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Statin Associated Rhabdomyolysis

RHABDOMYOLYSIS BACKGROUND

Bayerís voluntary withdrawal of cerivastatin (Baycol) from the U.S. market in August, 2001 has prompted questions about the safety of all hydroxymethylglutaryl-coenzyme A reducatase inhibitors (statins). Interest in rhabdomyolysis, the most serious statin toxicity, has also increased.

While the terminology used to describe muscle toxicity has been imprecise and sometimes inconsistent, the ACC/AHA/NHLBI CLINICAL ADVISORY ON STATINS has chosen to standardize the terms as follows:

Myopathyóa general term referring to any disease of muscles; myopathies can be acquired or inherited and can occur at birth or later in life.

Myalgiaómuscle ache or weakness without creatine kinase (CK) elevation.

Myositisómuscle symptoms with increased CK levels.

Rhabdomyolysisómuscle symptoms with marked CK elevation (typically substantially greater than 10 times the upper limit of normal) and with creatinine elevation (usually with brown urine and urinary myoglobin).

After the withdrawal of cerivastatin , the FDA performed a detailed review of all reports of fatal rhabdomyolysis in their Adverse Event Reporting System.  They also obtained the number of prescriptions dispensed since marketing of each statin began in the U.S. 866 cases of rhabdomyolysis had been reported to the FDA. Over half of the cases involved cerivastatin. Over half involved a statin alone, less than half involved a statin with gemfibrozil. 308 cases involved other drugs known to affect the cytochrome P450 system. More than 80% of patients were hospitalized, 24% developed renal failure and 14% required dialysis. Among the 866 cases, there were 80 fatalities. When the FDA investigators charted the deaths compared to the number of prescriptions written, fatal rhabdomyolysis was extremely rare (less than 1 death/million prescriptions). The rate of fatal rhabdomyolsis for cerivastatin was far greater than that for other statins (16 to 80 times higher). Even after excluding cases in which cerivastatin was administered with gemfibrozil, the reporting rate for fatal rhabdomyolysis with cerivastatin monotherapy (1.9 deaths per million prescriptions) was 10 to 50 times higher than for other statins.

TABLE 1  FDA Data

Variable

lovastatin

pravastatin

simvastatin

fluvastatin

atorvastatin

cerivastatin

Total

Date Approved

8/31/87

10/31/91

12/23/91

12/31/93

12/17/96

6/26/97

 
Fatal Cases of rhabdomyolysis *

19

3

14

0

6

31

73

Millions of prescriptions

99.2

81.4

116.1

37.4

140.4

9.8

484.3

Reporting rate / million prescriptions

0.19

0.04

0.12

0

0.04

3.16

0.15

*Cases reported to FDA before June 26, 2001 (Adopted without permission from Staffa et al N Engl J Med 2002; 346:539-540.)

Similar data have been charted by the United Kingdom and World Health Organization's drug safety divisions and are presented in the following tables:

 

TABLE 2 United Kingdom Data

Variable* simvastatin pravastatin fluvastatin atorvastatin cerivastatin
Total # prescriptions (1/1/94 to 1-1-2002) 22,836,747 6,016,920 2,830,006 12,704,854 2,541,792
Total # of musculoskeletal adverse events 875 177 129 438 258
Frequency of musculoskeletal adverse events (% total prescriptions)                   0.004 0.003 0.005 0.003 0.01
Total # of reported rhabdomyolysis cases 38 3 2 13 12
Frequency of rhabdomyolysis 0.0002 0.00005 0.00007 0.0002 0.0004

*Adverse event data obtained from the UK Medicines Control Agency.  Prescription data as assessed by Merck Sharp & Dohme using UK Mediplus data from IMS Health.  (Adopted without permission from Evans, et al.  Drug Safety 2002;25:649-663).

TABLE 3 World Health Organization Data

 (These data are not adjusted for number of prescriptions.)

