Similar issues arise with the approach toward dyslipidemia. Niacin is effective in reducing TGs and raising HDL but it can increase insulin resistance and deteriorate glycemic control 254, 255 . Nicotinic acid, cholestyramine, fenofibrate and possibly clofibrate increase the concentrations of homocysteine, an independent risk factor for CHD 256, 257 . A report that benzafibrate, another fibric acid derivative, did not increase CHD after a 5-year follow-up, may indicate that the rise in homocysteine should be of concern 257 .
Are cholesterol cut-offs arbitrary?
It should be noted that Taubes’ extensive review of the literature and the tapes of the 1984 Cholesterol Consensus Conference showed quite clearly that serum cholesterol levels of 200 to 240 mg/dl were definitely in the normal cholesterol range for which there was no increased risk of heart mortality in males and even above 240 mg/dl there was a decrease in risk for women. 105 The decision to make the serum cholesterol cutoff at 200 mg/dl is said to be a political one set to capture more patients to place on drugs and test rather than a prudent treatment concern based on data or scientific evidence. 258
The National Institutes of Health, through its national cholesterol education program (NCEP), recently has issued sweeping new clinical practice and management guidelines designed to lower cholesterol levels. 259, 260 If followed, these recommendations will at least triple the number of Americans on statin drugs from as estimated 13 million to 36 million (about 20 percent of adults. 260 While lifestyle changes were recommended in addition to statin agents, they were merely paid lip service. The American Diabetes Association also advocates the liberal use of statin agents 261 which would not only be costly but there are no long term studies to tell us what the ramifications of this approach will be in twenty years.
Is long-term use of statins safe?
Should you be comfortable placing a young patient on a drug for the rest of his or her life, when the long-term effects have been studied for only five to ten years? 262 It can take much longer to detect unwanted effects such as drug induced tumors. Studies show that all members of the two most popular lipid-lowering drugs (the fibrates and statins) cause benign and malignant tumors of liver, thyroid, parotid, and other organs in rodents at levels of exposure close to or above those prescribed in humans 263 . In the CARE trial, cases of breast cancer were seen more often in the treatment vs the control group (13 vs 1). In the EXCEL trial the increase of total mortality in the treatment group after just one year was borderline significant, and the trial was stopped before further observations could be made. 264-266 Recent studies suggest that the HMG-CoA reductase inhibitor simvastatin — similar to vascular endothelial growth factor (VEGF) — may promote angiogenesis by activation of a protein kinase Akt-nitric oxide synthase dependent pathway in endothelial cells, an effect that may induce angiogenesis by VEGF. While perhaps therapeutic in CHF, this may contribute to the blood supply of developing tumors and tumor metastases as well. Thus, it can be hypothesized that chronic systemic treatment of elderly patients with a drug, e.g., simvastatin, that induces angiogenesis by a VEGF-like manner will also promote tumor growth. 267-269
Statin drugs may also cause impotence 270 , and human studies show that these cholesterol lowering agents deplete the body of antioxidants (e.g., vitamin E, and beta carotene), 271 272 while raising insulin levels and lowering and CoQ-10 (ubiquinone). 272 The latter is a potentially severe problem that is associated with mitochondrial dysfunction 273 that can exacerbate cardiomyopathy. Declining levels of CoQ-10 may actually be contributing significantly to the increasing prevalence of CHD 274 and perhaps CHF failure (CHF). 275
A recent case-control study demonstrates that exposure to statins may substantially increase the risk of polyneuropathy. 276, 277 There was a 16.1-fold risk of developing definite idiopathic neuropathy in those currently taking statins and a 4.6 fold risk considering all cases of idiopathic neuropathy. For patients treated with statins for 2 or more years, risk of developing definite idiopathic neuropathy was 26.4 times that of control patients. Elevation of liver enzymes and rhabdomyolysis are side effect of all statins, and the statin Baycol (cerivastatin) was recently pulled from the world market because of its association with 52 deaths caused by rhabdomyolysis. Yet this drug had been studied and declared safe for long term use. 278
Is the benefit worth the risks?
