Statin Drugs – the JAMA Debate
The April 14th issue of the Journal of the American Medical Association inaugurated a new feature called "Viewpoint" -- an "in magazine" debating forum for arguing out key medical issues of the day. Think of it like a civilized version of Dan Aykroyd and Jane Curtain's Point/Counterpoint sketches on Saturday Night Live.1
The subject of the first debate is statin drugs -- or more precisely, "Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 250 mg/dL, and no family history of premature CHD [coronary heart disease] be treated with a statin?" The debate is worth looking at for a number of reasons:
- Although the medical community often seems to speak with one unified voice, in truth, it is often very divided on key issues such as the concern over statin side effects.
- Despite the stance of the AMA against alternative therapies to naturally lower cholesterol, there is actually a growing movement in the medical community for more natural approaches.
- And even though it seems as if the medical community is firmly behind statin drugs to lower cholesterol -- even to the point of debating whether or not they should be added to the public water supply -- there are a number of strongly dissenting voices…and a number of studies that back that dissent.
With that in mind, let's take a look at the debate.
The argument for statins
The pro position cardiologists2 did take note of the importance of lifestyle changes such as a healthy diet and exercise in lowering the risk of cardiovascular disease, stating, "As always, lifestyle change is the first-line therapy." But after giving that brief acknowledgement, they then went for the throat of the argument, "However, if this patient's cholesterol level remains abnormal, despite sustained attempts at lifestyle optimization, statin therapy should be considered, with the goal of reducing CHD (coronary heart disease) risk."
To support their argument, they cited three major placebo-controlled studies that "showed" that when statin therapy is used to reduce cholesterol -- in particular LDL cholesterol -- it reduced the incidence of heart attack and death significantly among people who had high cholesterol levels but were otherwise at low risk for developing heart disease. The three studies were:
- The WOSCOPS trial, which showed that treatment with 40 mg of pravastatin resulted in a 31% reduction in heart attacks and related deaths.3
- AFCAPS/TexCAPS, which found that 20-40 mg of lovastatin reduced the incidence of first major coronary events by 37% and myocardial infarction by 40%.4
- The Jupiter trial, which found that treating patients who had normal cholesterol levels but high C-reactive protein levels with 20 mg of rosuvastatin reduced the risk of myocardial infarction, stroke, and revascularization by some 44%.5
Sounds really impressive, doesn't it? But in truth, these studies -- and particularly the Jupiter trial -- are much less than they first appear. In fact, what the Jupiter trial found is that whether you used the statin drug or not, your chances of having a heart attack were essentially the same: 1%. Or more precisely, if you take it out one more decimal place, that dramatic 44% improvement they talk about comes down to a drop from a 1.4% chance of having a coronary event to a 0.8% chance if you use statin drugs. You're talking about maybe one person in every hundred seeing any benefit. Pitching that as a 44% improvement is number jerking, plain and simple!
The pro cardiologists also suggested that a way to sort out who would be the best candidates for statin therapy is to offer them a coronary artery calcium (CAC) scan, an imaging test that directly shows the amount of calcification in heart arteries that can lead to a heart attack. They cited large studies published by Johns Hopkins researchers that have confirmed the usefulness of CAC in determining risk among their patients, helping doctors decide who needed statin therapy to lower their risk. But are cholesterol and arterial calcification actually linked? Not necessarily, according to a 2006 study that found that calcium plaque continues to accumulate in coronary arteries even in the face of aggressive cholesterol reduction (-53% LDL cholesterol) with a statin drug.6 In fact, calcification of arteries is more closely linked to a lack of vitamins K and D, magnesium, and higher acidity levels in the muscle tissue surrounding arterial walls. For example, people who consume the highest amounts of vitamin K exhibit more than a 50% reduction in coronary heart disease mortality and aortic calcium scores.7,8 And high blood levels of vitamin D, likewise, have been shown to correlate with the absence of extensive arterial calcification.9
They further argued that statin side effects, such as muscle pain, are infrequent and reversible when the medication is stopped (although you may question how reversible it is for a significant number of people when you search for anecdotal evidence on the internet). They also contended that there is no evidence from randomized trials that statins lead to cognitive impairment or memory loss. On the contrary, they said reliable data suggests just the opposite, that statins may actually improve memory. (I'm not sure the FDA agrees with that statement.) And finally, they suggested that the risk of type 2 diabetes associated with statins is minimal, especially compared with the benefits in reducing heart attacks. And improvements in diet and weight can negate modest increases in blood sugar associated with statins. But in fact, all of those assumptions were effectively refuted by the "anti" cardiologists as we will see in a moment. In addition, a recent study found that statin drugs increased the risk of diabetes by 48-71 percent.10 And, finally, in February 2012, the FDA issued a directive that all statin labels are now to carry a warning about the increased risk of raised blood sugar levels and the development of Type 2 diabetes, not to mention an increased risk of cognitive impairment.11 It seems the FDA doesn't necessarily agree with the pro position on this particular issue.
