[en] [en] OBJECTIVE: Peroxisome proliferator activated receptor γ-activating drugs show various salutary effects in preclinical models of neurodegenerative disease. The decade-long clinical usage of these drugs as antidiabetics now allows for evaluation of patient-oriented data sources.
METHODS: Using observational data from 2004-2010, we analyzed the association of pioglitazone and incidence of dementia in a prospective cohort study of 145,928 subjects aged ≥60 years who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. We distinguished between nondiabetics, diabetics without pioglitazone, diabetics with prescriptions of <8 calendar quarters of pioglitazone, and diabetics with ≥8 quarters. Cox proportional hazard models explored the relative risk (RR) of dementia incidence dependent on pioglitazone use adjusted for sex, age, use of rosiglitazone or metformin, and cardiovascular comorbidities.
RESULTS: Long-term use of pioglitazone was associated with a lower dementia incidence. Relative to nondiabetics, the cumulative long-term use of pioglitazone reduced the dementia risk by 47% (RR = 0.53, p = 0.029). If diabetes patients used pioglitazone <8 quarters, the dementia risk was comparable to those of nondiabetics (RR = 1.16, p = 0.317), and diabetes patients without a pioglitazone treatment had a 23% increase in dementia risk (RR = 1.23, p < 0.001). We did not find evidence for age effects, nor for selection into pioglitazone treatment due to obesity.
INTERPRETATION: These findings indicate that pioglitazone treatment is associated with a reduced dementia risk in initially non-insulin-dependent diabetes mellitus patients. Prospective clinical trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; German Center for Neurodegenerative Diseases, Bonn, Germany ; Clinical Neurosciences, Department of Neurology, University of Bonn, Bonn, Germany ; Department of Medicine, University of Massachusetts Medical School, Worcester, MA
Fink, Anne; German Center for Neurodegenerative Diseases, Bonn, Germany ; Rostock Center for the Study of Demographic Change, Rostock, Germany
Doblhammer, Gabriele; German Center for Neurodegenerative Diseases, Bonn, Germany ; Rostock Center for the Study of Demographic Change, Rostock, Germany ; Institute for Sociology and Demography, University of Rostock, Rostock, Germany ; Max Planck Institute for Demographic Research, Rostock, Germany
External co-authors :
yes
Language :
English
Title :
Effect of pioglitazone medication on the incidence of dementia.
Yki-Järvinen H,. Thiazolidinediones. N Engl J Med 2004; 351: 1106-1118.
Rangwala SM, Lazar MA,. Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 2004; 25: 331-336.
Heneka MT, Landreth GE, Hüll M,. Drug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders. Nat Clin Pract Neurol 2007; 3: 496-504.
Heneka MT, Landreth GE,. PPARs in the brain. Biochim Biophys Acta 2007; 1771: 1031-1045.
Biessels GJ, Staekenborg S, Brunner E, et al., Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006; 5: 64-74.
Crane PK, Walker R, Hubbard RA, et al., Glucose levels and risk of dementia. N Engl J Med 2013; 369: 540-548.
Barnes DE, Yaffe K,. The projected effect of risk factor reduction on Alzheimer's disease prevalence. Lancet Neurol 2011; 10: 819-828.
Imfeld P, Bodmer M, Jick SS, Meier CR,. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc 2012; 60: 916-921.
Moore EM, Mander AG, Ames D, et al., Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 2013; 36: 2981-2987.
Taylor DH Jr, Østbye T, Langa KM, et al., The accuracy of Medicare claims as an epidemiological tool: the case of dementia revisited. J Alzheimers Dis 2009; 17: 807-815.
Doblhammer G, Fink A, Fritze T,. Short-term trends in dementia prevalence in Germany between the years 2007 and 2009. Alzheimers Dement 2015; 11: 291-299.
Breteler MM,. Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging 2000; 21: 153-160.
