Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study

Abstract

Objective: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study.

Research design and methods: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA_1c increase ≥0.5% from baseline).

Results: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA_1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05).

Conclusions: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

Trial registration: ClinicalTrials.gov NCT01779362 NCT01779375.

Figure 1

Change from baseline in glycemia at M12 (on treatment) and M21 (9 months after treatment withdrawal). Top panel: Glycemic worsening based on absolute increase in HbA_1c in adults and youth from baseline to M12 (left panel) and M21 (right panel). The vertical lines depict 0.5% worsening in absolute HbA_1c. On the left, there are no significant differences between adults and youth at M12. On the right, youth experienced greater glycemic worsening at M21 (P = 0.041). Bottom panel: Glycemic worsening based on the percentage (relative) increase in HbA_1c in adults and youth from baseline to M12 (left panel) and M21 (right panel). The vertical lines are shown at 5% worsening. Youth experienced greater glycemic worsening when defined as the percentage increase in HbA_1c at M12 (P < 0.001) and at M21 (P < 0.001).

Figure 2

Life table estimate to progression from IGT to type 2 diabetes. A: Cumulative incidence of type 2 diabetes in youth over the duration of the study among youth with IGT at baseline. The progression to type 2 diabetes did not differ in youth between glargine, followed by metformin (G-MET) or metformin alone (MET) at M12 (P = 0.28) or M21 (P = 0.40). B: Cumulative incidence of type 2 diabetes in adults over the duration of the study among adults with IGT at baseline. The progression to type 2 diabetes was borderline significant between the four intervention arms at M12 (P = 0.06 for overall comparison) but not at M21 (P = 0.20 for overall comparison). C: Cumulative incidence of type 2 diabetes in youth and adults randomized to metformin (MET) alone vs. glargine, followed by metformin (G-MET), over the duration of the study, among youth and adults with IGT at baseline. The progression to type 2 diabetes did not differ between youth and adults in either intervention arm.