Hypercholesterolaemia treatment in a patient with family hypercholesterolaemia and myopathy due to carnitine palmitoyltransferase II deficiency with PCSK9 inhibitors

Dear Editor:

Carnitine palmitoyltransferase (CPT) deficiency is the most frequent metabolic myopathy.¹ This condition follows an autosomal recessive inheritance pattern, and presents with 2 phenotypes: the childhood-onset form (type I, hepatic CPT1 deficiency), and the adult-onset form (type II, muscle CPT2 deficiency). CPT2 deficiency typically presents between the 2nd and 3rd decades of life and is characterised by myalgia, cramps, weakness, and myoglobinuria with onset after a clear trigger event.^1,2

These patients may present episodes of rhabdomyolysis triggered by prolonged exercise, infections, fasting, or the use of statins, among other factors.¹ Therefore, we should be very cautious when using statins to treat concomitant dyslipidaemia. A new family of drugs, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, decreases blood low-density lipoprotein cholesterol (LDL-C) levels without the muscle toxicity of statins; therefore, they may be used in this type of patients.

The 2 currently marketed drugs (alirocumab [Praluent®] and evolocumab [Repatha®]) are 100% human monoclonal antibodies that selectively bind to PCSK9 and largely inhibit the degradation of LDL-C receptors; thus, by increasing the number of receptors, they reduce the level of LDL-C in the blood.³ In Spain, the healthcare system only finances these drugs for the following indications: 1) patients with established cardiovascular disease and LDL-C > 100 mg/dL despite maximally tolerated statin therapy or with contraindications for statin treatment; or 2) patients with heterozygous familial hypercholesterolaemia (HFH) and LDL-C levels > 100 mg/dL despite maximally tolerated statin therapy or with contraindications for statin treatment.⁴ We present the case of a patient with myopathic CPT2 deficiency and HFH that shows the relevance of the new PCSK9 inhibitors in the treatment of patients with muscle disorders contraindicating statin treatment. Our patient was 56-year-old woman with HFH who was referred to our clinic for assessment and treatment of dyslipidaemia. She had recently been diagnosed with CPT deficiency. She reported episodes of myalgia and weakness after effort since a young age. Furthermore, the patient had presented several episodes of rhabdomyolysis requiring hospital admission; the last was associated with the use of simvastatin, with creatine phosphokinase levels of 8262 U/L. The physical examination and blood analysis yielded normal results. An electroneurography/electromyography study and muscle biopsy revealed no pathological findings. A genetic study showed CPT2 deficiency (with a pathogenic mutation and a mutation of uncertain significance: c.338C>T, p.Ser113Leu and c.1892G>A, p.Arg631His). The lipid profile revealed cholesterol levels of 298 mg/dL; HDL-cholesterol: 59 mg/dL; LDL-C: 206 mg/dL; triglyceride level: 167 mg/dL. Considering the risk of rhabdomyolysis due to the use of statins, we started treatment with a PCSK9 inhibitor: 75 mg alirocumab, administered subcutaneously every 15 days. The patient presented a cutaneous adverse drug reaction to alirocumab, and we switched treatment to 40 mg evolocumab every 15 days. She is currently receiving the same treatment with good tolerance, with LDL-C levels below 100 mg/dL in the follow-up visits.

Statins are the cornerstone of pharmacological therapy for atherosclerotic cardiovascular disease. Although these drugs are safe, a considerable percentage of patients present muscular side effects, such as myalgia, cramps, weakness, and rhabdomyolysis.³

Although the incidence of rhabdomyolysis associated with statin treatment amounts to approximately 0.70 cases per 100 000 person-years, up to 29% of patients receiving statins present muscular symptoms.⁵

Furthermore, in patients with muscle disorders, statins may exacerbate symptoms or trigger previously silent conditions.

In fact, the incidence of underlying genetic muscle disorders in patients with rhabdomyolysis induced by statins may reach up to 25% of cases.⁶

One study including 135 patients with myopathies induced by lipid-lowering drugs and undergoing genetic studies revealed that 10% of patients presented mutations causing the most frequent metabolic myopathies (CPT2 deficiency, myophosphorylase deficiency [McArdle disease], and myoadenylate deaminase deficiency). Thus, the frequency of carriers of CPT2 deficiency and McArdle disease was 13 and 20 times higher, respectively, than in the general population.⁷

Other genetic myopathies described in patients with statin intolerance include: glycogen storage disease type II (Pompe disease; acid maltase deficiency) and type IX (deficiency of glycogen phosphorylase kinase B), malignant hyperthermia (RYR1, CACNA1S), recurrent myoglobinuria (LPIN1 mutation), myotonic dystrophy type 1 (DMPK) and type 2 (CNBP), and MELAS syndrome.⁸

Furthermore, statins may adversely interact with such other neuromuscular disorders as myasthenia gravis, dermatomyositis/polymyositis, inclusion body myositis, and amyotrophic lateral sclerosis, among others.^7,8

Therefore, while genetic myopathies are frequently underdiagnosed, they should be considered in patients presenting muscular symptoms associated with the use of statins, particularly when symptoms or elevated levels of muscle enzymes persist after statin withdrawal. In these cases, the use of PCSK9 inhibitors as an alternative to the traditional treatment enables proper control of LDL-C levels without the associated risk of myopathy.