Statins may trigger muscle side effects by activating inflammatory danger signals

 Friends have discontinued statins because of side effects and always have never been believed.

• statin side effects (69 posts to December 2012)

Statins may trigger muscle side effects by activating inflammatory danger signals

New experimental findings reveal how statins may push vulnerable muscle cells into a stress state, suggesting future strategies to reduce muscle symptoms without compromising cardiovascular protection.

A recent study published in the journal Science Advances uncovered biological mechanisms that drive muscle-related side effects following statin therapy. The researchers found that statins reduced isoprenoid production, protein prenylation, and yes-associated protein (YAP) signaling.

In experimental models, statins also activated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasomes, promoted nuclear forkhead box O (FOXO) accumulation, and increased caspase-1 activity. These alterations increased atrogin-1 levels, promoted muscle atrophy, and reduced muscle function in experimental models. By better defining these pathways, the findings could inform future strategies to reduce statin-associated muscle effects while preserving cardiovascular benefit.

Healthcare providers routinely prescribe statin medications to people with lipid imbalances, such as elevated low-density lipoprotein (LDL) levels. These medications help reduce the risk of heart attacks, strokes, and death. However, some statin users experience muscle pain and weakness. Due to these side effects, they may take reduced doses or discontinue the drug altogether. These side effects may occur even when routine blood tests do not show evidence of muscle injury. However, the biological mechanisms underlying them are unclear. Most previous studies examined complications such as severe muscle toxicity and extensive muscle breakdown (rhabdomyolysis), but these are rarely observed among statin users.

About the Study

In the present study, researchers investigated why some people develop statin myopathy, or muscle-related side effects, following statin therapy. They developed a model of mild statin-related muscle problems for analysis. They exposed mouse muscle cells (C2C12 myotubes) to lipopolysaccharide (LPS), a bacterial component that stimulates the immune system. These LPS-primed cells developed an inflammasome-primed state and became much more sensitive to statins.

With LPS priming, a clinically relevant dose (1 μM) of fluvastatin increased atrogin-1 expression, an effect usually observed with 10 μM of the drug in cells without priming. As a result, lower statin doses could trigger molecular changes associated with muscle atrophy. Within 24 hours, atrogin-1 increased, followed by a decrease in muscle fiber diameter over 48 hours. In LPS-injected, statin-fed wild-type (WT) mice, fluvastatin reduced grip strength even though muscle mass did not decrease significantly, resembling the mild weakness experienced by many statin users. Human-derived muscle cells exposed to LPS and fluvastatin showed a reduction in actin alpha 1, skeletal muscle (ACTA1)-positive areas, indicating muscle-cell atrophy.

To investigate whether the muscle-related problems were due to cholesterol reduction or isoprenoid loss, the team added back an isoprenoid, geranylgeranyl pyrophosphate (GG). They then used 25-hydroxycholesterol to restore cellular cholesterol levels. They also used small interfering ribonucleic acid (siRNA) to reduce NLRP3 expression and MCC950 to inhibit NLRP3 inflammasome activity. The researchers compared the findings in WT mice, mice lacking the NLRP3 gene, and human-induced pluripotent stem cell (hiPSC)-derived myoblasts. Most mechanistic experiments focused on fluvastatin, although atorvastatin and cerivastatin supported a broader statin-class effect in LPS-primed muscle cells.

Results

The team found that statins block the mevalonate pathway that produces cholesterol, but this pathway also produces important molecules such as isoprenoids. A decrease in isoprenoid levels also reduces protein prenylation. These alterations lead to metabolic stress and act as danger signals that activate NLRP3 inflammasomes. Upon activation, the NLRP3 inflammasome initiates inflammatory signaling that contributes to muscle atrophy and cell death. Therefore, some side effects might arise from the loss of isoprenoids rather than from cholesterol reduction itself.

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Statin-fed WT mice exhibited more damaged muscle fibers, including centrally nucleated fibers, a hallmark of muscle injury and repair. These animals also contained necrotic myofibers. Mice lacking NLRP3 contained about 50% fewer abnormal muscle fibers and showed fewer signs of muscle damage and repair. These findings suggest that NLRP3 contributes considerably to statin-induced muscle injury.

Restoring isoprenoid levels with GG and inhibiting NLRP3 signaling in cellular models reduced muscle atrophy-related changes, further implicating these pathways in statin-associated muscle injury. Likewise, genetic deletion of NLRP3 protected mice from statin-induced muscle abnormalities. Upon GG addition, atrogin-1 levels decreased, and the reduction in phosphorylated FOXO was prevented, improving muscle-cell size.

Reduced protein prenylation impaired YAP, a protein that helps maintain muscle mass and function in skeletal muscles. Statins also altered muscle-cell metabolism by reducing glycolysis, a process that generates energy from glucose in cells. Reduced glycolysis may act as a metabolic danger signal capable of activating the NLRP3 inflammasome. Experiments using hiPSC-derived myoblasts supported the pathway changes observed in mouse cells and mice.

Conclusions

The findings suggest that statins may contribute to muscle weakness and atrophy by reducing isoprenoid levels and protein prenylation and activating NLRP3 inflammasome signaling. Statins also altered proteins involved in muscle growth and function and reduced glycolysis.

The findings suggest that the muscle-related effects are linked to impaired prenylation and inflammatory signaling rather than cholesterol reduction itself. If confirmed in future human studies, including research on inflammatory priming and gut-barrier-related signals, scientists could develop strategies to block NLRP3 inflammasome activation, modulate YAP-linked pathways, or carefully evaluate isoprenoid-related rescue approaches. These approaches could help mitigate muscle-related side effects without compromising statins' cholesterol-lowering benefits.

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Study finds statin symptoms usually nocebo

Friends who complained about statin side effects certainly thought they were real and never mentioned about a doctor suggesting there might be side effects.

Study finds statin symptoms usually nocebo

 

 

Naveed Saleh, MD, MS|October 20, 2021

Statin nonadherence is a major issue, with most patients who start the drugs eventually discontinuing them due to complaints over adverse effects. Ultimately, more than half the clinical benefit is lost to discontinuance.  

Approximately 50% of patients who start statins discontinue them at some point due to side effects. A new study sheds light on this issue.

Statins, or HMG-CoA reductase inhibitors, are used to treat high cholesterol and to lower the risk of heart attack, stroke, and other heart problems in individuals with coronary heart disease, type 2 diabetes, or other risk factors. 

