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Lalmohamed A.,University Utrecht | Vestergaard P.,University of Aalborg | Cooper C.,MRC Lifecourse Epidemiology Unit | Cooper C.,University of Oxford | And 8 more authors.
Stroke | Year: 2012

Background and Purpose: Stroke is a potentially fatal complication of total hip replacements (THR). However, timing of stroke in THR patients compared with matched controls and influence of drug use remain unknown. The objective of this study was to determine timing of stroke in patients with THR compared with matched control subjects. Methods: A nationwide cohort study was conducted within the Danish registers (1998-2007). Included patients were those with a primary THR in the study period (n=66 583) and were matched by age, sex, and region to three referent subjects without THR or total knee replacements. Time-dependent Cox models were used to derive hazard ratios and were adjusted for disease history and drug use. Results: A 4.7-fold increased risk of ischemic stroke (adjusted hazard ratio, 4.69; 95% CI, 3.12-7.06), and a 4.4-fold increased risk of hemorrhagic stroke (adjusted hazard ratio, 4.40; 95% CI, 2.01-9.62) were found within 2 weeks following THR, compared with matched controls. The risk remained elevated during the first 6 postoperative weeks for ischemic stroke, and the first 12 weeks for hemorrhagic stroke. Outpatient antiplatelet drug use lowered the 6-week hazard ratios for ischemic stroke by 70%, although not affecting risk of hemorrhagic stroke. Conclusions: This study shows, that THR patients have a 4.7-fold increased risk of ischemic stroke, and a 4.4-fold increased risk of hemorrhagic stroke during the first 2 weeks postsurgery. Risk assessment of stroke in individual patients undergoing THR (ie, evaluate other risk factors for stroke) should be considered during the first 6 to 12 weeks. © 2012 American Heart Association, Inc. Source

Eppenga W.L.,Radboud University Nijmegen | Lalmohamed A.,Utrecht Institute for Pharmaceutical science | Lalmohamed A.,University Utrecht | Geerts A.F.,Utrecht Institute for Pharmaceutical science | And 9 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: The objective of this study was to determine whether treatment with metformin in patients with renal impairment is associated with a higher risk of lactic acidosis or elevated lactate concentrations compared with users of a noninsulin antidiabetic drug (NIAD) who had never used metformin. RESEARCH DESIGN AND METHODS: A cohort of 223,968 metformin users and 34,571 diabetic patients who had never used metformin were identified from the Clinical Practice Research Datalink (CPRD). The primary outcome was defined as either a CPRD READ code lactic acidosis or a record ofaplasma lactate concentration >5 mmol/L. The associations between renal impairment, dose of metformin, and the risk of lactic acidosis or elevated lactate concentrations were determined with time-dependent Cox models and expressed as hazard ratios (HRs). RESULTS: The crude incidence of lactic acidosis or elevated lactate concentrations in current metformin users was 7.4 per 100,000 person-years (vs. 2.2 per 100,000 person-years in nonusers). Compared with nonusers, risk of lactic acidosis or elevated lactate concentrations in current metformin users was significantly associated with a renal function <60 mL/min/1.73 m2 (adjusted HR 6.37 [95% CI 1.48-27.5]). The increased risk among patients with impaired renal function was further increased in users of ≥730 g of metformin in the preceding year (adjusted HR 11.8 [95% CI 2.27-61.5]) and in users of a recent high daily dose (>2 g) of metformin (adjusted HR 13.0 [95% CI 2.36-72.0]). CONCLUSIONS: Our study is consistent with current recommendations that the renal function of metformin users should be adequately monitored and that the dose of metformin should be adjusted, if necessary, if renal function falls below 60 mL/min/1.73 m2. © 2014 by the American Diabetes Association. Source

