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This article is protected by copyright. To share or copy this article, se ISSN#10786791. To subscribe, THe FAILURe OF RISk FACTOR TReATmeNT FOR PRImARy PReVeNTION OF CHRONIC DISeASe mark A. Hyman, mD Mark A. Hyman, MD, is a contributing editor of Alternative
physical activity, and exposure to environmental toxins affecting Therapies in Health and Medicine. He launched the Functional
gene expression. Isolating one risk factor, or even separately Medicine Foundation, based in New York, New York, to pro-
treating multiple risk factors, will fail until it is done in the con- mote awareness of, fund research on, and educate the public
text of addressing the upstream drivers of disease. While dyslipi- about functional medicine. (Altern Ther Health Med.
demia, hyperglycemia, and hypertension are risk factors for chronic disease, they are not the cause of chronic disease. Distinguishing between risk factors and causes is necessary for arge drug trials have attempted to prove that targeting effective primary prevention and treatment of chronic disease.7 risk factors such as lipid or glucose levels with pharma- Treatment must focus on the system, not the symptom. cologic agents reduces the risk of important chronic dis- Dyslipidemia, hyperglycemia, and hypertension are symptoms ease endpoints such as cardiovascular events, diabetes, of upstream biological causes. They are the smoke, not the fire. and mortality. Despite hundreds of mil ions of research Unless medicine refocuses on treating the system rather than dol ars spent over many decades, aggressive risk factor treatment of symptoms (risk factors) through a comprehensive clinical and the two most important targets—lipids and glucose—has consis- social systems approach that addresses diet, exercise, stress man- tently failed to show benefit in primary prevention.
agement, and treatment of environmental toxic exposures, medi- Patients with metabolic syndrome and diabetes have as high cine will fail to stem the impending tsunami of chronic disease. a risk of adverse cardiac events as patients who have had a previ- Despite the elegant simplicity of single-drug treatment with ous myocardial infarction. Therefore, much focus has been statins or antihyperglycemic agents, they have not fulfilled their placed on aggressive risk factor reduction.1 However, as the promise of primary prevention. Despite the difficulty of behavior recent data show, we may have been focusing on the wrong tar- change and lifestyle and environmental treatment, they are the gets—lipids, glucose, and blood pressure, rather than insulin only proven model for preventing chronic disease. Risk factor resistance and its primary causes, which are the main drivers of treatment must be replaced with elimination of the drivers, trig- cardiovascular disease, diabetes, dementia, cancer, and most gers, and causes of chronic disease. Newer tools supporting chronic disease mortality. A recent 40-year prospective study of behavior change with regular feedback and social networks have 4857 Pima Indian children found that the most important pre- proven successful and should be widely adopted in policy and dictor of premature death was insulin resistance, not hyperten- medical practice.8 sion or hyperlipidemia. Those in the highest quartile of glucose Four recent large trials targeting blood pressure, lipids, and intolerance had a 73% increased death rate compared to those in glucose, while effective in lowering the risk factors (lower lipids, the lowest quartile.2 glucose, blood pressure), failed to show benefit in reducing pri- Recent trials from the Nateglinide and Valsartan in Impaired mary composite endpoints of nonfatal myocardial infarction, Glucose Tolerance Outcomes Research (NAVIGATOR) and Action nonfatal stroke, or death from cardiovascular causes. A dramatic to Control Cardiovascular Risk in Diabetes (ACCORD) Study paradigm shift is needed in the targets for primary prevention. Groups published in The New England Journal of Medicine have The era of individual risk factor reduction must now be sup- confirmed that we may not only be ineffective in preventing cardi- planted by treatment of the etiology of chronic disease through a ac events, diabetes, and mortality but causing harm by aggressive- systems or functional model of diagnosis and treatment.
ly treating risk factors.3-6 Lipids, glucose, and blood pressure were The ACCORD study was designed to test the effect of inten- all effectively reduced in these trials. But there was no reduction in sive treatment of blood glucose, blood pressure, and plasma lip- morbidity and mortality in any of the trials reported, and there ids on cardiovascular outcomes in 10 251 patients with type 2 were significant side effects. The question is why.
diabetes who were at high risk for cardiovascular disease. The Chronic disease is the result of complex network of biologi- lipid arm of the ACCORD trial studied 5518 patients over 4.7 cal disturbances driving systemic neuroendocrineimmune dys- years and found that adding fenofibrate to simvistatin showed no regulation induced by the effects of diet, levels of stress and benefit in primary outcomes despite improvements in HDL and 60 ALTERNATIVE THERAPIES, may/jun 2010, VOL. 16, NO. 3 The Failure of Risk Factor Treatment for Chronic Disease triglyceride profiles.5 Women had an increase in adverse effects. 2004 National Cholesterol education Program guidelines The ACCORD blood pressure trial of 4733 patients showed no expanded the previous guidelines to recommend that more peo- benefit of reducing systolic blood pressure from 140 mmHg to ple take statins (from 13 million to 40 million) and promote sta- 120 mmHg.6 The intensive blood pressure lowering arm had sig- tins for primary prevention (or about 75% of the patients taking nificant adverse side effects.