It should be noted that the above referenced study is not the only one that has found a connection between statin drugs and diabetes. An increased risk of diabetes among statin users was first seen in 2008 as a statin side effect in a randomized controlled trial of the drug Crestor.12 A 2011 analysis in the Journal of the American Medical Association13 and a 2010 analysis in The Lancet also found an increased risk of diabetes among statin users.14
As for waiting until a heart attack or stroke to prescribe statins for those with multiple risk factors, the pro cardiologists argued that "There's no apparent logic in waiting for a myocardial infarction (heart attack) or stroke to occur before starting a risk-reducing therapy." They indicated that cost is no longer a factor as generic statins now on the market cost only about $4 to $5 a month. And as for the argument that handing out statins to patients with high cholesterol might be seen by those patients as a free pass to continue their unhealthy lifestyle choices, they said that the evidence points to the contrary: that prescribing stains seems to motivate people to adopt more healthy behaviors. Whatever evidence they're talking about, though, would not seem to match the evidence walking about on the streets and lining up at fast food order counters.
In any case, it's certainly an interesting perspective, and perhaps that argument would make sense if statins actually saved lives among any group other than those with high cholesterol who have already had a heart attack. But they don't.
The argument against statins
The "anti" cardiologists15 focused on three key questions:
- Does treatment of elevated cholesterol levels with statins in otherwise healthy persons decrease mortality or prevent other serious outcomes?
- What are the statin side effects associated with treatment in healthy persons?
- Do the potential benefits outweigh the potential risks?
Do statin drugs work in healthy people?
According to this group of cardiologists from the editorial staff of the Archives of Internal Medicine, "Data from a meta-analysis of 11 trials including 65,229 persons with 244,000 person-years of follow-up in healthy (normal cholesterol levels) but high-risk men and women (the same group identified in the debate question) showed no reduction in mortality when treated with statins16 (a fact I haverepeatedly pointed out over the years.) In addition, a 2011 Cochrane review of treatment with statins among persons without documented coronary disease came to similar conclusions.17 The Cochranereview also observed that all but one of the clinical trials providing evidence on this issue were sponsored by the pharmaceutical industry. It is well established, as surprising as it might be to some in the medical community, that industry-sponsored trials are more likely than non--industry-sponsored trials to report favorable results for drug treatment because of biased reporting, biased interpretation, or both.18
What are the statin side effects?
According to the "con" cardiologists, "Data from observational studies show much higher rates of statin-associated muscle problems and other adverse events in actual use than the 1% to 5% rate reported in clinical trials and as cited by the pro doctors. This underestimation of adverse events occurs because these trials excluded up to 30% of patients with many common co-morbidities, such as those with a history of muscular pains, as well as renal or hepatic insufficiency."19 In addition, the doctors point out that many randomized trials of statin drugs also additionally excluded patients who had adverse effects from the treatment during an "open-label run-in period." In other words, the studies in question ran a "pre-test" phase in which any patient who either might be predisposed to develop a statin side effect or who actually demonstrated an adverse side effect was excluded from the actual test so their side effects would not count in the actual test. And yes, that's exactly what it sounds like: a way to deliberately make the drugs look safer than they actually are. In other words, if there's any indication you're going to have a statin side effect, you won't be allowed to participate in the trial and mess up the numbers. As an example, the anti doctors cite the Treat to New Targets trial, which excluded an astonishing 35% of eligible patients simply because they demonstrated adverse effects during an 8-week run-in phase. Further, the con doctors pointed out that statin trials also deliberately underestimate common symptoms such as myalgia, fatigue, and other minor muscle complaints by simply not counting them and limiting their data collection to much rarer specific muscle issues such as rhabdomyolysis (the rapid destruction of muscle fiber). Or to state it another way, "If you don't count a particular side effect, it doesn't count!"