Wlazlo N.,Catharina Hospital | Wlazlo N.,Maastricht University | Van Greevenbroek M.M.J.,Maastricht University | Ferreira I.,Maastricht University | And 7 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism-related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin. RESEARCH DESIGN AND METHODS-Serum ferritin, transferrin, total iron, non- transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers. RESULTS-Serum ferritin (b = 1.00% increase in adipocyte IR per 10 mg/L [95% CI 0.66- 1.34]), transferrin (4.18% per 0.1 g/L [2.88-5.50]), total iron (1.36% per mmol/L [0.61-2.12]), and NTBI (5.14% per mmol/L [1.88-8.52]) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P < 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P < 0.01). CONCLUSIONS-The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM.© 2013 by the American Diabetes Association. Source

Beijers H.J.B.H.,Postbox Inc. | Ferreira I.,Maastricht University | Ferreira I.,Cardiovascular Research Institute Maastricht CARIM | Ferreira I.,Care and Public Health Research Institute CAPHRI | And 8 more authors.
Atherosclerosis | Year: 2014

Objective: To investigate whether an adverse body composition is associated with endothelial dysfunction (ED) and the extent to which any such association could be explained by low-grade inflammation (LGI) and/or insulin resistance (HOMA2-IR). Methods: We studied 475 individuals from the Hoorn Study [mean (range) age, 68.9 (60-87) years, 245 women). Body composition was assessed by whole body dual-energy absorptiometry. Endothelial dysfunction was measured functionally, by flow-mediated dilation (FMD) and by circulating biomarkers. Associations were examined with multiple linear regression models and mediation analyses according to the ab product of coefficients method. Results: After adjustment for age, sex, glucose metabolism status, prior cardiovascular disease and lifestyle factors, total and central fat mass were positively associated with the ED score [. β=0.16 (95% CI 0.04-0.29) and β=0.18 (0.05-0.31), respectively] and inversely, although not statistically significantly, with FMD. Peripheral fat mass was not associated with the ED score or FMD. There was a significant favourable association between peripheral lean mass and FMD [. β=0.13 (0.00-0.26)], but not with the ED score. The association between total and central fat mass and the ED score was, to a great extent, mediated by LGI and HOMA2-IR. In contrast, LGI or HOMA2-IR did not mediate the association between peripheral lean mass and FMD. Conclusion: Higher levels of central, but not peripheral fat mass were adversely associated with ED, which was attributable to body composition-related LGI and insulin resistance. In contrast, peripheral lean mass was beneficially associated with ED, but this seemed to be unrelated to LGI or insulin resistance. © 2014 Elsevier Ireland Ltd. Source

Lalmohamed A.,University Utrecht | MacGregor A.J.,University of East Anglia | de Vries F.,University Utrecht | de Vries F.,Medical Research Council MRC Lifecourse Epidemiology Unit | And 6 more authors.
PLoS ONE | Year: 2013

Background: There are concerns that metal-on-metal hip implants may cause cancer. The objective of this study was to evaluate patterns and timing of risk of cancer in patients with metal-on-metal total hip replacements (THR). Methods: In a linkage study between the English National Joint Registry (NJR) and the Clinical Practice Research Datalink (CPRD), we selected all THR surgeries (NJR) between 2003 and 2010 (n = 11,540). THR patients were stratified by type of bearing surface. Patients were followed up for cancer and Poisson regression was used to derive adjusted relative rates (RR). Results: The risk of cancer was similar in patients with hip resurfacing (RR 0.69; 95% Confidence Interval [CI] 0.39-1.22) or other types of bearing surfaces (RR 0.96; 95% CI 0.64-1.43) compared to individuals with stemmed metal-on-metal THR. The pattern of cancer risk over time did not support a detrimental effect of metal hip implants. There was substantial confounding: patients with metal-on-metal THRs used fewer drugs and had less comorbidity. Conclusions: Metal-on-metal THRs were not associated with an increased risk of cancer. There were substantial baseline differences between the different hip implants, indicating possibility of confounding in the comparisons between different types of THR implants. © 2013 Lalmohamed et al. Source

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