Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus

Abstract

Context: The stepwise hyperglycemic clamp procedure (SHCP) is the gold standard for measuring the renal threshold for glucose excretion (RT(G)), but its use is limited to small studies in specialized laboratories.

Objective: The objective of the study was to validate a new method for determining RT(G) using data obtained during a mixed-meal tolerance test (MMTT) in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus (T2DM).

Design: This was an open-label study with 2 sequential parts.

Setting: The study was performed at a single center in Germany.

Patients: Twenty-eight subjects with T2DM were studied.

Interventions: No treatment intervention was given in part 1. In part 2, subjects were treated with canagliflozin 100 mg/d for 8 days. In each part, subjects underwent an MMTT and a 5-step SHCP on consecutive days.

Main outcome measures: For both methods, RT(G) was estimated using measured blood glucose (BG) and urinary glucose excretion (UGE); estimated glomerular filtration rates were also used to determine RT(G) during the MMTT. The methods were compared using the concordance correlation coefficient and geometric mean ratios.

Results: In untreated and canagliflozin-treated subjects, the relationship between UGE rate and BG was well described by a threshold relationship. Good agreement was obtained between the MMTT-based and SHCP-derived RT(G) values. The concordance correlation coefficient (for all subjects) was 0.94; geometric mean ratios (90% confidence intervals) for RT(G) values (MMTT/SHCP) were 0.93 (0.89-0.96) in untreated subjects and 1.03 (0.78-1.37) in canagliflozin-treated subjects. Study procedures and treatments were generally well tolerated in untreated and canagliflozin-treated subjects.

Conclusions: In both untreated and canagliflozin-treated subjects with T2DM, RT(G) can be accurately estimated from measured BG, UGE, and estimated glomerular filtration rates using an MMTT-based method.

Trial registration: ClinicalTrials.gov NCT01273558.

Figures

Figure 1.

(A–H) BG concentrations and UGE during the SHCP and MMTT procedures in part 1 (untreated subjects; A–D) and part 2 (canagliflozin-treated subjects; E–H). Results shown are mean ± SD. UGE rates shown are the average rates measured during the last 1.5 hours of each hyperglycemic clamp step (B and F) or during the time interval shown from the MMTT (D and H). (I and J) Determination of RTG from the SHCP. (I) Data from an individual subject. Measured UGE rate and mean BG concentration in each of the 5 clamp steps (dots) and the best fit obtained to equation 1 (line) are shown; the fit value of RTG = 203.6 mg/dL (11.3 mM) was obtained for this subject. (J) Data from all 14 subjects in part 1. Each dot represents data from an individual subject during 1 of the 5 clamp steps, where the UGE rate is shown on the y-axis and the difference between the BG concentration in the clamp step and the subject's RTG is shown on the x-axis. As in equation 1, subjects have virtually no UGE when BG < RTG and the rate of UGE increases in proportion to BG-RTG when BG > RTG. (K) BG vs UGE relationship in untreated and canagliflozin-treated subjects. Values shown are mean ± SD. (L) Relationship between RTG values determined by the MMTT and SHCP methods. Individual subject values (n = 11 each in part 1 and part 2) are shown as filled squares (part 1) or open circles (part 2); the dotted line represents the line of identity (exact agreement between the 2 methods).