This case study reflects clinical challenges in the diagnosis and management of familial hypercholesterolaemia (FH). Pharmacists can play a key role in the care of FH patients, counselling on the safe and effective use of pharmacotherapy as well as ensuring effective outcomes through monitoring for safety, medication adherence, adverse events and therapeutic efficacy.1
In this case study, once the diagnosis is made, there are points of pharmacist intervention that will contribute to the health of the patient and his family.
NOTE: This case study was sponsored by an unrestricted grant from CIPLA which had no control over the content and the experts participated voluntarily.
When answering the CPD questions you MUST read the expert comment as this is essential to the understanding of the Case Study.
Dr Dirk Blom Head of Division of Lipidology
Division of Lipidology
Department of Medicine
University of Cape Town
With comment from:
Dr Natie Finkelstein
Hons-BSc (Med Sci)
MSc, PhD, FPS (SA)
FRPharmS, FIPharmM, MSAChem
Visiting Professor: Faculty of Pharmacy
Patient: Mr S, 42-year-old male, Civil engineer
- Married with one son aged 12 years
- Never smoked
- Drinks one glass of wine with meals during the week, three to four glasses on weekend nights when socialising
- Jogs for 45 minutes five days of the week
- Admits to ‘not paying any attention to his diet’ and ‘eating what he likes’. He is particularly fond of cheese, bacon and pork ribs.
Reason for visit
Mr. S recently moved to a new town following a promotion, seeking new medical care
- Seasonal allergic rhinitis for which he uses an antihistamine as necessary
- Hypercholesterolaemia: He first became aware of high cholesterol at the age of 17 when his father, who was then 42 years old, had a myocardial infarction and he and his siblings had their cholesterol tested on the advice of their father’s cardiologist. Although his previous doctor advised him to take lipid-lowering medication he only did so briefly several years ago. His main reasons for not taking lipid-lowering medication are that he felt the medication ‘did not agree with him’ and he thought it not necessary because he was a non-smoker and exercised regularly.
Cetirizine 10mg/daily as needed
- Father: Myocardial infarction at age 42, untreated total cholesterol of 10.9mmol/l with triglycerides of 3.0mmol/l, PCI and stent insertion at age 45 followed by a CABG at age 52, takes rosuvastatin 40mg/day and ezetimibe 10mg/day for lipid control
- Paternal grandmother died suddenly at age 50 of a suspected myocardial infarction
- Mother: Well with no significant medical problems
- Siblings: One of four children. Older brother takes atorvastatin 40mg/daily for hypercholesterolaemia Older sister’s total cholesterol is 3.8mmol/l without medication Younger sister has a total cholesterol of 7.9mmol/l but will only take homeopathic remedies
- Height: 1.93m
- Weight: 90kg
- BMI: 24.2kg/m2
- Waist circumference: 94cm
- Pulse: 62 beats per minute
- Blood pressure: 122/74mmHg
- Bilateral inferior arcus cornealis
- Small nodule in right Achilles tendon
- Other systems: No abnormalities found
Initial Investigations (following an overnight fast)
This patient has the phenotype of heterozygous FH. There is a family history of autosomal dominant hypercholesterolaemia and/or premature cardiovascular disease spanning at least three generations. He also has an Achilles tendon xanthoma. Tendon xanthomata are the most useful clinical sign for the diagnosis of FH. Although tendon xanthomata are not found in all patients with FH, their presence in the setting of autosomal dominant LDL hypercholesterolaemia confirms the diagnosis.
Patients with familial combined hyperlipidaemia (FCH) or polygenic hypercholesterolaemia may have severe hypercholesterolaemia and a positive family history but do not have tendon xanthomata. Although diet can influence serum lipids, such marked elevation of LDL-C cannot be ascribed to diet alone. Triglycerides may be modestly elevated in some patients with FH (e.g. if they are obese or have insulin resistance) and the fact that his father has modest hypertriglyceridaemia does not detract from the diagnosis of FH. Framingham risk scoring underestimates risk markedly in patients with FH and should not be performed. Patients with FH are at high cardiac risk and vascular imaging is not routinely required to make treatment decisions.
Following the history and examination, the patient is told that he has FH, based on the family history of autosomal dominant LDL hypercholesterolaemia, premature coronary artery disease and the tendon xanthoma. His cardiovascular risk is very high and lipid-lowering therapy is required in addition to lifestyle changes.
