Some Patients Will Take Anything

Except What I Prescribe at the Pharmacy

The Cover of the Book Beth and I Edited on SAMS

Seven out of the eight most recent posts have dealt with statin-associated muscle symptoms (SAMS), but we are not yet finished with SAMS.

This post addresses how I manage muscle complaints in patients on statins. My opinion is based on clinical experience dealing with a lot of statin-intolerant patients and on my being the principle investigator on two, and a participating investigator on two more, NIH grants to our SAMS group at Hartford HealthCare.

Here’s my approach.

1. I take a history to see if the symptoms sound statin-related. The Taylor and Rosenson, National Lipid Association’s SAMS Clinical Index Score (1) with caveats (2) is a useful starting point. Like the Score, I am less suspicious if the symptoms are unilateral, associated with recent exercise, and occur in small muscle groups. I am more suspicious if the symptoms occurred after statin dose escalation.

2. I make sure the patient is not weak. Our studies demonstrate that weakness is rare with statin complaints. If the patient is weak, they might have Statin-Associated Autoimmune Myopathy (SAAIM), which can lead to serious, irreversible muscle damage.(3) We will discuss this important entity in a future post.

3. I look for other drugs that could have contributed to the statin becoming symptomatic, especially gemfibrozil and the -mycin antibiotics.

4. I measure creatine kinase (CK) levels. High CK levels are also an indicator of SAAIM. Most patient with SAMS do not have abnormal CK levels, but average CK levels are often slightly higher in true SAMS. We found this is the “SAMS verification phase” of our Co-enzyme Q10 grant discussed below. (4)

5. I stop the statin and monitor the response. Rapid resolution of symptoms within one-two weeks suggests that the statin is the culprit.

6. I reevaluate to make sure that the patient needs the statin. I don’t think statins should be in the water. Deciding if the patient needs the statin is always a difficult decision for me, because I do think statins benefit most patients, but some patients suffering with statins have no family history, no elevation in lipoprotein and no diabetes or prediabetes, so I wonder if they are really benefitting from lipid lowering. Coronary artery calcification scores imply a low 10-year risk of atherosclerotic cardiovascular disease (ASCVD), (5) but are not useful in the young because calcified disease has not had time to develop. But sometimes I am referred older patients with SAMS and a zero CAC. Such folks are unlikely to benefit from lipid-lowering so I cure the SAMS by stopping the statin.

7. I try another statin. My experience is that patients with SAMS get similar complaints with other statins. The exception may be pitavastatin, which is often, for unclear reasons, tolerated, but it is sometimes hard to get and sometimes not covered by insurance despite being generic.

8. If the symptoms went away with statin cessation, and the patient is willing, I try a lower dose of the statin. I have discussed previously that you get the largest LDL-C reduction per mg of statin at very low statin doses. (6) The longer-acting statins, atorvastatin and rosuvastatin, do not have to be given daily. We gave rosuvastatin, 5 or 10 mg, but primarily 5 mg, twice weekly to 40 of my clinic patients with possible statin myalgia and documented a 27% LDL-C reduction after only 4 weeks of treatment.(7). To my knowledge this only occurs with the longer acting statins.

9. I use ezetimibe 10 mg daily, either alone or preferably combined with a low-dose statin. I have discussed that doubling the dose of a statin produces only a 6% additional reduction in LDL-C whereas ezetimibe produces a 20% average LDL-C reduction if the patient is not on a statin and a 24% reduction if they are on a statin. (6) The larger percent reduction on a statin is probably due to the fact that the statin has already reduced the LDL-C, so the ezetimibe contribution is a larger percent of a similar reduction, or because statins increased intestinal cholesterol absorption. Many patients can reach their LDL-C goal with low dose or intermittent statin plus ezetimibe. Ezetimibe can also be given twice or thrice weekly because it also has a long half-life.

Some think that ezetimibe doesn’t work if the patient is already on a low-cholesterol diet. According to Dr. Google AI, the average American man or woman consumes about 348 and 242 mg of cholesterol daily whereas your liver excretes about 1000 mg daily in the bile. So, there is still plenty of intestinal cholesterol available for ezetimibe, even when the patient is not consuming much cholesterol.

