When deciding to initiate pharmacotherapy in FH (and during its management), it is necessary to at least build upon a basic general framework and recommendations. In accordance with the recommendations of the European Atherosclerosis Society (EAS), Canada, the United Kingdom and the National Lipid Association (NLA) in the USA, we recommend LDL-C target values > 3 mmol / L. In FH patients with high CV risk, we recommend LDL-C > 2.5 mmol / L; and > 1.8 mmol / L is recommended in patients at very high risk. Considering that it is difficult for FH patients to achieve these values, the goal of therapy is a more than 50% reduction of LDL-C.
The foundation of FH therapy is the highest tolerated dose of a statin. Statins also have unequivocal (and the most compelling) data in terms of influencing CVD. The current preferred combination in FH is atorvastatin or rosuvastatin with ezetimibe. However, even this combination dose is often not sufficient enough to come close to target values. Moreover, it should be noted that the highest doses of statins are also accompanied by a higher incidence of adverse effects in many patients, and we must then choose to either lower the dose, or switch to a less effective (but relatively safer) statin (e.g. fluvastatin and pravastatin).
To achieve (the narrowest approximation of) target values for FH, we often use combination therapy. Ezetimibe, which blocks cholesterol absorption in the intestines, is well tolerated and provides an additive (approximately) 20% decrease in LDL-C. It is also used as an option to reduce the dose of the statin in cases where high doses are not tolerated by the patient. Combination therapy with maximum statin dosage and ezetimibe result in as high as a 70% reduction in LDL-C. However, even this may not be sufficient to achieve target values.
In FH, we also use resins (and not only for the above reason). Resins have very strong data from the 1980s, both with respect to how they influence CVD, and their demonstrable regression of atherosclerosis (slowed progression) after therapy. Resin therapy is only problematic in terms of undesirable side effects in the digestive tract (persistent constipation), which sometimes makes resin administration virtually impossible. In truth, however, significantly improved patient compliance can be achieved at specialized centers after patients are given an explanation regarding the necessity and appropriateness of therapy. Otherwise, treatment is safe and provides an additive 15-20% reduction in LDL-C to the existing treatment. Not only can they be used in double combination, many FH patients use a combination of three drugs that reduce LDL-C (a statin, ezetimibe and resins). Of the resins, we have personal experience with cholestyramine and colestipol. In the USA, colesevelam is primarily used; it is better tolerated and is, therefore, the primary choice in treating FH in children. Interestingly, some findings have indicated that treatment with colesevelam improves DM compensation.
Niacin was a good option for combination therapy. For a short period of time, a fixed combination of niacin / laropiprant was available, but that is no longer the case.
Fibrates are not the drug of choice for combination therapy in FH. Nevertheless, it can be used in some patients who have borderline, or slightly elevated, triglyceride concentrations.
Statin adverse effects
Statins are generally well-tolerated drugs. Nonetheless, it is possible to encounter side effects that may be a limitation of therapy. Adverse effects occur more frequently with higher dosages. According to various data, side effects occur in < 10% of patients. In reality, however, clinically significant myopathy is found in 3-5% of patients, depending on the dose and other factors. The most frequently discussed side effect is myopathy. Fortunately, severe rhabdomyolysis occurs very rarely. Myositis with increased CK is more common and is most commonly encountered with muscle weakness; sometimes, it is accompanied by muscle pain (reminiscent of myalgia due to a viral illness), but without an increase in CK. Increased risk for the development of myopathy is seen in patients in older age (particularly in frail elderly patients), patients with hypothyroidism (more often in women), and patients with kidney disease and alcoholism. Polypharmacy, of course, increases the potential for drug interactions. Patients with FH very often use a variety of drugs simultaneously and are, therefore, at risk for drug interactions.
Hepatopathy was often discussed in the past, and I personally recommend checking liver enzymes when using high doses of statins. However, it is true that the Food and Drug Administration (FDA, USA) have backed away from recommending regular hepatic function panels.
Conversely, the issue of the diabetogenic effect of statins is often discussed; particularly when administered at high doses. This question is totally irrelevant for patients with FH. Diabetes develops in patients with prediabetes, insulin resistance, central obesity, a family history of Type 2 DM, and in patients with metabolic syndrome. None of these conditions are typical for FH (although they cannot be excluded entirely). In truth, the benefits outweigh the risks at a ratio of 9:1, and the number of patients that need to be treated for “induced” diabetes is 200-250.
Lp(a) is a separate, independent risk factor for developing cardiovascular diseases. It is doubly so in FH patients. No currently available treatments are capable of impacting Lp(a) levels. Niacin, which slightly decreased Lp(a), is no longer available. At present, we must use Lp(a) particularly when estimating the risk and selecting the intensity of hypolipidemic therapy. Elevated Lp(a) levels may necessitate moving patients who would otherwise not fulfill the criteria for severe heterozygous due to LDL-C levels alone into this category.