The patient agrees to see a dietitian for advice on improving his diet and also agrees to try taking lipid-lowering medication again. Because of his previous negative experience with statins he is started on a relatively low statin dose and prescribed atorvastatin 20mg/day with the aim of titrating the dose at four-weekly intervals depending on tolerability and LDL response. The patient is told that although there is quite a wide variation in individual statin responses, he will almost certainly require a high-dose statin because of his very high baseline LDL-C.
THE PHARMACIST’S PERSPECTIVE AND CONTRIBUTION TO THIS PATIENT’S CARE
Mr S arrives at the pharmacy and expresses his concern about taking statins again because of his FH. He is worried about the diagnosis, about taking statins and the implications of this condition for his teenage son.
Dr Finkelstein comments
The most important role of the pharmacist as part of the health care team is to encourage adherence to therapy.1
The pharmacist points out that Mr S was previously on simvastatin 40mg/day and that the dosage of atorvastatin, a more powerful statin in terms of its cholesterol-lowering effect, will result in lower statin levels in the blood and probably fewer side-effects. Also, he recommends that Mr S take his medication at night which may also reduce the risks of side-effects. He points out that adverse effects are normally transitory and research has shown that nonspecific muscle or joint aches and pains only occur in 5% of patients on statin therapy.2
With regard to the risk that his son carries the gene for FH, the pharmacist describes the risk and what can be done to determine this risk.
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1. What is the risk that his son, who is now 12 years old, will also have hypercholesterolaemia? His wife does not have high cholesterol and comes from a ‘very healthy’ family with no history of premature coronary artery disease or hypercholesterolaemia.
View Expert Comment »
Dr Blom comments
The inheritance of FH is autosomal dominant. Based on the information given, it is fair to assume that his wife does not carry a FH gene. His son therefore has a 50% chance of inheriting a mutated allele from him.
2. Mutations in which of the following genes can cause FH?
View Expert Comment »
LDL-receptor mutations are the commonest genetic cause of FH by far, but mutations in apoB and PCSK9 can cause FH as well. It is impossible to predict the mutated gene based on the patient’s phenotype. Biallelic mutations in the LDL-receptor adaptor protein 1 gene cause autosomal recessive hypercholesterolaemia (ARH). ARH only has a homozygous FH phenotype, as it is a recessive disorder. The diagnosis of FH is primarily clinical, but can be confirmed by identifying a disease-causing mutation in one of the FH genes. There are more than 2000 described mutations in the LDL-receptor alone and a ‘negative’ genetic test does not always rule out FH, as genetic testing may have been limited to certain genes and mutations depending on the testing laboratory.
The pharmacist checked that cetirizine does not have an interaction with statins.
3. Which of the following medications can lead to higher statin levels?
4. What are the risk factors associated with the development of muscle aches and diffuse body pain from statin use?
View Expert Comment »
Muscle symptoms may result from multiple disorders. Some disorders can cause muscle symptoms in their own right, such as hypothyroidism, vitamin D deficiency or polymyalgia rheumatica (PMR), while other conditions may increase the risk of developing statin-associated muscle symptoms (SAMS).
Increased circulating statin levels are associated with an increased risk of SAMS. Statin levels are higher in patients taking high-dose statins or when statins are prescribed with medications that lead to drug-drug interactions by inhibiting statin metabolism or excretion (e.g. azole antifungals, macrolides, HIV protease inhibitors, gemfibrozil, ciclosporin). Pharmacogenetic variations in drug metabolism (CYP450 isoenzymes) or drug excretion (organic anion transport protein 1B1 (OATP1B1), or P-glycoprotein 1 (P-gp1)) may also play a role in susceptibility to SAMS.
Other risk factors include:
Anthropometric Age >80 years old (general caution advised for age >75)
Low body mass index
Concurrent conditions Acute infection
Hypothyroidism (untreated or undertreated)
Impaired renal (chronic kidney disease classification 3, 4, and 5) or
Biliary tree obstruction
Organ transplant recipients
Human immunodeficiency virus
Vitamin D deficiency
Surgery Surgery with high metabolic demands Related history History of creatine kinase elevation, especially >10× the upper
limit of the normal range
History of pre-existing/unexplained muscle/joint/tendon pain
Inflammatory or inherited metabolic, neuromuscular/muscle defects (e.g.
McArdle disease, carnitine palmitoyl transferase II deficiency,
myoadenylate deaminase deficiency and malignant hyperthermia)
Previous statin-induced myotoxicity
History of myopathy while receiving another lipid-lowering therapy
Other risk factors High level of physical activity
Dietary effects (excessive grapefruit or cranberry juice)
Drug abuse (cocaine, amphetamines, heroin)
Table from Eur Heart J. 2015; 36(17):1012-1022. doi: 10.1093/eurheartj/ehv043.
