Diabetes NewsApril 2012

Fasting Plasma Glucose and Hemoglobin A1c in Identifying and Predicting Diabetes

Diabetes Care • February, 2011

Type 2 diabetes has emerged as an important public health and economic problem in the U.S. More than 18 million Americans have diabetes and are at risk for related complications including heart disease, stroke, retinopathy, leg vessel disease and kidney disease. Currently available therapeutic strategies in diabetes are only partially successful in preventing complications. Therefore, diabetes screening in undiagnosed participants and early identification of those at high risk for intervention to prevent diabetes onset is very important for reducing diabetes-associated complications and medical care costs.  

Criteria proposed for diagnosing incident diabetes by the American Diabetes Association (ADA) based upon fasting plasma glucose (FPG) have been used for a long time. Recently, an International Expert Committee recommended criterion based upon HBA1c. The cutoff point of an HBA1c ≥ 6.5% suggested in their report was based the association of HBA1c with the prevalence of retinopathy from large cross-sectional studies. The ADA recently added HBA1c as a diagnostic criterion of diabetes and suggested using either criterion. Therefore, it is important to know how these criteria perform in identifying prevalent in initial and successive diabetes screenings among undiagnosed participants and incident diabetic case subjects in a period of time and which risk factors predict incident diabetes from these criteria.

This report has used longitudinal data from two exams (1989-1992 and 1993-1995) of the Strong Heart Study (SHS), a study to assess the prevalence and incidence of cardiovascular disease (CVD) and its risk factors in American Indians. This population has high rates of diabetes, and data from this population may be considered to be reflective of other populations who are at high risk for diabetes and diabetic CVD. This research compares the diagnosis of diabetes by HBA1c and/or FPG and the risk factors for incidence diabetes defined by the three criteria and develops prediction equation for incidence diabetes using baseline HBA1c, FPG or both.    

Research Design and Methods - A total of 4,549 American Indian men and women, aged 45-74 years, in 13 Indian tribes/communities in Arizona, North/South Dakota and Oklahoma participated in the SHS baseline examination from 1989 to 1992 after providing written informed consent. The cohort was followed and reexamined in 1993-1995. The design and methods of the SHS have been previously reported in detail. Briefly, each examination included a personal interview and a physical examination. Blood was drawn at each examination after a 12-h fast, and total cholesterol (TC) LDL cholesterol, HDL cholesterol (HDL-C), triglycerides (TGs) and FPG were measured. Diabetes status was defined by ADA 2004 criteria based upon FPG (denoted as FPG-DM) as diabetes if FPG ≥ 126mg/dL or if on diabetes medications, as impaired fasting glucose (IFG) (or pre-diabetes) if 100 ≤ FPG ≥ 126 mg/dL and as normal fasting plasma glucose (NFG) if FPG < 100 mg/dL; by International Expert Committee criteria based upon HBA1c (denoted as A1C-DM) as diabetes if HBA1c ≥ 6.5% or if on diabetes medications, pre-diabetes if 6.0 ≤ HBA1c < 6.5%, and non-diabetes otherwise; and by current ADA criteria based on both HBA1c and FPG (denoted as FPG/A1C-DM) as diabetes if HBA1c  ≥ 6.5% or, FPG ≥  126 mg/dL or if on diabetes medications and non-diabetes otherwise.   

A urine sample was taken to measure albumin and creatinine. Albuminuria was classified by urinary albumin-to-creatinine ratio (UACR) as microalbuminuria if 30 ≤ UACR < 300mg/g. Obesity status was defined as obese if BMI ≥ 30kg/m2, overweight if 25 ≤ BMI < 30kg/m2 and normal if BMI < 25 kg/m2. Three measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were taken on the right arm with an appropriate sized cuff using a Baum mercury sphygmomanometer after the participant was in a seated position for 5 minutes. According to the Seventh Report of the Joint national Committee on Prevention, Detection, Elevation and Treatment of High Blood pressure, hypertension (HTN) was defined as SBP/DBP ≥ 140/90 mmHg or on antihypertensive medications, normal if SBP < 120 mmHg and DBP < 80 mmHg and pre-hypertension (Pre-HTN) otherwise. Leisure-time activities were measured at the baseline exam by the average exercise hours in the past week (AEHPW).

Metabolic syndrome traits described by the National Cholesterol Education Adult Treatment Panel III (APT III) were also used in classification. Participants with SBP/DBP ≥ 130/85 mmHg or on treatment for hypertension were considered as having elevated blood pressure; waist circumference (WAIST) > 102 cm in men or > 88 cm in women was considered high (highWAIST); fasting TG ≥ 150 mg/dL was considered hyper triglyceridemia (hyperTG); and HDL-C < 40 mg/dL in men or < 50 mg/dL in women was considered low (lowHDL-C).