Variable lovastatin simvastatin pravastatin atorvastatin fluvastatin cerivastatin
# Reports 21,541 15,149 6,208 3,188 2,061 387
% Myalgia 6.2% 8.4% 6.4% 7.6% 9.1% 14.4
% Myopathy 1.8% 0.9% 1.0% 0.1% 1.2% 0.02%
% Rhabdomyolysis 0.2% 0.4% 0.3% 0.5% 0.5% 2.1%

Reported to the World Health Organization's International Drug Information System database.  Hamilton-Craig, I.  Med J Aust;2001;175:486-489.

The Adverse Event Reporting system is acknowledged to represent only 1% of all serious events so this is only a partial survey of the toxicity of these drugs. Nevertheless, review of these data strongly suggests that there were no clinically important differences in the rate of fatal complications among the five statins still available in the U.S. (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin). The rates of severe myopathy appear to be equivalent among all of the approved statins.

While the FDA's Adverse Event Reporting system underestimates the frequency of this problem, even controlled studies suggest that rhabdomyolysis is rare.  Both randomized trials and community surveillance have demonstrated an extremely low incidence of one case per 10,000 person years for serious muscle toxicity in patients receiving statins.  

Patients presenting with rhabdomyolysis on statins have obvious muscle tenderness, weakness and systemic symptoms of malaise and fatigue.  Their statins should be discontinued immediately and the CK value determined.  A urinary myoglobin may be confirmatory if the diagnosis is in question.  Depending upon the patients debility and their ability to maintain hydration, the majority of cases require hospitalization. 

RHABDOMYOLYSIS RESEARCH

We are currently doing several studies of patients with post-rhabdomyolysis myopathy and have a major interest in acute statin-induced rhabdomyolysis.  If you have admitted a possible case of statin-associated rhabdomyolysis please contact us using the "CONTACT" link.  We have evaluated over 100 statin-induced rhabdomyolysis cases and have several evaluation and management recommendations that are not ready for web-publishing.

CONFOUNDING DRUG THERAPIES

Early reports of statin induced rhabdomyolysis suggested that the statin levels in many of these patients were significantly elevated.  This raised the possibility that many patients became intoxicated on their statins because of decreased clearance.  In fact, all statins except for pravastatin undergo metabolism via the cytochrome P 450 system and many drugs affecting this system have been associated with myopathic reactions.  Interference with the P450 system clearly doesn't explain the entire problem since the most common associated drug with statin induced myopathy is gemfibrozil which does not use this metabolic pathway.  Similarly, pravastatin which is not dependent on the P450 pathway for its breakdown has been associated with rhabdomyolysis when P450 affecting drugs were also involved.  The fact that one half of all drugs involve P 450 metabolism further confuses the case for this interaction.  Drugs and substances that have been associated with statin induced rhabdomyolysis are listed on the following table:

Drugs Affecting Lipid Metabolism Drugs Involving P450 Interactions Substances Involving P450 Interaction
gemfibrozil, clofibrate, benzafibrate cyclosporine grapefruit Juice
Niacin erythromycin, clarithromycin  
  azole antifungals: itraconazole, ketoconazole  

While the incidence of serious muscle toxicity or rhabdomyolysis due to statins is extremely low, minor muscle complaints are more common.  Many patients believe that their minor muscle complaints are attributable to statin therapy. Statin toxicities without muscle breakdown, with normal CK, are more difficult to diagnose.

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What is Known about Statin Associated Myopathy with Normal CK?

Success and Proliferation of Statins

Cholesterol lowering therapy with HMGCoA reductase inhibitors (statins) convincingly reduces death and myocardial infarction among patients with coronary heart disease Application of the National Cholesterol Education Programís ATP III guidelines could lead to as many as 36 million patients receiving this therapy in the United States.

The remarkable success and proliferation of statin therapy is largely due to the absence of significant toxicity occurring in more than 50,000 patients included in randomized controlled trials of statins over the last 16 years. Myopathyí defined as unexplained muscle pain or weakness accompanied by a CK greater than 10 times normal, occurred in only one case per 10,000 person years among subjects randomized to statin treatment in the 4S and Heart Protection Study trials. An identical incidence has been calculated when statins are used in the community at large. Despite this very low incidence of serious muscle toxicity, many patients in these trials have had minor muscle complaints. However, these minor muscle complaints occur with the same frequency among patients randomized to placebo. Consequently, it is generally believed that patients whose CK levels remain normal are not having a reaction to these drugs, despite complaints of muscle symptoms. Nonetheless, both minor and major muscle toxicities related to statin therapy are not well understood and have been poorly studied. The recent withdrawal of cerivastatin from the market has highlighted both our ignorance and the need for post-marketing surveillance of these therapies. Several lines of evidence suggest that there are common minor myopathic toxicities in addition to the rare rhabdomyolytic reactions to these drugs.