Risk VS benefits20 Preventing a heart attack is a meaningful outcome. However, by taking statins, 1 or more patients will develop diabetes and 20% or more will experience disabling symptoms, including muscle weakness, fatigue, and memory loss.21"
The con doctors also undermine the fundamental supposition of the pro position that just because statins reduce the risk of a second heart attack in those who have already suffered one, they "must" also be beneficial for patients without coronary disease.
"Recent history is rife with examples of interventions that are proven to work in patients with serious disease yet are not efficacious when generalized to patients without serious disease. For example, coronary artery bypass graft (CABG) surgery is lifesaving for patients with symptomatic left main disease. However, CABG surgery would not be a good choice for single-vessel coronary artery disease (CAD) because risks would outweigh benefits in less extensive CAD. Similarly, the benefits of carotid endarterectomy in preventing stroke outweigh the risks for symptomatic patients with tight carotid artery stenosis, but not for asymptomatic patients with less critical stenosis. In addition, the use of aspirin is similar to statins for prevention. The data show clear benefit for aspirin in secondary prevention of cardiovascular disease, but not for primary prevention.Practitioners should not be generalizing from other settings when good data indicate that statins are not effective in improving length or quality of life when used for primary prevention. "
The answers to the three questions posed by the anti cardiologists suggest that statin therapy should not be recommended for men with elevated cholesterol who are otherwise healthy. "Advising healthy patients to take a drug that does not offer the possibility to feel better or live longer and has significant adverse effects with potential decrement in quality of life is not in their interest."
Nondrug Approaches to Reducing Coronary Risk
Surprisingly, the anti's didn't end their discussion there. They actually added a section to their rebuttal to talk about non-medical alternatives for reducing cardiovascular risk in otherwise healthy men -- specifically, dietary modification, weight loss, and increased exercise. These strategies are effective in increasing longevity and also result in other positive benefits, such as naturally lowering cholesterol. Even small changes in diet and increases in physical activity and smoking cessation can lead to significant personal and population health benefits. Such positive lifestyle changes have the key advantage of helping patients feel better and live longer. And they conclude by stating, "Lifestyle counseling should remain the focus of primarily prevention efforts -- at the physician and public health levels."
(To listen to a 15 minute extension of the debate between two of the cardiologists involved, click here .)
So what can we take away from this debate? Well, pretty much what I said at the beginning.
- Although the medical community often seems to speak with one unified voice, in truth, it is often very divided on key issues. Unfortunately, the mainstream media does not do a good job of publicizing the "secondary" POV. This creates a huge misconception as to where the medical community stands on many issues.
- Despite the stance of the AMA, there is actually a growing movement in the medical community for more natural -- less interventionist -- approaches.
- And even though it seems as if the medical community is firmly behind statin drugs to lower cholesterol -- even to the point of debating whether or not they should beadded to the public water supply -- there are a number of strongly dissenting voices…and a number of studies that back that dissent. Again, virtually all of the contrary studies are independent, whereas virtually all of the studies in support of statin drugs are industry sponsored. You can decide which you think are more credible.
The bottom line is that if you don't like what you hear from your doctor, get a second opinion from a doctor more in tune with your sensibilities. You may be surprised at what you hear. It's your body, your health, and your life. Take charge of it.
