Treatment effects on measures of body composition in the TODAY clinical trial

Abstract

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial showed superiority of metformin plus rosiglitazone (M+R) over metformin alone (M), with metformin plus lifestyle (M+L) intermediate in maintaining glycemic control. We report here treatment effects on measures of body composition and their relationships to demographic and metabolic variables including glycemia.

Research design and methods: Measures of adiposity (BMI, waist circumference, abdominal height, percent and absolute fat, and bone mineral content [BMC] and density [BMD]) were analyzed as change from baseline at 6 and 24 months.

Results: Measures of fat accumulation were greatest in subjects treated with M+R and least in M+L. Although fat measures in M+L were less than those of M+R and M at 6 months, differences from M were no longer apparent at 24 months, whereas differences from M+R persisted at 24 months. The only body composition measure differing by race and/or ethnicity was waist circumference, greater in M+R than either M or M+L at both 6 and 24 months in whites. BMD and BMC increased in all groups, but increased less in M+R compared with the other two groups by 24 months. Measures of adiposity (increases in BMI, waist circumference, abdominal height, and fat) were associated with reduced insulin sensitivity and increased hemoglobin A1c (HbA1c), although effects of adiposity on HbA1c were less evident in those treated with M+R.

Conclusions: Despite differential effects on measures of adiposity (with M+R resulting in the most and M+L in the least fat accumulation), group differences generally were small and unrelated to treatment effects in sustaining glycemic control.

Trial registration: ClinicalTrials.gov NCT00081328.

Figure 1

LSmean change from baseline for BMI (A) and percent fat mass (B) at 6 and 24 months, by treatment. Treatment groups are denoted by M for metformin alone, M+R for metformin + rosiglitazone, and M+L for metformin + intensive lifestyle intervention. LSmeans and P values are output from an analysis modeling BMI and percent fat mass change from baseline (6 − 0 months and 24−0 months) as a function of baseline value, treatment, period (0–6 or 0–24 months), and the interaction of treatment by period. Significant treatment group differences for the 6- and 24-month change from baseline are indicated within the figure.

Figure 2

LSmean change from baseline for BMC (g) (A) and BMD (g/cm²) (B) at 6 and 24 months, by treatment. Treatment groups are denoted by M, M+R, and M+L. LSmeans and P values are output from an analysis modeling BMC and BMD change from baseline (6–0 and 24–0) as a function of baseline value, treatment, period (0–6 or 0–24 months), height, and age at the time of visit, and the interaction of treatment by period. Significant treatment group differences for the 6- and 24-month change from baseline are indicated within the figure (nonsignificant differences are indicated by NS).

Figure 3

Regression lines of change from baseline for insulin sensitivity (1/I_F µU/mL) versus BMI change, from baseline to 6 months (A) and baseline to 24 months (B); and regression lines of change from baseline for HbA_1c (%) vs. BMI change, from baseline to 6 months (C) and baseline to 24 months (D), by treatment. Treatment groups are denoted by M, M+R, and M+L. The horizontal axis scales represent the 5th–95th percentiles of the distribution of BMI change from baseline (−3 to 3 at 6 months and −4 to +7 at 24 months). Note that the 5th–95th percentile range of BMI change from baseline is greater for the 24-month period than for the 6-month one. Slopes indicate change in insulin sensitivity or HbA_1c per unit increase in BMI change and were evaluated from models including the baseline value of either insulin sensitivity or HbA_1c as a covariate.