Withdrawal of medications leads to worsening of OGTT parameters in youth with impaired glucose tolerance or recently-diagnosed type 2 diabetes

Abstract

Background: The RISE Pediatric Medication Study compared strategies for preserving β-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability.

Objective: Evaluate OGTT measures of glucose and β-cell response through 12 months of intervention and 9 months of medication washout.

Participants: Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D).

Methods: A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (G→Met) or metformin alone (Met) for 12 months. We report within-group changes from baseline to end of medication intervention (M12), baseline to 9 months post-medication withdrawal (M21), and end of medication (M12) to M21. OGTT C-peptide index [CPI] paired with 1/fasting insulin evaluated β-cell response.

Results: At M12, both treatments were associated with stable fasting glucose (G→Met baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2-hour glucose (G→Met baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (G→Met M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2-hour glucose (G→Met M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in β-cell response.

Conclusions: G→Met and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and β-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued.

Trial registration: ClinicalTrials.gov NCT01779375.

Keywords: glucose tolerance; impaired glucose tolerance; insulin glargine; insulin response; insulin secretion; insulin sensitivity; medication; metformin; pediatric; prediabetes; type 2 diabetes; β-cell.

Conflict of interest statement

Conflict of Interest Disclosure: S.A.A. and S.E.K. serve as paid consultants on advisory boards for Novo Nordisk. S.E.K. is a member of a steering committee for a Novo Nordisk sponsored clinical trial. S.A.A. is a participant in a Novo Nordisk-sponsored clinical trial. T.A.B. has received research support from Allergan and Apollo Endosurgery. No other potential conflicts of interest relevant to this article were reported.

© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

Figure 1.

CONSORT Diagram. The glargine followed by metformin group is presented in green boxes; the metformin alone group is presented in brown boxes. $4 participants included in the glargine followed by metformin group at M21 decompensated between Months 15 and 21 and have imputed data for M21 *2 participants included in the metformin alone group decompensated between months 9 and 12, and 1 participant decompensated between months 15 and 21, and have imputed data for M15 and/or M21 as appropriate †10 patients lost interest, 3 were non-compliant with run-in protocol, and 5 had poor iv access precluding studies requiring reliable iv access

Figure 2.

OGTT glucose, C-peptide and insulin curves by treatment group at baseline (BAS, blue), M06 (purple), M12 (green), M15 (orange) and M21 (red). Data are means ± SEM.

Figure 3.

BMI (panel A), HbA1c (panel B), OGTT fasting glucose (panel C) and 2-hr glucose (panel D) over time, by treatment group (glargine followed by metformin in green; metformin alone in brown). Data are unadjusted means with 95% CI bars. Solid lines represent time on active treatment; dashed lines represent the period following medication withdrawal. Significant within treatment group changes from baseline are denoted with (*) and changes from M12 with (†).

Figure 4.

Relationship of OGTT-derived β-cell responses of C-peptide index (CPI) and insulinogenic index (IGI) paired with 1/fasting insulin by intervention group and study visit. Changes are shown from baseline to M06, M12, M15 and M21. The black line depicts the joint relationship between β-cell response and 1/fasting insulin at baseline for the full cohort, with the mean value indicated by the black box with a 0. The dotted lines to boxes show the trajectory of values from baseline to M06, and then to M12 (time of medication withdrawal), and then from M12 to M15 (3 months after medication withdrawal) and then to M21 (9 months after medication withdrawal) for the glargine followed by metformin group (green) and the metformin alone group (brown). The lines to points at M06, M12, M15 and M21 show the average changes between these time points. Values above the bolded baseline line indicate improved β-cell function and values below poorer β-cell function. The ellipses depict the 95% confidence bands around data for each box. Panel A) CPI paired with 1/fasting insulin. Panel B) IGI paired with 1/fasting insulin.