10.If the statins are not tolerated, I consider bempedoic acid (BA) or Nexletol. Bempedoic acid has been documented to reduce ASCVD events in statin-intolerant subjects in the CLEAR Outcomes Trial.(8) Bempedoic acid works at a step in the stain pathway above hydroxy-methyl-glutaryl Co A reductase where statins work. Bempedoic acid does not appear to cause muscle effects. I previously discussed why this make sense. (9) To summarize that post, bempedoic acid is orally administered as a pro-drug. It has to be activated in the liver by a long-chain fatty acid reductase. This enzyme is present primarily in the liver with some in the kidney. If bempedoic acid slips by hepatic first pass metabolism and gets to skeletal muscle, the muscle does not have the enzyme to activate the drug.

I generally tell that metabolism story to patients because I think it helps them believe that the drug will not reproduce SAMS.

BA does have some baggage. It interferes with the renal excretion of creatinine and uric acid. The creatinine increase produces pseudo kidney impairment because the creatinine returns to baseline with drug cessation, but this creatinine increase often frightens patients and unaware clinicians. The CLEAR-Outcomes study documented that BA reduces cardiac events, (8) I was on that study’s executive committee and helped write the manuscript. I argued that we should not label the increase in creatinine “kidney injury” because it was not truly kidney injury. My objection failed. The increase in uric acid is more clinically significant because this can provoke gout so I do not use the drug in patients with a history of gout unless their uric acid is very low with treatment. Another issue with bempedoic acid is that some insurance companies won’t cover it or require a large copay.

11. I try red rice yeast (RRY) with or without ezetimibe. We participated in a study that failed to show that RRY was better tolerated than pravastatin in SAMS patients, (10) but RRY does contain a lot of lovastatin and does reduce LDL-C to a variable degree depending on the formulation. The use of RRY is discouraged by most authorities because it may contain citrinin, a renal toxin, if the citrinin is not removed by the manufacturers. The effect on LDL-C also varies by the batch of the product, which is another issue. But RRY does lower LDL-C and is often tolerated by those who do not like standard prescriptions. The usual over-the-counter dose is 1200 mg daily.

12.If the patient is willing, I might try colesevelam to reduce LDL. A packet of colesevelam before dinner can produce about a 17% reduction in LDL-C. Combined with ezetimibe, you can approach a 35% reduction. Bile-acid sequestrants are now out of favor because significant LDL-C reduction previously required large doses of the drug. For example, in the Lipid Research Clinics Primary Prevention Trial, we gave patients six packets of cholestyramine daily…the so-called “six pack.” But each molecule of cholestyramine had only one binding site for a molecule of bile acid. Colesevalam is engineered so that one molecule binds six molecules of bile acid/bile salt. Thus the six pack is now the one pack.

So, why before dinner? Dinner is usually the fattiest meal of the day and fat stimulates cholecystokinin, which stimulates contraction of the gall bladder to deliver bile to the gut. Thus, you get a bigger reduction if the drug is given near the fatty meal because it encounters more bile.

13.If the above does not work, I start the patient on a PCSK9 inhibitor, either the every-other-week monoclonal antibodies, Alirocumab or evolocumab, or the twice yearly mRNA inhibitor, inclisiran.

14.Sometimes I recommend Coenzyme Q10 (CoQ10)

Clinicians frequently ask me if Coenzyme Q10 (CoA10) works for patients with SAMS. CoQ10 is an important enzyme in mitochondrial function. Statins interfere with CoQ10 synthesis because CoQ10 is, like cholesterol, a product of the mevalonate synthetic pathway. CoQ10 blood levels decrease during statin therapy, but I had thought that this was due to the fact that CoQ10 is carried in lower density lipoproteins.(11) So, the decrease in CoQ10 could be due to the statin reducing the LDL or/and because statins had reduced CoQ10 production. I began to question my opinion that lower CoQ10 levels were due to lower LDL levels when I learned that blood CoQ10 did not decrease with bile-sequestrant resins or with PCSK9 inhibitors. There were some studies that suggested that CoQ10 did reverse symptoms in some SAMS patients, but these studies did not document that the patients’ symptoms were due to the statin before treatment. I have written about my skepticism. (11)

So, we did an NIH-funded Co-Q10 study, but we made sure we were only treating patients with SAMS. We randomized 120 of my patients, whom I thought had SAMS, to two, two-month preliminary trials of simvastatin 20 or placebo separated by a 4-week washout. (4) In other words, before entering the CoQ10 study, potential subjects were treated with placebo or simvastatin for two months and then switched to the other treatment. Only subjects who felt pain only on the statin were allowed into the CoQ10 protocol. Only 35.8% of my patients, whom I thought had SAMS, developed pain only on the statin. Another 17.5% experienced pain on both treatments; 29.2% felt pain only on placebo, and 17.5% did not develop any symptoms. With this approach only verified SAMS patients were entered into the CoQ10 Trial.