Results from a study published in the Journal of the American College of Cardiology in September indicate that most symptoms due to statin tablets were nocebo. “Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo,” they wrote. 

In the study, researchers assessed the daily symptom scores on statin, placebo, and no treatment in 60 patients randomized to complete a 12-month protocol including 1-month medication bottles: four containing atorvastatin (Lipitor) 20 mg; four, placebo; and four, empty. Of note, 49 participants completed the trial.

They found that the mean symptom score did not differ between statin and placebo months. The nocebo ratio was 0.90, and per individual data, neither symptom intensity on starting nor extent of symptom relief on stopping distinguished statin from placebo use. Notably, there was no difference in the stopping of statins and placebo, with symptom relief after stopping similar in both groups. Six months after the trial ended, 30 of 60 patients who started the study resumed taking statins.

The primary outcome was the nocebo ratio, which was calculated as: symptom intensity on placebo – symptom intensity on no-tablets/symptom intensity on statins – symptom intensity on no-tablets.

The authors of the current study provided three takeaways. First, even “severe, convincing, and intolerable symptoms” that patients complain of, do not resurface during formal evaluations entailing daily documentation. Second, formal documentation of symptom scores can implicate background fluctuations in symptom intensity to be the cause—despite the intake of tablets. Third, although there are more verifiable adverse effects due to statins, these adverse effects were similar in intensity in statin vs placebo arms. This last finding suggests that even reproducible induction of symptoms via statin tablets yields no information about whether the cause was the statin moiety or the tablet moiety.

Prepared for physicians, by physicians, Clinical Commentary brings critical medical research from benchtop to bedside.

The authors noted that it is incorrect to infer that the rapid symptom decline secondary to the cessation of tablets points to statins as the cause because such decline was evidenced in both statin and placebo users.

The authors described several possible reasons underlying statin adverse effects, which their study was designed to compensate for. Statins interfere with liver metabolism to reduce the production of cholesterol. The elevation of concentrations of liver enzymes does not lead to complaints of adverse effects. When a patient discovers they are taking statins, however, they then complain of adverse effects, according to the results of previous trials.

Patients who start statins may sense a fluctuation in background symptoms and correctly note that these have increased. 

Patients may be primed to expect symptoms by family members, media, and the internet, with adverse effects detailed in patient pamphlets. These pamphlets, for instance, don’t distinguish adverse effects secondary to statins or placebo. Moreover, when a physician addresses complaints of adverse effects by changing the dosage, frequency, or agent, the patient’s conception that the statin was the cause is reinforced. “Unfortunately, without a preplanned schedule, the statin tends to be stopped when symptoms are maximal (and naturally tend to decline) and restarted when symptoms have resolved (and can only get worse),” wrote the authors. “These informal experiments replace uncertainty with confident, incorrect conclusions.”

The authors cautioned against the current practice of informally experimenting with statin use in patients. Although the investigators found that the quick onset and cessation of symptoms does happen after starting or stopping tablets, this phenomenon is caused by the tablet itself and not the statin component. Of note, the kinetics are similar between the placebo and statin tablets.

Although such informal testing is recommended in North America, the United Kingdom, and Europe, even if symptoms are scored and a preplanned schedule instituted, without a placebo, nocebo symptoms are blamed on the statin. This misinterpretation contributes to the fact that 50% of those who start statins stop at some point. 

Association between statin use and cognitive function: A systematic review of randomized clinical trials and observational studies

 

Does this mean you are going to change the FDA warning?

FDA adds diabetes, memory loss warnings to statins - Reuters But did your doctor account for these?

Taking statins raises the risk of Type 2 diabetes by nearly a third: Findings reopens debate about the pills benefits and side effects

In a database study of nearly 26,000 beneficiaries of Tricare, the military health system, those taking statin drugs to control their cholesterol were 87 percent more likely to develop diabetes.

Or is your doctor using coffee to try to prevent diabetes? Making the assumption that it will translate from mice to humans.

Substance in coffee delays onset of diabetes in laboratory mice Your doctor can also consider this:

High-intensity statin therapy alters the progressive nature of diabetic coronary atherosclerosis, yielding regression of disease in diabetic and nondiabetic patients.

 

The latest here:

 

Association between statin use and cognitive function: A systematic review of randomized clinical trials and observational studies

Adhikari A, Tripathy S, Chuzi S, et al

Journal of Clinical Lipidology|November 2, 2020

Researchers conducted the study for analyzing the connection between statin use and cognitive status in a population age ≥ 60. Twenty-four studies were included in the review. The sample consisted of 1,404,459 participants. No evidence of adverse cognitive effects, including dementia incidence, global cognition deterioration, or particular cognitive domains associated with statin use, has been identified in people aged 60 or older.

Read the full article on Journal of Clinical Lipidology.

 

‘Nocebo effect’ may explain many cases of statin intolerance: SAMSON

 So now your doctor has clinical proof that YOU are to blame for those side effects. Hope that makes you feel better.

‘Nocebo effect’ may explain many cases of statin intolerance: SAMSON

Source: Adobe Stock

 

 

 

 

 

 

 

 

Patients who developed symptoms within 2 weeks of statin initiation reported similar side effects while on placebo, suggesting a large proportion of burden owed to the nocebo effect, according to findings from the SAMSON trial.

According to research presented at the virtual American Heart Association Scientific Sessions, when this nocebo effect was revealed to these patients, who had initially discontinued statin therapy due to adverse effects, half were open to resuming treatment.

“We frequently see patients who have stopped taking statins due to the side effects. Yet, studies actually show that more than half of patients abandoned statins completely within 2 years of starting them; and yet, in placebo-controlled trials, no more people stopped statins than stopped placebos,” James P. Howard, PhD, Wellcome Trust PhD Fellow and cardiology registrar at Imperial College London, said during his presentation. “So, we designed a study to solve this contradiction because a patient who is suffering side effects from statin tablets gains no help from the experience of thousands of other people in placebo-controlled trials because their key question is, ‘Why is this happening to me?’”

The study was simultaneously published in The New England Journal of Medicine.

For this double-blind, three-group, n-of-1 trial, investigators enrolled 60 patients (mean age, 66 years; 58% men; 90% white) who had previously discontinued statins due to side effects that occurred within 2 weeks of therapy initiation of treatment to determine whether symptoms attributed to discontinuation were caused by a statin or placebo.

