Impact of Insulin and Metformin Versus Metformin Alone on β-Cell Function in Youth With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes

Abstract

Objective: Pediatric type 2 diabetes prevalence is increasing, with β-cell dysfunction key in its pathogenesis. The RISE Pediatric Medication Study compared two approaches-glargine followed by metformin and metformin alone-in preserving or improving β-cell function in youth with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes during and after therapy withdrawal.

Research design and methods: Ninety-one pubertal, overweight/obese 10-19-year-old youth with IGT (60%) or type 2 diabetes of <6 months duration (40%) were randomized to either 3 months of insulin glargine with a target glucose of 4.4-5.0 mmol/L followed by 9 months of metformin or to 12 months of metformin alone. β-Cell function (insulin sensitivity paired with β-cell responses) was assessed by hyperglycemic clamp at baseline, 12 months (on treatment), and 15 months (3 months off treatment).

Results: No significant differences were observed between treatment groups at baseline, 12 months, or 15 months in β-cell function, BMI percentile, HbA_1c, fasting glucose, or oral glucose tolerance test 2-h glucose results. In both treatment groups, clamp-measured β-cell function was significantly lower at 12 and 15 months versus baseline. HbA_1c fell transiently at 6 months within both groups. BMI was higher in the glargine followed by metformin versus metformin alone group between 3 and 9 months. Only 5% of participants discontinued the interventions, and both treatments were well tolerated.

Conclusions: In youth with IGT or recently diagnosed type 2 diabetes, neither 3 months of glargine followed by 9 months of metformin nor 12 months of metformin alone halted the progressive deterioration of β-cell function. Alternate approaches to preserve β-cell function in youth are needed.

Trial registration: ClinicalTrials.gov NCT01779375.

Figure 1

Insulin doses and corresponding fasting glucose values over time while on glargine treatment. A: Mean fasting morning SMBG values every 2 weeks over 12 weeks. B: Mean glargine dose corresponding to each SMBG value. C: Corresponding percentage of participants who achieved the goal fasting SMBG of 4.4–5.0 mmol/L every 2 weeks. Data are mean (95% CI).

Figure 2

Glucose and C-peptide values during the hyperglycemic clamp at baseline, after 12 months of treatment, and 3 months after discontinuing the intervention (15 months). The glargine followed by metformin group (n = 44 [green]) and the metformin alone group (n = 47 [brown]) are shown. The steady-state glucose targets were 11.1 mmol/L between 90 and 120 min and >25 mmol/L at 150 min. Data are mean ± SEM.

Figure 3

Relationship of the two coprimary outcomes: hyperglycemic clamp-derived β-cell responses (steady-state C-peptide and ACPR_max) paired with M/I. Changes are shown from baseline to 12 and 15 months for the clamp-derived β-cell responses of steady-state C-peptide (A) and ACPR_max (B) paired with M/I. The black line depicts the joint relationship between β-cell response and M/I at baseline for the full cohort, with the mean value at baseline for the full cohort indicated by the black box with a 0. The dotted lines to boxes at months 12 and 15 show the trajectory of values from baseline to 12 months of intervention and then to 3 months after discontinuation of the intervention (15 months) for glargine followed by metformin (green) and metformin alone (brown). Values above the black line represent improved β-cell function, and values below the line represent poorer β-cell function. The ellipses depict the 95% confidence bands around the points at months 12 and 15. No significant differences were observed at any time point between treatment arms; however, significant within-group declines were seen from baseline while on active treatment through 12 months for steady-state C-peptide with M/I (glargine followed by metformin P = 0.019, metformin alone P = 0.025) and ACPR_max with M/I (glargine followed by metformin P < 0.001, metformin alone P = 0.001) and through 15 months for steady-state C-peptide with M/I (glargine followed by metformin P < 0.001, metformin alone P = 0.031) and ACPR_max with M/I (glargine followed by metformin P = 0.001, metformin alone P < 0.001).

Figure 4

BMI and glycemia over time. BMI (A), HbA_1c (B), fasting glucose (C), and OGTT 2-h glucose over 15 months (D). In the glargine followed by metformin group (n = 44 [green]), glargine insulin was given from baseline to 3 months followed by metformin from months 3 through 12. In the metformin alone group (n = 47 [brown]), metformin was given from baseline through 12 months. Treatment was discontinued in both groups at 12 months. Data are mean ± SEM. *P < 0.05 for the difference between treatment groups at the specified time point; §P < 0.05 for the difference within treatment group between the specified time point and baseline.