Why is the incidence of side effects from statins so low in clinical trials but appear to be so high out in the real world?
How Common Are Muscle Side Effects from Statins?
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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
There is now overwhelming evidence to support reducing LDL cholesterol—bad cholesterol—to reduce atherosclerotic cardiovascular disease, the number one killer of men and women. So, why is adherence to cholesterol-lowering statin drug therapy such a major challenge? The majority of studies reported at least 40 percent, and as much as 80 percent, of patients did not comply fully with statin treatment recommendations. Three-quarters may flat out stop taking them, or sometimes up to nearly 90 percent discontinue treatment.
When asked why, most former statin users, or discontinuers, cited muscle pain, a side effect, as the primary reason for stopping the pills. By far the most prevalent and important adverse events, up to 72 percent of all statin side effects are statin-associated muscle symptoms. Taking coenzyme Q10 supplements as a treatment for statin-associated muscle symptoms was a good idea in theory, but they don’t actually appear to help. Normally, side-effect symptoms go away when you stop the drug, but sometimes can linger a year or more. But there is evidently growing evidence that statin intolerance is predominantly psychosocial, not pharmacological. Wait; meaning maybe it’s mostly just in people’s heads?
Statins have developed a bad reputation with the public, one editorial read, “a phenomenon driven largely by proliferation on the Internet of bizarre and unscientific … criticisms of these drugs.” Maybe it’s Googling that leads to statin intolerance? But come on, people have been going off statins for decades before there even was an Internet. What kind of data has doctors suggesting that patients are falsely misattributing normal aches and pains to be statin side effects?
Well, if you take people who claim to have statin-related muscle pain, and randomize them back and forth between statins and an identical-looking placebo in three-week blocks, they can’t actually tell whether they’re getting the real drug or the sugar pill. The problem with that study, though, is that it may take months to not only develop statin-induced muscle pain, but months before it goes away; so, no wonder three-weeks-on and three-weeks-off may not be long enough for the participants to discern which is which.
But these data are more convincing. In the study, 10,000 people were randomized to a statin or sugar pill for a few years. But they had to stop the study early, because so many more people were dying in the sugar pill group. And so, everyone was then offered the statin. And what they noted was that there was no excess of reports of muscle-related adverse effects among patients assigned to the statin over those assigned to the placebo; but then, when the placebo phase was over and the people knew they were on a statin, then they reported more muscle side effects than those who knew they weren’t. These results illustrate the so-called nocebo effect––kind of like the opposite of the placebo effect.
Placebo effects are positive consequences falsely attributed to a treatment, whereas nocebo effects are negative consequences falsely attributed to a treatment, as was evidently seen here, as there was an excess rate of muscle-related adverse effects reported only when patients and their doctors were aware that statin therapy was being used, and not when its use was concealed. They hope these results will help assure both physicians and patients that most adverse effects associated with statins are not actually caused by the drug, and should help counter exaggerated claims about statin-related side effects. It’s these kinds of results from placebo-controlled randomized trials that are said to have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by the drug. Now, only a few patients will believe this, that their statin-associated muscle symptoms are of psychogenic origin––meaning all just in their head––but their denial may have deadly consequences. Discontinuing statin treatment may be a life-threatening mistake.
Here’s the mortality of those who stopped their statins after having a possible adverse reaction, compared to those who stuck with them. This translates into about 1 excess death for every 83 patients who discontinued treatment within a four-year period. So, when there are media reports about statin side effects and people stop taking them, this could result in thousands of fatal and disabling heart attacks and strokes, which would otherwise have been avoided. Seldom in the history of modern therapeutics have the substantial proven benefits of a treatment been compromised to such an extent by serious misrepresentations of the evidence for its safety.
But is it a misrepresentation to suggest statin therapy causes side effects in up to one-fifth of patients? That is actually what you see in clinical practice. Between 10 percent to 25 percent of patients placed on statins complain of muscle problems, but because we don’t see anywhere near those kinds of numbers in controlled trials, patients are accused of being confused. Why in clinical trials is the incidence of side effects from statins so low, but out in the real world appear to be so high?
For example, take this meta-analysis of clinical trials, finding muscle problems not in 1 in 5, but only 1 in 2,000 patients. So hey, maybe everyone over a certain age should be on them. But, of course, every single one of those trials was funded by the statin manufacturers themselves. So, for example, how could the randomized controlled trials miss detecting statin-related adverse side effects such as muscle pain? By not asking. A review of 44 statin trials revealed that only 1 directly asked about muscle-related adverse effects. So, are the vast majority of side effects just being missed in all these trials, or are the vast majority of side effects seen in clinical practice just some figment of patients’ imagination? The bottom line is we don’t know, but there is certainly an urgent need to figure it out.
Please consider volunteering to help out on the site.
- Ward NC, Watts GF, Eckel RH. Statin Toxicity. Circ Res. 2019;124(2):328-50.
- Chee YJ, Chan HH, Tan NC. Understanding patients' perspective of statin therapy: can we design a better approach to the management of dyslipidaemia? A literature review. Singapore Med J. 2014;55(8):416-21.
- Diamond DM, de Lorgeril M, Kendrick M, Ravnskov U, Rosch PJ. Formal comment on "Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease". PLoS One. 2019;14(1):e0205138.
- Wei MY, Ito MK, Cohen JD, Brinton EA, Jacobson TA. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013;7(5):472-83.
- Zaleski AL, Taylor BA, Thompson PD. Coenzyme Q10 as Treatment for Statin-Associated Muscle Symptoms-A Good Idea, but…. Adv Nutr. 2018;9(4):519S-23S.
- Banach M, Serban C, Sahebkar A, et al. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2015;90(1):24-34.
- Armour R, Zhou L. Outcomes of statin myopathy after statin withdrawal. J Clin Neuromuscul Dis. 2013;14(3):103-9.
- Tobert JA. Statins - Good drugs, not so good reputation. Int J Cardiol. 2018;262:28-9.
- Nissen SE. Statin Denial: An Internet-Driven Cult With Deadly Consequences. Ann Intern Med. 2017;167(4):281-2.
- Khan S, Holbrook A, Shah BR. Does Googling lead to statin intolerance. Int J Cardiol. 2018;262:25-7.
- Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301-10.
- Akinboro O, Williams L, Pomerantz D. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;161(7):531.
- Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017;389(10088):2473-81.
- Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-61.
- Pedro-Botet J, Climent E, Benaiges D. Muscle and statins: from toxicity to the nocebo effect. Expert Opin Drug Saf. 2019;18(7):573-9.
- Zhang H, Plutzky J, Shubina M, Turchin A. Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study. Ann Intern Med. 2017;167(4):221-7.
- Kriegbaum M, Liisberg KB, Wallach-Kildemoes H. Pattern of statin use changes following media coverage of its side effects. Patient Prefer Adherence. 2017;11:1151-7.
- Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J. 2014;168(1):6-15.
- Majeed A, Molokhia M. Urgent need to establish the true incidence of the side effects of statins. BMJ. 2014;348:g3650.
- Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-90.
- Ebrahim S, Casas JP. Statins for all by the age of 50 years? Lancet. 2012;380(9841):545-7.
- Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin?. BMJ. 2013;347:f6123.
- Thompson PD. What to Believe and Do About Statin-Associated Adverse Effects. JAMA. 2016;316(19):1969-70.
Video production by Glass Entertainment
Motion graphics by Avo Media
Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
There is now overwhelming evidence to support reducing LDL cholesterol—bad cholesterol—to reduce atherosclerotic cardiovascular disease, the number one killer of men and women. So, why is adherence to cholesterol-lowering statin drug therapy such a major challenge? The majority of studies reported at least 40 percent, and as much as 80 percent, of patients did not comply fully with statin treatment recommendations. Three-quarters may flat out stop taking them, or sometimes up to nearly 90 percent discontinue treatment.