Participants were given four bottles of atorvastatin 20 mg, four bottles of a placebo and four empty bottles, with each bottle taken for a 1-month period according to a random sequence.

Via smartphone app, participants reported daily symptom scores, which ranged from 0, or no symptoms, to 100, the worst imaginable symptoms.

“If the side effects were caused by the statin molecules, the placebo months would have been down at the level of the empty months. But if the side effects were caused by the nocebo effect, then the placebo would be just as bad as the statin,” Howard said during the presentation. “We also wanted to see if taking part in SAMSON could directly help our patients. So, we asked each of them 6 months after they finished this trial if they had been able to go back onto clinical status, which they had previously believed they needed to abandon for good.”

Symptom severity

Overall, the mean reported symptom severity scores were:

• 8 for no treatment (95% CI, 4.7-11.3);
• 15.4 for placebo (95% CI, 12.1-18.7); and
• 16.3 for statin therapy (95% CI, 13-19.6).

Investigators found that difference in symptom severity reported for placebo compared with statin therapy was not clinically significant (P < .388); however, side effect severity was significant for both stain and placebo compared with no treatment (P for both < .001).

According to the results, the calculated nocebo ratio was 0.9.

“What does SAMSON tell us? SAMSON leaves no doubt that patients rarely do get side effects from statin tablets, [but] 90% of this burden is elicited by placebo tablets too,” Howard said during the presentation. “Therefore, the most important message from SAMSON is that side effects from statin tablets are very real, but they are mainly caused by the act of taking tablets and not the statin contained within.”

Understanding nocebo and resuming therapy

In addition, 6 months after the conclusion of the trial, half of all participants resumed statin therapy.

“Regarding what SAMSON will change; first, patients need to be taken seriously when they report side effects,” Howard said. “Second, because this n-of-1 design has built-in no-tablet periods, participants could see as clearly as we could the surprisingly powerful magnitude of the nocebo effect, and this led to half of them happily restarting statins. Finally, we hope that this novel study will be able to help our patients and other researchers answer questions about medications in their own fields. We believe that SAMSON could be a truly seminal trial design.”

Discussant Francine K. Welty, MD, PhD, associate professor of medicine at Harvard Medical School and cardiologist at Beth Israel Deaconess Medical Center, said during the press conference: “The most important implication is those with symptoms within 2 weeks of starting the statins should be reassured that about half will be able to successfully restart. In practice, many patients do develop symptoms later than 2 weeks, so these findings cannot be generalized to them. For example, in the SEARCH trial, 85% to 90% develop their myalgias after the first month of treatment.

“There was also no wash-out period between each 1-month treatment arm,” Welty said. “If subjects developed symptoms during atorvastatin and then went to placebo, there is possibility that there was carryover of symptoms into the placebo arm.”

Reference:

• Wood FA, et al. N Engl J Med. 2020;doi:10.1056/NEJMc2031173.

Statins Not Linked to Cognitive Decline, Study Shows

Does this mean you are going to change the FDA warning?

FDA adds diabetes, memory loss warnings to statins - Reuters But did your doctor account for these?

Taking statins raises the risk of Type 2 diabetes by nearly a third: Findings reopens debate about the pills benefits and side effects

In a database study of nearly 26,000 beneficiaries of Tricare, the military health system, those taking statin drugs to control their cholesterol were 87 percent more likely to develop diabetes.

Or is your doctor using coffee to try to prevent diabetes? Making the assumption that it will translate from mice to humans.

Substance in coffee delays onset of diabetes in laboratory mice Your doctor can also consider this:

High-intensity statin therapy alters the progressive nature of diabetic coronary atherosclerosis, yielding regression of disease in diabetic and nondiabetic patients.

 

The latest here:

Statins Not Linked to Cognitive Decline, Study Shows

No changes in brain volume seen over time, either

by Judy George, Senior Staff Writer, MedPage Today November 18, 2019

Statins were not linked to any greater decline in cognition or memory over 6 years, a longitudinal study of elderly adults in Australia showed.
People, ages 70 to 90, showed no difference in the rate of decline in either memory or global cognition regardless of whether they ever used statins, reported Katherine Samaras, MBBS, PhD, of St. Vincent's Hospital in Sydney, and colleagues in the Journal of American College of Cardiology.
Several longitudinal studies have shown no adverse association between statins and cognition, but many of them have limitations including short observation periods. Case reports of cognitive decline in statin users have concerned some people, and up to half of people prescribed statin therapy do not fill their prescription largely due to this concern, Samaras noted.
"We carried out the most comprehensive analysis of cognition in elderly statin users to date, and found no results to support that cholesterol-lowering statins cause memory impairment," Samaras said in a statement. "There was also no difference in the change in brain volumes between the two groups."
"Many factors can contribute to the cognitive symptoms that isolated case reports describe," she added. "What we've come away with from this study is a reassurance for consumers to feel more confident about their statin prescription."
The study used data from the Sydney Memory and Aging Study, an observational study of older community-dwelling Australians that started in 2005 to research the effects of aging on cognition over time. The Mini Mental State Examination (MMSE) was used to screen participants and exclude people with a score <24.
In this analysis, researchers followed 1,037 people with an average age of 79, including 395 statin never-users and 642 ever-users (including 99 people who started statins during the study period), to follow changes in memory and global cognition over 6 years. Complete data were available for 573 participants (55%) over the study period. In a subgroup of 526 people, the researchers also looked at brain volume on MRI.
To measure memory, the researchers developed a comprehensive assessment that incorporated a battery of tests evaluating new learning, short- and long-term recall, and visual and verbal retention. To measure global cognition, the researchers incorporated memory tests and assessments of processing speed, language, visuospatial ability, and executive function. Over the 6-year follow-up period, psychologists and nurses conducted neuropsychological testing every 2 years.
The average duration of statin use was 9.1 years at baseline and 68% of statin users were continuous users. Statin users were slightly younger, had higher BMI, more vascular disease, and more cardiovascular risk factors.
At baseline, statin ever-users and never-users showed similar total brain volume, hippocampal, and parahippocampal brain volumes. They demonstrated no significant differences on MRI 2 years later.
Memory and global cognition scores also were similar between statin ever-users and never-users at baseline after adjusting for covariates, and there was no significant difference in the rate of decline in either memory or global cognition 6 years later. In the 99 people who started statins during the study period, statin initiation was associated with a lessening in the rate of decline of memory (B=0.066, P=0.038), at the test-wise significance level.
Participants who took statins continuously had significantly higher baseline performance in memory and global cognition compared with never-users but over 6 years, the rate of decline in memory and global cognition was similar between continuous statin users and never-users.
In exploratory analyses, ever-user patients with heart disease displayed a slower rate of decline on a learning memory test than never-users. Similarly, ever-users who carried the APOE-4 genotype showed a slower rate of decline in long-delayed recall performance (B=0.157, P=0.005).
In an accompanying editorial, Costantino Iadecola, MD, and Neal Parikh, MD, both of Weill Cornell Medicine in New York City, wrote: "These data support the view that worries about cognitive impairment should not limit statin use and raise the possibility that statins may favorably alter cognitive trajectories in a group of elders at high risk of Alzheimer's disease." The last point is of great interest and requires additional clarification and validation, they added.
But the study has significant limitations, Iadecola and Parikh noted, including the loss of 45% of participants to follow-up, the small sample size especially for new statin users, and likely unmeasured confounding.
Last month, the NIH's National Institute on Aging (NIA) announced that it has funded a trial to look at benefits and risks of statins in adults, ages ≥75, without cardiovascular disease. The Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults (PREVENTABLE) study will help determine whether statins can help prevent dementia and disability in older adults while not increasing other risks.

