- Email: [email protected]
Peripheral neuropathy
Correspondence
statin doses were well within the recommended range. The mechanism of statin-induced neuropathy could be related to inhibition of HMG Co-A reductase, the enzyme responsible for the production of mevalonate and ultimately cholesterol. Statins also decrease concentrations of coenzyme Q10 (ubiquinone), which plays a crucial part in the mitochondrial respiratory process that controls energy use in nerve and striated muscle tissue. Administration of coenzyme Q10 might prevent or diminish neuromuscular damage from statins, as has been shown for other complications. Pharmaceutical manufacturers have long been aware of this possibility, and Merck & Co4 has had two patents on a statin-coenzyme Q10 combination product since 1990. Because symptoms of neuropathy are subjective and can be confused with peripheral vascular problems that are probably more prevalent in patients taking statins, many cases likely remain undiagnosed. Although peripheral neuropathy is probably an uncommon complication, a large population might be affected in view of recommendations5 that would increase the number of patients eligible for cholesterol lowering drugs from 13 million to 36 million, and their possible availability without a prescription. Since there is no way to predict who will be at risk, and there are no readily available diagnostic laboratory tests, drug companies are being petitioned to warn patients, doctors, and other health-care professionals about this potential hazard.
Paul J Rosch [email protected] Department of Medicine and Psychiatry, New York Medical College, American Institute of Stress, 124 Park Avenue, Yonkers, NY 10703, USA 1 2
3
4
1664
England JD, Asbury AK. Peripheral neuropathy. Lancet 2004; 363: 2151–61. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology 2002; 58: 1333–37. Silverberg C. Atorvastatin-induced polyneuropathy. Ann Intern Med 2004; 139: 792–93. Merck & Co Inc Patent 4929437, issued May 29, 1990, and US Patent 4933165,
5
issued June 12, 1990, both titled Coenzyme Q10 with HMG-CoA Reductase Inhibitors. Grundy SM, Cleeman JI, Bairey Merz CN. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227–39.
In their scholarly Seminar on peripheral neuropathy,1 John England and Arthur Asbury do not emphasise the fact that, in patients with small-fibre neuropathy in whom diabetes mellitus or impaired glucose tolerance is detected, the duration of neuropathic symptoms can precede the diagnosis by 3–240 months (median 54)—ie, diabetic neuropathy can arise in the absence of long-term diabetes.2–4
*Ajit Singh Kashyap, Kuldip Parkash Anand, Surekha Kashyap, Abhijeet Anand [email protected] *Departments of Medicine (ASK) and Hospital Administration (SK), Armed Forces Medical College, Pune 411 040, India; Department of Medicine, Command Hospital (Eastern Command), Alipore, Kolkata, India (KPA); and Population Council, New Delhi, India (AA) 1 2
3
4
England JD, Asbury AK. Peripheral neuropathy. Lancet 2004; 363: 2151–61. Singleton JR, Smith AG, Bromberg MB. Painful sensory neuropathy associated with impaired glucose tolerance. Muscle Nerve 2001; 24: 1225–28. Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001; 24: 1229–31. Summer CJ, Sheth S, Griffin JW. Cornblath DR, Polydefkis M. The spectrum of diabetes and impaired glucose tolerance. Neurology 2003; 60: 108–11.
Authors’ reply We thank Paul Rosch for his thoughtful comments with respect to the potential association of statins and polyneuropathy. As he points out, several reports suggest a possible relation between statin use and polyneuropathy. However, considering that millions of people have been exposed to statins, the published work on this subject is sparse and consists mostly of case reports. Only a few studies provide more substantial evidence for this possible asso-
ciation. In one study,1 in a group of 745 patients on lovastatin for a median duration of 5·2 years, a single case of peripheral neuropathy was reported, and the neuropathy was not attributed to the drug. The highest quality of evidence, suggesting that long-term exposure to statins increases the risk of polyneuropathy, is provided by two epidemiological trials.2,3 In a cohort study2 based on data from British family doctors, statin users showed a relative risk of 2·5 for polyneuropathy compared with the background population. A larger population-based, casecontrol study3 showed an increased odds ratio (3·7 for all cases and 14·2 for definite cases), linking polyneuropathy with statin use. In this study,3 nine of 166 patients with idiopathic polyneuropathy had used statins for a median duration of 2·8 years. The study was well designed, but the investigators could not account for all possible confounders. In particular, there was no accounting for the possible presence of impaired glucose tolerance (prediabetes) or extreme hyperlipidemia, both of which might also be associated with polyneuropathy.4,5 Taken together, the results of these studies indicate that exposure to statins might increase the risk of polyneuropathy, but proof of a cause and effect relation is lacking. Continued surveillance of patients on statins and further research with respect to the potential association between statins and polyneuropathy are warranted. Until more information is available, the relation between statins and polyneuropathy should be considered unproven.
