Context: Cardiovascular disease is a very common and serious problem in the western world. Statin drug therapy is used in primary, secondary prevention and familial hypercholesterolemia. However, these are frequently associated with adverse effects, causing poor adherence and thus putting patients at risk for future cardiovascular events. Aim: The objective of this study was to review the statin intolerance in lipid patients and to assess the impact of alternative lipid lowering therapy on lipid parameters and cardiovascular outcome in statin intolerant patients. Methodology: 50 patients attending the out-patient lipid clinic of our hospital with statin intolerance were identified. Clinical data on the study patients were gathered retrospectively relating to statin intolerance and the clinical effectiveness of alternative lipid lowering therapy on lipid parameters and cardiovascular outcome. Results: Rosuvastatin was the most intolerable whereas pravastatin or fluvastatin was the most tolerable statin in our study patients. Myalgia was the commonly reported adverse effect of statin. The low dose statin monotherapy or combination of low dose statin and ezetemibe was the most tolerable alternative lipid lowering therapy in statin intolerant patients. After an average period of 10 months of initiation of alternative lipid lowering therapy; combination of low dose statin plus ezetimibe showed the largest reduction in serum total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Conclusions: Pravastatin should be preferred in statin intolerant patients. A combination of low dose statin plus ezetimibe appeared to be the most tolerable and clinically effective therapy in statin intolerant patients.
Cardiovascular disease is associated with significant mortality and morbidity worldwide; it is the most prevalent medical condition in Western societies [
Management of hypercholesterolemia includes lifestyle changes such as smoking cessation, healthy diet, weight loss and regular exercise [
Nevertheless, statin use is associated with adverse effects including raised liver enzymes, muscle problems (myalgia, myositis, rhabdomyolysis), transient proteinuria, sleep problems, sexual dysfunction, renal failure, glucose elevations, neurological problems (haemorrhagic stroke, cognitive decline, peripheral neuropathy), depression and alopecia [
When patients with primary or secondary prevention and familial hypercholesterolemia develop statin intolerance continuation of their lipid-lowering therapy, it is essential to reduce their cardiovascular risk. According to American College of Cardiology and American Heart Association (2013) recommendation [
The aim of this study was to review the statin intolerance in our lipid clinic patients, assessing the tolerability and clinical effectiveness of alternative lipid lowering therapy in statin intolerant patients on lipid parameters (total cholesterol and LDL cholesterol) and cardiovascular outcome.
50 patients attending the lipid outpatient clinic with statin intolerance were identified from clinic letters. The data on statin intolerance was collected including statin dose, length of time (before intolerance presented) and side effects experienced.
The statin intolerant patients were categorised into primary prevention, secondary prevention and familial hypercholesterolemia. The alternative lipid lowering therapy, which was either alternative low dose statin only, combination of statin with non-statin lipid modifying medication or only non-statin therapy was initiated in patients after they presented with statin intolerance.
Impact of alternative lipid lowering therapy in statin intolerant patients (study cohort) was analysed by calculating the absolute reduction (%) in serum total cholesterol, LDL-cholesterol after the introduction of this change in lipid lowering therapy. Besides this data on occurrence of cardiovascular events during the therapy was also collected to assess the clinical effectiveness of alternative lipid lowering therapy in statin intolerant patients.
Statin intolerant patients (n = 50) were being treated for primary prevention (n = 29), secondary prevention (n = 15) and familial hypercholesterolemia (n = 6), with an average age of 59.2 years (range 31 - 90); consisting of 30 women (average age 64.1 years, range 49 - 90) and 20 men (average age 54.4 years, range 31 - 78).
In this cohort of 50 patients; intolerance to rosuvastatin (n = 19), simvastatin (n = 17), atorvastatin (n = 16), pravastatin (n = 9), fluvastatin (n = 1) and intolerance to more than one statin (n = 11).
13 female, 6 male, average age 58.5 years. 1 patient diagnosed with familial hypercholesterolemia, 6 patients were with secondary prevention and 12 patients were on rosuvastatin for primary prevention. Intolerance was caused by doses ranging from 5 mg to 40 mg (patients; n = 9 on 5 mg; n = 8 on 10 mg; n = 1 on 20 mg; n = 1 on 40 mg). The length of time before discontinuing due to intolerance varied from 3 months to 3 years with no apparent relationship between this and dose. Muscle aches were the most common side effect experienced. None of the patients developed diabetes mellitus.