Data collected at the baseline and second exams for those participants who had HBA1c and FPG measured and did not receive insulin treatment or an oral agent for diabetes, were not on renal dialysis, and did not have a kidney transplant were used to compare the performances of HBA1c and FPG in identifying diabetes in undiagnosed participants. The risk factors data from the baseline exam and the incident diabetes status data from the second exam collected from participants without FPG-DM, A1C-DM, and FPG/A1C-DM, respectively and to compare the effects of the baseline HBA1c and/or FPG in predicting the incident FPG/A1C-DM.
 
Results - For cases of diabetes identified by FPG ≥ 126 mg/dL, using HBA1c ≥ 6.5% at the initial and 4 year follow-up diabetes screenings (or in identifying incident cases in 4 years) among undiagnosed participants left 46% and 59% of the cases of diabetes undetected, respectively, whereas for cases identified by HBA1c ≥ 6.5%, using FPG ≥ 126 mg/dL left is 11% and 59% unidentified, respectively. Age, waist circumference, urinary albumin-to-creatinine ratio, and baseline FPG and HBA1c levels were common significant risk factors for incident diabetes defined by either FPG or HBA1c; triglyceride levels were significant for diabetes defined by HBA1c alone, and blood pressure and sibling history of diabetes were significant for diabetes defined by FPG alone. Using both the baseline for FPG and HBA1c in diabetes prediction identified more people at risk than using either measure alone.

Conclusions - The study found that using HBA1c alone in the initial diabetes screening among undiagnosed adults in a population-based sample identified fewer cases of prevalent diabetes than using FPG alone. However, for identifying cases of prevalent diabetes in a 4 year periodic successive diabetes screening or identifying incident diabetes in 4 years in undiagnosed participants, each criterion missed cases of diabetes identified by the other. The study also showed that using HBA1c and FPG identified a larger group of people at risk.

The discordances between diabetes identified by HBA1c and glucose criteria were also found in U.S. 2003-2006 National Health and Nutrition Examination Survey data and several other studies in different ethnic groups. In general, HBA1c detected lower prevalence of diabetes than glucose criteria in U.S. and other populations, especially in undiagnosed participants, which is consistent with the findings in American Indians.

The discordances between diabetes identified by HBA1c and FPG among undiagnosed participants may be caused in part by the fact that HBA1c levels reflects an integrated measure of glycemia over a 2-3 month period, whereas FPG reflects the influence of hepatic glucose output on the day of the visit.  

The study found that in the initial screening, among undiagnosed participants at baseline exam FPG ≥ 126 mg/dL identified more cases of diabetes than HBA1c ≥ 6.5%, but in a successive diabetes screening four years later, among undiagnosed participants the percentages were equal. The difference between the initial and successive diabetes screenings may be because at the baseline exam those newly diagnosed participants might have had unrecognized diabetes for many years, while those newly diagnosed participants might have had undiagnosed diabetes for many years, while those newly diagnosed at the successive exam might have had undiagnosed diabetes for at most four years. This supports the contention that HBA1c ≥ 6.5% represents sustained daily hyperglycemia sufficient to meaningfully influence glycation, whereas FPG ≥ 126 mg/dL may be a transient phenomenon that happens occasionally to people. With a four year window, there is much less time to develop sustained hyperglycemia, and thus the two indicators are more comparable. Since in the usual clinical situation there has not been a screening in the near past, the discrepancy between HBA1c and FPG would likely prevail. The similar difference between the initial and successive diabetes screenings by using FPG and 2-h post plasma glucose also reported in American Indians.

The data show that a large number of people at risk can be indentified using both HBA1c and FPG. One cost-effective diabetes screening procedure could be to 1) measure HBA1c for all participants and 2) further measure FPG only for those participants with 4.75% ≤ HBA1c < 6.5%, since the data show this would result in the identification of the most of the remainder of those who have diabetes by FPG criterion. Others have also reported that using a method based upon FPG and HBA1c in diabetes screening was more efficient.

This study has many strengths including population-based sampling and systematic measures at two exams; further, this is a unique population that may become a reference for other populations with high rates of diabetes and diabetic CVD. Due to the high prevalence (~46%) of diabetes in American Indians, we are only able to use data collected from about half of the 4,549 participants in the SHS cohort to derive predictive equations. Although the proposed models were internally validated, they should be tested and validated in other populations.

In conclusion, FPG and HBA1c criteria do not identify identical groups of individuals from a population-based sample as having diabetes. Using HBA1c alone to conduct initial diabetes screening in undiagnosed participants detects fewer cases of prevalent diabetes than FPG alone. However, for identifying prevalent cases of diabetes in a four year periodic successive diabetes screening or identifying cases of incident diabetes in four years in undiagnosed participants, using either FPG or HBA1c alone was not effective. Baseline FPG or HBA1c levels, WAIST, and UACR were common, significant and independent risk factors for incident diabetes defined by either FPG of HBA1c– based criteria. Using both the baseline FPG and HBA1c to predict incident FPG/A1C-DM identified more people at risk. The proposed models can be applied to assess risk of incident HBA1c, FPG-FM, FPG/A1C-DM in American Indians and have potential applicability to other populations.

Reprinted with permission from the American Diabetes Association