Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY

TODAY Study Group, Silva Arslanian, Laura Pyle, George Washington, Marisa Payan, Fida Bacha, Sonia Caprio, Morey W Haymond, Lynne L Levitsky, Robin Goland, Neil H White, Steven M Willi, TODAY Study Group, Silva Arslanian, Laura Pyle, George Washington, Marisa Payan, Fida Bacha, Sonia Caprio, Morey W Haymond, Lynne L Levitsky, Robin Goland, Neil H White, Steven M Willi

Abstract

Objective: The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that combination therapy with metformin plus rosiglitazone provided superior durability of glycemic control compared with metformin alone, with significantly lower treatment failure rates (38.6 vs. 51.7%), and metformin plus lifestyle was intermediate. Herein we describe the temporal changes in measures of β-cell function and insulin sensitivity over a 4-year period among the three treatments.

Research design and methods: TODAY participants (699) were tested periodically with an oral glucose tolerance test to determine insulin sensitivity (1/fasting insulin [1/IF]), insulinogenic index (ΔI(30)/ΔG(30)) or C-peptide index (ΔC(30)/ΔG(30)), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]).

Results: During the first 6 months, metformin plus rosiglitazone exhibited a significantly greater improvement in insulin sensitivity and oDI versus metformin alone and versus metformin plus lifestyle; these improvements were sustained over 48 months of TODAY. Irrespective of treatment, those who failed to maintain glycemic control had significantly lower β-cell function (~50%), higher fasting glucose concentration, and higher HbA1c at randomization compared with those who did not fail.

Conclusions: The beneficial change in insulin sensitivity and the resultant lower burden on β-cell function achieved in the first 6 months with metformin plus rosiglitazone appear to be responsible for its superior glycemic durability over metformin alone and metformin plus lifestyle. However, initial β-cell reserve and HbA1c at randomization are independent predictors of glycemic durability. Therefore, efforts to preserve β-cell function before significant loss occurs and to reduce HbA1c may be beneficial in the treatment of youth with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00081328.

Figures

Figure 1
Figure 1
Baseline adjusted geometric mean ± SE asymmetric limits (obtained as exp[mean ± SE of log values]) of OGTT-derived measures of insulin sensitivity (1/IF) (A), insulinogenic index (△I30/△G30) (B), and oDI ([1/IF] × [△C30/△G30]) (C) in the three treatment groups over 48 months of follow-up in TODAY, analyzed using log-transformed values. The P value refers to the overall effect of treatment group assignment in the longitudinal models for the various parameters under question within the groups.
Figure 2
Figure 2
Baseline adjusted geometric mean ± SE asymmetric limits (obtained as exp[mean ± SE of log values]) of OGTT-derived measures by treatment failure with the three treatment groups combined, analyzed using log-transformed values. A: Insulin sensitivity (1/IF). B: Insulinogenic index (△I30/△G30). C: oDI ([1/IF] × [△C30/△G30]). The P value refers to the overall effect of failed vs. not failed group assignment in the longitudinal models for the various parameters under question within the two groups.