I believe we designed the CoQ10 treatment protocol well. We used CoQ10 purchased from Tishcon Corp, a CoQ10 producer recognized in the CoQ10 research community. We loaded the patients with 600 mg of CoQ10 for two weeks before placing them on 600 mg daily therapy. The usual CoQ10 dose is 200 mg daily. We used the high CoQ10 dose of 600 mg daily, to avoid criticisms from the supplement community that we underdosed the subjects.

Serum CoQ10 levels increased from 1.3 ± 0.4 to 5.2 ± 2.3 mcg/mL with simvastatin plus CoQ10 treatment, and decreased slightly with simvastatin plus placebo treatment (1.3 ± 0.3 to 0.8 ± 0.2) (p < 0.05). Pain scores for severity and interference with daily activities increased with simvastatin therapy, but did not differ whether or not the subjects were treated with CoQ10 or not. There was no change in muscle strength or exercise performance measured as VO2max with simvastatin with or without CoQ10. CoQ10 also did not affect the time to pain onset. We concluded that CoQ10 did not prevent or reduce SAMS.

An interesting observation is that those patients who had verified SAMS (n=43) from our verification study had higher creatine kinase (CK) levels on simvastatin that those who were not verified (n=77), 152±80 vs 117±68 U/L, respectively, p<0.05. That observation just confirms my belief that SAMS is real in some patients.

Even though we did not find a CoQ10 effect, I have had patients who swear by it. So if patients suggest it or want to try it or a have a friend who recommended it, I encourage them to do it. I especially do this in those patients who are fans of over-the-counter (OTC) remedies, the ones who will “take anything except what I write on a prescription pad,” and in whom I wonder if their symptoms are due to SAMS. My standard line is, “Our studies suggest that CoQ10 does not work, but I have had some patients who swear by it. It just might work for you.” The usual dose is 200 mg of the OTC brands, but they are often expensive. Sometimes it works, possibly because it was the patient’s idea, but I don’t really care how it works. My goal is to get patients who need statins to take them.

1. Taylor BA, Sanchez RJ, Jacobson TA, Chibedi-De-Roche D, Manvelian G, Baccara-Dinet MT, Khan I, Rosenson RS. Application of the Statin-Associated Muscle Symptoms-Clinical Index to a Randomized Trial on Statin Myopathy. J Am Coll Cardiol. 2017 Sep 26;70(13):1680-1681. PMID: 28935043

2. https://pauldthompsonmd.substack.com/p/nothing-cures-statin-muscle-complaints

3. Mammen AL. Statin-Associated Autoimmune Myopathy. N Engl J Med. 2016 Feb 18;374(7):664-9 PMID: 26886523

4. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015 Feb;238(2):329-35. PMID: 25545331

5. https://pauldthompsonmd.substack.com/p/you-got-a-ticket-to-ride

6. https://pauldthompsonmd.substack.com/p/the-statin-rule-of-6

7. Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol. 2008 Jun 15;101(12):1747-8. PMID: 18549851

8. https://pauldthompsonmd.substack.com/p/bempedoic-acid-for-patients-with

9. Nissen SE, … Thompson PD,… et.al Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023 Apr 13;388(15):1353-1364. PMID: 36876740

10.Halbert SC, … Thompson PD, Rader DJ, Becker DJ. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010 Jan 15;105(2):198-204. PMID: 20102918

11.Zaleski AL, Taylor BA, Thompson PD. Coenzyme Q10 as Treatment for Statin-Associated Muscle Symptoms-A Good Idea, but . Adv Nutr. 2018 Jul 1;9(4):519S-523S. PMID: 30032220

#statinsideeffects; #skeletalmuscle; #statins; #exercise; #statinmyopathy #exercisemuscleinjury; #atorvastatin; #SAMS; #clinicaltrials #coq10