Evidence for Statin Toxicity without Rhabdomyolysis from Trials

When statin therapy is used in larger than conventional doses, the incidence of both rhabdomyolysis and of minor muscle complaints increases. While the incidence of muscle complaints with normal CK in patients participating in statin trials has been similar in the treated and placebo groups there is a tendency to increased minor muscle complaints and to rhabdomyolysis at higher dosages of statin. In the EXCEL trial in which patients were treated with low (40 mg) or high (80 mg) dose lovastatin, the group that received 80 mg daily demonstrated a trend to more muscle complaints than the placebo group (9.3% of 1352 high dose patients vs. 7.5% of 1352 low dose patients and 7.5% of placebo patients). Similarly while simvastatin 80 mg daily was associated with only 2.3% myalgias with normal CK, myalgias occurred in 5.7% of patients receiving a 160-mg daily preparation. This increase in minor muscle complaints and the occurrence of rhabdomyolysis caused Merck to withdraw plans to market the larger dose of simvastatin.

Evidence for Statin Toxicity without Rhabdomyolysis from Laboratory Models

Cell culture studies and animal models of statin toxicity have repeatedly demonstrated that histochemical and biochemical toxicity develops at doses well below those which cause rhabdomyolysis or CK enzyme leakage. In myocyte cell culture, statin toxicity causing morphological abnormalities, decreased protein synthesis and decreased ATP levels occurs at doses lower than those required to produce enzyme leakage or CK elevations. In a rabbit model, muscle toxicity and myotonia are not always associated with elevated CK. There is thus evidence that muscle toxicity occurs at statin dosages well below those required to cause rhabdomyolysis and it is reasonable that the muscle complaints of some patients on statins with normal serum CK might represent a toxicity below the threshold needed to trigger CK elevation.

Evidence for Statin Toxicity without Rhabdomyolysis from Case Reports

Despite the remarkable safety record of statins in clinical trials, there are a number of small studies and credible case reports describing myopathic complaints in patients on statins with normal CK levels. One of our co-investigators described 15 patients from a single cholesterol clinic with muscle stiffness and tenderness that had normal CK tests. Muscle biopsies in these patients revealed ragged red fibers consistent with mitochondrial myopathy. Others have described patients with reproducible muscle pain on statins despite normal CK. Isoprostane levels are elevated in some patients with muscle aches on statins despite normal CK suggesting an oxidation injury to the muscle.

Despite the success of these therapies, several lines of evidence suggest that there may indeed be a poorly studied minor muscle toxicity related to statin use. Our preliminary work suggests that certain patients with muscle complaints on statins are indeed suffering from myotoxicity despite normal CK levels.  In a brief report published in the Annals of Internal Medicine, October 1, 2002, we present four such patients.  These patients were repeatedly able to identify blinded statin therapy due to their symptoms.  They had measurable weakness while on statins which reversed on placebo.  Biopsies of these patients while toxic on statins revealed similar histopathology indicating myopathy due to mitochondrial dysfunction.  The IMPOSTER (Is Myopathy Part Of Statin ThERapy?) Trial is a double blinded placebo controlled crossover evaluation designed to clarify the clinical description of statin myopathy with normal CK. 

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How to Evaluate Patients with Muscle Symptoms on Statins?

We have been evaluating patients in both the IMPOSTER trial and in consultative practices since 1998.  Certain patterns of symptoms seem to reliably predict the patients with the most severe myopathy on muscle biopsy.  These patients usually complain of muscle aching in the quadriceps, gluteals and biceps femoris.  They describe burning pain in these muscle groups during exercise such as mounting stairs.  Some patients complain of weakness particularly of the hip musculature.  They often complain of progressive inability to rise from a low chair a bed or from squatting position.  The most myopathic patients have noted increased dyspnea on exertion while on statins. 

