Statin-associated muscle symptoms? Rechallenge!

 

New Orleans – An effective and well-tolerated, evidence-based strategy for managing statin-associated muscle complaints is to rechallenge with the same statin, Douglas S. Paauw, MD, said at the annual meeting of the American College of Physicians.

That being said, it must be recognized that statin-associated muscle symptoms remain an enigma. This was underscored in a recent study by investigators at Hartford (Conn.) Hospital, which suggested a need to reassess the whole concept of statin-associated muscle symptoms, according to Dr. Paauw, professor of medicine at the University of Washington, Seattle.

The researchers randomized 120 patients with rigorously verified prior statin-related muscle complaints to 8 weeks of simvastatin at 20 mg/day and placebo in a double-blind crossover trial. Thirty-six percent of patients experienced muscle pain on simvastatin, but not while on placebo. Twenty-nine percent had pain on placebo, but not on simvastatin. Eighteen percent had pain on both, and another 18% didn’t have pain on either (Atherosclerosis. 2017 Jan;256:100-4).

“This study just blows my mind,” Dr. Paauw said. “The bottom line here is we just don’t know. A third of our patients might have true statin-associated muscle symptoms, but the other two-thirds would fall into these other groups, where they don’t have symptoms if we give them a statin again or they might get worse with placebo. So, we’ve got to rethink this.”
 

First things first

Before embarking on same-statin rechallenge, several things should first be done. Step 1 is to check the patient’s thyroid-stimulating hormone, creatine kinase, and serum vitamin D levels. Step 2 is to look for possible explanatory drug interactions, with verapamil and diltiazem being particularly common offenders in statin users.

If a patient with statin-associated muscle symptoms has a low serum vitamin D level, Dr. Paauw will give high-dose supplemental vitamin D. This strategy is supported by a University of Cincinnati prospective study of 146 patients with intolerable muscle symptoms on two or more statins, all of whom had a serum vitamin D below 32 ng/mL. They were placed on long-term vitamin D₂ at 50,000-100,000 units per week and rechallenged with a statin. At 2 years of follow-up while still on supplemental vitamin D, 91% of patients had a normal serum vitamin D, and 95% of these previously statin-intolerant patients were on statin therapy without muscle complaints (N Am J Med Sci. 2015 Mar;7[3]:86-93).

 

Hypothyroidism increases statin toxicity. “I can’t overstate how important it is to check the thyroid-stimulating hormone to see if we’re dealing with something really simple,” Dr. Paauw said, “because trust me, treating hypothyroidism is much easier than treating statin-associated muscle symptoms.”

It has long been known that fibrates increase the risk of statin toxicity. Much less well recognized is that not all fibrates are the same in this regard: The risk is 15 times greater with gemfibrozil than with fenofibrate. The risk is also higher with verapamil or diltiazem than with nifedipine or amlodipine. Other important causes of drug interactions that increase statin toxicity include amiodarone, azole antifungals, protease inhibitors, erythromycin, and clarithromycin, but not azithromycin.

“Simvastatin and lovastatin are probably the worst as far as drug interactions,” Dr. Paauw cautioned. “They’re cheap, they’ve been generic for a long, long time, and a lot of times insurance companies want to move people to them. I try to move patients away from those two, because they are the dirtiest of the statins as far as side effects and drug interactions.”

When a drug interaction simply cannot be avoided, it’s best to have patients take the drugs 12 hours apart so peak levels don’t overlap, he added.

 

Same-statin rechallenge

If the checks of TSH, vitamin D, and possible drug interactions don’t turn up anything that needs fixing, it makes sense to launch same-statin rechallenge.

This management strategy was greenlighted by Canadian investigators in a retrospective study of 118 patients who presented to a tertiary lipid clinic with a history of muscle-related symptoms on at least two different statins.

At a median follow-up of 17 months, 71% of rechallenged patients were tolerating the same statin, compared with 53% of those who were switched to a different statin and 57% who were switched to ezetimibe or another nonstatin LDL-lowering drug. Moreover, 50% of patients in the same-statin rechallenge group achieved their target LDL, compared with only 15% switched to nonstatin therapy (Can J Cardiol. 2017 May;33[5]:666-73).

“I like this study; it helps a lot,” Dr. Paauw noted. “I think it’s worthwhile the first time they have muscle pain to get them off the statin and see if they feel better, so you become convinced that the statin may have had something to do with it. Then tell the patient, ‘Let’s just give it another try.’ ”
 

 

Alternative strategies

In the event of recurrent symptoms after same-statin rechallenge, it’s reasonable to switch to extended-release fluvastatin at 80 mg/day or low-dose rosuvastatin daily. Only if the patient remains symptomatic after trials of a couple of other statins does Dr. Paauw recommend turning to 5 mg of rosuvastatin twice weekly as a last resort.