*John D England, Arthur K Asbury [email protected] *Department of Neurosciences, Deaconess Billings Clinic, 2825 Eighth Avenue North, Billings, MT 59107, USA (JDE); and Department of Neurology, University of Pennsylvania School of Medicine, PA, USA (AKA) 1
2
Lovastatin Study Groups I Through IV. Lovastatin 5-year safety and efficacy study. Arch Intern Med 1993; 153: 1079–87. Gaist D, Garcia Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol 2001; 56: 931–33.
www.thelancet.com Vol 364 November 6, 2004
statin doses were well within the recommended range. The mechanism of statin-induced neuropathy could be related to inhibition of HMG Co-A reductase, the enzyme responsible for the production of mevalonate and ultimately cholesterol. Statins also decrease concentrations of coenzyme Q10 (ubiquinone), which plays a crucial part in the mitochondrial respiratory process that controls energy use in nerve and striated muscle tissue. Administration of coenzyme Q10 might prevent or diminish neuromuscular damage from statins, as has been shown for other complications. Pharmaceutical manufacturers have long been aware of this possibility, and Merck & Co4 has had two patents on a statin-coenzyme Q10 combination product since 1990. Because symptoms of neuropathy are subjective and can be confused with peripheral vascular problems that are probably more prevalent in patients taking statins, many cases likely remain undiagnosed. Although peripheral neuropathy is probably an uncommon complication, a large population might be affected in view of recommendations5 that would increase the number of patients eligible for cholesterol lowering drugs from 13 million to 36 million, and their possible availability without a prescription. Since there is no way to predict who will be at risk, and there are no readily available diagnostic laboratory tests, drug companies are being petitioned to warn patients, doctors, and other health-care professionals about this potential hazard.
Paul J Rosch [email protected] Department of Medicine and Psychiatry, New York Medical College, American Institute of Stress, 124 Park Avenue, Yonkers, NY 10703, USA 1 2
3
4
1664
England JD, Asbury AK. Peripheral neuropathy. Lancet 2004; 363: 2151–61. Gaist D, Jeppesen U, Andersen M, et al. Statins and risk of polyneuropathy: a case-control study. Neurology 2002; 58: 1333–37. Silverberg C. Atorvastatin-induced polyneuropathy. Ann Intern Med 2004; 139: 792–93. Merck & Co Inc Patent 4929437, issued May 29, 1990, and US Patent 4933165,
5
issued June 12, 1990, both titled Coenzyme Q10 with HMG-CoA Reductase Inhibitors. Grundy SM, Cleeman JI, Bairey Merz CN. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 2004; 110: 227–39.
In their scholarly Seminar on peripheral neuropathy,1 John England and Arthur Asbury do not emphasise the fact that, in patients with small-fibre neuropathy in whom diabetes mellitus or impaired glucose tolerance is detected, the duration of neuropathic symptoms can precede the diagnosis by 3–240 months (median 54)—ie, diabetic neuropathy can arise in the absence of long-term diabetes.2–4
*Ajit Singh Kashyap, Kuldip Parkash Anand, Surekha Kashyap, Abhijeet Anand [email protected] *Departments of Medicine (ASK) and Hospital Administration (SK), Armed Forces Medical College, Pune 411 040, India; Department of Medicine, Command Hospital (Eastern Command), Alipore, Kolkata, India (KPA); and Population Council, New Delhi, India (AA) 1 2
3
4
England JD, Asbury AK. Peripheral neuropathy. Lancet 2004; 363: 2151–61. Singleton JR, Smith AG, Bromberg MB. Painful sensory neuropathy associated with impaired glucose tolerance. Muscle Nerve 2001; 24: 1225–28. Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001; 24: 1229–31. Summer CJ, Sheth S, Griffin JW. Cornblath DR, Polydefkis M. The spectrum of diabetes and impaired glucose tolerance. Neurology 2003; 60: 108–11.
Authors’ reply We thank Paul Rosch for his thoughtful comments with respect to the potential association of statins and polyneuropathy. As he points out, several reports suggest a possible relation between statin use and polyneuropathy. However, considering that millions of people have been exposed to statins, the published work on this subject is sparse and consists mostly of case reports. Only a few studies provide more substantial evidence for this possible asso-
ciation. In one study,1 in a group of 745 patients on lovastatin for a median duration of 5·2 years, a single case of peripheral neuropathy was reported, and the neuropathy was not attributed to the drug. The highest quality of evidence, suggesting that long-term exposure to statins increases the risk of polyneuropathy, is provided by two epidemiological trials.2,3 In a cohort study2 based on data from British family doctors, statin users showed a relative risk of 2·5 for polyneuropathy compared with the background population. A larger population-based, casecontrol study3 showed an increased odds ratio (3·7 for all cases and 14·2 for definite cases), linking polyneuropathy with statin use. In this study,3 nine of 166 patients with idiopathic polyneuropathy had used statins for a median duration of 2·8 years. The study was well designed, but the investigators could not account for all possible confounders. In particular, there was no accounting for the possible presence of impaired glucose tolerance (prediabetes) or extreme hyperlipidemia, both of which might also be associated with polyneuropathy.4,5 Taken together, the results of these studies indicate that exposure to statins might increase the risk of polyneuropathy, but proof of a cause and effect relation is lacking. Continued surveillance of patients on statins and further research with respect to the potential association between statins and polyneuropathy are warranted. Until more information is available, the relation between statins and polyneuropathy should be considered unproven.
*John D England, Arthur K Asbury [email protected] *Department of Neurosciences, Deaconess Billings Clinic, 2825 Eighth Avenue North, Billings, MT 59107, USA (JDE); and Department of Neurology, University of Pennsylvania School of Medicine, PA, USA (AKA) 1
2
Lovastatin Study Groups I Through IV. Lovastatin 5-year safety and efficacy study. Arch Intern Med 1993; 153: 1079–87. Gaist D, Garcia Rodriguez LA, Huerta C, Hallas J, Sindrup SH. Are users of lipid-lowering drugs at increased risk of peripheral neuropathy? Eur J Clin Pharmacol 2001; 56: 931–33.
www.thelancet.com Vol 364 November 6, 2004