When we analyzed preliminary data from the IMPOSTER trial, patients who correctly identified blinded statin therapy had significant weakness on standardized muscle testing including:  hip abduction measured by Nicholas Manual Muscle Testerô, standing time from a low chair, and stair stepping. 

Many of the myopathic patients had felt markedly improved when they stopped their statin therapy for two weeks before entry into the trial. 

While our findings are preliminary, we have developed a pathway for evaluating patients who feel that their muscle aches are due to statin therapy.  We evaluate patients who need statin for secondary prevention or are diabetic somewhat differently from those who are receiving statins as primary prevention.  This evaluation starts with administration of a myopathy patient questionnaire to search for alternate causes of myopathy.  Next we measure CK, sedimentation rate (ESR) and thyroid-stimulating hormone (TSH).  If the CK is elevated we search for alternate explanations such as exercise or hypothyroidism.  If no alternative presents itself we retest the CK off statins for 6 weeks.  In a patient requiring statin for secondary prevention whose CK remains elevated we proceed directly to percutaneous muscle biopsy.  If the CK returns to normal we consider the patient to have a likely reaction to statins and choose alternaitve cholesterol lowering therapies.  Patients with normal CK, ESR and TSH are divided into those with typical symptoms and those atypical symptoms.  In patients with atypical symptoms we generally search for alternative explanations for their symptoms.  In patients with typical symptoms we stop statin therapy for 2 weeks.  If their symptoms resolve and they were receiving statins for primary prevention we recommend alternate lipid lowering therapies.  If their symptoms resolve and they require statins for secondary prevention a higher level of evidence is sometimes required.  In a patient with typical myopathic symptoms that improve off statins for whom statin therapy is an indispensable part of their risk modification program a percutaneous biopsy may be necessary to decide whether statin should be stopped.  These patients are placed back on statins and biopsied after they have been on therapy for at least 6 weeks.

 

Evaluation of Muscle Symptoms in Patients on Statins

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How to Treat Patients with Hypercholesterolemia Who Can't Take Statin Therapy

We see many patients who have already suffered statin induced rhabdomyolysis or who have suspected statin associated myopathy with normal CK.  Many of these patients have biopsy proven myopathy.  Some have less certain diagnoses because of typical symptoms or marked improvement during a two week trial off of statins.  For each of theses patients, the decision about how best to treat their hyperlipidemia is based on the balance between how important it is to lower their plasma lipids and how certain the diagnosis of statin associated myopathy is.  At one extreme are patients whose statin therapy was based on elevated lipid levels in a low risk individual (primary prevention) and who may have a solid diagnosis of statin induced myopathy by biopsy.  These patients are told to remain off of statins and depending on the severity of their lipid disorder we may recommend some combination of the therapies below.  At the other extreme are high risk individuals, e.g. post myocardial infraction with diabetes, in whom the suspicion of statin associated myopathy is less certain.  Barring pathological evidence of myopathy or severe weakness we usually continue these patients on a reduced dose of statin therapy in combination with some of the therapies described below.

No matter where the patient falls on the spectrum of atherosclerotic risk vs. certainty of myopathic diagnosis, we explain the uncertainties and give them this hand out so that they can participate in the treatment plan (patient handout).

The therapeutic options which we offer to patients with hyperlipidemia who can not take statins include:

1. Low Fat Diet 

The best low fat diets are also high in viscous fiber and in plant sterols.  The best tested of these diets, known as the Portfolio Diet uses additional dietary options to increase the effectiveness of a diet already consisting of reduced saturated fats and dietary cholesterol. This diet conforms to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III recommendations. In clinical trials, the Portfolio Diet reduced LDL Cholesterol levels up to 29% comparable to some statin therapies. The main components of the Portfolio Diet are summarized here:

  • this is a vegetarian diet

  • margarine enriched in plant sterol esters is used daily

  • 10 grams of viscous fiber daily per 1000 calories of diet consumed:  oats, barley and psyllium (Metamucil)

  • okra and eggplant are included as vegetable sources of viscous fiber, with 100 and 200 grams of these vegetables on alternate days

  • 21.4 grams of soy protein daily per 1000 calories consumed:  soy milk, soy meat alternatives

  • 14 grams of whole almonds daily per 1000 calories consumed

A typical dayís diet is formatted in the "Further Reading" section below.