Initial management of patients with potential SAMS should focus on:
- Confirming that statins are indeed indicated and required
- Assessing the patient for potential other diagnoses – hypothyroidism is often overlooked and it is almost always worthwhile checking the TSH level
- Documenting the CK to guide further management and help with the identification of rhabdomyolysis
- Documenting the response to discontinuation of the statin
5. The pharmacist called the prescriber and discussed the patient’s options, which included:
View Expert Comment »
The decision, in view of the fact that the patient will have to take statins chronically, was to discontinue atorvastatin and rechallenge with rosuvastatin, as it is associated with fewer drug interactions. The pharmacist informed the patient and explained why the blood tests needed to be done.
6. Which of the following statements about CK measurement in statin-treated patients is correct?
View Expert Comment »
Dr Blom comments
The clinical presentation of muscle symptoms in patients taking statins is highly heterogeneous and there is also no single, universally accepted definition or terminology. The term ‘statin myopathy’ or ‘myalgia’ is frequently used, but a broader term such as SAMS better describes the spectrum of symptoms and also makes no assumptions about the pathogenesis.
The European Atherosclerosis Society recently proposed a clinical classification of SAMS that takes into account the nature of the muscle symptoms, the elevation in CK levels and their temporal association with statin initiation, discontinuation and rechallenge (Eur Heart J 2015; 36(17):1012-1022. doi: 10.1093/eurheartj/ehv043.
Symptoms Biomarker Comment Muscle symptoms Normal CK Often called ‘myalgia’. May be related to statin therapy. Causality
is uncertain in view of the lack of evidence of an excess of muscle symptoms
in blinded randomised trials comparing statin with placebo
Muscle symptoms CK >ULN <4× ULN Minor elevations of CK in the context of muscle symptoms
are commonly due to increased exercise or physical activity, but may also
be statin related; this may indicate an increased risk for more severe,
underlying muscle problems
CK >4 <10× ULN Muscle symptoms CK >10× ULN Often called ‘myositis’ or ‘myopathy’ by regulatory agencies and other
groups (even in the absence of a muscle biopsy or clinically demonstrated
muscle weakness). Blinded trials of statin vs placebo show an excess with
usual statin doses of about 1 per 10 000 per year. Pain is typically generalised
and proximal and there may be muscle tenderness and weakness. May be associated
with underlying muscle disease
Muscle symptoms CK >40× ULN Also referred to as rhabdomyolysis when associated with renal impairment
None CK >ULN <4× ULN Raised CK found incidentally may be related to statin therapy or may
be exercise related. Consider checking thyroid function
None CK >4× ULN Small excess of asymptomatic rises in CK have been observed in randomised
blinded trials in which CK has been measured regularly. Needs repeating
but if persistent, then clinical significance is unclear
CLINICAL PICTURE AFTER STATIN DISCONTINUATION AND RECHALLENGE
The patient returns to the clinician for a repeat consultation a week after discontinuing the statin. He had blood tests done a day prior to discontinuing the statin. These are his results.
Investigation Result Comment CK 360IU/l CK elevation is best defined in terms of elevation above the upper limit
of normal (ULN) as the exact range varies according to the assay. This result
is 2 X ULN for the particular laboratory
TSH 1.2mIU/l Normal, excludes hypothyroidism Creatinine 82μmol/l Document renal function Urine dipstick Normal Myoglobinuria in rhabdomyolysis will give a false positive reading for
blood on urine dipstick. However, there will not be a commensurate amount
of red blood cells on urine
It is not necessary to routinely measure CK in all patients receiving statins. It is useful to obtain a baseline value before starting statins, but CK values on statins are not predictive of more serious muscle-related problems. Routine CK measurement may lead to inappropriate interruption or discontinuation of statins. Almost all patients with statin-associated muscle symptoms can be rechallenged with statins and a level >4 × ULN does not require permanent statin discontinuation. Exercise, especially unaccustomed heavy physical exertion, may cause massive CK elevations >50 × ULN.
The patient reports that he feels ‘much better’ since stopping the statin. His muscle symptoms resolved within a few days of stopping the statin and he can once again complete his regular exercise routine.