When asked why, most former statin users, or discontinuers, cited muscle pain, a side effect, as the primary reason for stopping the pills. By far the most prevalent and important adverse events, up to 72 percent of all statin side effects are statin-associated muscle symptoms. Taking coenzyme Q10 supplements as a treatment for statin-associated muscle symptoms was a good idea in theory, but they don’t actually appear to help. Normally, side-effect symptoms go away when you stop the drug, but sometimes can linger a year or more. But there is evidently growing evidence that statin intolerance is predominantly psychosocial, not pharmacological. Wait; meaning maybe it’s mostly just in people’s heads?
Statins have developed a bad reputation with the public, one editorial read, “a phenomenon driven largely by proliferation on the Internet of bizarre and unscientific … criticisms of these drugs.” Maybe it’s Googling that leads to statin intolerance? But come on, people have been going off statins for decades before there even was an Internet. What kind of data has doctors suggesting that patients are falsely misattributing normal aches and pains to be statin side effects?
Well, if you take people who claim to have statin-related muscle pain, and randomize them back and forth between statins and an identical-looking placebo in three-week blocks, they can’t actually tell whether they’re getting the real drug or the sugar pill. The problem with that study, though, is that it may take months to not only develop statin-induced muscle pain, but months before it goes away; so, no wonder three-weeks-on and three-weeks-off may not be long enough for the participants to discern which is which.
But these data are more convincing. In the study, 10,000 people were randomized to a statin or sugar pill for a few years. But they had to stop the study early, because so many more people were dying in the sugar pill group. And so, everyone was then offered the statin. And what they noted was that there was no excess of reports of muscle-related adverse effects among patients assigned to the statin over those assigned to the placebo; but then, when the placebo phase was over and the people knew they were on a statin, then they reported more muscle side effects than those who knew they weren’t. These results illustrate the so-called nocebo effect––kind of like the opposite of the placebo effect.
Placebo effects are positive consequences falsely attributed to a treatment, whereas nocebo effects are negative consequences falsely attributed to a treatment, as was evidently seen here, as there was an excess rate of muscle-related adverse effects reported only when patients and their doctors were aware that statin therapy was being used, and not when its use was concealed. They hope these results will help assure both physicians and patients that most adverse effects associated with statins are not actually caused by the drug, and should help counter exaggerated claims about statin-related side effects. It’s these kinds of results from placebo-controlled randomized trials that are said to have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by the drug. Now, only a few patients will believe this, that their statin-associated muscle symptoms are of psychogenic origin––meaning all just in their head––but their denial may have deadly consequences. Discontinuing statin treatment may be a life-threatening mistake.
Here’s the mortality of those who stopped their statins after having a possible adverse reaction, compared to those who stuck with them. This translates into about 1 excess death for every 83 patients who discontinued treatment within a four-year period. So, when there are media reports about statin side effects and people stop taking them, this could result in thousands of fatal and disabling heart attacks and strokes, which would otherwise have been avoided. Seldom in the history of modern therapeutics have the substantial proven benefits of a treatment been compromised to such an extent by serious misrepresentations of the evidence for its safety.
But is it a misrepresentation to suggest statin therapy causes side effects in up to one-fifth of patients? That is actually what you see in clinical practice. Between 10 percent to 25 percent of patients placed on statins complain of muscle problems, but because we don’t see anywhere near those kinds of numbers in controlled trials, patients are accused of being confused. Why in clinical trials is the incidence of side effects from statins so low, but out in the real world appear to be so high?
For example, take this meta-analysis of clinical trials, finding muscle problems not in 1 in 5, but only 1 in 2,000 patients. So hey, maybe everyone over a certain age should be on them. But, of course, every single one of those trials was funded by the statin manufacturers themselves. So, for example, how could the randomized controlled trials miss detecting statin-related adverse side effects such as muscle pain? By not asking. A review of 44 statin trials revealed that only 1 directly asked about muscle-related adverse effects. So, are the vast majority of side effects just being missed in all these trials, or are the vast majority of side effects seen in clinical practice just some figment of patients’ imagination? The bottom line is we don’t know, but there is certainly an urgent need to figure it out.