References

    1. Flint A, Arslanian S. Treatment of type 2 diabetes in youth. Diabetes Care 2011;34(Suppl. 2):S177–S183
    1. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 2002;25:89–94
    1. Zeitler P, Hirst K, Pyle L, et al. TODAY Study Group A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 2012;366:2247–2256
    1. Zeitler P, Epstein L, Grey M, et al. TODAY Study Group Treatment options for type 2 diabetes in adolescents and youth: a study of the comparative efficacy of metformin alone or in combination with rosiglitazone or lifestyle intervention in adolescents with type 2 diabetes. Pediatr Diabetes 2007;8:74–87
    1. Gungor N, Bacha F, Saad R, Janosky J, Arslanian S. Youth type 2 diabetes: insulin resistance, beta-cell failure, or both? Diabetes Care 2005;28:638–644
    1. Bacha F, Gungor N, Lee S, Arslanian S. In vivo insulin sensitivity and secretion in obese youth: what are the differences between normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes? Diabetes Care 2009;32:100–105
    1. Elder DA, Woo JG, D’Alessio DA. Impaired β-cell sensitivity to glucose and maximal insulin secretory capacity in adolescents with type 2 diabetes. Pediatr Diabetes 2010;11:314–321
    1. Weiss R, Caprio S, Trombetta M, Taksali SE, Tamborlane WV, Bonadonna R. β-Cell function across the spectrum of glucose tolerance in obese youth. Diabetes 2005;54:1735–1743
    1. Tfayli H, Bacha F, Gungor N, Arslanian S. Phenotypic type 2 diabetes in obese youth: insulin sensitivity and secretion in islet cell antibody-negative versus -positive patients. Diabetes 2009;58:738–744
    1. Gungor N, Arslanian S. Progressive beta cell failure in type 2 diabetes mellitus of youth. J Pediatr 2004;144:656–659
    1. Bacha F, Gungor N, Lee SJ, Arslanian SA. Progressive deterioration of β-cell function in obese youth with type 2 diabetes. Pediatr Diabetes 2013;14:106–111
    1. Kahn SE, Lachin JM, Zinman B, et al. ADOPT Study Group Effects of rosiglitazone, glyburide, and metformin on β-cell function and insulin sensitivity in ADOPT. Diabetes 2011;60:1552–1560
    1. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC, UK Prospective Diabetes Study (UKPDS) Group UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabet Med 1998;15:297–303
    1. Kahn SE. Clinical review 135: the importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001;86:4047–4058
    1. Bacha F, Pyle L, Nadeau K, et al. TODAY Study Group Determinants of glycemic control in youth with type 2 diabetes at randomization in the TODAY study. Pediatr Diabetes 2012;13:376–383
    1. Laffel L, Chang N, Grey M, et al. TODAY Study Group Metformin monotherapy in youth with recent onset type 2 diabetes: experience from the prerandomization run-in phase of the TODAY study. Pediatr Diabetes 2012;13:369–375
    1. Copeland KC, Zeitler P, Geffner M, et al. TODAY Study Group Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab 2011;96:159–167
    1. George L, Bacha F, Lee S, Tfayli H, Andreatta E, Arslanian S. Surrogate estimates of insulin sensitivity in obese youth along the spectrum of glucose tolerance from normal to prediabetes to diabetes. J Clin Endocrinol Metab 2011;96:2136–2145
    1. Burns SF, Bacha F, Lee SJ, Tfayli H, Gungor N, Arslanian S. Declining β-cell function relative to insulin sensitivity with escalating OGTT 2-h glucose concentrations in the nondiabetic through the diabetic range in overweight youth. Diabetes Care 2011;34:2033–2040
    1. Sjaarda LG, Bacha F, Lee S, Tfayli H, Andreatta E, Arslanian S. Oral disposition index in obese youth from normal to prediabetes to diabetes: relationship to clamp disposition index. J Pediatr 2012;161:51–57
    1. Arslanian SA, Saad R, Lewy V, Danadian K, Janosky J. Hyperinsulinemia in african-american children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. Diabetes 2002;51:3014–3019
    1. Osei K, Schuster DP, Owusu SK, Amoah AG. Race and ethnicity determine serum insulin and C-peptide concentrations and hepatic insulin extraction and insulin clearance: comparative studies of three populations of West African ancestry and white Americans. Metabolism 1997;46:53–58
    1. Saad R, Gungor N, Arslanian S. Progression from normal glucose tolerance to type 2 diabetes in a young girl: longitudinal changes in insulin sensitivity and secretion assessed by the clamp technique and surrogate estimates. Pediatr Diabetes 2005;6:95–99
    1. Faulenbach MV, Wright LA, Lorenzo C, et al. Impact of differences in glucose tolerance on the prevalence of a negative insulinogenic index. J Diabetes Complications 2013;27:158–161
    1. Kahn SE, Haffner SM, Heise MA, et al. ADOPT Study Group Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427–2443
    1. Rosen CJ. The rosiglitazone story-lessons from an FDA Advisory Committee meeting. N Engl J Med 2007;357:844–846

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere