Elevated Alanine Aminotransferase Predicts New-Onset Type 2 Diabetes Independently of Classical Risk Factors, Metabolic Syndrome, and C-Reactive Protein in the West of Scotland Coronary Prevention Study

Naveed Sattar; Olga Scherbakova; Ian Ford; Denis St. J. O'Reilly; Adrian Stanley; Ewan Forrest; Peter W. MacFarlane; Chris J. Packard; Stuart M. Cobbe; James Shepherd

Disclosures

Diabetes. 2004;53(11) 

In This Article

Research Design and Methods

The design of WOSCOPS has been described in detail.[10,11,12] Briefly, 6,595 moderately hypercholesterolemic men (LDL cholesterol 4.5-6.0 mmol/l and triglycerides <6.0 mmol/l) with no history of myocardial infarction were randomized to 40 mg pravastatin daily or placebo and followed for an average of 4.9 years.

A battery of risk factors and other demographic variables were assessed at baseline,[10,11,12] and, of particular relevance to this study, fasting glucose measurements at six monthly visits were recorded throughout the study, enabling us to determine the transition to and timing of diabetes development. We excluded men with frank diabetes (72 subjects with self-reported diabetes and 76 who had a baseline blood glucose ≥7.0 mmol/l [n = 148]). New-onset diabetes was defined by at least two postrandomization glucose measurements ≥7.0 mmol/l · mg-1 · dl-1 or commencement of hypoglycemic drugs. In addition, because we were primarily interested in examining subjects who experienced significant deterioration in their glucose control, a further restraint was incorporated into the definition whereby one glucose measurement must be ≥2.0 mmol/l above baseline, an approach validated in previous relevant publications.[6,13] Inevitably, this strategy restricted the number of subjects classified as newly diabetic but increased our level of confidence that the subjects labeled as newly diabetic in this study were truly thus. Finally, subjects' time to becoming glucose intolerant was taken as the 6-month visit at which they first had two postrandomization glucose measurements of ≥7.0 mmol/l and one or more postrandomization glucose measurement of >2.0 mmol/l above the baseline glucose level or at the postrandomization visit at which they first indicated taking hypoglycemic drugs.[6,13] Due to nonattendance at visits or end of study (with varying length of follow-up), subjects' time to becoming glucose intolerant was censored at the last 6-month visit at which their glucose level was measured. Since only 5,974 men had two or more postrandomization fasting glucose measurements, the analyses relating to new-onset diabetes used this reduced cohort. We used modified criteria for characterizing men with the metabolic syndrome, as described in detail previously.[9] Men with ALT and AST levels >70 and >60 units/l, respectively, were excluded from entry into WOSCOPS.

Laboratory Analyses and Determination of Alcohol Intake

All biochemical analyses were performed in the biochemistry department at Glasgow Royal Infirmary, which is a Centers for Disease Control and Prevention (Atlanta) reference laboratory and accredited by Clinical Pathology Accreditation U.K. Plasma lipids and lipoproteins were measured twice before randomization, and the baseline level was taken as the average.[10,11,12] Lipoprotein profiles were determined according to the Lipid Research Clinics protocol. Details of the CRP assay are given in the article by Packard et al..[11] Stored samples for CRP analysis were available for 5,657 men.[11] ALT and AST were determined on fresh samples using standard reagents by reaction rate assay based on the conversion of NADH to NAD. All AST and ALT analyses were conducted in the same laboratory with adherence to external quality control. The between-batch coefficient of variation for their determination was <5%. Alcohol intake was determined by a nurse-administered standardized questionnaire.

Statistics

Data are presented as means ± SD for continuous variables and number of subjects (percentage) for categorical variables. The relationships among serum AST, ALT, and other continuous variables were measured using Spearman's rank correlations. Plasma triglycerides and CRP were log transformed. Univariate and multivariate Cox proportional hazards models were fitted to identify predictors of new-onset diabetes. The models contained a set of conventional risk factors known to predict diabetes, metabolic syndrome classification, and CRP. A stepwise regression model was also examined incorporating all individual metabolic syndrome criteria, CRP, and ALT. Cumulative time-to-event survival curves were estimated using the Kaplan-Meier method.

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