Editor's Corner | LDL-C and Coronary Disease: Enigmatic Partners

Much of the attention at ACC.18 was focused on the effects of PCSK9 inhibition in patients with coronary artery disease. Clinical studies have hypothesized that we could reduce the incidence of coronary events by lowering LDL-C with a drug that blocks PCSK9, an enzyme that’s involved in the degradation of LDL receptors in the liver. By blocking the PCSK9 activity with monoclonal antibodies, degradation of LDL receptors is reduced and LDL receptors increase in number. This, in turn, increases the clearance of LDL-C.

Theoretically, inhibition of PCSK9 should result in a reduction in LDL-C. Indeed, initial studies showed a potent effect on the lowering of LDL-C with PCSK9 inhibitors — to levels difficult to achieve with statin therapy. The therapeutic assumption is that the reduction in LDL-C would bring with it a reduction in coronary disease events.

Two cardiovascular outcomes trials — FOURIER presented at ACC.17 and ODYSSEY Outcomes presented at ACC.18 — have provided results that raise some questions for us related to this therapeutic assumption and what may be appropriate for clinical practice.

The FOURIER investigators designed a trial that was adequately powered to answer the question of whether mortality or coronary events were decreased by PCSK9 inhibition in patients with stable coronary disease.1 Their data showed a significant reduction in coronary events with evolocumab over the mean 2.2 years of follow-up. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction (MI), stroke, hospitalization for unstable angina or coronary revascularization.

At about one year, the reduction in LDL-C levels with evolocumab, compared with placebo, was 59 percent from a median baseline value of 92 mg/dL to 30 mg/dL (p<0.001). Evolocumab treatment significantly reduced the risk of the primary endpoint from 11.3 percent to 9.8 percent. The secondary endpoint of cardiovascular death, MI or stroke was reduced from 7.4 percent to 5.9 percent. These positive results included the patients in the lowest quartile for baseline LDL-C (median, 74 mg/dL).

Importantly, in FOURIER, safety outcomes (including new-onset diabetes and neurocognitive events) showed no significant difference between the study groups. Not surprisingly, injection-site reactions were more common with evolocumab (2.1 vs. 1.6 percent).

Because the absolute reduction in primary endpoint events was small (1.5 percent) in FOURIER, many questioned the impact of the small change in a real-world clinical practice in light of the high cost of the drug. Like many trials, there’s likely to be a subset of patients who would gain more than others and subsequent analyses should identify those who would benefit most from evolocumab.

The ODYSSEY Outcomes trial demonstrated a similar reduction in LDL-C with another PCSK9 inhibitor — alirocumab. In patients who had an acute coronary syndrome within the previous year, the trial showed a significant 15 percent reduction in the primary endpoint (combination of MI, stroke, death from coronary heart disease or unstable angina requiring hospitalization) over the mean 2.8 years of follow-up. There were no safety signals.

But the absolute reduction in the primary endpoint in ODYSSEY Outcomes, as in FOURIER, was small. There was only a 1.6 percent absolute reduction (from 11.1 percent with placebo to 9.5 percent with alirocumab) in the incidence of recurrent heart attack, stroke, heart-related death or serious chest pain. Other components of the endpoint were also significantly lower with alirocumab than with placebo, respectively: nonfatal MI 6.6 vs. 7.6 percent; ischemic stroke 1.2 vs. 1.6 percent; and unstable angina 0.4 vs. 0.6 percent. Coronary heart disease mortality, however, was similar in the two groups at 2.2 percent.

The absolute reduction in the primary endpoint in ODYSSEY Outcomes, as in FOURIER, was small.

In ODYSSEY Outcomes, the greatest benefit — a 24 percent improvement in the primary composite endpoint — was found in patients with a baseline LDL-C ≥100 mg/dL. This finding came from a post hoc analysis of prespecified baseline LDL-C subgroups.

However, outcomes were not different in patients with lower baseline LDL-C values in the alirocumab arm compared with control patients. Why would this be? One answer is that treatment with alirocumab in ODYSSEY Outcomes was designed to be closely aligned with “clinical practice.” Treatment with alirocumab varied! The drug dose was reduced if the LDL-C dropped to extremely low levels. In fact, mean LDL-C levels in ODYSSEY Outcomes were 53 mg/dL.

Many lipidologists think the lower the LDL-C, the better the outcomes. Perhaps patients who entered the trial with LDL-C below 100 mg/dL were not treated as aggressively if their LDL-C dropped after initiating treatment to levels that might be considered clinically worrisome. Could it be that these patients would have had even greater benefit and greater differences from controls if their treatment had not been adjusted?

Another issue is that both FOURIER and ODDYSSEY Outcomes are not long-term trials — especially in the context of the natural history of coronary artery disease. Outcome curves in ODYSSEY Outcomes diverged after one year. It likely takes that long for the drug to begin to show mortality benefit. Longer term outcomes might be striking. These of course are speculations.

Looking at both FOURIER and ODYSSEY Outcomes, for patients with LDL-C levels in the range of 100 mg/dL, we see an absolute improvement between 1.5 percent and 1.6 percent for those with chronic stable coronary disease and those with an acute coronary syndrome.

The data from both trials leave the clinician with an incentive to lower lipids with conventional oral therapy to minimize the cost of treatment. And to only consider using a PCSK9 inhibitor in patients with high LDL-C, at levels often found in patients with familial hyperlipidemia. Use of statins and ezetimibe to achieve LDL-C levels in the 50 to 70 mg/dL range might be adequate therapy for most patients.

Will the small incremental benefits of PCSK9 inhibitors lead to an increase in use of either drug? Both drugs come with a high price tag — usually more than $10,000 a year for the patient’s co-payment. Insurance companies have not embraced PCSK9 inhibitors for reimbursement and physicians consistently find it difficult to obtain approval of these drugs even for their high-risk patients. The results of ODYSSEY Outcomes will likely not alter this dynamic. Analyses of their cost effectiveness may result in a lowering of their cost for certain high-risk patients and guidelines for identifying the highest risk patients who might be eligible for discounts will likely appear in the future.

Finally, it’s clear that LDL-C is not the whole story in lowering the incidence of coronary disease. Similar clinical outcomes were achieved with anti-inflammatory therapy — without lowering LDL-C — with the monoclonal antibody canakinumab in the CANTOS trial.2

Efforts to encourage continuous adherence to all the therapies we have at our disposal is essential to achieve desirable therapeutic outcomes. Remember that in both FOURIER and ODYSSEY Outcomes patients were first treated with “standard” statins. This is always a good first step. Programs to encourage compliance with the lipid-lowering drugs should be an integral part of therapy to achieve optimal lipid levels.


  1. Sabatine MS, Giugliano RP, Keech AC, et al. N Engl J Med 2017;376:1713-22.
  2. Ridker PM, Everett BM, Thuren T, et al. N Engl J Med 2017;377:1119-31.

Keywords: ACC Publications, Cardiology Magazine, ACC18, ACC Annual Scientific Session, Antibodies, Monoclonal, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Acute Coronary Syndrome, Receptors, LDL, Incidence, Motivation, Lipids, Cost-Benefit Analysis, Research Personnel, Coronary Vessels, Follow-Up Studies, Brain Ischemia, Stroke, Antibodies, Monoclonal, Angina, Unstable, Myocardial Infarction, Coronary Disease, Hospitalization, Diabetes Mellitus, Liver, Hyperlipidemias

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