Twice-weekly rosuvastatin is a popular treatment strategy in patients with intolerable muscle complaints on daily statin therapy. In a study of 40 such patients, twice-weekly rosuvastatin proved to be tolerated by 80% of them (Am J Cardiol. 2008 Jun 15;101[12]:1747-8). But the long-term effectiveness remains unknown.

“I think this is a really good option for our very statin-intolerant patients when nothing else works,” Dr. Paauw explained. “My only concern about this is we have no outcome data. Is twice-weekly rosuvastatin going to help reduce MI risk, especially if we give it for secondary prevention, as well as a daily statin? We know from this study that twice-weekly rosuvastatin can lower the lipids, but we also believe statins do more than just lower lipids. So, daily statin therapy is preferential.”

What about giving coenzyme Q₁₀? It makes sense mechanistically: Coenzyme Q₁₀ is an antioxidant, ubiquinone, and patients with statin-associated muscle symptoms are ubiquinone depleted.

 

But while oral coenzyme Q₁₀ is a popular OTC treatment for statin-associated muscle complaints, it’s not supported by any good evidence. A meta-analysis of six randomized trials totaling 302 participants found coenzyme Q₁₀ had no impact on symptoms (Mayo Clin Proc. 2015;90[1]:24-34).

In Dr. Paauw’s view, however, those trials didn’t address the proper question.

“The studies that have been done aren’t the right study,“ he said. “The study that needs to be done is for prevention: Do patients who start a statin and coenzyme Q₁₀ at the same time stay on the statin and feel better?”

He reported having no financial conflicts of interest regarding his presentation.

[email protected]

 

New Orleans – An effective and well-tolerated, evidence-based strategy for managing statin-associated muscle complaints is to rechallenge with the same statin, Douglas S. Paauw, MD, said at the annual meeting of the American College of Physicians.

That being said, it must be recognized that statin-associated muscle symptoms remain an enigma. This was underscored in a recent study by investigators at Hartford (Conn.) Hospital, which suggested a need to reassess the whole concept of statin-associated muscle symptoms, according to Dr. Paauw, professor of medicine at the University of Washington, Seattle.

The researchers randomized 120 patients with rigorously verified prior statin-related muscle complaints to 8 weeks of simvastatin at 20 mg/day and placebo in a double-blind crossover trial. Thirty-six percent of patients experienced muscle pain on simvastatin, but not while on placebo. Twenty-nine percent had pain on placebo, but not on simvastatin. Eighteen percent had pain on both, and another 18% didn’t have pain on either (Atherosclerosis. 2017 Jan;256:100-4).

“This study just blows my mind,” Dr. Paauw said. “The bottom line here is we just don’t know. A third of our patients might have true statin-associated muscle symptoms, but the other two-thirds would fall into these other groups, where they don’t have symptoms if we give them a statin again or they might get worse with placebo. So, we’ve got to rethink this.”
 

First things first

Before embarking on same-statin rechallenge, several things should first be done. Step 1 is to check the patient’s thyroid-stimulating hormone, creatine kinase, and serum vitamin D levels. Step 2 is to look for possible explanatory drug interactions, with verapamil and diltiazem being particularly common offenders in statin users.

If a patient with statin-associated muscle symptoms has a low serum vitamin D level, Dr. Paauw will give high-dose supplemental vitamin D. This strategy is supported by a University of Cincinnati prospective study of 146 patients with intolerable muscle symptoms on two or more statins, all of whom had a serum vitamin D below 32 ng/mL. They were placed on long-term vitamin D₂ at 50,000-100,000 units per week and rechallenged with a statin. At 2 years of follow-up while still on supplemental vitamin D, 91% of patients had a normal serum vitamin D, and 95% of these previously statin-intolerant patients were on statin therapy without muscle complaints (N Am J Med Sci. 2015 Mar;7[3]:86-93).

 

Hypothyroidism increases statin toxicity. “I can’t overstate how important it is to check the thyroid-stimulating hormone to see if we’re dealing with something really simple,” Dr. Paauw said, “because trust me, treating hypothyroidism is much easier than treating statin-associated muscle symptoms.”

It has long been known that fibrates increase the risk of statin toxicity. Much less well recognized is that not all fibrates are the same in this regard: The risk is 15 times greater with gemfibrozil than with fenofibrate. The risk is also higher with verapamil or diltiazem than with nifedipine or amlodipine. Other important causes of drug interactions that increase statin toxicity include amiodarone, azole antifungals, protease inhibitors, erythromycin, and clarithromycin, but not azithromycin.

“Simvastatin and lovastatin are probably the worst as far as drug interactions,” Dr. Paauw cautioned. “They’re cheap, they’ve been generic for a long, long time, and a lot of times insurance companies want to move people to them. I try to move patients away from those two, because they are the dirtiest of the statins as far as side effects and drug interactions.”