It is very positive that some of the newly developed hypolipidemics are capable of positively influencing Lp(a) levels (by approximately 20-30%).
Pharmacotherapy and experimental treatments: What’s new?
Although it appears that the most promising are proprotein convertase subtilisin / kexin type 9 (PCSK9) antibodies (or inhibitors), I will begin with drugs that are already approved for use (for the treatment of homozygous FH, at least). Lomitapide is approved by both the FDA and European Medicines Agency (EMA) and therefore can be used in the Czech Republic (although negotiations regarding the reimbursement system are not yet complete). Mipomersen, another promising drug, has only been approved by the FDA for use in the United States.
MTP inhibitors: lomitapide (Lojuxta)
Microsomal transfer protein (MTP) plays a significant role in the transport and production of cholesterol, triglycerides, VLDL and chylomicrons. It operates in two locations: in the liver it prevents the formation of VLDL, and in the intestines it prevents the formation of chylomicrons. Lomitapide reduces LDL-C by approximately 50%, and triglycerides by 40% (or more).
The problem with lomitapide is that, after treatment, there is an accumulation of lipids in the liver with a potential increase in aminotransferases; moreover, there is even the potential for chronic hepatopathy after long-term treatment. The problem of hepatotoxicity received (similarly to mipomersen, see below) a black box warning from the FDA and EMA.
Antisense treatment, mipomersen
From a certain perspective, mipomersen treatment can be regarded as genetic therapy. It blocks apolipoprotein B synthesis so that RNA transcription does not occur for the protein.
Mipomersen reduces LDL-C concentrations by 25% in FH patients; this decrease is also accompanied by a decrease in Lp(a) levels.
Mipomersen is parenterally administered in the form of subcutaneous injections – this administration is also associated with the most adverse effects. Local reactions at the injection site are common, as are flu-like symptoms.
Proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors
PCSK9 inhibitors are the most promising group of drugs for FH patients, as well as other patients for whom it is necessary to significantly reduce LDL-C. These drugs (which are antibodies against PCSK9) prevent degradation of LDL receptors and increase their number, thereby increasing clearance of LDL particles from plasma.
As this book goes to print, a number of these inhibitors are in development. At this point, we will mention evolocumab (AMG 145) from Amgen and alirocumab (REGN 727) from Sanofi. These two molecules are closest to clinical use, and we will briefly describe select results from their massive preclinical and clinical trial programs below. Next in the pipeline is bococizumab (RN316) from Pfizer. Other PCSK9 inhibitors are in various phases of clinical testing at Novartis, Roche, Bristol-Myers Squibb and others.
Evolocumab (Amgen) is being verified in the PROFICIO program and alirocumab (Sanofi) is being verified in the ODYSSEY study program. These studies are being conducted in various patient populations (e.g. FH in homozygous and especially heterozygous forms, patients intolerant of statins, patients at high risk of CVD, and others), both in the context of monotherapy, and especially in cases where the PCSK9 inhibitor is added “on top” of statin therapy. A study comparing it with ezetimibe has already been completed.
It is almost unbelievable how consistent the results have been. LDL-C decreases by 50–70% in virtually all treatment regimens. Treatment (subcutaneous injections at bi-weekly intervals) was very well tolerated and the incidence of adverse events usually corresponds to placebo. The results thus far are short-term; the longest of the studies lasted 52 weeks, and one of the studies (ODYSSEY long-term) lasted 78 weeks. Therefore, a reduction in cardiovascular events cannot yet be claimed.
Here, I would ask the readers to interpret what follows with great consideration. An analysis of the ODYSSEY long-term study not only shows a positive CV trend, but also a statistically significant reduction in CV events (more than 50%). Nonetheless, these are small numbers and involve short-term administration. For a final assessment of how this class of drugs impacts CVD, we must wait for results from the ODYSSEY and FOURIER mega-studies.
At this time, a very beneficial (although, perhaps secondary) effect of treatment is a 20-30% reduction in Lp(a) concentrations.
To summarize PCSK9 inhibitor treatment, I would like to present a few charts from clinical studies with evolocumab and alirocumab.
As of now, the DESCARTES study with evolocumab has been the longest of its kind, the results of which were published in the New England Journal of Medicine (NEJM) in the summer of 2014.
Great hopes have been invested in the (as yet) ambiguously evaluated CETP inhibitors, which inhibit cholesteryl ester transfer protein. These are drugs that primarily dramatically affect HDL-C, but their potential to reduce LDL-C by at least 30% is equally significant. At present, we are anxiously anticipating the results of interventional studies with anacetrapib and evacetrapib.