Last Updated November 18, 2019

Disclaimer

This study was supported by the Australian Government's National Health and Medical Research Council.
Researchers disclosed relevant relationships with the Nutricia Australia Advisory Board and the Australian Advisory Board of Biogen.
Iadecola and Parikh disclosed no relevant relationships with industry.

Primary Source

Journal of the American College of Cardiology

Source Reference: Samaras K, et al "Effects of statins on memory, cognition, and brain volume in the elderly" J Am Coll Cardiol 2019; DOI: 10.1016/j.jacc.2019.09.041.

Secondary Source

Journal of the American College of Cardiology

Source Reference: Iadecola C and Parikh N "Statins and Cognitive Impairment" J Am Coll Cardiol 2019; DOI: 10.1016/j.jacc.2019.09.040.

Taking statins raises the risk of Type 2 diabetes by nearly a third: Findings reopens debate about the pills benefits and side effects

Be careful out there, don't stop taking statins without your doctors approval. 30% or 87%?  But is it statins or the underlying disease that causes your doctor to prescribe statins? Your doctor should have warned you about this and be monitoring your condition since May 2015;

In a database study of nearly 26,000 beneficiaries of Tricare, the military health system, those taking statin drugs to control their cholesterol were 87 percent more likely to develop diabetes.

Or is your doctor using coffee to try to prevent diabetes? Making the assumption that it will translate from mice to humans.

Substance in coffee delays onset of diabetes in laboratory mice

Your doctor can also consider this:

High-intensity statin therapy alters the progressive nature of diabetic coronary atherosclerosis, yielding regression of disease in diabetic and nondiabetic patients.

Taking statins raises the risk of Type 2 diabetes by nearly a third: Findings reopens debate about the pills benefits and side effects

• Six million Britons take the pills every day to fight cholesterol and heard disease
• Study tracked overweight people already at risk of diabetes who take statins
• Decade-long study found them 30 per cent more likely to develop condition 

By Ben Spencer for the Daily Mail

Published: 19:28 EDT, 23 October 2017 | Updated: 20:17 EDT, 23 October 2017

Taking statins increases the risk of type 2 diabetes by nearly a third, researchers found.

A decade-long study of more than 3,200 patients found those who took statins were 30 per cent more likely to develop the condition.

Some six million Britons take statins every day to reduce their cholesterol and ward off heart disease.

The pills are proven lifesavers, slashing the chance of a repeat attack, yet a scientific row over benefits and side effects has dragged on for years.A study of more than 3,200 patients found people taking statins are 30 per cent more likely to develop type 2 diabetes 

Experts have long known there was a link between statins and diabetes – but doctors have always stressed that the advantages of the pills far outweigh the small chance of getting diabetes.

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Previous research had put the chance of developing type 2 diabetes at no more than 10 to 12 per cent greater than if someone did not take statins. The latest study, however, suggests the medication increases the risk by 30 per cent.

The researchers, from Albert Einstein College of Medicine in New York, think this may be because statins impair insulin production. In the journal BMJ Open Diabetes Research & Care, they called for regular blood sugar tests of people taking statins.

‘Glucose status should be monitored and healthy lifestyle behaviours reinforced in high-risk patients who are prescribed statins for cardiovascular disease [prevention],’ they wrote.

The scientists tracked overweight people already considered at risk of diabetes for ten years. At the start, 4 per cent took statins, but by the end roughly a third were taking the pills.

No link was found between the potency of the statins used and diabetes risk.

Statins have been shown to significantly reduce the risk of heart attacks and strokes 

The researchers stressed that the additional risk of developing diabetes should be balanced against ‘the consistent and highly significant’ reduction in risk of heart attacks, strokes and death. Last night experts said that although the relative risk of diabetes may seem high, in reality the absolute numbers of people it would affect would be small.

The New York researchers did not include absolute numbers in their study. But Dr Tim Chico, consultant cardiologist at Sheffield University, estimated the findings would mean an increase in risk from roughly 0.16 per cent to roughly 0.2 per cent.

‘This study further confirms that there is a small increase in risk of diabetes with statin treatment,’ Dr Chico said. But he added: ‘Type 2 diabetes is largely caused by being overweight, and having a poor diet and a sedentary lifestyle, and more attention must be directed to addressing these.’

Pav Kalsi, of Diabetes UK, said: ‘Statins can significantly reduce risk of heart attacks and strokes, so it is important that people who have been prescribed statins continue to take their medication.’

Professor Stephen O’Rahilly of Cambridge University, said the study ‘relies on modelling to take into account confounding factors underlying the reasons for prescribing statins … Therefore, these results cannot be viewed as definitive’

Read more: http://www.dailymail.co.uk/health/article-5010431/Statins-raise-risk-Type-2-diabetes-nearly-third.html#ixzz4wQwSdtNU
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Stopping statins for side effects could be deadly

Be careful out there.
https://www.mdlinx.com/internal-medicine/medical-news-article/2017/07/26/statins-heart-attack-stroke-side-effects-death-annals-of-internal-medicine/7261188/?category=last-month&page_id=1

Reuters Health News | July 26, 2017

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By Andrew M. Seaman (Reuters Health) – Stopping a statin because of a muscle ache or stomach pain can be dangerous in the long run, suggests a new study. Researchers found that people who stopped taking statins after reporting a side effect were 13% more likely to die or have a heart attack or stroke over the next four years than people who kept taking the drugs. Despite the overwhelming evidence in favor of statins, a quarter to a half of patients stop taking the drugs within 6 months to a year, Dr. Alexander Turchin, of Brigham and Women's Hospital in Boston, and colleagues wrote July 24 online in Annals of Internal Medicine. To see whether people who continue taking statins, including those who switch to a different type or a lower dose, end up with better outcomes than people who stop taking the drugs, the researchers analyzed data drawn from the Massachusetts General Hospital and Brigham and Women's between 2000 and 2011. During that period, more than 200,000 adults were treated with statins. Nearly 45,000 of them reported a side effect they thought might be related to the medication. From those 45,000 with possible side effects, the research team focused on 28,266 people. Most of them – 19,989 individuals – kept taking statins anyway, with 44% of those continuing to take the same drug. Roughly four years after the side effects were reported, 3,677 patients had died or suffered a heart attack or stroke. Among those who continued to take their statins, 12.2% fell into that group, compared with 13.9% of those who stopped statins after a possible side effect. Overall, the researchers found that people who stopped taking statins after a possible side effect were 13% more likely to die or have heart attack or stroke during the study period than people who kept taking their medicine. The new findings expand on previous studies showing people benefit when they continue to take their statins, said Dr. Robert Rosenson, a professor of cardiology at the Icahn School of Medicine at Mount Sinai in New York City. Rosenson, who was not involved with the new study, said patients should be encouraged to tell their doctors about any possible side effects from statins, and they should understand that there may be other options, including a lower dose or a different drug. In an editorial, Dr. Steven Nissen of the Cleveland Clinic in Ohio writes that some people may steer clear of statins due to misinformation published online or promoted in fad diets. "We must work together to educate the public and enlist media support, and we must take the time to explain to our patients that discontinuing statin treatment may be a life–threatening mistake," he writes.

Researchers identify a common genetic variant linked to muscle pains in statin users

In case you get muscle pain from statins. Of course no real solution is provided, just switch to something else.
http://www.alphagalileo.org/ViewItem.aspx?ItemId=178364&CultureCode=en

28 August 2017 European Society of Cardiology (ESC)

• Under embargo until 29 August 2017 23:05 GMT

People who have been prescribed statins to lower their cholesterol levels sometimes complain of muscle aches and pains and therefore stop taking their medication in the belief that it is causing their symptoms. This puts them at higher risk of developing diseases of the heart and blood vessels which the statins had been prescribed to prevent.
Now, researchers have found that there is a common variant in a gene that predisposes people to developing muscle aches, regardless of whether they are taking statins. However, they also found that there is a genetic sub-group of people who have a higher risk of statins-induced muscle aches.
The findings, which are published today (Wednesday) in the European Heart Journal [1], open the possibility of screening people for this and other genetic variations to identify those who are most likely to have an adverse reaction to statins and who could be prescribed an alternative drug. Those genetically predisposed to muscle aches could be forewarned about the possibility of developing symptoms and be closely monitored.
Previous research had found that a genetic variant of the LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B member 5) gene was associated with lower levels of enzymes called creatine phosphokinase (CK) and lactate dehydrogenase (LDH). These enzymes are released from injured muscle tissue. Raised CK levels are often taken as clinical confirmation of adverse muscle-based reactions to statin therapy. This suggested to the researchers that the LILRB5 variant could be involved in muscle-related symptoms; they hypothesised that the variant would reduce the risk of muscle-based symptoms, while the more common form of the gene, seen in 60% of the Caucasian population, might increase risk.
In this current study, an international team led by researchers at the University of Dundee’s Ninewells Hospital and Medical School (Dundee, UK) looked at the association between the LILRB5 variant and statin intolerance. They selected statin users who had not been adherent to their therapy and then divided them into two groups: the first in which patients had raised CK levels (general statin intolerance), and the second in which patients were intolerant to the lowest approved dose of a statin before switching or discontinuing therapy (low dose intolerance). This was done because some patients do not necessarily show the expected raised CK levels, but do experience muscle aches.
Among 11,912 Scottish statin users taking part in the Genetics of Diabetes Audit and Research, Tayside Scotland (GoDARTS) study, the researchers found that the likelihood of statin intolerance was increased in patients who carried two identical copies of the common form of the LILRB5 gene; there was a two-fold increased risk of general statin intolerance and a 1.4-fold increased risk of low dose intolerance after taking into account important factors that could affect the results, such as the patients’ use of other medications, type of statin and its dosage, diabetes status, age and sex.
These results were replicated when the researchers examined two other studies, one of a more severe type of intolerance, statin-induced myopathy (or muscle disease), in 661 patients (229 cases and 432 controls) from centres in Sweden and the UK; and the other was an international clinical trial to evaluate the efficacy of a statin called rosuvastatin in 8,749 patients from 26 countries who developed muscle aches. A meta-analysis of these studies and of a third one, in which no significant effect could be seen, showed that patients with two copies of the common form of the gene had 1.3-fold increased risk of suffering adverse effects associated with statin intolerance compared to those without identical copies.
In the international clinical trial, the researchers could determine how many patients receiving statin therapy developed muscle aches, as opposed to those who were given placebo. Statins were not associated with an increased risk, while the common form of the LILRB5 gene was clearly associated with an overall increased risk of muscle aches. However, true statin-specific muscle aches could only be observed in patients who had one or both copies of the variant form of the gene, which would normally have protected them from muscle aches that were not caused by statins.
The leader of the research team, Professor Colin Palmer from the University of Dundee, said: “We found that there are people in the general population who carry a genetic factor that predisposes them to muscle aches. If these people are put on statins, they might discontinue their medication in the erroneous belief that it is the statin that is making their muscles ache. At the same time, we observed that there is a genetic sub-group of patients who are susceptible to statin-specific muscle ache, although at this stage we don’t understand the mechanism responsible for this effect.
“This means that it would be possible to test prospective statin users for key genetic variants, including LILRB5, to prevent people being put on statins if they are likely to have an adverse reaction to them. Adverse reactions are the driving reason for therapy cessation, which puts the patient at an increased risk of a cardiovascular event. This is the first time a genetic variant thought to be involved in the repair and regeneration of muscles has been found to be associated with this side effect.”
The researchers say further work needs to be done to confirm exactly how the genetic variant is involved in the repair of muscles. “All we know as facts are that the immune system is involved in the repair and regeneration of muscles, that our gene (LILRB5) is involved in the immune system, and, more specifically, that people with two identical copies of the genetic variant have lower expression of a key factor, called Foxp3, that enables the mechanism by which the immune system repairs muscle cells. So, we have a strong hypothesis for the involvement of our gene in the process of muscle repair and recovery,” said Dr Moneeza Siddiqui, the first author of the study.
Statins are the first choice for doctors who need to lower cholesterol in patients to prevent or treat heart and blood vessel diseases. However, between approximately 7-29% of users complain of muscle aches. For people who cannot tolerate statins, alternative treatments include ezetimibe and a new class of drugs called PCSK9-inhibitors.

• Full bibliographic information[1] “A common missense variant of LILRB5 is associated with statin intolerance and myalgia”, by Moneeza K. Siddiqui et al.
  European Heart Journal. doi:10.1093/eurheartj/ehx324

Fake news about statins is discouraging the use of these life-saving drugs, expert warns

It is never acknowledged here that cholesterol is not really the problem, inflammation is. But the medical profession has been going down this secondary intervention for so long nothing will change until lots of people die.  Be careful out there and listen to your doctor, not me.
http://www.latimes.com/science/sciencenow/la-sci-sn-statin-denial-20170724-story,amp.html

By

Melissa HealyContact Reporter

Denial is not just for climate-change anymore. In a political environment in which charges of puffery, deception and fake news abound, a new controversy has been joined, and it returns to grounds that have long proved fertile for conspiracy theories: medicine.
The newest charge of “fake news” has been lodged against those who would argue that statin medications cause more harm than good, and that fad diets, natural remedies and wishful thinking will protect you better from heart disease than these ubiquitous prescription drugs.
They are everywhere on the Internet, says Cleveland Clinic cardiologist Dr. Steven Nissen. Type the term “statin risks” into a search engine, and you’ll get about 3.5 million hits. Those overwhelmingly lodge misleading charges against statins and hawk some alternative whose effectiveness has not been demonstrated by science, says Nissen.
Nissen says he was incredulous to find that some online sites suggest that patients with higher levels of LDL cholesterol (the kind that cardiologists call “bad cholesterol”) are healthier. Perhaps, he said, they were taking their cue from climate-change deniers who sing the praises of more carbon dioxide in the atmosphere.
Type in “statin benefits,” by contrast, and you’ll get a skimpier 655,000 results, Nissen reported.
“Statins have developed a bad reputation with the public, a phenomenon driven largely by proliferation on the Internet of bizarre and unscientific but seemingly persuasive criticism of these drugs,” Nissen wrote in an editorial published Monday in the Annals of Internal Medicine.
“We are losing the battle for the hearts and minds of our patients to websites developed by people with little or no scientific expertise, who often peddle ‘natural’ or ‘drug-free’ remedies for elevated cholesterol levels,” adds Nissen. This “Internet-driven cult” denies statins’ benefits and whips up fears of side effects, then profits from the resulting confusion by peddling snake oil.
Nissen’s incendiary remarks come against the backdrop of what had seemed mostly settled science: that statin medications can — and have — cut rates of heart attack and stroke when they’re taken by people who need them.

But this consensus of cardiologists has hardly prompted a nation of devotees, leaving experts like Nissen to wonder why statins have not been more widely embraced, and why they are abandoned by so many.
Of the 56 million Americans who are considered candidates for drugs with names like simvastatin, lovastatin, pravastatin and atorvastatin, just about half that number take them. And among those who get a statin prescription from a doctor — even among patients who’ve had a heart attack or stroke and would dramatically reduce their odds of having another — the rate at which statin medications are abandoned falls between 40 and 60%.
For a nation that loses almost a billion dollars a day to heart attacks and strokes, the opportunity costs of such statin-refusal are high. But steep costs are also incurred by patients who abandon a statin regimen prescribed by the doctor, or refuse to consider taking the medications when they’re indicated.
In 19 separate studies, researchers have found that patients who discontinue a statin medication are anywhere from 22% to five times likelier than those who stay on statins to develop cardiovascular disease.Those same studies have placed statin-abandoners’s odds of dying prematurely somewhere between 25% higher and 2½ times higher than those of patients who stayed on statins.
Nissen’s editorial charges comments came in response to yet another study showing that patients abandoning a statin prescription are running a significant risk — though one more modest than past research suggests.
The new research, also published Monday in the Annals of Internal Medicine, draws on the medical records of more than 28,000 patients at Beth Israel Hospital in Boston who got a statin medication and registered a complaint with their doctor about an unpleasant side effect. It compared the outcomes over four years of the roughly 70% of complainers who continued on one statin to those of the 30% who did not.
The new study found that those patients who quit taking their statin medication were 14% more likely than patients who stayed on their medication to suffer a heart attack or stroke or die from such a cardiovascular event. It suggests that for every 59 patients who stop statin therapy, one would incur a stroke, heart attack or death over the next four years. And one additional statin-abandoner would die for every 83 who stop taking the medication.
But researchers are more divided over why people abandon statins. Their debate turns on the relative impact of real side effects, and the magnifying effects of patients’ expectations, which are often fomented by dramatic online accounts.
As many as 20% of patients who are prescribed a statin medication to lower their cholesterol complain of side effects such as muscle pain and weakness, stomach upset or forgetfulness.
For many, the muscular and stomach problems are very real. But, as difficult as it is for doctors to tell us, there’s growing evidence that sometimes, those side effects have been induced by suggestion.
This is the inverse of the placebo effect — often called the “nocebo effect” — and researchers in recent years have been engaged in a heated debate over how common statins’ side effects truly are.
In one clinical trial, in which researchers warn of possible side effects like muscle aches, 10% of subjects who got a statin complained of muscle aches. But 5% of those who got a placebo treatment did. In a widely cited study that Nissen helped conduct, the rate of “nocebo-induced” side effects was far higher.
Given the mind’s power over the body, the suggestion of a possible side effect can make it so.
“We now are a generation of people who go to Twitter and Facebook and the Internet for medical information, and there is this largely cultlike opposition to these drugs out there,” said Nissen. “These alternative facts that are out there, and they seem like truth to many people.”
Dr. Paul D. Thompson, chief of cardiology at Hartford Hospital and professor of Medicine at University of Connecticut, has long warned that side effects — real side effects — are a problem with statins that must be addressed. He thinks Dr. Nissen may be playing the provocateur with his inflammatory charges.