When a drug interaction simply cannot be avoided, it’s best to have patients take the drugs 12 hours apart so peak levels don’t overlap, he added.

 

Same-statin rechallenge

If the checks of TSH, vitamin D, and possible drug interactions don’t turn up anything that needs fixing, it makes sense to launch same-statin rechallenge.

This management strategy was greenlighted by Canadian investigators in a retrospective study of 118 patients who presented to a tertiary lipid clinic with a history of muscle-related symptoms on at least two different statins.

At a median follow-up of 17 months, 71% of rechallenged patients were tolerating the same statin, compared with 53% of those who were switched to a different statin and 57% who were switched to ezetimibe or another nonstatin LDL-lowering drug. Moreover, 50% of patients in the same-statin rechallenge group achieved their target LDL, compared with only 15% switched to nonstatin therapy (Can J Cardiol. 2017 May;33[5]:666-73).

“I like this study; it helps a lot,” Dr. Paauw noted. “I think it’s worthwhile the first time they have muscle pain to get them off the statin and see if they feel better, so you become convinced that the statin may have had something to do with it. Then tell the patient, ‘Let’s just give it another try.’ ”
 

 

Alternative strategies

In the event of recurrent symptoms after same-statin rechallenge, it’s reasonable to switch to extended-release fluvastatin at 80 mg/day or low-dose rosuvastatin daily. Only if the patient remains symptomatic after trials of a couple of other statins does Dr. Paauw recommend turning to 5 mg of rosuvastatin twice weekly as a last resort.

Twice-weekly rosuvastatin is a popular treatment strategy in patients with intolerable muscle complaints on daily statin therapy. In a study of 40 such patients, twice-weekly rosuvastatin proved to be tolerated by 80% of them (Am J Cardiol. 2008 Jun 15;101[12]:1747-8). But the long-term effectiveness remains unknown.

“I think this is a really good option for our very statin-intolerant patients when nothing else works,” Dr. Paauw explained. “My only concern about this is we have no outcome data. Is twice-weekly rosuvastatin going to help reduce MI risk, especially if we give it for secondary prevention, as well as a daily statin? We know from this study that twice-weekly rosuvastatin can lower the lipids, but we also believe statins do more than just lower lipids. So, daily statin therapy is preferential.”

What about giving coenzyme Q₁₀? It makes sense mechanistically: Coenzyme Q₁₀ is an antioxidant, ubiquinone, and patients with statin-associated muscle symptoms are ubiquinone depleted.

 

But while oral coenzyme Q₁₀ is a popular OTC treatment for statin-associated muscle complaints, it’s not supported by any good evidence. A meta-analysis of six randomized trials totaling 302 participants found coenzyme Q₁₀ had no impact on symptoms (Mayo Clin Proc. 2015;90[1]:24-34).

In Dr. Paauw’s view, however, those trials didn’t address the proper question.

“The studies that have been done aren’t the right study,“ he said. “The study that needs to be done is for prevention: Do patients who start a statin and coenzyme Q₁₀ at the same time stay on the statin and feel better?”

He reported having no financial conflicts of interest regarding his presentation.

[email protected]

 

New Orleans – An effective and well-tolerated, evidence-based strategy for managing statin-associated muscle complaints is to rechallenge with the same statin, Douglas S. Paauw, MD, said at the annual meeting of the American College of Physicians.

That being said, it must be recognized that statin-associated muscle symptoms remain an enigma. This was underscored in a recent study by investigators at Hartford (Conn.) Hospital, which suggested a need to reassess the whole concept of statin-associated muscle symptoms, according to Dr. Paauw, professor of medicine at the University of Washington, Seattle.

The researchers randomized 120 patients with rigorously verified prior statin-related muscle complaints to 8 weeks of simvastatin at 20 mg/day and placebo in a double-blind crossover trial. Thirty-six percent of patients experienced muscle pain on simvastatin, but not while on placebo. Twenty-nine percent had pain on placebo, but not on simvastatin. Eighteen percent had pain on both, and another 18% didn’t have pain on either (Atherosclerosis. 2017 Jan;256:100-4).

“This study just blows my mind,” Dr. Paauw said. “The bottom line here is we just don’t know. A third of our patients might have true statin-associated muscle symptoms, but the other two-thirds would fall into these other groups, where they don’t have symptoms if we give them a statin again or they might get worse with placebo. So, we’ve got to rethink this.”
 

First things first

Before embarking on same-statin rechallenge, several things should first be done. Step 1 is to check the patient’s thyroid-stimulating hormone, creatine kinase, and serum vitamin D levels. Step 2 is to look for possible explanatory drug interactions, with verapamil and diltiazem being particularly common offenders in statin users.