statins).17 eight of the nine experts on the panel who developed The NAVIGATOR glucose-lowering trial found no reduction these guidelines had financial ties to the drug industry. Thirty- in cardiovascular outcomes or development of diabetes using an four other non–industry-affiliated experts sent a petition to pro- insulin secretagogue, nateglinide, and resulted in significant test the recommendations to the National Institutes of Health, hypoglycemia in one in five study participants.3 Not surprisingly, saying the evidence was weak. postprandial glucose levels were more elevated after 1 year of If these medications were without side effects, then we treatment with the insulin secretagogue because the drug- might be able to justify the risk, but they cause myopathy18 (even induced hyperinsulinemia increased insulin resistance and hence in the absence of pain and elevated creatine phosphokinase), sex- postprandial glucose levels. This study joins other trials of first- ual dysfunction, liver and nerve damage, and other problems in and second-generation oral hypoglycemic agents in failing to 10% to 15% of patients who take them.19 Recent evidence points show a reduction in progression to diabetes or cardiovascular to the occurrence of not only myositis, rhabdomyolysis, elevation disease. The NAVIGATOR trial of valsartan, an angiotensin- of serum creatine kinase levels, myalgias, muscle weakness, mus- converting enzyme inhibitor, also failed to show a reduction of cle cramps, exercise intolerance, and persistent myalgias from cardiovascular events but reduced the incidence of diabetes from statin therapy but also asymptomatic myopathy, mitochondrial 36% to 33% compared to placebo.4 injury, apoptosis, and neuromuscular injury.20 Previously published data from the ACCORD trial in more than 10 000 patients showed an increase in adverse cardiovascu- RetHiNkiNg tARgets FoR tReAtMeNt
lar outcomes and mortality with intensive lowering of glucose.9 If the evidence indicates that lowering lipids, glucose, or Other data focused on lowering of lipids also failed to show a blood pressure—in other words, aggressively reducing cardio- benefit to statin therapy for the primary prevention of cardio- vascular or diabetes risk factors—doesn't produce the desired vascular disease and mortality with increased risk of adverse outcome, namely, less cardiovascular disease, diabetes, and outcomes.10 There are abundant data calling into question the death, we must wonder what the treatment targets should be.
benefit of statin therapy focusing on risk factor reduction If lipids are implicated in the development of atherosclero- despite widespread use and marketing of this medication class. sis, then the right question is not, "How low is the LDL target The JUPITeR trial showed that lowering low-density lipoprotein level?" Rather, the right questions are "What causes lipids to cholesterol (LDL-C) without reductions in inflammation (mea- become atherogenic, and how do we treat that?" Conventional sured by C-reactive protein) showed no benefit.11,12 yet this study methods of lipid analysis are outdated because we now under- is touted as proof of the effectiveness of statin therapy in prima- stand that atherogenic particles are small, dense HDL and LDL ry prevention through lipid lowering. There is no proven benefit and large very low-density lipoprotein particles.21 Insulin resis- for statins in healthy women with dyslipidemia or in anyone tance, oxidative stress, and inflammation cause this atherogenic over 69 years old.10 The eNHANCe trial showed that aggressive lipid phenotype, and although statins may lower inflammation cholesterol treatment with two medications (simvastatin and marginally, they do not have a significant effect on increasing ezetimibe) lowered cholesterol much more than one drug alone lipid particle size.