Statin | Number of intolerant Patients | Most common dose | Average length of time before intolerance | Side effects experienced | Most common side effect (number) |
---|---|---|---|---|---|
Simvastatin | 17 | 40 mg | 7.6 months | Muscle problems, raisedcreatine kinase, headache, fatigue, joint pain, Itching, eczema, neuropathy, sleep disturbance, Depression | Muscle aches (6) |
Atorvastatin | 16 | 40 mg | 8.25 months | Muscle problems, raisedcreatine kinase, joint pain, Itching, neuropathy, decreased appetite, abdominal pains, raised liver function tests | Muscle aches (8) |
Pravastatin | 9 | 10 mg | 14 months | Muscle problems, itching, nightmares, urinary problems | Muscle aches (5) |
Rosuvastatin | 19 | 5 mg | 5.8 months | Muscle problems, fatigue, joint pain, memory loss, gastrointestinal bleed, diarrhoea | Muscle aches (13) |
Fluvastatin | 1 | 10 mg | 6 months | Gastrointestinal problem | Gastrointestinal problem |
12 females, 5 males, average age 60.5 years. 2 patients diagnosed with familial hypercholesterolemia, 2 patients were with secondary prevention and 13 patients with primary prevention. Intolerance was caused by doses ranging from 10 mg to 80 mg (patients; n = 4 on 10 mg; n = 5 on 20 mg; n = 7 on 40 mg; n = 1 on 80 mg). The length of time before discontinuing due to intolerance varied from 2 weeks to 3 years, with no apparent relationship between this and dose. A wide variety of side effects were experienced, with the most common being muscle aches. None of the patient developed diabetes mellitus whilst on simvastatin.
7 female, 9 male, average age 62.6 years. 4 patients diagnosed with familial hypercholesterolemia, 5 patients were with secondary prevention and 7 patients were on atorvastatin for primary prevention. Intolerance was caused by doses ranging from 10 mg to 80 mg (patients; n = 3 on 10 mg; n = 2 on 20 mg; n = 7 on 40 mg; n = 1 on 60 mg and n = 3 on 80 mg). The length of time before discontinuing due to intolerance varied from 2 months to 2.5 years with no apparent relationship between this and dose. Muscle aches again being the most common side effects experienced. One patient developed impaired glucose tolerance whilst on 40 mg atorvastatin after 12 months.
5 female, 4 male, average age 59.6 years. 1 patient diagnosed with familial hypercholesterolemia, 4 patients with secondary prevention and 4 patients on pravastatin for primary prevention. Intolerance was caused by doses ranging from 10 mg to 40 mg (patients n = 7 on 10 mg; n = 1 on 20 mg; n = 1 on 40 mg). The length of time before discontinuing due to intolerance varied from 3 months to 3 years with no apparent relationship between this and dose. The most common side effect experienced was muscle aches. One patient developed diabetes mellitus whilst on 10 mg pravastatin for 18 months.
One 52-year-old male developed intolerance to fluvastatin 10 mg whilst being treated for secondary prevention; stopping due to gastrointestinal problems after 6 months.
11 patients were intolerant to multiple statins, with one patient intolerant to 3 statins (atorvastatin, rosuvastatin and pravastatin); the rest being intolerant to 2 statins. Majority patients (n = 8) were intolerant to rosuvastatin.
The patients intolerant to statins were commenced on alternative lipid lowering therapy, which was either low dose alternative statin only, combination of low dose alternative statin with non-statin lipid modifying therapy or only non-statin lipid modifying therapy. The data was collected with respect to total cholesterol, LDL cholesterol, and new cardiovascular eventafter an average period of ten months of starting the alternative lipid lowering therapy.
Alternative statin only therapy (n = 15)
Overall reduction in both total cholesterol and LDL cholesterol was seen on statin only therapy (13%, 17% respectively). 1 patient was on atorvastatin (10 mg for 4 months), 4 patients on pravastatin (10 - 40 mg for average 9.5 months), 10 patients were on rosuvastatin (patients n = 9 on 5 mg, n = 1 on 20 mg for an average of 11 months). Pravastatin had a reducing effect on all 4 patients’ lipids, with an average reduction of 23% in total cholesterol and 33% reduction in LDL-cholesterol. Those on rosuvastatin had an average reduction in both total cholesterol (10%) and LDL-cholesterol (14%).
