Growing Doubt on Statin Drugs: The Problem of Drug-Lifestyle Interaction
Medscape June 2014
John MandrolaMy mind is changing about statins. I'm growing increasingly worried about the irrational exuberance over these drugs, especially when used for prevention of heart disease that is yet to happen.
An elderly patient called my office last week to tell me thank you . . . not for a successful procedure or surgery, but rather for helping with a problem that had dogged her for a decade.
How did an electrophysiologist help a patient without doing a procedure?
I stopped her statin. A few weeks later, the patient said, her muscle and joint pain were gone. "I thought it was arthritis. I'm walking now. I haven't felt this good in years. I've even lost five pounds."
So why was this elderly patient on a statin?
It was being used to lower cholesterol in the hopes that it would lower the risk of a future heart attack or stroke. This is called primary prevention. The patient had no vascular disease but had a high cholesterol level. The problem, of course, is that statins have not been well-studied in elderly women. Her doctor and the medical establishment writ large have extrapolated findings of clinical trials on younger, mostly male, patients to all patients with high cholesterol levels. This is a striking jump to make, given that low cholesterol levels in the elderly are associated with higher death rates.
Anecdotes are not evidence, but this one moved me to review some of the statin evidence. And to think (again) about treating people vs disease. As always, let's start with the truth — absolute, not relative values. Then I will move on to some new revelations about statins, and then an interesting theory of why potent cholesterol-lowering drugs have such painfully small effects on overall cardiovascular outcomes.
The Truths
When statins are used in low-risk patients without heart disease (primary prevention) there is no mortality benefit.
That's right. Your chances of dying are the same on or off the drug, regardless of how much the statin lowers the cholesterol level.
When statins are used for primary prevention, there is a small lowering of future vascular events (stroke/heart attack) over five to 10 years.
The absolute risk reduction is in the range of seven per 1000. That means you have to treat 140 patients with a statin (for five years) to prevent one event. Or this: for 99.3% of statin-treated patients, there is no benefit. I like to call this the PSR, or percent same result.
There is also general agreement that statins increase the risk of developing diabetes, especially in women, and that risk is about the same as preventing a stroke or heart attack, approximately 1%.
Another fact is that patient-level (raw) data from the industry-sponsored cholesterol trials have not been independently analyzed.
Systematic reviews from the Cochrane group have analyzed only published data rather than the raw data. There is likely a difference [1].
There is great debate about the incidence of statin side effects, such as muscle pain, cognitive issues, decreased energy, sexual problems, and kidney and liver injury, among others.
In the industry-sponsored randomized controlled clinical trials, discontinuation of statins was not significantly different from placebo.
Observational data and the observations of any clinician provide a different picture[2]. New Revelations
Individuals prescribed statin therapy consumed more calories and more fat than nonstatin users.
A study presented in April 2014 at the Society of General Internal Medicine meeting in San Diego showed that individuals prescribed statin therapy for high cholesterol consumed more calories and more fat than nonstatin users. And, not surprisingly, this increase in calories paralleled an increase in BMI in statin users.An analysis of a prospective cohort study of men (published in JAMA Internal Medicine) revealed that physical-activity levels were "modestly" lower among statin users compared with nonusers independent of other cardiac medications and of medical history.
Possible Connecting Theory: Drug-Lifestyle Interaction
These two recent studies are troublesome.
As pointed out in the excellent coverage from heartwire journalist Michael O'Riordan, there may be an interaction between medication and lifestyle.
Namely, if statin users consume more calories, gain weight, and exercise less, it becomes easy to see why cardiovascular benefits are so small.
It's been really hard to explain why the striking reductions in LDL cholesterol—up to 30% to 50%—from statins haven't translated into significant future benefit.
One possibility is that cholesterol levels are a lousy surrogate for outcomes.
That surely seems true in the elderly, but what about in younger patients and those with familial high cholesterol? These patients are definitely at increased cardiovascular risk. So cholesterol levels are surely not unimportant.
There are convincing data, for instance, that higher HDL levels are associated with lower CV risk.
Another possibility for lack of statin benefit is analogous to AF rhythm control and high blood-pressure issues.