Whitmer RA, Sidney S, Selby J, et al., Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005; 64: 277-281.
Kwok CS, Loke YK, Hale R, et al., Atrial fibrillation and incidence of dementia: a systematic review and meta-analysis. Neurology 2011; 76: 914-922.
Snapinn S, Jiang Q, Iglewicz B,. Illustrating the impact of a time-varying covariate with an extended Kaplan-Meier estimator. Am Stat 2005; 59: 301-307.
Klein J, Moeschberger M,. Survival analysis: techniques for censored and truncated data. New York, NY: Springer, 2003.
Skoog I,. Psychiatric epidemiology of old age: the H70 study-the NAPE lecture 2003. Acta Psychiatr Scand 2004; 109: 4-18.
Gao S, Hendrie HC, Hall KS, Hui S,. The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry 1998; 55: 809-815.
Haag MDM, Hofman A, Koudstaal PJ, et al., Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J Neurol Neurosurg Psychiatry 2009; 80: 13-17.
Hajjar I, Schumpert J, Hirth V, et al., The impact of the use of statins on the prevalence of dementia and the progression of cognitive impairment. J Gerontol A Biol Sci Med Sci 2002; 57: M414-M418.
Fewell Z, Hernan MA, Wolfe F, et al., Controlling for time-dependent confounding using marginal structural models. Stata J 2004; 4: 402-420.
Schneider JA, Arvanitakis Z, Bang W, Bennett DA,. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007; 69: 2197-2204.
Nissen SE, Wolski K,. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457-2471.
Rosen CJ,. Revisiting the rosiglitazone story-lessons learned. N Engl J Med 2010; 363: 803-806.
Azoulay L, Yin H, Filion KB, et al., The use of pioglitazone and the risk of bladder cancer in people with type 2 diabetes: nested case-control study. BMJ 2012; 344: e3645.
Colmers IN, Bowker SL, Majumdar SR, Johnson JA,. Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis. CMAJ 2012; 184: E675-E683.
Miller D, Fincke B, Davidson J, Weill J,. Thiazolidinedione use is associated with lower incidence of Alzheimer's disease. Pharmacoepidemiol Drug Saf 2006; 15: S260-S261.
Lampert T,. Smoking, physical inactivity, and obesity: associations with social status. Dtsch Arztebl Int 2010; 107: 1-7.
Risner ME, Saunders AM, Altman JFB, et al., Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 2006; 6: 246-254.
Gold M, Alderton C, Zvartau-Hind M, et al., Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 2010; 30: 131-146.
Harrington C, Sawchak S, Chiang C, et al., Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res 2011; 8: 592-606.
Geldmacher DS, Fritsch T, McClendon MJ, Landreth G,. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol 2011; 68: 45-50.
Sato T, Hanyu H, Hirao K, et al., Efficacy of PPAR-γ agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging 2011; 32: 1626-1633.
Sastre M, Dewachter I, Landreth GE, et al., Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase. J Neurosci 2003; 23: 9796-9804.
Sastre M, Dewachter I, Rossner S, et al., Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A 2006; 103: 443-448.
Yamanaka M, Ishikawa T, Griep A, et al., PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci 2012; 32: 17321-17331.
Mandrekar-Colucci S, Karlo JC, Landreth GE,. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-γ-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer's disease. J Neurosci 2012; 32: 10117-10128.
Heneka MT, Sastre M, Dumitrescu-Ozimek L, et al., Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 2005; 128: 1442-1453.
Nicolakakis N, Aboulkassim T, Ongali B, et al., Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist. J Neurosci 2008; 28: 9287-9296.
Fujisawa K, Nishikawa T, Kukidome D, et al., TZDs reduce mitochondrial ROS production and enhance mitochondrial biogenesis. Biochem Biophys Res Commun 2009; 379: 43-48.
Mawuenyega KG, Sigurdson W, Ovod V, et al., Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 2010; 330: 1774-1774.