- 2.Michael J. Blaha, Khurram Nasir, Roger S. Blumenthal. "Statin Therapy for Healthy Men Identified as “Increased Risk”." JAMA. 2012;307(14):1489-1490. <http:\jama.ama-assn.org\content\307\14\1489.full.pdf+html>
- 3.Shepherd J, Cobbe SM, Ford I, et al. "West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia." N Engl J Med. 1995;333(20):1301--1307. <http://www.nejm.org/doi/full/10.1056/NEJM199511163332001#t=articleTop>
- 4.Downs JR, Clearfield M, Weis S, et al. "Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study."JAMA. 1998;279(20):1615--1622. <http://jama.ama-assn.org/content/279/20/1615.abstract?ijkey=ee13b85ae77f3863f177797cb2bb97cb94f866d7&keytype2=tf_ipsecsha>
- 5.Ridker PM, Danielson E, Fonseca FA, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195--2207. <http://www.nejm.org/doi/full/10.1056/NEJMoa0807646#t=articleTop>
- 6.E S Houslay, S J Cowell1, R J Prescott, et al. "Progressive coronary calcification despite intensive lipid-lowering treatment: a randomised controlled trial." Heart 2006;92:1207-1212 doi:10.1136/hrt.2005.080929. <http://heart.bmj.com/content/92/9/1207>
- 7.Johanna M. Geleijnse, Cees Vermeer, Diederick E. Grobbee, et al: "Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study." J. Nutr. November 1, 2004 vol. 134 no. 11 3100-3105. <http://jn.nutrition.org/content/134/11/3100.full.pdf+html>
- 8.Beulens JW, Bots ML, Atsma F, et al. "High dietary menaquinone intake is associated with reduced coronary calcification."Atherosclerosis Volume 203, Issue 2 , Pages 489-493, April 2009. <http://www.atherosclerosis-journal.com/article/S0021-9150(08)00507-8/abstract>
- 9.Karol E. Watson, MD; Marla L. Abrolat, MD; Lonzetta L. Malone,et al. "Active Serum Vitamin D Levels Are Inversely Correlated With Coronary Calcification." Circulation. 1997; 96: 1755-1760. <http://circ.ahajournals.org/content/96/6/1755.full>
- 10.Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med. Published online 2012 Jan 9. <http://archinte.ama-assn.org/cgi/content/abstract/archinternmed.2011.625v2>
- 11."FDA Expands Advice on STATIN RISKS." FDA Consumer Health Information. Feb 2012. <http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM293705.pdf>
- 12.Ridker op. cit.
- 13.David Preiss, Sreenivasa Rao Kondapally Seshasai, Paul Welsh, et al. "Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy." JAMA. 2011;305(24):2556-2564. <http://jama.ama-assn.org/content/305/24/2556.short>
- 14.Sattar N, Preiss D, Murray HM, Welsh P, et al. "Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials." Lancet. 2010 Feb 27;375(9716):735-42. Epub 2010 Feb 16. <http://www.ncbi.nlm.nih.gov/pubmed/20167359>
- 15.Rita F. Redberg, MD; Mitchell H. Katz, MD. "Healthy Men Should Not Take Statins." JAMA. 2012;307(14):1491-1492. <http://jama.ama-assn.org/content/307/14/1491.full.pdf+html%3e%22>
- 16.Ray KK, Seshasai SR, Erqou S, et al. "Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants." Arch Intern Med. 2010;170(12):1024--1031. <http://archinte.ama-assn.org/cgi/reprint/170/12/1024.pdf?ijkey=0490a19d9a2a092d57029b423deab38112bef2cd>
- 17.Taylor F, Ward K, Moore TH, et al. "Statins for the primary prevention of cardiovascular disease." Cochrane Database SystRev. 2011;(1):CD004816. <http://www.ncbi.nlm.nih.gov/pubmed/21249663 >
- 18.Lexchin J, Bero LA, Djulbegovic B, Clark O. "Pharmaceutical industry sponsorship and research outcome and quality: systematic review." BMJ. 2003;326(7400):1167--1170. <http://www.bmj.com/content/326/7400/1167.abstract?ijkey=9130651a991766c57c1a168de2819b23fe677709&keytype2=tf_ipsecsha>
- 19.Fernandez G, Spatz ES, Jablecki C, Phillips PS. "Statin myopathy: a common dilemma not reflected in clinical trials." Cleve Clin J Med. 2011;78(6):393--403. <http://www.ccjm.org/content/78/6/393.full.pdf+html>
- 20.LaRosa J, Grundy SM, Waters DD, et al. "Intensive lipid lowering with atorvastatin in patients with stable coronary disease." N Engl J Med. 2005;352(14):1425--1435 <http://www.nejm.org/doi/full/10.1056/NEJMoa050461#t=articleTop>
- 21.Fernandez, op. cit.