The lower, the better? - Extremely low LDL values in CHD prevention

One study provides answers to optimal LDL values

With the availability of the new PCSK9 inhibitors Alirocumab and Evolocumab, LDL values can be reduced to below 20 mg/dl for the first time. What is the advantage of such low values? Are patients at risk? A new study provides information.

It is undisputed that the so-called "bad" LDL cholesterol (low-density lipoprotein cholesterol) plays a decisive role in the development of arteriosclerosis. Many studies have impressively shown that the cardiovascular risk decreases linearly with decreasing LDL levels in the blood. But up to what values can an LDL reduction still be justified in terms of the benefits and side effects achieved? This question takes on a completely new meaning against the background of the approval of protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Extremely low LDL values are no longer a rarity even in clinical routine. So far, no study has really taken up the subject, often because patients hardly ever achieved such values.

Subgroup analysis of the FOURIER study

With the new data from the FOURIER study (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), this is now possible for the first time. For your information: In the FOURIER study, approximately 27,000 patients with known cardiovascular disease were randomized to the PCSK9 inhibitor evolocumab or to a double-blind placebo and observed over a little more than two years. Evolocumab reduced LDL cholesterol by approximately 60% and reduced the risk of cardiovascular events by 20% (endpoint of cardiovascular death, heart attack, stroke). The FOURIER data were used as a basis for a subgroup analysis and the subjects were divided into five groups according to their LDL values achieved after four weeks. 10% of the subjects had an LDL below 20 mg/dl, 31% an LDL of 20 to 50 mg/dl, 13% an LDL of 50 to 70 mg/dl, 29% achieved an LDL of 70 to 100 mg/dl and 17% had an LDL above 100 mg/dl.

Linear risk reduction even with LDL values below 20 mg/dl

The evaluation showed that the risk of cardiovascular death, heart attack or stroke, decreases linearly with decreasing LDL cholesterol - even at extremely low LDL levels. For example, the group with the lowest LDL values (below 20 mg/dl) had a 31% lower risk compared to the group with the highest LDL values (above 100 mg/dl). A post hoc analysis of patients with even lower LDL values below 10 mg/dl even showed a risk reduction of 41%.

Extremely low LDL levels without side effects

But can such low LDL levels endanger health? The authors of the study found no evidence of this. It was found that the side effects observed in the FOURIER study were independent of the level of LDL in the blood. In particular, there was no clear evidence of cognitive deficits at extremely low LDL (p = 0.15). This was confirmed once again by the analysis of approximately 1100 patients who participated in the EBBINGHAUS substudy and underwent several special neurocognitive tests.

The motto "the lower the better" applies

Overall, the authors believe that the known linear correlation between LDL and cardiovascular risk continues even at extremely low LDL levels without reaching a plateau. The data presented here fits into the well-known trend and extends the often cited motto "the lower the better" in this context to LDL ranges beyond 50 mg/dl. Clinical data is also supported by imaging data. For example, the GLAGOV study presented in 2016 showed that with LDL levels falling to 20 mg/dl, the volume of coronary arteriosclerotic plaques also decreased.

Long-term effects not known

Moreover, the low LDL values do not seem to harm the body, at least not after about two years. Nothing is yet known about long-term effects. LDL values below 20 mg/dl are naturally extremely rare in humans. The only known fact is that patients with a missense mutation in the PCSK9 gene often have life-long values of around 50 mg/dl. In any case, there were no health impairments here.

1. Giugliano RP et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017; 390: 1962-71st Published Online August 28, 2017, S0140-6736(17)32290-0
2. Cohen JC et al. Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease. March 23, 2006 N Engl J Med 2006; 354:1264-1272 DOI: 10.1056/NEJMoa054013

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