Statin-based therapy remains the mainstay of lipid-lowering even in patients with statin- associated symptoms. Statins should therefore not be abandoned too quickly as a therapeutic class and multiple efforts should be made to re-establish patients on statins. Strategies for restarting statins include:
- Careful explanation by the doctor regarding the benefits of statin therapy
- Ongoing support by the healthcare team
- Using an alternative statin, often initially at a lower dose
- Using alternative dosing strategies. Highly efficacious statins such as atorvastatin and rosuvastatin can be dosed on alternate days or twice weekly. Many patients who are not able to tolerate daily statins can tolerate intermittent dosing
After careful discussion of the risk associated with a very high LDL-C, the patient agrees to try another statin, but refuses to take atorvastatin again. He starts taking rosuvastatin 5mg/day but experiences recurrent muscle symptoms. Following another washout and subsequent reduction in dose to 5mg three times a week he is asymptomatic. However, he refuses to try another statin or to increase the rosuvastatin dose.
These are his lipid levels on rosuvastatin 5mg on three days of the week.
Investigation Result Interpretation Triglycerides 0.8mmol/l Slight reduction from baseline Total cholesterol 7.8mmol/l Approximately 25% reduction HDL-C 1.3mmol/l Unchanged LDL-C 6.1mmol/l Approximately 30% reduction
Although the patient’s LDL-C has been reduced by approximately 30%, his LDL-C remains markedly elevated at >6.0mmol/l. Ezetimibe 10mg/day is added. It is the first choice if additional lipid-lowering therapy is required as it is generally easy to take, well tolerated and reduces LDL-C by about 15-20%. Ezetimibe can be combined with a statin or used as monotherapy in patients who cannot tolerate statin therapy at all. Adding ezetimibe to simvastatin-based therapy has also been shown to reduce cardiovascular events.
THE PHARMACIST’S ROLE IN THE NEW THERAPEUTIC STRATEGY
The change in therapy requires more support from the pharmacist, as costs escalate and the patient becomes more concerned about his lipid control.
With the change to rosuvastatin therapy, the pharmacist measured the patients’ cholesterol levels using a point-of-care test. He encouraged the patient to take his medication as prescribed (three days of the week) and to return to exercising regularly as he did before the pains began.
7. Rosuvastatin 5mg/day is equivalent to what dosage of atorvastatin
View Expert Comment »
Rosuvastatin is highly potent and is less likely to interact with other drugs. Interestingly, studies have shown that either alternate-day or twice-weekly dosing strategies are tolerated by 70% of previously intolerant patients.3 Rosuvastatin and atorvastatin, with their longer half-lives, are more appropriate for this alternate type of dosing strategy.
8. Ezetimibe reduces LDL-C levels by what percentage on average when added to statins?
View Expert Comment »
Recent evidence has shown that ezetimibe added to a statin reduced the risk of cardiovascular death, major coronary event or non-fatal stroke by a further 9% as compared to statin monotherapy.4 In this study there was a further reduction in LDL-C at one year of 0. 43mmol/l, which is equivalent to a relative risk reduction (RRR) of 24% without any safety concerns over the six-year period. Following this positive cardiovascular outcome trial with ezetimibe, the NICE guidelines in the UK have recommended its use in heterozygous familial and non-familial hypercholesterolaemia.
9. What other therapies could the clinician have considered?
View Expert Comment »
Nicotinic acid can also lower LDL-C by 15-20%, but is difficult to take (possibly causing flushing and urticaria) and was associated with a significant excess of adverse events and a failure to reduce cardiovascular outcomes in a recent outcome study. Bile acid sequestrants can reduce LDL-C by up to 25%, but older agents such as cholestyramine are often poorly tolerated, because of gastrointestinal adverse effects. Fenofibrate can also reduce LDL-C by 15-20%, but is not considered a first-line agent in patients without hypertriglyceridaemia.
10. What further advice would you consider giving to this patient?
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Learning title: Hypertension
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We suggest an answer for this module – “Relevance to South African circumstances. This module was provided online with useful additional linked-in resources.”
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1 Krass I, Walker AT, Watts GF. Detection and care of familial hypercholesterolaemia in the community: is there a role for the pharmacist? Int J Clin Pharm 2012; 34: 501-505.
2 Ramsunder N. Side-effects of statins. S Afr J Diabetes Vasc Dis 2015; 12: 48-50.
3 Murphy SA, Cannon CP, Blazing MA, et al. Reduction in total cardiovascular event with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-it Trial. J Am Coll Cardiol 2016; 67(4): 353-361.
4Stroes ES, Thompson PD. Statin-associated muscle symptoms: impact on statin therapy —European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36(17): 1012-1022.
Disclaimer: This case study is intended to facilitate continuing medical education. The views and answers to the questions expressed in this case study are those of the presenters and do not necessarily reflect the views of Cipla. Cipla does not recommend the use of its products in any manner inconsistent with that described in the local package insert. Before using any product mentioned in this case study, please refer to the full local prescribing information.