Statin agents can also deteriorate glucose control in patients with type 2 diabetes 279 , increase insulin levels 272 and raise fibrinogen concentrations 280 281 thereby possibly increasing the long-term risk of CHD 257 . Statin drugs do appear to lower the short-term risk of dying from an MI, at least in patients who already have had one, but is the benefit worth the risk? Consider that the size of the benefit is not very impressive. In the CARE trial for instance, the 5-year survival from an MI for a patient with known CHD was 94.3%, which improved only slightly to 95.4% with statin treatment. 265 For healthy people with high cholesterol the effect is even smaller. In the WOSCOPS trial, the figures were 98.4% and 98.8%, respectively. 265 According to the Heart Protection Study which included 20,536 persons ages 40 to 80 years who were followed on average for more than 5 years. The magnitude of the benefit was similar regardless of the subgroups studied, including those with lower than average cholesterol levels. More than 3,000 patients had LDL levels below 100 mg/dL. They had a 40- to 60-mg/dL reduction in LDL levels and experienced the same one-third reduction in events as the entire cohort—strongly suggesting that vascular events reduced by statins are independent of lipid values. 282 Interestingly, although cholesterol levels are not related to stroke, simvastatin reduced the risk of stroke by about one third, which further suggests a mechanism independent of lipid lowering. Furthermore, in the Heart Protection Study, simvastatin increased the five-year total mortality by only 1.7% (85.4% to 87.1%)—substantially worse than the previous Scandinavian simvastatin survival study (4S), which showed only a 3.3% increase in mortality with the statin drug. 283, 284
According to a study of over 500 patients begun on one of three statins, three out of four experience LDL reductions that are less than predicted from the package insert. The data, from the Cleveland Clinic and presented at the American Heart Association Scientific Sessions 2001, showed some 66% of patients experienced LDL cholesterol reductions below expected, and 18% experienced either no reduction or an increase in LDL cholesterol. The results, which were consistent for all three statins examined, were attributed to lack of full adherence by patients. 285 This is particularly disturbing in light of recent findings suggesting that patients with CAD and chest pain, who have been on statin therapy, are at increased risk of death and nonfatal myocardial infarction (MI) if statins are withdrawn after the onset of symptoms. 286
As mentioned previously, statins have been shown to prevent the activation of monocytes into macrophages, inhibit the production of pro-inflammatory cytokines, C- reactive protein, and cellular adhesion molecules, and decrease the adhesion of monocyte to endothelial cells. 287 Independent of their lipid lowering, statins reduce inflammation and improve endothelial function, 287-290 which is associated with lower triglycerides, elevated HDL, and larger, fluffier LDL particles. 291, 292 HDL and its apolipoproteins have anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, and pro-fibrinolytic activities that are all anti-atherogenic. 293 HDL may also have a direct in normalizing endothelium-dependent vasodilation by increasing NO bioavailability. 294 Perhaps the effects of statins, which are unrelated to direct lipid lowering, improve endothelial function and indirectly lead to a rise in HDL and lowering of TG. HDL and TG may be the most important of the “lipid” markers because of their association with endothelial function, and the TG/HDL ratio has been demonstrated to be a powerful predictor of cardiac events. 126, 127
Can cholesterol be reduced too low?
Statins have recently been suggested for preventing and treating dementia, especially Alzheimer’s disease. 295 Again, here their potential benefit is most likely due to, again, to their reducing inflammation and endothelial dysfunction in the brain in the short term, and, in the long term, lowering brain cholesterol and altering its metabolism may create and worsen memory deficits and neuropsychological dysfunction which has been reported with these drugs. 296 Low serum cholesterol has also been associated with depression and suicidal behavior. 297-301
Low serum cholesterol levels have been associated with increased risk for hemorrhagic stroke. 302 (Interestingly, increased consumption of total and saturated fat has been associated with reduced risk of ischemic stroke in men. 303 ) Consider also that in 1986, just one year after the NIH launched the National Cholesterol Education Program, a review of the MRFIT data showed that men with very low cholesterol levels seemed prone to premature death; below 160 milligrams per deciliter (mg/dl), the lower the cholesterol level, the greater the risk of dying. Subsequent data analysis from 19 studies demonstrated a U-shaped relationship for men and flat for women. Above a serum cholesterol of 240mg/dl there was a direct association with deaths due to CHD while there was an inverse relation between cholesterol levels below 160 mg/dl and deaths caused by some cancers, respiratory diseases, digestive, and other diseases. This held up after accounting for pre-existing disease. 304
Before concluding statin drugs are superior to lifestyle changes, perhaps we should examine and revise the dietary, exercise, and other lifestyle approaches in question prior to concluding they are not as efficacious. For example, high MUFA diets have been shown to lower blood pressure and improve lipids in patients with and without diabetes 6 146 . In patients with type 2 diabetes, fish oil supplementation alone has been shown to improve dyslipidemia and endothelial function without adverse effects on glycemia or body weight 198 199 .