Alternative statin plus non-statin lipid lowering therapy (n = 25)
Majority of the patients (n = 19), were on a low dose statin (rosuvastatin 5 - 10 mg daily was the most commonly used statin) plus non-statin lipid lowering drug (ezetimibe, fibrate, bile acid sequestrant). Patients on statin plus ezetemibe (n = 15) showed a reduction in both their total cholesterol and LDL-cholesterol with average
Alternative lipid lowering therapy | Number of Patients | Absolute change in lipid parameters | Average duration of therapy (Months) | Cardiovascular event during therapy | ||
---|---|---|---|---|---|---|
Total Cholesterol (%) | LDL-cholesterol (%) | |||||
Alternative statin only | Low dose statin | 15 | −10.3 | −14 | 10.2 | 1 |
Alternative statin plus non-statin lipid lowering therapy | Statin plus ezetemibe | 15 | −28.5 | −37.3 | 10.9 | 1 |
Statin plus fibrate | 3 | −11.2 | −16.2 | 6 | 0 | |
Statin plus bile acid sequestrant | 1 | 0 | +2.2 | 10.0 | 0 | |
Statin plus more than one non-statin therapy | 6 | −16 | −4 | 9.8 | 0 | |
Non-statin lipid lowering therapy only | Ezetemibe | 3 | +17.7 | +21.7 | 9.6 | 0 |
Fibrate | 2 | −29 | −32.1 | 10.5 | 0 | |
Bile acid sequestrant | 2 | +5.5 | 0 | 11 | 0 | |
Omega 3 fatty acid | 3 | +5.1 | +25 | 15.5 | 0 |
reductions of 28.5% and 37.3% respectively after an average of 10.9 months. Three patients were on statin plus fibrate combination and showed an average reduction in total cholesterol (11.2%) and LDL-cholesterol (16.2%) after an average 6 months on this combination. Only one patient was on statin plus bile acid sequestrant and showed no change in their total cholesterol but an increase in LDL-cholesterol (2.2%). Six patients were taking a statin plus multiple non-statin lipid lowering therapies and showed a reduction in both total and LDL-cholesterol (16% and 4% respectively) after 10 months on average.
Non-statin lipid lowering therapy only (n = 10)
A non-statin lipid lowering therapy included ezetimibe, fibrates, bile acid sequestrants, and omega 3 fatty acid. Only 2 of these patients on fenofibrate showed any reduction in their total cholesterol level, the rest having either no change at all or an increase in total cholesterol.
One patient experienced a myocardial infarction and underwent a coronary artery bypass graft whilst on a combination of pravastatin 40 mg and ezetimibe 10 mg. Another patient who was only on pravastatin 40 mg also had myocardial infarction whilst on this medication. Both these patients were on lipid lowering therapy for primary prevention.
Recent years have seen tremendous increase in statin prescription [
Several risk factors have been proposed to potentiate the statin related adverse effect on muscles. This includes, dose and intensity of statin, advanced age, gender particularly female sex, low body mass index and concomitant medications. There were more women (n = 30) than men (n = 20) in our study group; with the female group having an average age nearly 10 years older than that of the male group. The statin intolerance was seen with all doses and intensity of statins in our study patients. It has been suggested that statin dose may be responsible for muscle effect by increasing the serum concentration of statin, nevertheless no link has been seen between intramuscular statin concentration and myopathy [
Statin intolerance can be managed by changing either the dose or type of statin or through using other non- statin lipid lowering therapy such as ezetimibe, fibrates, omega-3 fatty acid and bile acid sequestrants. Our study patients who were intolerant to statins were able to tolerate either alternative low dose statin only or combination of alternative low dose statin plus ezetimibe. The most tolerable alternative lipid lowering therapy in our cohort of patients waseither low dose rosuvastatin (5 - 10 mg daily) or pravastatin monotherapy or in combination with ezetemibe.
We assessed the impact of this lipid lowering therapy by calculating the change in total cholesterol and LDL cholesterol after starting the alternative lipid lowering therapy in statin intolerant patients. Recent meta-analysis has shown that reduction in LDL cholesterol by 2 - 3 mmol/L reduces the cardiovascular risk by 40% - 50% [
The lipid lowering therapy in statin intolerant patients resulted in reduction in total cholesterol and LDL cholesterol after an average period of ten months (
Number of patients | Average reduction in total cholesterol (%) | Average reduction in LDL-Cholesterol (%) | |
---|---|---|---|
Primary Prevention | 29 | 16 | 19 |
Secondary Prevention | 15 | 13.2 | 22.2 |
Familial Hypercholesterolemia | 6 | 13.2 | 13 |
There are limitations to our study as it is a small observational study of shorter duration. Further pragmatic long term clinical trials are required to determine the most clinically effective alternative lipid lowering therapy in patients intolerant to statins.
Our study suggests that alternative lipid lowering therapy in statin intolerant patients is able to reduce total cholesterol and LDL cholesterol. Pravastatin is the most tolerant statin whereas rosuvastatin is the most intolerant statin. Combination of low dose statin (pravastatin or rosuvastatin) and ezetemibe is clinically effective and tolerant alternative lipid lowering therapy in statin intolerant patients. Non-statin lipid lowering monotherapy is clinically ineffective in statin intolerant patients