Prevalence and diagnosis

Over half of all patients with premature coronary heart disease (CHD) have a familial disorder of lipid metabolism. Specifically, patients with FH are phenotypically characterized by markedly elevated LDL-C levels starting in infancy, as well as a predisposition to early-onset CHD. Typically, FH is a monogenic, autosomal dominant disorder involving defects in the gene that encodes the hepatic LDL receptor. While patients with homozygous FH are exceedingly rare (∼1 in 1,000,000), patients with heterozygous FH are one of the more common serious genetic disorders with prevalence of 1 in 300 to 500 adults in most populations.

Genetic screening is not routinely recommended for diagnosis of patients with FH. Rather, the diagnosis is most often made clinically based on LDL-C levels, physical examination findings, and a personal or family history of CHD. In 2011, the National Lipid Association released an executive summary providing clinical guidance for the diagnosis and management of patients with FH. Their recommendations included universal lipid screening for FH in all individuals during late childhood or early adulthood. Patients who are ≥20 years old with an LDL-C >190 mg/dl were recommended to undergo further work-up, including review of their family history, looking for relatives with a history of elevated cholesterol or CHD events, as well as undergoing a physical examination for signs of FH such as tendon xanthomas, tuberous xanthomas, or premature arcus cornea. Patients with LDL-C levels of >190, >220, and >250 mg/dl were considered to have an 80% probability of FH in patients aged <20, 20–29, and ≥30 years, respectively. Cascade screening (i.e., the process of screening first-, second-, and third-degree relatives) is recommended for relatives of patients with probable or confirmed FH. All first-degree relatives of the index case are recommended to undergo a screening lipid panel with subsequent testing of all first-degree relatives of any additional cases that are found via screening. Cascade screening has been found to be the most cost-effective approach for identifying new cases of FH.

Treatment

Regardless of the genetic defect responsible for FH, the treatment approach is unlikely to differ. Among the general population, LDL-C is only a modest risk factor for CHD and is not associated with improved discrimination in the prediction of future CHD events. However, due to their markedly elevated LDL-C levels, patients with FH are universally considered to be a high-risk group for CHD events. For this reason, the National Lipid Association and the 2013 American College of Cardiology/American Heart Association ACC/AHA cholesterol guidelines recommend treatment without further risk stratification. In accordance with the ACC/AHA guidelines, a high-intensity statin as first-line therapy for all adults with an LDL-C of ≥190 mg/dl is recommended.

In the general population, the role for of nonstatin agents is unclear. However, patients with FH frequently have LDL-C levels that remain elevated even after treatment with a high-intensity statin. Additionally, FH patients may not tolerate a high-intensity statin. With both groups, the addition of a nonstatin agent should be considered especially in those with known CVD, diabetes mellitus, or multiple other CVD risk factors. Given the results of the recent Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, in which the addition of ezetimibe to statin therapy resulted in reductions of both LDL-C concentrations and CVD events, ezetimibe may be the preferred second-line agent at this time, although the population studied in the IMPROVE-IT trial did not include individuals with FH, and the study was performed with patients who had recently experienced acute coronary syndrome rather than in primary prevention. The novel proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors recently approved by the US Food and Drug Administration have a significantly higher efficacy in terms of reducing LDL-C and should also be a consideration; however, the evidence that PCSK9 inhibitors reduce hard outcomes is currently lacking, and cost considerations need to be taken into account. Bile acid-binding resins and niacin therapy may also offer further LDL-C reduction in patients with FH, although studies demonstrating that these medications reduce CVD events when added to a statin are lacking. Finally, in extreme cases, apheresis of LDL-C can be considered.

Patient case

JP is a 48-year-old man with no clinical history of CVD and no previously diagnosed CVD risk factors. He is a nonsmoker and takes no prescribed medications. He is physically active; he bikes and plays basketball several times per week without any cardiovascular symptoms. He has never smoked but freely admitted he had not been following a heart-healthy diet. His body mass index is 26.4 kg/m ² . He recently underwent a medical screening for life insurance and was told his cholesterol was significantly elevated. He saw his primary care provider and was referred to a cardiovascular prevention clinic.

