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Metformin Plus Rosiglitazone Treatment Effects in Children with Type 2 Diabetes — ADA

by Juan D. Vanpelt

The TODAY study looked at treatment with metformin plus rosiglitazone to help determine whether it was beneficial in youth with obesity and type 2 diabetes.

In children and adolescents, the incidence of both obesity and type 2 diabetes is increasing. Previous evidence has evaluated the risks of excess visceral adipose tissue (VAT) and its impact on diabetic outcomes. What needed to be further studied was the effects of diabetic treatment specifically on redistribution of adipose tissue and its effects in adolescents in terms of their diabetes risks.

The current study used the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study to determine the treatment effects on redistribution of adipose tissue and analyze relationships between visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and insulin sensitivity, beta-cell function; and metabolic risk factors. In the TODAY study, patients were randomized into different treatment arms, either metformin monotherapy (M), metformin plus rosiglitazone (M + R), or metformin plus intensive lifestyle intervention (M + L). 626 patients of the 699 from the TODAY study had recorded data on DXA scans from baseline, 6 months, and 24 months. DXA scan measurements were necessary to determine whole-body adiposity. From the estimates of VAT and SAT mass, area, and volume, due to similar results, the current study only focused on mass.

Data from baseline, 6 months, and 24 months were analyzed and presented as mean + SD or percent. Linear mixed models were used to present longitudinal data. Models split treatment groups to examine body composition differences over time. The researchers adjusted models for the densitometry system type used to collect data at the study site. Models were also used to evaluate regression slopes between body composition measures with the diabetes-specific measures.

To determine the treatment effects on redistribution of adiposity, the researchers used SAT and VAT. SAT varied per group at 6 months, in the M + L group it declined, increased in the M group, and stayed steady in the M + R. The SAT changes were significant when comparing the M (P = 0.0129) and M + R (P = 0.0348) groups with the M + L group. Similar results occurred for VAT, but the changes seen were of small clinical significance. At month 24, significant increases were seen in VAT and SAT in the M + R group compared to the other two groups. VAT increased 13.1% in the M + R group compared with M (6.5%, P = 0.0146) or M + L (3.9%, P = 0.0006). Similarly, SAT increased 13.3% in the M + R group compared to the M group (6.4%, P = 0.0005) or M + L (5.4%, (P < 0.0001).

To determine the effects of sex and race-ethnicity, data was compared at each month between groups. At baseline, women compared to men, had a higher SAT (P < 0.0001), but not VAT. In women, VAT:SAT ratio was found to be lower, compared to men (P < 0.0001). After 24 months, females had greater increases in SAT versus males (P < 0.0001), but no difference in changes for VAT was seen between both sexes at 24 months. Further looking at race-ethnicity, NHBs had higher SAT (P = 0.0274) and lower VAT (P < 0.0001) at baseline compared to NHWs and Hispanics. At month 6, NHBs had greater increases in VAT in M versus M + L (P = 0.0362). And at month 24, NHWs were found to have greater increases in M + R versus M (P = 0.0192) or M + L (P = 0.0482). Comparing VAT:SAT ratio between groups, at month 6, Hispanics had a significant increase; however, at month 24, there was no difference in the VAT:SAT ratio due to treatment by race-ethnicity.

Next, the authors determined, the increase in VAT and SAT from baseline correlated with higher HbA1c and lower insulin sensitivity and lower C-peptide oDI at both 6 and 24 months. The unadjusted regression analysis only showed a positive association between VAT accumulation on HbA1c was higher in the M + R group at month 6 compared to the M + L group (P = 0.0344). After adjustment, this association was no longer significant. The M + L group at 6 months, had lower insulin sensitivity with VAT accumulation compared to M (P = 0.0305). And lastly, the M + R group at month 6 significantly blunted the effect of visceral adiposity change on C-peptide oDI compared to M + L (P = 0.0427).

Lastly researchers observed in each treatment arm there was an increase in adiponectin. At 6 months, the highest mean percent change in high molecular-weight adiponectin (HMWA) was seen in M + R compared to M and M + L (P < 0.0001). At 24 months a similar pattern was noted. At every time point, an increase in HMWA from baseline correlated with higher insulin sensitivity and C-peptide oDI and lower HbA1c. While the association was seen, it did not differ by treatment group. Furthermore, significant associations were found at each time point between change in VAT or SAT and change in adiponectin, even after adjustment.

The authors believed their findings represented similar previous findings. Overall, differences seen between treatment arms were not due to differences in BMI or whole-body adiposity, nor VAT and SAT. While the authors acknowledged treatment with M + R is superior in maintaining glycemic control compared to other treatment options, it also led to an overall larger weight gain and an increased visceral and subcutaneous adiposity. After 24 months, a strong association was seen between VAT and SAT and the accumulation with adiponectin. Though patients in the M + R group showed an increase in adiponectin levels, no glucose-lowering effect was seen in the study. Further studies should explore its role in glycemic control and insulin sensitivity to better future treatment options. While this study had a decent sample size, due to patients having obesity, authors felt their data may not be generalizable to the population without obesity. Having a normal-weight control group may have benefited their findings; however, they felt as though their findings still correlate to most of the youth with obesity and type 2 diabetes.

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