PCSK9 Inhibitors More Cost-Effective in Diabetes Patients?

Lisa Nainggolan and Becky McCall

June 26, 2018

ORLANDO — When looking at absolute risk reduction, new results from ODYSSEY Outcomes suggest that the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab (Praluent, Sanofi/Regeneron) may reduce the risk of future cardiac events in patients with diabetes and prior acute coronary syndrome (ACS) by more than double that of similar patients with prediabetes or normoglycemia.

Dr Kausik Ray

However, no difference was seen in relative risk reduction when patients with different glycemic status were compared, said Kausik Ray, MD, MBChB, from Imperial College, London, UK, a trial co-investigator who presented the results from the late-breaking poster in a press conference here at the American Diabetes Association (ADA) 2018 Scientific Sessions.    

"In this high-risk population with low-density lipoprotein cholesterol [LDL-C] levels above 70 mg/dL, the guidelines suggest an LDL-C goal of around 55 mg/dL. These data suggest that moving that goal to 25–50 mg/dL would give a bigger absolute benefit in these patients [with diabetes] even though the relative risk remains constant," explained Ray.

"This absolute benefit is statistically...significant, and twice as large in the patients [with diabetes] compared to patients with normal glycemia," he noted.

Commentators welcomed further details on this newer class of injectable lipid-lowering drugs. Although one saw the findings in a somewhat positive light, indicating the number needed to treat to prevent one event in patients with diabetes would be lower than in the overall population, theoretically making it more cost-effective in this patient group, another said he didn't feel these data really change anything.

Importantly however, the new subgroup analysis still needs to be considered in light of the very high cost of PCSK9 inhibitors, they stressed, which means they will remain, for the time being, out of reach for many.

Costs Per Event Prevented "Remain the Major Barrier"

John Mandrola, MD, a cardiologist from Baptist Health Louisville, Kentucky, who also blogs for theheart.org | Medscape Cardiology, said in an email that the results are, "neither bad nor good news for the drug, but just suggest there are no heterogeneous treatment effects."

This is in contrast to ezetimibe, "with which there seemed to be more major adverse cardiovascular event [MACE] reduction in patients with diabetes," he noted, "but we don't see that here."

"Alirocumab reduces events in patients with diabetes to the same degree as in others — neither more nor less."

Mandrola says the greater reduction in absolute risk reduction in patients with diabetes "is to be expected. That's because the number of events is higher — patients with diabetes are higher risk."

"I think this analysis changes little surrounding the decision to use these drugs. Costs per event prevented remain the major barrier," he emphasized. 

Darren McGuire, MD, a cardiologist from UT SouthWestern Medical Center, Dallas, Texas, who specializes in the treatment of diabetes, believes the new analysis shifts the needle a little bit in favor of patients with diabetes.

"While there is no difference in the relative risk reduction when the cohort is stratified by glucometabolic status, there is higher absolute risk in the patients with diabetes and this yields a larger absolute risk reduction in this group," he said.

"These data support the notion that the therapy [alirocumab] would be more cost-effective in patients with, compared to without, diabetes," McGuire told Medscape Medical News.

For those with diabetes, 43 patients would need to be treated for 2 years to prevent one MACE, while in the other subgroups, that number is 83, according to these presented results, McGuire estimates.

But he doesn't dispute the fact that the current price of these agents remains a significant barrier to use.

"By 'back of the envelope' estimates, at least in United States, at present pricing somewhere between $10,000 and $14,000 per year, this still ranges from $200,000 to $300,000 annualized to prevent one event over 2 years. This financial limitation, even in the highest risk patients with the lowest number needed to treat, remains a serious roadblock to applying these data to contemporary clinical care," he commented.

Sanofi and Regeneron have recently announced that they will lower the net price of alirocumab in the United States in exchange for straightforward, more affordable patient access from Express Scripts.

Dr Robert Eckel

Effective July 1, alirocumab will become the exclusive PCSK9 inhibitor therapy on the Express Scripts national formulary, which "significantly simplifies the documentation necessary to secure insurance coverage and may help reduce out-of-pocket costs for eligible patients," say the companies.

When asked how these data might shape decisions in the clinic, press conference moderator Robert Eckel, MD, from the University of Colorado, Aurora, said, "When we look at a clinical trial, we can't subgroup and draw conclusions because the trial was powered for the primary outcome."

