Better control of hypercholesterolemia: a new LDL cholesterol treatment that is well tolerated but with gender differences in efficacy!

How can we better treat hypercholesterolemia in 2023?
For the treatment of excess cholesterol in the blood, the most effective medication available until now has been statins, which reduce the amount of cholesterol produced by the liver (up to 80%), and can be combined with ezetimibe, which reduces digestive absorption (around 20%); the two molecules are often prescribed simultaneously, as they act synergistically, and are also available together in a single tablet. The results are interesting, and this combination can reduce blood cholesterol levels by around 65%.
However, there are a number of patients for whom the ideal LDL cholesterol value (LDL-c = bad cholesterol) is not reached; some have poor tolerance to statins and do not receive the highest dosage, and others have a genetic form: Familial Hypercholesterolemia (HF) in which a gene mutation leads to very high levels and a very poor response to treatment.
For this reason, "anti-PCSK9 monoclonal antibodies" have been developed, and deserve some explanation:
Circulating cholesterol is captured by specific receptors in the liver, enabling it to be incorporated and recycled. These receptors are regulated by a protein called PCSK9, which is involved in their degradation. An antibody is a molecule specifically directed against a particular substance called an antigen, and its binding neutralizes the function of this antigen. We all have antibodies which protect us from infection, or sometimes attack a part of the body, as in autoimmune diseases with autoantibodies.
In this case, the antigen is represented by the PCSK9 protein linked to LDL-c receptors.
The antibody (called "monoclonal" because it is derived from a single cell that has been cloned and duplicated), by reducing the destruction of these receptors, increases their number on the surface of the liver, thereby significantly increasing cholesterol uptake and leading to a collapse in circulating cholesterol.


Given the nature of these products, their cost is high (considered prohibitive by some) and their prescription is very restricted, particularly in France. The indications treated are rare genetic forms, patients who have suffered a cardiovascular accident (secondary prevention) and whose cholesterol levels remain too high despite taking the maximum-dose statin, which must be combined with ezetimibe, and, more recently, patients with proven statin intolerance.
Once prescribed, this 3-molecule treatment delivers remarkable results on LDL-c levels, with a reduction of at least 85% and a very favorable safety profile.
The only drawback is that subcutaneous injections are required every 15 days or every month (soon every 6 months, and perhaps in tablet form).
These data on efficacy and tolerability come from therapeutic trials in which patients are largely "selected" to obtain the most favourable possible outcome. Available data suggest that the reduction in LDL-c is lower in women than in men for the same dose administered, without it being clear why: different metabolism, as has been proven for statins? Generally speaking, it is always important to look at what happens in "real life", where all patients are treated, and such real-life data are rare, hence the value of follow-up registries.

A recent study on the differing efficacy and tolerability of new anti-PCSK9 treatments
Dutch researchers studied the outcome of patients with hypercholesterolemia, followed up in a department specializing in this management with the aim of assessing gender differences in the efficacy and safety of anti-PCSK9 antibodies.
All patients starting treatment with one of the 2 products used were included in a so-called prospective registry, i.e. all patients will be followed a priori for their results on mean LDL-c levels at baseline and during treatment. In addition, side effects and treatment discontinuations will be recorded.

In terms of results, 436 patients were studied, including 209 women with an average age of 58. Women had higher baseline LDL-c levels than men (1.82 g/l versus 1.59 g/l). Anti-PCSK9 antibodies resulted in a smaller reduction in LDL-c in women than in men: 50% versus 61% initially. This difference reduced slightly over time, but persisted at 1 and 2 years.
Logically, women were less likely than men to reach their LDL-c target levels (the recommended values): 50% versus 72%. There was no difference between the sexes in terms of side effects or treatment discontinuation (13% in women, 10% in men). This result on the tolerability of anti-PCSK9 is interesting, as women generally tolerate satins and ezetimibe less well than men.
In summary, in clinical practice, anti-PCSK9 antibodies are less effective in reducing LDL-c levels in women than in men, and just as safe, implying the importance of gender differences in the use of this treatment.

Comment:
Once again, women are different from men... This is about the efficacy of a major treatment in cardiovascular risk reduction, and women seem to be at a disadvantage. The question is whether this 10% difference in risk reduction makes sense. The answer is yes, because risk reduction is directly proportional to LDL-c reduction. In practice, does 10% less reduction correspond to 10% more accidents? This seems plausible. The problem, then, is that gender differences are not taken into account in the objectives to be achieved with identical recommendations. What's needed - and this has become a classic - are studies carried out specifically on women, in order to determine what is most appropriate in terms of treatment dosage. It's never just a question of personalizing a treatment with tailor-made adaptation. To do this, however, you need to have the necessary data, which the data from classic studies with two subgroups of men and women have difficulty capturing.

Reference
A.M.H Galema-Boers et al. Sex differences in efficacy and safety of PCSK9 monoclonal antibodies: A real-world registry. Atherosclerosis March 28 2023