Precision and accuracy of hyperglycemic clamps in a multicenter study

Abstract

Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Two-stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. The RISE approach produced high overall precision (3%-9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD < 10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs. adult, IGT vs. diabetes status) and differences in physiology induced by study treatments. The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers.NEW & NOTEWORTHY The Restoring Insulin Secretion (RISE) study centers undertook hyperglycemic clamps using a simplified methodology and a decision guidance algorithm implemented in an easy-to-use spreadsheet. This approach, combined with active management including ongoing central data surveillance and routine feedback to study centers, produced technically excellent standardization of achieved glucose concentrations on repeat studies within and across study centers.

Keywords: accuracy; glucose clamp; methodology; multicenter; precision.

Graphical abstract

Figure 1.

Achieved glucose values. Data are means ± SD for values at each time point; for some time points, the error is smaller than the size of the marker. Statistical evaluations of the achieved values relative to the 200 mg/dL target (dashed line) for selected time points are presented in Table 2. Sample sizes vary, please refer to text. A: presents data for all studies combined, separating studies performed in youth and adults. B: presents data for all studies combined, separating studies performed in individuals with IGT versus diabetes at screening. C and D: present data from the adult medication study only, presenting baseline (C) and 12-mo on-treatment data (D). SS1, SS2, and SS3 represent the three measurement time points that together comprised the steady state (SS); the actual timing of these was generally 100 through 120 min after the start of the procedure (T = 0 min); see text for further details. The initial negative time points represent sampling in the fasting state prior to commencing glucose administration at time 0. IGT, impaired glucose tolerance.

Figure 2.

Differences in selected versus guidance glucose infusion rates in stage 1 of the clamp procedure. Sample sizes vary, please refer to text. A and C: present the calculated guidance provided by the algorithm. B and D: present differences from guidance, calculated as (selected rate − guidance rate). A and B: show these data separated by studies performed in youth and adults. C and D: show these data separated by studies performed in individuals with IGT or diabetes status at screening. IGT, impaired glucose tolerance.