But, he added, "I think those with higher LDLs are more likely to receive approval for a prescription for a PCSK9 inhibitor, at least in the United States, and I prescribe whichever drug is approved."

One Third of ODYSSEY Patients Had Diabetes

Data for this latest analysis were drawn from ODYSSEY Outcomes. This trial randomly assigned 18,924 individuals who had had an ACS within the past year and were on maximal-intensity statins and optimal medical therapy, to an alirocumab injection of 75 mg every 2 weeks, increased to 150 mg if the LDL-C goal of 25 to 50 mg/dL was not reached, versus placebo.

At the start, all patients had an LDL-C above 70 mg/dL and non-high-density lipoprotein cholesterol (HDL-C) above 100 mg/dL. The primary endpoint was length of time to first MACE.

The main results were reported at the American College of Cardiology (ACC) 2018 Annual Scientific Session in March and provided the first evidence of a survival advantage for this pricey class of drugs, at least in this patient population who had had an ACS and high cholesterol despite maximal statin therapy. The earlier FOURIER trial with the competitor evolocumab (Repatha, Amgen) had studied a less risky patient population.

Ray presented the ODYSSEY Outcomes data, stratified by baseline glycemic status as well as HbA1c levels over the trial. Of study participants, 5444 (28.8%) had diabetes, 8246 (43.6%) had prediabetes, and 5234 (27.7%) had normal glucose levels.

"In patients with ACS, around a third have diabetes and another third have prediabetes, so metabolic abnormality is common," said Ray.

"Patients with diabetes who have had a heart attack have a very high absolute risk, and data suggest that high-intensity statin versus low-intensity statin can lead to a greater absolute benefit."

MACE event rates increased across the subgroups from normoglycemia to prediabetes to diabetes at 7.3%, 8.0%, and 14.1% for patients taking alirocumab, and 8.5%, 9.2%, and 16.4% for patients taking placebo, respectively, showing a higher event rate in patients with diabetes.

"The overall treatment effect for MACE over 30 months is a 15% risk relative reduction and the benefit between the three groups was found to be constant," said Ray.

"However...you see a much bigger absolute benefit in people with diabetes that is twice as large as in the other two groups with a significant interaction," he reiterated.

"The reason we see the bigger absolute treatment effect is not driven by the baseline LDL-C level but by the fact they have diabetes and their experience of ACS."

"In a population with diabetes and ACS where LDL-C is > 60 mg/dL and you maximize your high-intensity statin, your current treatment options are to add in ezetimibe, or based on the data, to get a bigger absolute benefit use this [alirocumab]," he ventured. 

Safety Reassuring but Follow-Up Still Relatively Short

Some prior studies have suggested lowering LDL-C with a PCSK9 inhibitor might convert patients with prediabetes to diabetes, Ray said.

But they saw no evidence of increased fasting glucose or HbA1c in those without diabetes at baseline taking alirocumab compared with placebo. Nor was there any overall increase in new-onset diabetes with active drug compared with placebo.

Mandrola said the results with regard to new-onset diabetes "are somewhat reassuring, but follow-up of 34 months is quite short."

"There is still concern about yet-to-be discovered adverse events of these highly potent drugs," he added.

Ray has served as a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Esperion Therapeutics, Kowa Pharmaceuticals America, Merck Sharp & Dohme, Novo Nordisk, Pfizer, Regeneron, Sanofi, The Medicines Company. He has received research support from Amgen, Merck Sharp & Dohme, Pfizer, Regeneron and Sanofi. McGuire has served as clinical trial leadership for AstraZeneca, sanofi-aventis, Ortho-McNeil-Janssen, Boehringer Ingelheim, Merck, Novo Nordisk, Lexicon Pharmaceuticals, Eisai, GlaxoSmithKline, Esperion Therapeutics. He has served as a consultant for AstraZeneca, sanofi-aventis, Eli Lilly, Boehringer Ingelheim, Merck, Pfizer, and Novo Nordisk. Mandrola has reported no relevant financial relationships. 

American Diabetes Association 2018 Scientific Sessions. June 25, 2018; Orlando, Florida. Abstract 6-LB.

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