but led to more arterial plaque and no fewer cardiac events.13 What does reduce total and cardiovascular mortality and Other data also challenge the importance of LDL-C as a cardio- diabetes are lifestyle changes including a low glycemic load, phy- vascular risk factor. Using statins to lower LDL-C in patients tonutrient-rich, plant-based diet that is rich in omega-3 fatty with low high-density lipoprotein cholesterol (HDL-C) also acids and fiber, and exercise that reduces atherogenic lipid parti- reveals no benefit.14 An often-ignored data point is that 50% to cles, oxidative stress, and inflammation. Niacin also can increase 75% of people who have myocardial infarction have normal cho- lipid particle size and raise HDL-C and reverse atherosclerotic lesterol.15 The Honolulu Heart Study showed that older patients plaque.22 We use the tools we have, not necessarily the right with lower cholesterol have higher risks of death than those with "medicine" for the problem. The right "medicine" for both pre- higher cholesterol.16 venting and treating heart disease is a healthy lifestyle, which While there is benefit to treatment of those with existing works better than medication. Statin use is not without risk, and disease with statin therapy for secondary prevention, there is no the benefit is overstated, especially for its major indication— good evidence for primary prevention. For high-risk males primary prevention. The question then becomes, "What are the younger than 69 years of age, there is some evidence of benefit, true contributors to cardiovascular disease?" but the number needed to treat is 50 to 100 for reduction of one event.6 The absolute risk reduction is from 2% to 3%. Seventy-five PRiMe CoNtRibutoRs to CARDiovAsCulAR DiseAse
percent of statin prescriptions are written for primary preven- The interaction of genes, lifestyle, and environment deter- tion at a cost of more than $20 billion per year. However, the mines risk. This dynamic interaction leads to the primary drivers The Failure of Risk Factor Treatment for Chronic Disease ALTERNATIVE THERAPIES, may/jun 2010, VOL. 16, NO. 3 61 of cardiovascular disease, including insulin resistance, inflam- and our body burden of environmental toxins. We focus on cho- mation, oxidative stress and inflammation,23 environmental lesterol or glucose or hypertension because they are the risk fac- toxins,24 and stress. tors for which we have the best medication. As the evidence The data show that preventing heart disease has very little shows, they may be only the downstream symptoms of a much to do with simply lowering LDL cholesterol with statins or inten- more important biological process of insulin resistance that must sive glucose or blood pressure lowering. Our current thinking be treated directly. Insulin resistance is a complex metabolic dys- about how to treat and prevent heart disease is at best misguided regulation that results from multiple insults, including a high- and at worst harmful. We believe we are treating the causes of glycemic load, low-fiber, nutrient-poor diet, sedentary lifestyle, heart disease by lowering cholesterol, blood pressure, and glu- chronic stress, environmental toxins, latent infections, and aller- cose with medication. But we are treating surrogate risk factors, gens. Those factors must be the targets for primary and second- not causes. The real question is what causes dyslipidemia, hyper- ary prevention of chronic disease.
tension, and dysglycemia in the first place.3 A comprehensive approach to treating the system and not The environment influencing gene expression is what deter- the symptom using a whole-food, plant-based diet rich in mines risk. In other words, the way we eat, how much we exer- omega-3 fats, antioxidants, and phytonutrients; supplements; cise, how we deal with stress, and the effects of environmental exercise; stress management; and strategies for treating chronic toxins are the underlying causes of dyslipidemia, hypertension, low-level environmental toxicity can have a dramatic impact on and dysglycemia. Those factors—not a lack of medication—are the risk of heart disease. And there is a good side effect—this what determine the risk of heart disease.
approach reduces the risk of nearly all chronic diseases.
The research clearly shows that changing how we live is a much more powerful intervention for preventing heart disease than any medication. The ePIC (european Prospective 1. Haffner Sm, Lehto S, Rönnemaa T, Pyöräla k, Laakso m. mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and Investigation Into Cancer) study published in the Archives of without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234.
Internal Medicine studied 23 000 people's adherence to four sim- 2. Franks PW, Hanson RL, knowler WC, Sievers mL, Bennett PH, Looker HC. Childhood obesity, other cardiovascular risk factors, and premature death. N Engl J Med. ple behaviors (not smoking, exercising 3.5 hours a week, eating a healthy diet [fruits, vegetables, beans, whole grains, nuts, seeds, 3. The NAVIGATOR Study Group. effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010 mar 14. [epub ahead of print] and limited amounts of meat], and maintaining a healthy weight 4. The NAVIGATOR Study Group. effect of valsartan on the incidence of diabetes and [BmI <30]). In those adhering to these behaviors, 93% of diabe- cardiovascular events. N Engl J Med. 2010 mar 16. [epub ahead of print] 5. The ACCORD Study Group. effects of combination lipid therapy in type 2 diabetes tes, 81% of heart attacks, 50% of strokes, and 36% of all cancers mellitus. N Engl J Med. 2010 mar 18. [epub ahead of print] were prevented.25 6. The ACCORD Study Group. effects of intensive blood-pressure control in type 2 diabe- tes mellitus. N Engl J Med. 2010 mar 14. [epub ahead of print] The INTeRHeART study, published in The Lancet in 2004, 7. mozaffarian D, Wilson PW, kannel WB. Beyond established and novel risk factors: life- followed 30 000 people and found that changing lifestyle could style risk factors for cardiovascular disease. Circulation. 2008;117(23):3031-3038. 8. Goetz T. The Decision Tree: Taking Control of Your Health in the New Era of Personalized prevent at least 90% of all heart disease.26 Medicine. New york, Ny: Rodale Books; 2010.