Nissen’s got a point, says Thompson, who was not involved in research published Monday. But doctors cannot easily dismiss their patients’ complaints, he adds.
“No, I don’t think it’s entirely an Internet conspiracy. I do think there’s a lot of poorly documented information on the Internet that confuses people,” said Thompson. “But that is partly our fault: A patient will take mediations if they trust their doctor and think their doctor is doing the best for them.”
As for dealing with side effects, Thompson cautions that “it doesn’t do any good in my experience to tell people they’re full of it or they’re nutty.”
Physicians need to acknowledge their patients’ concerns and stop the medicine to see if symptoms go away, says Thompson. And then they need to try again, either with a lower dose or a different statin medication, and make the case that staying on a statin can make a big difference for the patient, Thompson added.
Nissen, too, says he tries hard to convince patients who need them to stick with statins.
“We have to trust patients with scientific facts and speak about the science.” He’ll discuss what research has shown, tell them about the “nocebo effect,” and often send them home with some reading. But in the end, he won’t mince words about the dangers they are running if they quit, he adds.
Physicians, Nissen wrote, “must take the time to explain to our patients that discontinuing statin treatment may be a life-threatening mistake. Passive acceptance of harmful pseudoscience is not an option.”

Concerns over side effects of statins stopping stroke survivors taking medication

Be careful out there.
https://eurekalert.org/pub_releases/2017-07/uoc-cos071217.php
Negative media coverage of the side effects associated with taking statins, and patients' own experiences of taking the drugs, are among the reasons cited by stroke survivors and their carers for stopping taking potentially life-saving drugs, according to research published today.
Individuals who have had a stroke are at risk of a second stroke, which carries a greater risk of disability and death than first time strokes. In fact, one third of all strokes occur in individuals who have previously had a stroke. To prevent this recurrence, patients are offered secondary preventative medications; however, adherence is a problem with 30% of stroke patients failing to take their medications as prescribed.
To examine the barriers to taking these medications, researchers at the University of Cambridge and Queen Mary University, London (QMUL), analysed posts to TalkStroke, a UK-based online forum hosted by the Stroke Association, across a seven year period (2004-2011). The forum was used by stroke survivors and their carers.
The team, led by Dr Anna De Simoni, a lecturer in Primary Care Research at QMUL and visiting researcher at the Department of Public Health and Primary Care, University of Cambridge, has previously used the forum to explore issues such as the impairment that can make it difficult for stroke survivors to maintain a job.
The findings of the study, which looked at posts by 84 participants, including 49 stroke survivors and 33 caregivers, are published today in the journal BMJ Open. The Stroke Association gave the researchers permission to analyse the results, and to prevent identification of individuals, the team did not use verbatim comments.
Among the reasons cited by the forum users, side effects were a major factor in decisions to stop taking medication. Several contributors had experienced negative side effects and as a result had stopped taking the medication, sometimes in consultation with their GP and other times unilaterally. Others reported that they, or the person they were caring for, had stopped taking the medication after reading negative stories in the press about side effects.
Other users expressed concerns over the medication they were offered. There were conflicting views about the efficacy of the medications - some contributors believed they were very important, while others believed that their risk could be managed by lifestyle changes alone.
Contributors also reported mixed views of healthcare professionals -- some felt confident in their doctor's decision, while others questioned their decisions, some even questioning their motivation for prescribing particular drugs.
"These findings have highlighted the need for an open, honest dialogue between patients and/or their carers, and healthcare professionals," says Dr De Simoni. "Doctors need to listen to these concerns, discuss the benefits and drawbacks of taking the medication, and be willing to support a patient's informed decision to refuse medications."
However, perceptions did not present the only barriers to adherence: there were often practical considerations. Drugs were sometimes too large and difficult to swallow, or a drug regime was too burdensome. The complexities of the drug regimes sometimes meant having to develop routines and strategies to ensure patients kept to them. One survivor described having to pay for the medications by credit card as she was unable to work and had no money or benefits coming in.
"By analysing people's views as expressed in online forums, where they are more open and less guarded, we've seen some valuable insights into why some stroke survivors have difficulty adhering to their medication," says PhD candidate and first author James Jamison from the Department of Public Health and Primary Care at Cambridge.
"Challenging negative beliefs about medication and adopting practices that make routines for taking medication simpler, particularly for those patients who have suffered disability as a result of stroke, should increase adherence and ultimately improve health outcomes."

The research was supported by the National Institute of Health Research, the Stroke Association and the British Heart Foundation.
For more information about statins, visit http://www.nhs.uk/conditions/Cholesterol-lowering-medicines-statins/Pages/Introduction.aspx.
Reference
Jamison, J et al. Barriers and facilitators to adherence to secondary stroke prevention medications after stroke: Analysis of survivors' and caregivers' views from an online stroke forum. BMJ Open; 19 July 2017; DOI: 10.17863/CAM.10458

CardioBrief: Study Questions Extent of Statins' Muscle-Pain Effect

A friend thought the pain was quite real and quit taking statins.
https://www.medpagetoday.com/Cardiology/CardioBrief/64977?

