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New Noninvasive Type 2 Diabetes Screening:
Superior sensitivity to fasting plasma glucose and A1C
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Diabetes Care, May 2007
John D. Maynard, MS1, Mark Rohrscheib, MD2, Jeffrey F. Way, BS3, Catriona M. Nguyen, BSC3 and Marwood N. Ediger, PHD1
1 VeraLight, Albuquerque, New Mexico
2 University of New Mexico School of Medicine, Albuquerque, New Mexico
3 InLight Solutions, Albuquerque, New Mexico
ABSTRACT
OBJECTIVE-This study compared the performance of a novel noninvasive technology to fasting plasma glucose (FPG) and A1C tests for detecting undiagnosed diabetes and impaired glucose tolerance.
RESEARCH DESIGN AND METHODS-The design was a head-to-head evaluation in a naive population. Consented subjects received FPG and A1C tests and an oral glucose tolerance test (OGTT). Subjects were also measured by a noninvasive device that detects the fluorescence of skin advanced glycation end products. A total of 351 subjects participated.
RESULTS-Subjects with 2-h OGTT values 140 mg/dl defined the positive screening class. A total of 84 subjects (23.9% prevalence) screened positive. The performances of the noninvasive device, FPG, and A1C were evaluated for sensitivity and specificity against this classification. At the impaired fasting glucose threshold (FPG =100 mg/dl), the FPG testing sensitivity was 58% and the specificity was 77.4%. At that same specificity, the sensitivity for A1C testing was 63.8%, while the noninvasive testing sensitivity was 74.7%. The sensitivity advantage of the noninvasive device over both blood tests for detecting diabetes and precursors was statistically significant (P < 0.05).
CONCLUSIONS-The noninvasive technology showed clinical performance advantages over both FPG and A1C testing. The sensitivity differential indicated that the noninvasive device is capable of identifying 28.8% more individuals in the OGTT-defined positive screening class than FPG testing and 17.1% more than A1C testing. The combination of higher sensitivity and greater convenience-rapid results with no fasting or blood draws-makes the device well suited for opportunistic screening.
INTRODUCTION
The U.S. is facing a dangerous epidemic in type 2 diabetes. Of the estimated 20.6 million individuals with diabetes, 30% are undiagnosed (1). Another 54 million people have some form of pre-diabetes, and many will progress to frank diabetes within 3 years (1-3). Numerous studies have shown that with early detection and effective intervention, diabetes can be prevented or delayed (2-7). In patients with diagnosed diabetes, other studies have shown that glucose control can lower the incidence of complications (8,9).
Diagnosis is typically initiated during a physical exam with a primary care physician. However, current screening methods for type 2 diabetes and pre-diabetes are inadequate due to their inconvenience and inaccuracy. Specifically, the most widely applied screening test in the U.S., fasting plasma glucose (FPG) testing, has convenience barriers in the form of an overnight fast and a blood draw. FPG also suffers from poor sensitivity (40-60%) contributing to late diagnoses (10). In fact, about one-half of diabetic patients present with one or more irreversible complications at the time of diagnosis (11,12). A more accurate and convenient screening method could dramatically improve early detection of type 2 diabetes and its precursors, facilitating interventions that can prevent or at least delay the development of type 2 diabetes and its related micro- and macrovascular complications.
Several studies, including the DCCT (Diabetes Control and Complications Trial) and EDIC (Epidemiology of Diabetes Interventions and Complications Study), have demonstrated that elevated skin advanced glycation end products (AGEs) are biomarkers of diabetes, are highly correlated with the complications of diabetes, and are predictive of future diabetic retinopathy and nephropathy (13-15). Individuals with diabetes accumulate skin AGEs faster than individuals with normal glucose regulation (16). Thus, skin AGEs constitute a sensitive summary metric for the integrated glycemic exposure that the body has endured.
However, until the recent development of novel noninvasive technology to measure AGEs, a punch biopsy was required to quantify skin AGE levels. This method, Spectroscopic measurement of dermal AGEs (SAGE), measures skin fluorescence due to AGEs in vivo and provides a quantitative diabetes risk score based on multivariate algorithms applied to the spectra (17). SAGE does not require fasting and creates no biohazards. It automatically compensates for subject-specific skin differences caused by melanin, hemoglobin, and light scattering. The measurement time is approximately 1 min, thus providing an immediate result.
The concept of quantifying dermal AGEs noninvasively was successfully tested in a previous in vitro study. In that work, concentrations of a well-studied fluorescent AGE, pentosidine, were accurately quantified in a porcine dermis model by noninvasive fluorescence spectroscopy (18). Subsequently, an early noninvasive prototype was evaluated in a diabetic versus normal (case-control) human subject study, demonstrating that SAGE could accurately classify disease in a case-control population (19). This led to the premise of the current work: We hypothesize that SAGE can detect undiagnosed diabetes and pre-diabetes with sufficient performance to serve as a screening tool.
CONCLUSIONS--
SAGE significantly outperforms FPG and A1C testing for detection of abnormal glucose tolerance. SAGE identified 29% more individuals with undiagnosed abnormal glucose tolerance than FPG testing and about 17% more than A1C testing. In addition, SAGE provides rapid results and does not require fasting or blood draws, factors that are convenience barriers to opportunistic screening.
The low sensitivity for detection of abnormal glucose tolerance with FPG testing reported here is not unexpected. A review of studies of FPG screening for undiagnosed diabetes has found that sensitivities ranged from 40 to 65% (10). Since negative screening results are not subject to confirmatory testing, the large false-negative rate for FPG testing is a latent problem and contributes to the growing number of undiagnosed cases of type 2 diabetes.
The results presented here are consistent with the pathogenesis of abnormal glucose regulation, in which excessive postprandial glucose levels accelerate accumulation of skin AGEs, although fasting levels may remain normal. Since dermal AGEs represent the integrated damage due to hyperglycemia, noninvasive measurement of these biomarkers is a promising means for early detection of abnormal glucose regulation.
Given the increasing worldwide prevalence of type 2 diabetes and pre-diabetes, a move to earlier detection and treatment is necessary to help mitigate the diabetes epidemic. In the U.S., if current trends continue, the prevalence of diabetes is expected to more than double by 2025 and affect 15% of the population (25). The recent estimate of $135 billion for annual diabetes-related health care costs in the U.S. means that the cost of the diabetes epidemic threatens to overwhelm the nation's health care system (26).
Fortunately, once detected, diabetes is now more treatable than ever. Large clinical studies such as the DCCT (Diabetes Complications and Control Trial) and UKPDS (UK Prospective Diabetes Study) have shown that tight control of glucose levels has significant health benefits for those with established diabetes (8,9).
Moreover, if pre-diabetes is detected and treated, progression to frank type 2 diabetes can be delayed or prevented. The DPP (Diabetes Prevention Program), FDPS (Finnish Diabetes Prevention Study), and DREAM (Diabetes Rduction Assessment With Ramipril and Rosiglitazone Medication) trials have shown that it is possible to prevent or at least delay the development of type 2 diabetes in patients with pre-diabetes (3-5). This may be accomplished with aggressive diet and exercise modification and/or therapeutics such as metformin (DPP) and rosiglitazone (DREAM trials).
The combination of accuracy and convenience of SAGE make it well suited for opportunistic screening and earlier detection of diabetes and pre-diabetes. This noninvasive technology is a promising tool to facilitate early intervention for preventing or delaying the development of diabetes and its devastating complications.
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