Treating and “improving” lab numbers without considering the underlying effects is like pushing the peaks of an iceberg just below the surface. You may be comforted because on the surface things look good, but therein lays greater danger.
The response to the suggestion of withholding drugs in someone with an abnormal lab value is the reflexive, “So what do we do – nothing?” Actually, that would be preferable than to give them something that will make their numbers look better but worsen their mortality risk. Implement lifestyle changes…This is not nothing; it is a very prudent, relatively harmless and effective intervention.
Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-1997). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject.
254. Garg A, Grundy S. Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes. JAMA 1990; 264:723-726.
255. Kahn S, Beard J, Schwartz M, et al. Increased beta-cell secretory capacity as mechanism for islet adaptation to nicotinic acid-induced insulin resistance. Diabetes 1989; 38:562-568.
256. Townsend J, O’Sullivan J, Wilde J. Hyperhomocysteinaemia and vascular disease. Blood Rev 1998; 12:23-24.
257. de Lorgeril M, Salen P, Paillard F, Lacan P, Richard G. Lipid-lowering drugs and homocysteine. Lancet 1999; 353:209-210.
258. Enig M, Fallon S. The oiling of America. Nexus Magazine.
259. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama 2001; 285:2486-97.
260. Fedder DO, Koro CE, L’Italien GJ. New National Cholesterol Education Program III Guidelines for Primary Prevention Lipid-Lowering Drug Therapy: Projected Impact on the Size, Sex, and Age Distribution of the Treatment-Eligible Population. Circulation 2002; 105:152-156.
261. Association AD. Management of dyslipidemia in adults with diabetes. Diabetes Care 1999; 22 (Suppl 1):S56-S59.
262. Bjerre LM, LeLorier J. Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am J Med 2001; 110:716-23.
263. Newman T, Hulley S. Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275:55-60.
264. Bradford RH, Shear CL, Chremos AN, et al. Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia. Am J Med 1991; 91:18S-24S.
265. Ravnskov U. The Cholesterol Myths: Exposing the fallacy that cholesterol and saturated fat cause heart disease. Washington, DC: New Trends Publishing, Inc., 2000.
266. Ravnskov U. New guidelines for converting healthy people into patients (electronic response). BMJ 2001; 322:1270.
267. Ungvari Z, Pacher P, Csiszar A. Can simvastatin promote tumor growth by inducing angiogenesis similar to VEGF? Med Hypotheses 2002; 58:85-6.
268. Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow–derived endothelial progenitor cells. J Clin Invest 2001; 108:399-405.
269. Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. Journal of Clinical Investigation 2001; 108:391-397.
270. Halkin A, Lossos I, Mevorach D. HMG-CoA reductase inhibitor-induced impotence (letter). Ann Pharmacother 1996; 30:192.
271. Human J, Ubbink J, Jerlling J, et al. The effect of Simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolemia. Clin Chim Acta 1997; 263:67-77.
272. Jula A, Marniemi J, Huupponen R, Virtanen A, Rastas M, Ronnemaa T. Effects of diet and simvastatin on serum lipids, insulin, and antioxidants in hypercholesterolemic men: a randomized controlled trial. Jama 2002; 287:598-605.
273. De Pinieux G, Chariot P, Ammi-Said M, et al. Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol 1996; 42:333-7.
274. Hughes K, Lee BL, Feng X, Lee J, Ong CN. Coenzyme Q10 and differences in coronary heart disease risk in Asian Indians and Chinese. Free Radic Biol Med 2002; 32:132-8.
275. Tran MT, Mitchell TM, Kennedy DT, Giles JT. Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy 2001; 21:797-806.
276. Donaghy M. Assessing the risk of drug-induced neurologic disorders: statins and neuropathy (editorial). Neurology 2002; 58:1321-1322.
277. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk o polyneuropathy: a case-control study. Neuorology 2002; 58:1333-1337.
278. Isaacsohn J, Insull W, Jr., Stein E, et al. Long-term efficacy and safety of cerivastatin 0.8 mg in patients with primary hypercholesterolemia. Clin Cardiol 2001; 24:IV1-9.
279. Daubresse J, Machowski R, Pulinx E. Efficacy of simvastatin for lowering cholesterol in non-insulin dependent diabetic patients with hypercholesterolemia. Acta Clin Belg 1994; 49:68-75.