Unique analysis suggests many reports of pain are 'nocebo effect'

• by Larry Husten
  CardioBrief May 02, 2017

A new study helps debunk the widespread belief that statins cause muscle-related pain and weakness in large numbers of patients. The "nocebo effect" may be the cause of the epidemic of muscle pain among statin users, say the study investigators and outside commentators.
There are few more broadly relevant and contentious questions in modern medicine than who should take statins. Observational studies and anecdotal reports indicate that adverse events in people taking statins are common. As many as 20% of people who take statins report some sort of problem. But in randomized controlled trials of statins reports of adverse events have been similar in the placebo and active treatment groups, suggesting little or no pharmacologic adverse effect. (All parties agree that statins can cause the rare and extremely serious adverse effect of rhabdomyolysis in about 1 in 10,000 patients, and that statins also cause a small increase in the risk of developing diabetes, though the clinical implications of the latter finding are still unclear.)
Now a new report in The Lancet compares the rate of side effects in a group of patients both during and after their participation in a randomized controlled trial, the ASCOT-LLA trial. During the trial more than 10,000 patients were blinded to treatment assignment. After the trial was completed participants were invited to take part in a follow-up study in which they were offered open-label statin treatment.
During the randomized portion of the study there was no difference in the rate of muscle-related symptoms between the two groups: 2.03% per year in the atorvastatin group versus 2% in the placebo group. In the open-label follow-up study, in which about two-thirds of the patients were taking atorvastatin, there was a small but statistically significant larger percentage of patients in the atorvastatin group who reported muscle-related symptoms: 1.26% per year versus 1.00% per year (hazard ratio 1.41, 95% CI CI 1.10-1.79, P=0.006).
"Just as the placebo effect can be very strong, so too can the nocebo effect," said Peter Sever (Imperial College London), lead author of the study, in a press release. "This is not a case of people making up symptoms, or that the symptoms are 'all in their heads'. Patients can experience very real pain as a result of the nocebo effect and the expectation that drugs will cause harm. What our study shows is that it's precisely the expectation of harm that is likely causing the increase in muscle pain and weakness, rather than the drugs themselves causing them."
The authors speculated that they may have underestimated the nocebo effect, since ASCOT-LLA was performed during 1998-2005, "before claims that statin therapy causes high rates of side effects had become as common as they are now."
Statin critics have argued that adverse event rates in trials have been lower than real life because most trials have enrolled patients who have already been shown to tolerate statins. But, wrote Juan Pedro-Botet and Juan Rubiés-Prat (Barcelona) in an accompanying editorial, in ASCOT-LLA "no run-in period existed to exclude patients intolerant to therapy, and few patients had previously taken any statins."
Rita Redberg (UCSF) doesn't think that a nearly 20-year-old trial can address the situation today. She repeated her call for the Cholesterol Treatment Trialists (CTT) to release the patient-level data of their trials. "I think if they truly want to contribute to the discussion of the incidence of statin related adverse events in clinical trials, they should make the CTT held trial data publicly available, as Rory Collins said he would do two years ago, but has not happened." Collins is a leader of the CTT and a co-author of the new Lancet paper.
In their conclusion the study authors chastised the media: "The widespread media coverage that has arisen from claims that statin therapy causes side-effects in up to one fifth of patients, and the failure to correct such misleading claims rapidly and fully, has led to patients at high risk of major vascular events with established cardiovascular disease stopping their statin therapy. Such reductions in statin use have been estimated to 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. We hope that the demonstration in the ASCOT-LLA of not only the absence of adverse effects of statin therapy on muscle-related and other AEs, but also the effect of ascertainment bias in non-blinding studies (which have been the basis of many of the misleading claims), will help to counter the adverse effect on public health of exaggerated claims about statin side effects."
The editorialists agreed that patient reports about muscle pain "might result from patients' perceptions about statins in light of negative press reports of statin use or even poor understanding of warnings about statin-associated side-effects."
Given the established cardiovascular benefits of statins, they write, "clinicians should be fully informed about potential nocebo effects, including patients' previous knowledge or perceptions of statin therapy, and discuss the evidence ... with patients."
Asked to comment on the study, Harlan Krumholz (Yale University) said that "the evidence is growing regarding the safety of statins. They remain one of the most remarkable breakthrough drugs ever produced ... Vigilance in evaluating drug effects, especially in popular drugs, must continue – but this study shows just how hard it can be to disentangle adverse effects from perceptions of adverse effects."
Marilyn Mann, a highly respected patient advocate, offered the following comment: "Patients often experience muscle symptoms while taking a statin. This study adds to the evidence that these symptoms are often not caused by the statin. However, it is rarely productive for a patient to simply be told that the drug isn't causing the symptoms the patient is feeling. Rather, patients and their doctors need to work together over a period of time to try to determine whether the symptoms are related to the statin. Drug discontinuation followed by rechallenge is often successful. In addition, many people can tolerate a lower dose, a different statin, or a different dosing schedule. In some cases, other cholesterol drugs are an option."

Interpretation of the evidence for the efficacy and safety of statin therapy

This rehashing of the statin controversy just proves that these people do not understand cause and effect at all. Cholesterol does not cause plaques. Inflammation grabs the cholesterol out of the bloodstream packing it into plaque. The shortcut taken many years ago of reducing cholesterol was incorrect. The focus should have been on how to stop inflammation. But now that statins are a huge pharma business we will likely never go back and solve the real problem. I myself have been sucked into this mindset from my doctor, taking statins to reduce my cholesterol, so far I haven't noticed side effects of brain fuzziness.
You can see a video of how plaque forms here:
Inflammation In Atherosclerotic Plaque Formation  
 

Interpretation of the evidence for the efficacy and safety of statin therapy

Prof Rory Collins, FRSPress enter key for correspondence informationPress enter key to Email the author

,

Christina Reith, FRCP (Glasg.)

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Jonathan Emberson, PhD

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Prof Jane Armitage, FRCP

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Prof Colin Baigent, FRCP

,

Lisa Blackwell, BSc

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Prof Roger Blumenthal, MD

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Prof John Danesh, FMedSci

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Prof George Davey Smith, DSc

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Prof David DeMets, PhD

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Prof Stephen Evans, MSc

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Prof Malcolm Law, FRCP

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Prof Stephen MacMahon, FMedSci

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Seth Martin, MD

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Prof Bruce Neal, PhD

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Prof Neil Poulter, FMedSci

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David Preiss, PhD

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Prof Paul Ridker, MD

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Prof Ian Roberts, PhD

,

Prof Anthony Rodgers, MBChB

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Prof Peter Sandercock, DM

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Prof Kenneth Schulz, PhD

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Prof Peter Sever, FRCP

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Prof John Simes, MD

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Prof Liam Smeeth, FRCGP

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Prof Nicholas Wald, FRS

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Prof Salim Yusuf, DPhil

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Prof Richard Peto, FRS

DOI:

• Summary

• Full Text
• Tables and Figures
• References
• Supplementary Material

Summary

This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy—ie, adverse effects of the statin—are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50–100 patients (ie, 0·5–1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials 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 it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.