As in, yes, it's better to be in regular sinus rhythm and have normal blood pressure, but getting to those goals with pills isn't the same as being there naturally.
With rhythm-control and blood-pressure drugs, the achievement of the desired outcome is muted by side effects from the drugs.
Perhaps it's the same with statin drugs?
You don't have to posit malfeasance on the part of big pharma here.
All you have to do is think past the disease-specific mind-set of modern-day medicine.
We are much more than our cholesterol level.
A statin drug, like so many drugs that block enzyme pathways far upstream in major cellular pathways, is going to have much more biologic action than just moving an easily measured cholesterol level.
When you step back and look at medications as chemical modifiers of cellular processes in complex biologic systems like our body, it's easy to understand that health comes not from pills.
Not even statins.
Related Links
• Reduced Activity Raises Cautions in Older Men Using Statins
• Statin Users Eating More, Gaining Weight, Study Shows
Reduced Activity Raises Cautions in Older Men Using Statins
CHICAGO,
IL — Physical-activity levels were "modestly" lower among statin users
compared with nonusers independently of other cardiac medications and of
medical history, but activity wasn't further inhibited over time,
in a prospective community-based cohort of men aged >65 followed for
about seven years[1].
Whereas activity levels declined similarly in prevalent statin users and statin nonusers, "new statin use was associated with a more rapid decline in physical activity than nonuse," according to the authors of the new analysis, led by Dr David SH Lee (Oregon State University, Portland).
The observational study suggests that in men like those in the cohort, "statins are associated with less physical activity for as long as statins are used." It wasn't possible to discern a cause-and-effect relationship, but "possible reasons for lower physical-activity levels in statin users may be general muscle pain caused by statins (a well-known adverse effect), exercise-endured myopathy, or muscular fatigue."
The group's report, based on participants in the Osteoporotic Fractures in Men Study (MrOS) enrolling from 2000 to 2002, was published June 9, 2014 in JAMA Internal Medicine.
The men self-reported activity levels at baseline and at two follow-up visits using the Physical Activity Scale for the Elderly (PASE). The second follow-up also included accelerometer-based measurements of metabolic equivalents (METs) and minutes of moderate activity, vigorous activity, or sedentary behavior.
Among the 4137 persons in the baseline analysis, 24% were statin users and 76% were statin nonusers. Statin users scored a mean of 5.8 points lower than nonusers (p=0.03) on the PASE assessment controlled for age, clinical site, MI, stroke, hypertension, diabetes, perceived health, body-mass index, and total-cholesterol levels.
Of the 3039 patients in the longitudinal analyses, 24% were already on statins, 48% did not take statins, and 28% initiated statins during follow-up. PASE scores fell an average of 2.5 per year in statin nonusers and 2.8 per year for the prevalent users, not a significant difference. They dropped a significant 0.9 points further for new users than for nonusers, according to the group. However, the overall adjusted difference in PASE score changes across the three groups wasn't significant (p=0.07).
Of note, statin users achieved a mean of 0.03 kcal/kg/h fewer METS (p<0.001), engaged in significantly less moderate and vigorous activity, and were more often sedentary compared with nonusers.
Statin User-to-Nonuser Ratios for Three Median Physical-Activity Levels* (minutes per day) by Accelerometer in an MrOS Cohort
The
group proposed "two possible reasons" that prevalent statin use didn't
seem to cause a more rapid fall in physical activity, as hypothesized:
those most susceptible to muscle symptoms may have stopped their use
during the study, or they may have gone off the drugs after a decline
in health, they write. Indeed, 11% of statin users had gone off the
drugs before the second follow-up visit.
"Some might imagine that reduced activity in new statin users should be managed by urging statin users to exercise more, but this approach is not without hazard," writes Dr Beatrice Alexandra Golomb (University of California San Diego, La Jolla) in an accompanying editorial[2]. "Statins compromise muscle in part by marring cell energy (by mitochondrial and oxidative mechanisms). Adding exercise aggravates risk of energy shortfall relative to demand."
