if the LDL-C goal of 0.65-1.30 mmol/L (25-50 mg/dL) was not reached, or placebo.

The current prespecified analysis stratified patients by baseline glycemic status. Of the study participants, 5444 (28.8%) had diabetes (the vast majority had type 2 diabetes), 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normal glucose levels.

After 2.8 years, 16.4% of patients with diabetes, 9.2% of patients with prediabetes, and 8.5% of patients with normal glucose had an incident CV event.

There was no difference in the relative risk reduction in CV events observed with alirocumab when the cohort was stratified by glucometabolic status, but because there is a higher absolute risk in patients with diabetes, this yields a larger absolute risk reduction in this group, the researchers observe.

The number needed to treat to prevent one CV event during the 2.8-year follow-up was 43 for people with diabetes versus 82 for people without diabetes.

"Cholesterol-lowering injections, such as alirocumab, are effective but they are expensive," Ray comments in a press release by Imperial College. "So we need to consider targeting them to where they will have the most impact. Diabetes patients make up about one third of all heart attacks and these patients have roughly twice the risk as those without diabetes."

Only a Small Proportion of Study Cohort Received Ezetimibe

In their editorial, Raal and Mohamed note that studies of therapies "aimed at treating other components of diabetic dyslipidemia such as hypertriglyceridemia and low HDL-C have so far been disappointing."

Although icosapent ethyl in the REDUCE-IT trial, as reported by Medscape Medical News, reduced CV events to a similar extent as that achieved with alirocumab in ODYSSEY OUTCOMES — despite no reduction in LDL-C — they point out that this could not be explained by the modest reduction in triglyceride concentrations. So "since many previous trials with n-3 fatty acids have been disappointing, confirmation of these findings with further studies is necessary."

And they note that newer fibrates are under development and the large global CV outcomes study PROMINENT "is being done to assess whether pemafibrate can reduce the risk of cardiovascular disease in high-risk patients with diabetes." However, they stress that because the CV benefit of these drugs "remains unproven, they should not currently be considered for the treatment of diabetic dyslipidemia."

What is important, Khera said, "is not what lipid parameter is in the blood; it's what drugs or therapies have been shown to reduce risk."

"We do have pretty good data for icosapent ethyl from the REDUCE-IT trial, so that is certainly something we're all thinking about," he said. "We know now that statins, ezetimibe, and now PCSK9-inhibitors lower risk" of CV events.

And although a recent study found that low LDL-C levels in patients with diabetes were tied to an increased risk of diabetic neuropathy, Khera noted that this was an observational study with a lot of confounding.

"I wouldn't say [ezetimibe or a PCSK9 inhibitor] is better than the other," he summarized. "Both classes of drugs seem to have enhanced benefit in patients with diabetes."

And Raal and Mohamed do note one limitation of the ODYSSEY OUTCOMES study — the fact that, despite most participants being on high-intensity statin therapy, "only a small proportion were on ezetimibe."

The study was funded by Sanofi and Regeneron. Khera was site principal investigator for ODYSSEY OUTCOMES at UT Southwestern, but turned it over to a colleague in April 2016 because he was working on a guideline. Raal has reported receiving research grants, honoraria, and consulting fees for professional input and lectures from Amgen, Regeneron, Sanofi, and The Medicines Company. Mohamed has reported no relevant financial relationships. Ray has reported receiving personal fees from AbbVie, AstraZeneca, Medco, Resverlogix, Akcea, Boehringer Ingelheim, Novo Nordisk, Takeda, Kowa, Algorithm, Cipla, Cerenis, Dr Reddy's, Lilly, Bayer, and Zuellig Pharma; and research grants and personal fees from Amgen, Sanofi, Regeneron, MSD, and Pfizer. Disclosures for the other authors are listed in the article.

Lancet Diabetes & Endocrinol. Published online July 1, 2019. Abstract, Editorial

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