Please consider volunteering to help out on the site.
- Ward NC, Watts GF, Eckel RH. Statin Toxicity. Circ Res. 2019;124(2):328-50.
- Chee YJ, Chan HH, Tan NC. Understanding patients' perspective of statin therapy: can we design a better approach to the management of dyslipidaemia? A literature review. Singapore Med J. 2014;55(8):416-21.
- Diamond DM, de Lorgeril M, Kendrick M, Ravnskov U, Rosch PJ. Formal comment on "Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease". PLoS One. 2019;14(1):e0205138.
- Wei MY, Ito MK, Cohen JD, Brinton EA, Jacobson TA. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013;7(5):472-83.
- Zaleski AL, Taylor BA, Thompson PD. Coenzyme Q10 as Treatment for Statin-Associated Muscle Symptoms-A Good Idea, but…. Adv Nutr. 2018;9(4):519S-23S.
- Banach M, Serban C, Sahebkar A, et al. Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc. 2015;90(1):24-34.
- Armour R, Zhou L. Outcomes of statin myopathy after statin withdrawal. J Clin Neuromuscul Dis. 2013;14(3):103-9.
- Tobert JA. Statins - Good drugs, not so good reputation. Int J Cardiol. 2018;262:28-9.
- Nissen SE. Statin Denial: An Internet-Driven Cult With Deadly Consequences. Ann Intern Med. 2017;167(4):281-2.
- Khan S, Holbrook A, Shah BR. Does Googling lead to statin intolerance. Int J Cardiol. 2018;262:25-7.
- Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301-10.
- Akinboro O, Williams L, Pomerantz D. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;161(7):531.
- Gupta A, Thompson D, Whitehouse A, et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet. 2017;389(10088):2473-81.
- Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388(10059):2532-61.
- Pedro-Botet J, Climent E, Benaiges D. Muscle and statins: from toxicity to the nocebo effect. Expert Opin Drug Saf. 2019;18(7):573-9.
- Zhang H, Plutzky J, Shubina M, Turchin A. Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study. Ann Intern Med. 2017;167(4):221-7.
- Kriegbaum M, Liisberg KB, Wallach-Kildemoes H. Pattern of statin use changes following media coverage of its side effects. Patient Prefer Adherence. 2017;11:1151-7.
- Ganga HV, Slim HB, Thompson PD. A systematic review of statin-induced muscle problems in clinical trials. Am Heart J. 2014;168(1):6-15.
- Majeed A, Molokhia M. Urgent need to establish the true incidence of the side effects of statins. BMJ. 2014;348:g3650.
- Cholesterol Treatment Trialists' (CTT) Collaborators, Mihaylova B, Emberson J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-90.
- Ebrahim S, Casas JP. Statins for all by the age of 50 years? Lancet. 2012;380(9841):545-7.
- Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin?. BMJ. 2013;347:f6123.
- Thompson PD. What to Believe and Do About Statin-Associated Adverse Effects. JAMA. 2016;316(19):1969-70.
Video production by Glass Entertainment
Motion graphics by Avo Media
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Title
How Common Are Muscle Side Effects from Statins?
LicenseCreative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
Content URLDoctor's Note
To understand risks versus benefits, you first have to understand The Actual Benefit of Diet vs. Drugs.
I have more videos on statins coming out over the next few months, but if you want to see them now, they are available on a digital download of How Effective Are Statins and Stents?––a webinar I did last year on statins and stents.
August 2021 Update. Here are those newer statin videos:
- Who Should Take Statins?
- Are Doctors Misleading Patients About Statin Risks and Benefits?
- The True Benefits vs. Side Effects of Statins
- How Much Longer Do You Live on Statins?
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