These studies are among a large evidence base documenting 9. Ray kk, Seshasai SR, Wijesuriya S, et al. effect of intensive control of glucose on cardio- vascular outcomes and death in patients with diabetes mellitus: a meta-analysis of ran- that lifestyle intervention is often more effective in reducing car- domised controlled trials. Lancet. 2009;373(9677):1765-1772.
diovascular disease, hypertension, heart failure, stroke, cancer, dia- 10. Abramson J, Wright Jm. Are lipid-lowering guidelines evidence-based? Lancet. betes, and deaths from al causes than almost any other medical 11. mora S, Ridker Pm. Justification for the Use of Statins in Primary Prevention: an intervention.27 It is because a healthy lifestyle not only reduces risk Intervention Trial evaluating Rosuvastatin (JUPITeR)—can C-reactive protein be used to target statin therapy in primary prevention? Am J Cardiol. 2006;97(2A):33A-41A.
factors such as high blood pressure, glucose, and cholesterol; our 12. Ridker Pm, Danielson e, Fonseca FA, et al; JUPITeR Study Group. Rosuvastatin to pre- lifestyle and environment influence the fundamental causes and vent vascular events in men and women with elevated C-reactive protein. N Engl J Med. biological mechanisms leading to disease: changes in gene expres- 13. Brown BG, Taylor AJ. Does eNHANCe diminish confidence in lowering LDL or in sion, which modulate inflammation, oxidative stress, and metabol- ezetimibe? N Engl J Med. 2008;358(14):1504-1507.
14. Barter P, Gotto Am, LaRosa JC, et al; Treating to New Targets Investigators. HDL cho- ic dysfunction. An unhealthy lifestyle and environment, not a lesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. statin deficiency, are the real reasons for cardiovascular disease.
15. Hansson Gk. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. Ignoring or giving lip service to the underlying causes and treating only risk factors is somewhat like mopping up the floor 16. Schatz IJ, masaki k, yano k, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. Lancet. around an overflowing sink rather than turning off the faucet, which is why medications usually have to be taken for a lifetime. 17. US Department of Health and Human Services. National Institutes of Health. National Heart Lung and Blood Institute. National Cholesterol Education Program. Available at: When the underlying lifestyle causes are addressed, patients http://www.nhlbi.nih.gov/about/ncep/index.htm. Accessed march 19, 2010.
often are able to stop taking medication and avoid surgery.
18. Sirvent P, mercier J, Lacampagne A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol. 2008;8(3):333-338.
Dyslipidemia and hypertension are only a couple of many 19. kuncl RW. Agents and mechanisms of toxic myopathy. Curr Opin Neurol. factors that lead to cardiovascular disease, and they may not even 2009;22(5):506-515. 20. Tsivgoulis G, Spengos k, karandreas N, Panas m, kladi A, manta P. Presymptomatic be the most important ones. Inflammation and insulin resistance neuromuscular disorders disclosed following statin treatment. Arch Intern Med. are the primary drivers of cardiovascular disease and are driven 21. Decewicz DJ, Neatrour Dm, Burke A, et al. effects of cardiovascular lifestyle change on by what we eat, how much we exercise, how we deal with stress, lipoprotein subclass profiles defined by nuclear magnetic resonance spectroscopy. 62 ALTERNATIVE THERAPIES, may/jun 2010, VOL. 16, NO. 3 The Failure of Risk Factor Treatment for Chronic Disease

Lipids Health Dis. 2009 Jun 29;8:26.
22. Cziraky mJ, Watson ke, Talbert RL. Targeting low HDL-cholesterol to decrease residu- al cardiovascular risk in the managed care setting. J Manag Care Pharm. 2008;14(8 Suppl):S3-S28; quiz S30-31.
23. Hansson Gk. Atherosclerosis—an immune disease: The Anitschkov Lecture 2007. F INALLY, A HOLISTIC WAY TO LOSE
24. menke A, muntner P, Batuman V, Silbergeld ek, Guallar e. Blood lead below 0.48 WEIGHT AND KEEP IT OFF.
micromol/L (10 microg/dL) and mortality among US adults. Circulation. 25. Ford eS, Bergmann mm, kröger J, Schienkiewitz A, Weikert C, Boeing H. Healthy liv- ing is the best revenge: findings from the european Prospective Investigation Into Cancer and Nutrition-Potsdam study. Arch Intern Med. 2009;169(15):1355-1362.
26. yusuf S, Hawken S, Ounpuu S, et al; INTeRHeART Study Investigators. effect of potentially modifiable risk factors associated with myocardial infarction in 52 coun- tries (the INTeRHeART study): case-control study. Lancet. 2004;364(9438):937-952.
27. American College of Preventive medicine. ACPm lifestyle medicine initiative. ACPm. Available at: www.acpm.org/Lifestylemedicine.htm. Accessed march 19, 2010.
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