2. Mediterranean Diet
3. Exercise
4. Resins and Cholesterol Absorbing Drugs:

Brand Name Generic Name
WelChol colesevelam
Questran cholestyramine
Colestid colestipol

5. Non-statin Cholesterol Lowering Drugs

Brand Name Generic Name
(n/a) niacin*
Lopid gemfibrozil
Tricor fenofibrate
Zetia ezetimibe

* niacin is available in multiple slow release formulations

We have discovered that over half of patients who are intolerant of statins have muscle side effects on these other cholesterol lowering drugs as well.  Despite the fact that some of these drugs are marketed as a safe alternative for patients where statin muscle toxicity is a concern, they have not been tested in this patient group.  We have now published our experience with a high incidence of ezetimibe causing muscle symptoms in patients with previously diagnosed statin muscle toxicity and a report of ezetimibe monotherapy causing myopathy is in review.  Our preference as of 2005 is to proceed with resin therapy as the first alternative lipid-lowering option in any patient who is statin intolerant.

6. Plant Stanols and Sterols 2 grams a day at lunch are advised (see 1. above)

7.  Policosinol (an aliphatic alcohol made from sugar cane wax with HMG-CoA reductase properties and no described myopathy).  This neutraceutical is not regulated by the FDA and has been tested and used in Cuba.  Available data are tabulated and referenced on the policosanol page.  There is also a patient information sheet available on the join a study page.  We have completed a preliminary study of 25 patients with prior statin intolerance using a U.S. source of policosanol (Greco T, 2003 pending publication).  While there was no myopathy in this indicator patient group, the U.S. formulation did not lower cholesterol levels as the Cuban formulations have.  Thus we advise caution before recommending this unregulated neutraceutical.

8.  Red yeast rice   This product is included in a number of neutraceuticals which have been banned by the FDA.  They contain active statin and have been associated with both myopathy and rhabdomyolysis.  These products are dangerous in patients with prior reactions to statins.

We inform the patients that none of these options will be as powerful as a statin in lowering cholesterol.  However, we reassure them that many therapies such as the Mediterranean Diet and Niacin have benefits in preventing atherosclerosis and its complications beyond those which can be explained by lowering cholesterol alone. We are all eager to see our patients cholesterol levels fall as a good sign that a therapy is working but some of these therapies work well despite producing less cholesterol reduction than statins.

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Percutaneous Muscle Biopsy

We believe that one of the reasons that statins have been used for so long without evidence of statin myopathy with normal CK is that standard muscle biopsy techniques are not easily applied to patients with cardiovascular disease.  The standard procedure involving surgery and often anesthesiology is not likely to be requested in patients with serious cardiovascular conditions especially if they have muscle symptoms with a normal CK.  The percutaneous technique is relatively painless and can be performed in an outpatient surgicenter in under 20 minutes.  We have modified this technique that is well described in the literature.  We use a lidocaine bicarbonate mixture in both the superficial skin and in the vastus lateralis fascia.  Conscious sedation is required in only half of the patients.  Our patients remain on aspirin although we stop warfarin for five days in patients who are anticoagulated.  They are discharged with a pressure dressing which they remove the following morning when they return to full activity.  We ask patients to keep their wound dry for four days.

The procedure is well tolerated.  Patients describe the discomfort as similar to an intramuscular injection.  Occasional patients experience cramping with each biopsy in which case we use midazolam for its anti-spasm effects.  The day following the procedure patients feel soreness in their lateral thigh that does not interfere with activity.

We send fresh specimens to pathology for processing and standard muscle stains.  We also request COX and SDH stains as well as full electron microscopy in this patient group.

Bergstom Muscle Biopsy Needle

Post-Rhabdomyolysis Syndromes

We have discovered that a significant number of patients remain impaired after and acute episode of statin-induced rhabdomyolysis.  Others who feel they have returned to normal have persistent measurable metabolic abnormalities.  Some of these patients derive benefit from therapies directed at their metabolic defects. 

We have shown that exhaled gas analysis may provide insight into patients with persistent symptoms after myositis or rhabdomyolysis.  Most of these patients have a respiratory quotient (respiratory exchange ratio) of over 0.85 when measure in the fasting state.  Normally the respiratory quotient in the fasting state is 0.75 ± 0.03 which is consistent with oxidation of fatty acids.  The elevation in respiratory quotient suggests impaired fatty acid oxidation in these individuals as does the myo-pathology.  We now use exhaled gas analysis in fasted patients to discern the significance of post-myopathy symptoms.

If you have patients that fit this category we are happy to evaluate them or include them in IRB-approved evaluations of their muscle defects.  You can contact us via the contact link below.

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Further Reading

Statin Advisory

Joint American College of Cardiology, American Heart Association, National Heart Lung and Blood Institute Statins Advisory (June, 2002).

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins (view)

ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins (PDF)

Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults

Rhabdomyolysis

McKelvie PA, Dennett X. Myopathy Associated with HMG-CoA Reductase Inhibitors (Statins: A Series of 10 Patients and Review of the Literature. J Clin Neuromusc Dis 2002;3:143-148.

Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis [letter]. N Engl J Med 2002; 346:539-540.

Chang JT, Green L, Parks M, Staffa J. Clinical characteristics of U.S. cases of rhabdomyolysis associated with statin use [abstract].                

Graham DJ, Staffa A, Shatin D, Andrade SE, Schech SD, La Grenade L, Gurwitz JH, Chan KA, Goodman MJ, Platt R.  Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs.  JAMA 2004; 292:2585-2590.

Statin Myopathy with Normal CK

Paul S. Phillips, MD, Richard H. Haas, MD, Sergei Bannykh, MD, PhD, Stephanie Hathaway, RN, Nancy L. Gray, RN, Bruce J. Kimura, MD, Georgirene D. Vladutiu, PhD, John D.F. England, MD and the Scripps Mercy Clinical Research Center. Statin Associated Myopathy with Normal Creatine Kinase. Ann Int Med 2002;137:581-585.

Abstract


Background: Muscle symptoms in patients treated with statins who have normal creatine kinase levels are not well understood. Objective: To report four patients with biopsy confirmed myopathy and normal creatine kinase associated with statin use. Design: Case reports from preliminary analysis of an ongoing clinical trial.  Setting: A clinical research center in a community hospital.  Patients: Four patients with muscle complaints on statins which reversed during placebo use. Measurements: 1) Patientsí ability to identify blinded statin therapy and 2) standard measures of functional capacity and muscle strength.
Results: All four patients repeatedly distinguished blinded statin therapy from placebo. Strength testing confirmed weakness during statin therapy that reversed during placebo use. Muscle biopsies demonstrated evidence of mitochondrial dysfunction including abnormally increased lipid stores, fibers that did not stain for cytochrome oxidase activity, and ragged red fibers. These findings reversed in the three patients who had repeated biopsy when they were not receiving statins. Creatine kinase levels were normal in all four patients despite the presence of significant myopathy.  Conclusions: Some patients who develop muscle symptoms while receiving statin therapy have demonstrable weakness and histopathological findings of myopathy despite normal serum creatine kinase levels. (© 2002 American College of Physicians-American Society of Internal Medicine)
 

Phillips P, Haas R, Barshop B, et al. Utility of Abnormal 3-Methylglutaconic Aciduria (3MGA) in Diagnosing Statin Associated Myopathy. Atheroscler Thromb Vasc Biol Online Journal 2002; 22:878.

Kordas KC, Phillips PS, Golomb BA.  Clinical characteristics of 1053 patients with statin associated muscle complaints [abstract].  Arteriosclero Thromb Vasc Biol 2004;24:e51-e136.

Phillips PS.  Ezetimibe Muscle Toxicity [letter].  Ann Int Med 2004;141:649.

Alternatives to Statin Therapy

Diet

Denke MA. Dietary Prescriptions to Control Dyslipidemias. Circulation 2002;105:132-135.

American Dietetic Association on Plant Stanols

University of Texas, Southwestern on Plant Stanols

Cleveland Clinic Nutritional Advice

WebMD on Dietary Control of Cholesterol

Lipids Online Educational Resource Slides on Stanols

Dietary Portfolio References:

Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of cholesterol lowering foods vs lovastatin on serum lipids and c-reactive protein. JAMA 2003; 290:502-510.

Jenkins DJ, Kendall CW, Faulkner D, et al. A dietary portfolio approach to cholesterol reduction: combined effects of plant sterols, vegetable proteins and viscous fibers in hypercholesterolemia. Metabolism. 2002; 51:1596-1604.

Jenkins DJ, Kendall CW, Marchie A, et al. Direct comparison of a dietary portfolio of cholesterol-lowering foods with a statin in hypercholesterolemic participants. Am J Clinical Nutrition 2005; 81:380-7.
 

A typical day with the Dietary Portfolio:

Breakfast:
Hot oat bran cereal
Soy beverage
Blueberries
Sugar and psyllium (mixed with 10 ounces of water)
Oat bran bread
Margarine enriched with plant sterols
Double fruit jam
 

Snack
Almonds
Soy beverage
Fresh fruit
 

Lunch
Lentil soup with curry
Soy meat substitute
Oat bran bread
Margarine enriched with plant sterols
Lettuce
Tomato
Cucumber


Snack
Almonds
Soy beverage
Psyllium (mixed with 10 ounces of water)
Fresh fruit

Dinner
EntrÈe:
Tofu with eggplant ratatouille (eggplant, onions, peppers and tomatoes)
Pearled barley
Vegetables (broccoli, cauliflower)

Snack
Apple
Psyllium (mixed with 10 ounces of water)
Soy beverage
 

Neutraceuticals

National Institute of Health Center for Complementary and Alternative Medicine

Myopathy

National Institute of Neurological Disorders and Stroke (NINDS) Myopathy Page

Percutaneous Muscle Biopsy

Edwards R, Young A, Wiles M.  Needle biopsy of skeletal muscle in the diagnosis of myopathy and the clinical study of muscle function and repair.  N Engl J Med 1980; 302:261-271.

Evidence for Abnormal Fatty Acid Oxidation in Patients with Post-Myopathy Syndromes

Phillips PS, Phillips CT, Sullivan M, Naviaux RK, Haas RH and the Scripps Mercy Clinical Research Center.  Statin Myotoxicity is Associated with Changes in cardiopulmonary function.  Atherosclerosis 2004;177:183-188.

ABSTRACT   

The mechanism of the muscle toxicity associated with lipid-lowering therapy remains obscure. Pathological and biochemical findings in patients with statin myotoxicity suggest impaired fatty acid oxidation. Exhaled gas analysis can be used to assess substrate utilization including fatty acid oxidation. In order to determine if muscle toxicity due to lipid-lowering therapy might be related to abnormalities in lipid oxidation, exhaled gas analysis was performed in the fasted state on eleven patients subsequent to statin-associated myositis reactions. Results were compared to those of sixteen normal controls who were measured both on and off statin therapy. Post-myositis patients showed a depressed anaerobic threshold (AT) (p = 0.009) compared to controls while age-adjusted maximal oxygen consumption (VO2 max) and ventilatory efficiency (VE / VCO2) were not significantly different. The fasting respiratory exchange ratio (RER) of post-myositis patients off statins was abnormally increased (p = 0.00001) as was their S1-slope (p = 0.023). Controls demonstrated a significant increase in their RER while taking statins consistent with decreased lipid oxidation (p < 0.00001). These findings suggest that abnormal lipid oxidation in certain patients may predispose them to the myotoxicity caused by lipid-lowering therapies. (© 2004 Elsevier Ireland Ltd.)

Phillips PS, Ciaraldi TP, Dong-Lim K, Somma KA, Henry RR.  Myotoxic Reactions to Lipid Lowering Therapies Are Mediated by Impaired Oxidation of Fats [abstract].  J Am Coll Cardiol 2005;45:413A.


 

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