His fasting lipid panel at that time showed a total cholesterol level of 341 mg/dl, a high-density lipoprotein cholesterol (HDL-C) level of 48 mg/dl, triglycerides of 132 mg/dl, and an LDL-C of 234 mg/dl. Additional laboratory studies evaluating thyroid, liver, and renal function were unremarkable. JP reported a family history of high cholesterol in his father, paternal grandfather, and paternal uncle. His paternal uncle suffered a myocardial infarction at age 49, and his father underwent bypass surgery at age 54. Given his markedly elevated LDL-C and family history, JP was given a formal diagnosis of FH. He was counseled regarding the importance of a heart-healthy diet to improve his lipids and, more importantly, reduce his CVD risk. He was also started on a high-intensity statin (rosuvastatin 40 mg daily) with plans for a 3-month follow-up. Cascade screening of his first-degree relatives was recommended.

JP appropriately followed up and was happy to report he had lost 14 pounds since his initial visit. A follow-up lipid panel showed an excellent response to lifestyle modification and lipid-lowering therapy with a total cholesterol level of 192 mg/dl, a triglyceride level of 72 mg/dl, an HDL-C level of 49 mg/dl, and an LDL-C of 105 mg/dl. Consideration was given to adding ezetimibe, but given the excellent response to his initial therapy, JP’s treating physician elected to continue his current regimen without any changes. His 42-year-old brother underwent lipid screening and was found to have FH. Two other siblings reportedly had lipid levels within normal limits.

Prevalence

Statin intolerance is one of the most common and difficult clinical conundrums in CVD prevention today. Importantly, discontinuation of and/or nonadherence to statin therapy has been associated with an increased risk for CVD events. Statin therapy is associated with an increased risk of diabetes mellitus, although patients who develop diabetes mellitus derive the same clinical cardiovascular benefit as those who do not develop diabetes mellitus while on statin therapy. Statin therapy has also been reported to adversely affect cognitive function although clinical data supporting this theory are lacking. However, the majority of adverse events related to statin therapy are statin-associated muscle symptoms (SAMS).

In randomized controlled trials, the rate of SAMS as well as other side effects and adverse events have been similar between the statin and placebo groups. However, in observational studies, the rate of SAMS in patients on statin therapy has ranged from 7% to 29%. In the Prediction of Muscular Risk in Observational Conditions study, 7,924 patients were surveyed regarding their history of muscular symptoms while on statin therapy. The rate of reported SAMS was 10.5% with onset usually within 1 month of starting statin therapy. A personal history of muscle pain on a lipid-lowering agent was the strongest predictor of SAMS (odds ratio 10.12, 95% confidence interval 8.23 to 12.45; p <0.0001). The stark difference between the randomized controlled trial data and observational data is difficult to reconcile. The lack of a placebo group in the observational studies precludes establishing a causal relationship between statin therapy and SAMS.

Additionally, previous research has demonstrated that up to 90% of patients who reported SAMS were subsequently able to tolerate an alternative statin. In a recent PCSK9 trial examining the LDL-lowering effect of alirocumab, inclusion criteria for the trial included statin intolerance of at least 2 statin medications with at least 1 statin at its lowest approved dose. Participants were randomized to alirocumab, ezetimibe, or atorvastatin 20 mg daily. When blinded, 78% of previous statin-intolerant participants randomized to atorvastatin were able to tolerate the medication for the duration of the 6-month trial. The rate of discontinuation due to muscle symptoms was not statistically different between the 3 medications (alirocumab 15.9%, ezetimibe 20.2%, and atorvastatin 22.2% [p value for comparison to alirocumab 0.24]). After 6 months, all study participants were unblinded and offered to continue alirocumab for the next 18 months. Once unblinded, the rate of discontinuation of alirocumab due to muscle-related symptoms was 0.7%.

However, there is evidence to suggest that there may be a causal relationship between statin therapy and muscular side-effects. Preclinical studies have shown statin therapy to be associated with attenuated intracellular energy production, decreased mitochondrial function, and altered degradation of muscle proteins. The Effects of Statins on Muscle Performance study was a randomized trial designed to exclusively evaluate the impact of statin therapy on SAMS and muscle performance. In individuals randomized to atorvastatin 0 mg, the rate of myalgia was 9.4%, compared with 4.6% in the placebo group (p = 0.054). However, there was no difference in measured muscle strength or exercise performance.