Activity and fitness have salutary effects on overall health, including but not limited to cardiovascular, metabolic, cognitive, functional, sleep-related, and healing-related benefits, she notes. In this light, statin-related activity reduction is "a reminder that all medications bear risks, and prescribing them involves trade-offs. When considering statin use in a given patient, effects on function and the spectrum of outcomes, not merely cause-specific ones, should be considered."
Golomb also pointed out that the current analysis is limited in not including women, "who have shown more statin-related muscle problems compared with men," and people with metabolic syndrome "or other risk factors for statin-related muscle problems."
The analysis was funded by a grant from the Medical Research Foundation of Oregon; neither Lee nor the other authors had disclosures, nor did Golomb.
Whereas activity levels declined similarly in prevalent statin users and statin nonusers, "new statin use was associated with a more rapid decline in physical activity than nonuse," according to the authors of the new analysis, led by Dr David SH Lee (Oregon State University, Portland).
The observational study suggests that in men like those in the cohort, "statins are associated with less physical activity for as long as statins are used." It wasn't possible to discern a cause-and-effect relationship, but "possible reasons for lower physical-activity levels in statin users may be general muscle pain caused by statins (a well-known adverse effect), exercise-endured myopathy, or muscular fatigue."
The group's report, based on participants in the Osteoporotic Fractures in Men Study (MrOS) enrolling from 2000 to 2002, was published June 9, 2014 in JAMA Internal Medicine.
The men self-reported activity levels at baseline and at two follow-up visits using the Physical Activity Scale for the Elderly (PASE). The second follow-up also included accelerometer-based measurements of metabolic equivalents (METs) and minutes of moderate activity, vigorous activity, or sedentary behavior.
Among the 4137 persons in the baseline analysis, 24% were statin users and 76% were statin nonusers. Statin users scored a mean of 5.8 points lower than nonusers (p=0.03) on the PASE assessment controlled for age, clinical site, MI, stroke, hypertension, diabetes, perceived health, body-mass index, and total-cholesterol levels.
Of the 3039 patients in the longitudinal analyses, 24% were already on statins, 48% did not take statins, and 28% initiated statins during follow-up. PASE scores fell an average of 2.5 per year in statin nonusers and 2.8 per year for the prevalent users, not a significant difference. They dropped a significant 0.9 points further for new users than for nonusers, according to the group. However, the overall adjusted difference in PASE score changes across the three groups wasn't significant (p=0.07).
Of note, statin users achieved a mean of 0.03 kcal/kg/h fewer METS (p<0.001), engaged in significantly less moderate and vigorous activity, and were more often sedentary compared with nonusers.
Statin User-to-Nonuser Ratios for Three Median Physical-Activity Levels* (minutes per day) by Accelerometer in an MrOS Cohort
| Activity Level | Ratio | p |
| Moderate physical activity | 0.91 | 0.003 |
| Vigorous physical activity | 0.92 | 0.01 |
| Sedentary behavior | 1.006 | 0.003 |
*Controlled for
clinical site and season of the year, age, body-mass index,
beta-blockers, ACE inhibitors or angiotensin-receptor blockers, total
cholesterol, MI, stroke, hypertension, diabetes, and perceived health
"Some might imagine that reduced activity in new statin users should be managed by urging statin users to exercise more, but this approach is not without hazard," writes Dr Beatrice Alexandra Golomb (University of California San Diego, La Jolla) in an accompanying editorial[2]. "Statins compromise muscle in part by marring cell energy (by mitochondrial and oxidative mechanisms). Adding exercise aggravates risk of energy shortfall relative to demand."
Activity and fitness have salutary effects on overall health, including but not limited to cardiovascular, metabolic, cognitive, functional, sleep-related, and healing-related benefits, she notes. In this light, statin-related activity reduction is "a reminder that all medications bear risks, and prescribing them involves trade-offs. When considering statin use in a given patient, effects on function and the spectrum of outcomes, not merely cause-specific ones, should be considered."
Golomb also pointed out that the current analysis is limited in not including women, "who have shown more statin-related muscle problems compared with men," and people with metabolic syndrome "or other risk factors for statin-related muscle problems."
The analysis was funded by a grant from the Medical Research Foundation of Oregon; neither Lee nor the other authors had disclosures, nor did Golomb.
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