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Longitudinal Modeling of the Relationship Between Mean Plasma Glucose and HbA1c Following Antidiabetic Treatments.

ABSTRACT: Late-phase clinical trials within diabetes generally have a duration of 12-24 weeks, where 12 weeks may be too short to reach steady-state glycated hemoglobin (HbA1c). The main determinant for HbA1c is blood glucose, which reaches steady state much sooner. In spite of this, few publications have used individual data to assess the time course of both glucose and HbA1c, for predicting HbA1c. In this paper, we present an approach for predicting HbA1c at end-of-trial (24-28 weeks) using glucose and HbA1c measurements up to 12 weeks. The approach was evaluated using data from 4 trials covering 12 treatment arms (oral antidiabetic drug, glucagon-like peptide-1, and insulin treatment) with measurements at 24-28 weeks to evaluate predictions vs. observations. HbA1c percentage was predicted for each arm at end-of-trial with a mean prediction error of 0.14% [0.01;0.24]. Furthermore, end points in terms of HbA1c reductions relative to comparator were accurately predicted. The proposed model provides a good basis to optimize late-stage clinical development within diabetes.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e82; doi:10.1038/psp.2013.58; advance online publication 30 October 2013.

SUBMITTER: Moller JB

PROVIDER: S-EPMC3817378 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Project description:ObjectiveSince there is a paucity of reference data in the literature to indicate the relationship between HbA1c, and 24 h mean blood glucose (MBG) from continuous glucose monitoring (CGM) in Chinese populations, we described the above relationship in adult Chinese subjects with different glucose tolerance status.MethodsSeven-hundred-and-forty-two individuals without history of diabetes were included to the study at 11 hospitals in urban areas across China from 2007-2009 and data of 673 subjects were included into the final analysis. Oral glucose tolerance test (OGTT) classified the participants as nondiabetic subjects, including those with normal glucose regulation (NGR; n?=?121) and impaired glucose regulation (IGR; n?=?209), or newly diagnosed type 2 diabetes (n?=?343). All participants completed testing for HbA1c levels and wore a CGM system for three consecutive days. The 24 h MBG levels were calculated. Spearman correlations and linear regression analyses were applied to quantify the relationship between glucose markers.ResultsThe levels of HbA1c and 24 h MBG significantly increased with presence of glucose intolerance (NGR<IGR<type 2 diabetes; both, P<0.001). Analysis of the total population indicated that HbA1c was strongly correlated with 24 h MBG (r?=?0.735). The correlation was also found to be significant for the subgroup of participants with newly diagnosed type 2 diabetes (r?=?0.694, P<0.001). Linear regression analysis of the total study population yielded the following equation: 24 h MBG(mmol/L?)=?1.198×HbA1c-0.582 (24 h MBG(mg/dL?)=?21.564×HbA1c-10.476) (R(2)=?0.670, P<0.001). The model fit was not improved by application of exponential or quadratic modeling. When HbA1c was 6.5%, the calculated 24 h MBG was 7.2 (6.4-8.1) mmol/L (130 (115-146) mg/dL); and when HbA1c was 7.0%, the 24 h MBG was 7.8 (6.9-8.7) mmol/L (140 (124-157) mg/dL).ConclusionsOur study provided the reference data of the relationship between HbA1c and CGM in Chinese subjects.

Project description:The prevalence of diabetes in Singapore is high. Screening to facilitate early detection and intervention has been shown to be cost-effective. Current clinical practice guidelines in Singapore recommend screening with fasting plasma glucose (FPG), followed by an oral glucose tolerance test (OGTT) in those with FPG 6.1-6.9?mmol/L. Glycated haemoglobin A1c (HbA1c) has robust stability at ambient temperature, and can be performed on non-fasted capillary blood samples, making it an attractive potential alternative for screening. However, limitations of HbA1c include differential performance in different races, and its performance as a screening test has not been well characterized in Asian populations. This study compares HbA1c and FPG as diabetes screening modalities in 3540 community-dwelling Singapore residents of Chinese, Malay and Indian race to detect diabetes mellitus diagnosed based on blood glucose (FPG???7.0?mmol/L, 2?hr OGTT???11.1?mmol/L). The area under the receiver-operating-characteristic curve (AUC) was higher for FPG compared to HbA1c in the overall population and age, race and age-race strata, but these differences were not statistically significant. HbA1c >?=?7.0% identified 95% of individuals with diabetes mellitus, and the remainder had impaired glucose tolerance (IGT). HbA1c cut-off at 6.1% had better sensitivity (0.825) to FPG at 6.1?mmol/L. The positive predictive value of HbA1c at 6.1% was 40-50% in different age-race combinations with a negative predictive value of about 98%. If follow-up screening with FPG is used, a lower cut-off at 5.6?mmol/L is appropriate in identifying people with pre-diabetes, as about 85% of people with HbA1c 6.1-6.9% and FPG 5.6-6.9?mmol/L had IFG/IGT or diabetes in the study sample. HbA1c is an appropriate alternative to FPG as a first-step screening test, and the combination of Hba1c?>?=?6.1% and FPG?>?=?5.6?mmol/L would improve the identification of individuals with diabetes mellitus and prediabetes.

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Longitudinal Modeling of the Relationship Between Mean Plasma Glucose and HbA1c Following Antidiabetic Treatments.

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