Diagnosis and management of SAMS

In 2015, the European Atherosclerosis Society (EAS) published a statement on the assessment, etiology, and management of patients with SAMS. The Society recommended classifying complaints including pain, weakness, and cramping as “muscle symptoms” with further subclassification based on the presence or absence of creatine kinase (CK) elevation. For patients with SAMS and a CK >4 times the upper limit of normal, the EAS recommends reassessing the clinical indication for statin therapy. If the patient has a high CVD risk, EAS recommends continuing statin therapy with close monitoring for worsening symptoms or a further increase in CK. For patients with SAMS and a CK >10 times, the upper limit of normal, and no other secondary cause, they recommended stopping statin therapy due to the risk of rhabdomyolysis. In clinical trials, the risk for rhabdomyolysis with statin therapy has been ∼1 per 10,000 patients per year. For patients who have a high risk for CVD, a repeat trial of statin therapy should be considered once the patient is stable.

Most patients with SAMS have no or minimal CK elevation. For these patients who have subsequently stopped statin therapy, the clinical indication for such therapy needs to be reassessed. For patients who are at low risk for CVD, the benefit of a small reduction in absolute risk for future CVD events needs to be weighed against the potential compromise in quality of life. For patients who are at high risk for CVD (known CVD, diabetes mellitus, LDL-C ≥190 mg/dl, or high absolute CVD risk), a repeat trial of statin therapy with considerations for switching to an alternative statin or utilizing a low-dose approach is recommended. For instance, 5 mg of rosuvastatin can be presented to the patient as only about 1/8 of a full dose of rosuvastatin, yet on average, it produces a 40% reduction in LDL-C. For patients at high CVD risk, who consistently experience side effects while on statin therapy, consideration should be given to nonstatin agents with a preference for ezetimibe therapy. Additionally, bile acid-binding resins or niacin therapy can be considered. Once accepted for this indication, one of the novel PCSK9 inhibitors could be considered, especially in high CVD-risk patients. As always, lifestyle modification should be reinforced as well regardless of the degree of tolerance to statin therapy.

Patient case

LH is a 64-year-old female with hypertension, hyperlipidemia, and known CVD, having undergone percutaneous coronary intervention at age 58 due to unstable angina. She has done well since without any recurrent events or symptoms. Her blood pressure is well controlled on lisinopril and hydrochlorothiazide. She is physically active, taking daily walks and swimming without any cardiovascular symptoms. Her body mass index is 25.8 kg/m ² . She was referred to a cardiovascular prevention clinic due to issues with statin intolerance.

Upon presentation, her fasting lipid panel showed total cholesterol of 226 mg/dl, an HDL-C of 51 mg/dl, triglycerides of 105 mg/dl, and an LDL-C of 142 mg/dl. Her history of statin intolerance was reviewed in detail. She had been taking simvastatin and atorvastatin at varying doses on several occasions over the past 6 years. She had concerns about taking statin therapy after hearing several friends describe significant musculoskeletal side-effects. She noted shoulder pain and bilateral knee pain after starting statin therapy, which led her to stop the statin. Her symptoms did initially improve after stopping statin therapy, although she does note that shoulder pain has waxed and waned over the past decade, including episodes of pain while not on statin therapy. She also notes a previous diagnosis of knee arthritis. Recurrent episodes of knee and shoulder pain led her to discontinue statin therapy on several subsequent occasions. The risks and benefits of statin therapy were discussed with her in detail, including the clear mortality benefit in the setting of secondary prevention, as well as the excellent safety profile seen in the randomized controlled trials. Consideration was given to a trial of a nonstatin lipid-lowering agent, but after reviewing the statin data, the patient was interested in pursuing a low-dose statin approach.

She was started on 5 mg of rosuvastatin; at follow-up 2 months later, LH was happy to report that she generally felt well with only some mild shoulder and knee pain, similar to her baseline. A repeat lipid panel showed total cholesterol of 158 mg/dl, an HDL-C level of 53 mg/dl, a triglycerides level of 84 mg/dl, and an LDL-C of 74 mg/dl. Her treating physician elected to not titrate the rosuvastatin given her history of potential side effects.