Advances in LDL Cholesterol Management for Familial Hypercholesterolemia: From Statins to Innovative PCSK9 and CETP Inhibitors

While the arrival of PCSK9 inhibitors has changed the paradigm in the control and reduction of LDL cholesterol in patients with familial hypercholesterolemia ( FH ), new clinical studies anticipate that the therapeutic arsenal will expand with other types of antibodies that inhibit this protein or others whose therapeutic target is CEPT inhibition.

However, these innovations will coexist with the gold standard treatment for regulating cholesterol levels, statins, which, according to the specialists gathered during the 11th Symposium on Familial Hypercholesterolemia, organized by the Familial Hypercholesterolemia Foundation ( FHF ), continue to demonstrate safety and efficacy.

Expanding treatment options for LDL Cholesterol with PCSK9 and CETP inhibitors alongside proven statin therapy

The greater variety of pharmacological options for people with this pathology is in line with the motto that accompanies this annual meeting: ‘The value of data in Personalized Medicine’ , one of whose tables has focused on the future horizons for the treatment of LDL cholesterol.

Regarding statins, Dr. Francisco Javier Carrasco, from the Juan Ramón Jiménez University Hospital (Huelva), highlights the real-world results obtained in studies with inclisiran, a drug that he acknowledges is usually funded “relatively easily.”

He concludes that it is “effective and safe” based on the evidence obtained, achieving a 63% reduction in LDL levels in patients on baseline statin therapy, and reaching a “significant reduction” in all subgroups evaluated. Similarly, in patients with familial hypercholesterolemia, the reduction when administering combination statin therapy was less than 70 mg/dL.

While statins are one option, PCSK9 inhibitors have “changed the paradigm ,” continues Dr. José López Miranda , Reina Sofía University Hospital (Cordoba).

The average reductions in LDL-c levels with innovative drugs, such as PCSK9 inhibitors or CETP, are greater than 50%

With the goal of achieving the lowest possible LDL levels for patients to “have a normal life expectancy, just like the general population,” the specialist analyzes the results of the Vesalius-CV study with evolocumab (and placebo arm).

The antibody achieved a 55% reduction compared to previous LDL levels, with overall reductions of 36% in the probability of suffering a first event; 21% in cardiovascular mortality and 20% in death from any cause.

In this new scenario, oral PCSK9 inhibitors are also being used. Dr. Luis Beltrán, from the Virgen del Rocío University Hospital (Seville), highlights their innovative nature and the improved results they are showing due to the increasing number of patients (in studies such as Safeheart ). Among the administered molecules, enlicitide decanoate is the best positioned, already in phase III; while laroprovstat is in phase II.

Following a review, Dr. Beltrán concludes that, regardless of the specific circumstances, oral PCSK9 inhibitors “represent a new tool in the therapeutic arsenal applicable to patients with familial hypercholesterolemia .” In this regard, enlicitide has demonstrated sustained LDL reductions of between 53% and 60% over one year, and this is further supported by specific data from patients with hereditary familial hypercholesterolemia.

Similar data is shown by laroprovstat, with reductions of 51% at 12 weeks, and a phase III study (Azure) is already underway that will include patients with hereditary familial hypercholesterolemia.

One of the key findings for Dr. Beltrán is that both drugs are achieving high adherence . However, he points out that the most critical evidence —data on the reduction of cardiovascular events—is still lacking.

A decade of innovation

The specialists, gathered at a table moderated by Drs. Raimundo de Andrés , from the Jiménez Díaz Foundation (Madrid), and Miguel Ángel Barba, from the University Hospital of Albacete, also analyzed some drugs whose therapeutic target is not new, but in which promising results are being obtained.

As Dr. Francisco J. Fuentes of the Reina Sofía University Hospital (Córdoba) observes, CETP inhibitors are entering a new phase with the development of obicetrapib, a “drug different from previous ones, with promising clinical development and very promising results that I believe will have significant applications in familial hypercholesterolemia and severe forms” of this disease. This drug achieves 98% inhibition of CETP protein activity with a daily dose of 10 mg.

The reductions translate to a 45% decrease in LDL levels , sustained over time. However, research is underway to confirm the tolerability, efficacy, and safety profile of this molecule in patients with this condition.

In this regard, other studies have focused on analyzing how it reduces cardiovascular events, concluding that it effectively lowers the likelihood of experiencing one. However, Dr. Fuentes notes that there is a “robust clinical program” of phase III trials with obicetrapib underway, including the Broadway, Brooklyn, Prevail, Tandem, and Rembrandt studies.

The specialist is confident that this drug will help “certain patients through its LDL receptor-independent mechanism,” and therefore ventures that obicetrapib “will probably play a very interesting role” in enabling a new personalized therapeutic option.

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