If a patient with statin-associated muscle symptoms has a low serum vitamin D level, Dr. Paauw will give high-dose supplemental vitamin D. This strategy is supported by a University of Cincinnati prospective study of 146 patients with intolerable muscle symptoms on two or more statins, all of whom had a serum vitamin D below 32 ng/mL. They were placed on long-term vitamin D₂ at 50,000-100,000 units per week and rechallenged with a statin. At 2 years of follow-up while still on supplemental vitamin D, 91% of patients had a normal serum vitamin D, and 95% of these previously statin-intolerant patients were on statin therapy without muscle complaints (N Am J Med Sci. 2015 Mar;7[3]:86-93).

 

Hypothyroidism increases statin toxicity. “I can’t overstate how important it is to check the thyroid-stimulating hormone to see if we’re dealing with something really simple,” Dr. Paauw said, “because trust me, treating hypothyroidism is much easier than treating statin-associated muscle symptoms.”

It has long been known that fibrates increase the risk of statin toxicity. Much less well recognized is that not all fibrates are the same in this regard: The risk is 15 times greater with gemfibrozil than with fenofibrate. The risk is also higher with verapamil or diltiazem than with nifedipine or amlodipine. Other important causes of drug interactions that increase statin toxicity include amiodarone, azole antifungals, protease inhibitors, erythromycin, and clarithromycin, but not azithromycin.

“Simvastatin and lovastatin are probably the worst as far as drug interactions,” Dr. Paauw cautioned. “They’re cheap, they’ve been generic for a long, long time, and a lot of times insurance companies want to move people to them. I try to move patients away from those two, because they are the dirtiest of the statins as far as side effects and drug interactions.”

When a drug interaction simply cannot be avoided, it’s best to have patients take the drugs 12 hours apart so peak levels don’t overlap, he added.

 

Same-statin rechallenge

If the checks of TSH, vitamin D, and possible drug interactions don’t turn up anything that needs fixing, it makes sense to launch same-statin rechallenge.

This management strategy was greenlighted by Canadian investigators in a retrospective study of 118 patients who presented to a tertiary lipid clinic with a history of muscle-related symptoms on at least two different statins.

At a median follow-up of 17 months, 71% of rechallenged patients were tolerating the same statin, compared with 53% of those who were switched to a different statin and 57% who were switched to ezetimibe or another nonstatin LDL-lowering drug. Moreover, 50% of patients in the same-statin rechallenge group achieved their target LDL, compared with only 15% switched to nonstatin therapy (Can J Cardiol. 2017 May;33[5]:666-73).

“I like this study; it helps a lot,” Dr. Paauw noted. “I think it’s worthwhile the first time they have muscle pain to get them off the statin and see if they feel better, so you become convinced that the statin may have had something to do with it. Then tell the patient, ‘Let’s just give it another try.’ ”
 

 

Alternative strategies

In the event of recurrent symptoms after same-statin rechallenge, it’s reasonable to switch to extended-release fluvastatin at 80 mg/day or low-dose rosuvastatin daily. Only if the patient remains symptomatic after trials of a couple of other statins does Dr. Paauw recommend turning to 5 mg of rosuvastatin twice weekly as a last resort.

Twice-weekly rosuvastatin is a popular treatment strategy in patients with intolerable muscle complaints on daily statin therapy. In a study of 40 such patients, twice-weekly rosuvastatin proved to be tolerated by 80% of them (Am J Cardiol. 2008 Jun 15;101[12]:1747-8). But the long-term effectiveness remains unknown.

“I think this is a really good option for our very statin-intolerant patients when nothing else works,” Dr. Paauw explained. “My only concern about this is we have no outcome data. Is twice-weekly rosuvastatin going to help reduce MI risk, especially if we give it for secondary prevention, as well as a daily statin? We know from this study that twice-weekly rosuvastatin can lower the lipids, but we also believe statins do more than just lower lipids. So, daily statin therapy is preferential.”

What about giving coenzyme Q₁₀? It makes sense mechanistically: Coenzyme Q₁₀ is an antioxidant, ubiquinone, and patients with statin-associated muscle symptoms are ubiquinone depleted.

 

But while oral coenzyme Q₁₀ is a popular OTC treatment for statin-associated muscle complaints, it’s not supported by any good evidence. A meta-analysis of six randomized trials totaling 302 participants found coenzyme Q₁₀ had no impact on symptoms (Mayo Clin Proc. 2015;90[1]:24-34).

In Dr. Paauw’s view, however, those trials didn’t address the proper question.

“The studies that have been done aren’t the right study,“ he said. “The study that needs to be done is for prevention: Do patients who start a statin and coenzyme Q₁₀ at the same time stay on the statin and feel better?”

He reported having no financial conflicts of interest regarding his presentation.

[email protected]