280. Wierbzicki A, Lumb P, Semra Y, Crook M. Effect of atorvastatin on plasma fibrinogen. Lancet 1998; 351:569-70.
281. Maison P, Mennen L, Sapinho D, et al. A pharmacoepidemiological assessment of the effect of statins and fibrates on fibrinogen concentration. Atherosclerosis 2002; 160:155-60.
282. Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract 2002; 56:53-6.
283. Smaller meals. Boston Globe. Boston, A14.
284. Ravnskov U, Anton C. Statins as the new aspirin (electronic response). BMJ 2002; 324:789.
285. Kuzner W. Statin response varies; adherence blamed. Cardiology Review 2002; 19:9.
286. Heeschen C, Hamm CW, Laufs U, Snapinn S, Bohm M, White HD. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002; 105:1446-52.
287. Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability [In Process Citation]. Cardiovasc Res 2000; 47:648-57.
288. Laight DW, Carrier MJ, Anggard EE. Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy. Diabetes Metab Res Rev 1999; 15:274-82.
289. Aengevaeren WR. Beyond lipids – the role of the endothelium in coronary artery disease. Atherosclerosis 1999; 147 Suppl 1:S11-6.
290. Mehta JL, Li DY, Chen HJ, Joseph J, Romeo F. Inhibition of LOX-1 by Statins May Relate to Upregulation of eNOS. Biochem Biophys Res Commun 2001; 289:857-861.
291. Pinkney JS, Coen D.A.; Coppack, Simon; Yudkin, John S. Endothelial Dysfunction : Cause of the Insulin Resistance Syndrome. Diabetes 1997; 46:s9-s13.
292. Vakkilainen J, Makimattila S, Seppala-Lindroos A, et al. Endothelial dysfunction in men with small LDL particles. Circulation 2000; 102:716-21.
293. Nofer JR, Kehrel B, Fobker M, Levkau B, Assmann G, Eckardstein A. HDL and arteriosclerosis: beyond reverse cholesterol transport. Atherosclerosis 2002; 161:1-16.
294. Spieker LE, Sudano I, Hurlimann D, et al. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 2002; 105:1399-402.
295. Rockwood K, Kirkland S, Hogan DB, et al. Use of lipid-lowering agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol 2002; 59:223-7.
296. Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on cognitive function and psychological well- being. Am J Med 2000; 108:538-46.
297. Brunner J, Parhofer KG, Schwandt P, Bronisch T. [Cholesterol, omega-3 fatty acids, and suicide risk: empirical evidence and pathophysiological hypotheses]. Fortschr Neurol Psychiatr 2001; 69:460-7.
298. Brunner J, Parhofer KG, Schwandt P, Bronisch T. Cholesterol, essential fatty acids, and suicide. Pharmacopsychiatry 2002; 35:1-5.
299. Ellison LF, Morrison HI. Low serum cholesterol concentration and risk of suicide. Epidemiology 2001; 12:168-72.
300. Sarchiapone M, Roy A, Camardese G, De Risio S. Further evidence for low serum cholesterol and suicidal behaviour. J Affect Disord 2000; 61:69-71.
301. Steegmans PH, Hoes AW, Bak AA, van der Does E, Grobbee DE. Higher prevalence of depressive symptoms in middle-aged men with low serum cholesterol levels. Psychosom Med 2000; 62:205-11.
302. Jacobs DR. The relationship between cholesterol and stroke. Health Rep 1994; 6:87-93.
303. Gillman MW, Cupples LA, Millen BE, Ellison RC, Wolf PA. Inverse association of dietary fat with development of ischemic stroke in men [see comments]. Jama 1997; 278:2145-50.
304. Jacobs D, Blackburn H, Higgins M, et al. Report of the Conference on Low Blood Cholesterol: Mortality Associations. Circulation 1992; 86:1046-60.
305. Ceriello A, Giugliano D, Quatraro A, Donzella C, Dipalo G, Lefebvre P. Vitamin E reduction of protein glycosylation in diabetes: new prospect for prevention of diabetic complications. Diabetes Care 1991; 14:68-72.
306. Tutuncu N, Bayraktar M, Varli K. Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes. Diabetes Care 1998; 21:1915-1918.
307. Stephens N, Parsons A, Schofield P, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996; 347:781-86.
308. Schwenke D, Behr S. Vitamin E combined with selenium inhibits atherosclerosis in hypercholesterolemic rabbits independently of effects on plasma cholesterol concentrations. Circ Res 1998; 83:366-77.