Effects of metformin and weight loss on serum alanine aminotransferase activity in the diabetes prevention program

Abstract

Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, insulin resistance, and impaired glucose tolerance. We investigated whether metformin or changes in metabolic measurements (weight, fasting plasma glucose (FPG), or fasting insulin (FI)) improved serum alanine aminotransferase (ALT) activity, as a marker for NAFLD, in the Diabetes Prevention Program (DPP). From 1996 to 1999, 2,153 participants without marked elevations of serum ALT at baseline were randomized (1,081 to placebo, 1,072 to metformin) and treated for an average of 3.2 years. ALT increased during the first 2 years of the study, and was slightly but significantly lower in the participants randomized to metformin. In regression models adjusted for sex, baseline age, FPG, and FI, these differences remained significant, but disappeared after adjustment for weight, FPG, and FI changes at each examination. The 3-year cumulative incidence for development of abnormal ALT concentrations was not significantly different ((mean +/- s.e.) 21.4 +/- 1.4% and 24.6 +/- 1.4%, P = 0.11) in the metformin vs. placebo groups but was lower in individuals in both groups that lost more weight by the end of year 1 (metformin: 19.4 +/- 2.4% vs. 27.5 +/- 3.7%, for highest vs. lowest quartile of weight loss; placebo: 18.7 +/- 3.4% vs. 28.8 +/- 2.6%). Over 3 years of follow-up in persons at high risk for development of diabetes, serum ALT was consistently lower in those treated with metformin compared with placebo. This effect was mediated by weight loss, indicating that the effects of metformin therapy on ALT is via its effects on weight.

Figure 1

Mean ALT concentrations over time in study. ALT presented as geometric means. Overall difference in ALT values compared by treatment group using repeated-measures analysis of variance.

Figure 2

Mean ALT over time in study, adjusted for covariates. Means over study time calculated using repeated-measures regression models adjusted for baseline age, sex, weight, fasting plasma glucose, and fasting insulin and time in study (model 1), with further adjustments for change in weight, fasting plasma glucose and insulin concentrations at each visit (model 2). Groups compared by least squared means test. Error bars represent standard errors.

Figure 3

Three-year cumulative incidence for development of abnormal ALT by quartile of (a) change in weight, (b) change in fasting plasma glucose concentrations, (c) change in fasting insulin concentrations. Bars represent standard errors. Includes individuals with normal ALT at baseline (below 95% sex-specific National Health and Nutrition Examination Survey cutoffs of 46 U/l for men and 35 U/l for women), incidence rates for development of abnormal ALT were calculated by quartiles of change in weight, FPG, and fasting insulin concentrations at year 1 for both placebo and metformin groups. The log rank test was used to compare cumulative incidence over the quartiles.

Figure 4

Mean ALT concentration by quartile of change in weight over study. Quartiles by change in weight by end of study, quartile 1 (lowest) representing those with most weight loss.