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Prediabetes: The Gap between the Onset of Disease and Initiation of Treatment
by Michael Bergman, MD, FACP
New York University School of Medicine

The global shift from communicable to chronic, non-communicable diseases, including the increasing prevalence of obesity, prediabetes, and Type 2 Diabetes Mellitus (T2DM) creates a considerable challenge to the clinician and public health infrastructure. Despite substantial research efforts highlighting the considerable benefit of lifestyle modification in thwarting the insidious progression to diabetes and its complications, many individuals will progress even when initially responsive. Importantly, the vast majority of individuals with prediabetes remain undiagnosed and untreated. Therefore, the responsibilities of the medical and public health communities involve identifying new methods for the early identification of those at risk.

The International Diabetes Federation (IDF) estimates that 8.3% of the world’s population or 387 million individuals have diabetes with 592 million, or 1 in 10, expected to develop diabetes by 2035. By the year 2050, it is estimated that 1 in 3 will have diabetes in conjunction with an ageing population. In addition, 316 million are considered at high-risk for developing diabetes with an expectation that this will increase to 500 million within a generation. The economic impact of this epidemic is monumental as one US dollar in nine is spent on diabetes, reaching $612 billion in 2014. Diabetes accounts for over 5 million deaths annually and 500 billion US dollars in health-related expenditures.

Forty per cent of adults face a life time risk of diabetes representing a substantial increase from 20% in the late 1980s. Delaying the diagnosis can result in at least one complication by the time an individual has been diagnosed. These statistics are particularly disturbing as more than 70% of cases, approximating 150 million cases by the year 2035, can be delayed or prevented by adopting a healthier lifestyle. Furthermore, up to 11% of total healthcare expenditure in every country could be saved by addressing risk factors for type 2 diabetes. Once progression to diabetes occurs, many are unaware of their status with “gaps” demonstrated in risk factor control. From 2007-2012, approximately 7.9 million individuals in the US with diabetes were unaware of their diagnosis although 85% had access to a care provider. The preponderance had HbA1c levels below therapeutic targets although above the diagnostic threshold (> 6.5%) with inadequate risk factor control and suboptimal use of blood pressure and lipid-lowering medications. The latter is fundamental as poor risk factor control exposes individuals to diabetes complications. Furthermore, in the US from 2011-2012 among those with new onset diabetes between 18-64 years having private insurance, participation in diabetes self-management education and training was very low (6.8%) within 1 year after diagnosis. The importance of this resides in that education is associated with increased use of primary and preventive services and less frequent need for acute hospitalization.

Thus, with the considerable benefits inherent in the prevention of diabetes, why does this remain so difficult to achieve? Fineberg describes the paradox of prevention which is “celebrated in principle” but “resisted in practice.” Among the obstacles he describes, “success of prevention is invisible, lacks drama, often requires persistent behavior change, and may be long delayed…Prevention of disease will succeed over time insofar as it can be embedded in a culture of health.” Elliot Joslin acknowledged in 1921 that “real headway against the ravages of a disease begins with its prevention rather than with its treatment…” Furthermore, the healthcare community has traditionally been schooled in addressing established conditions rather than in prevention so curricula therefore need to include greater emphasis on public health, increased professional training and practice towards prevention and integrated screening and prevention within the healthcare delivery system. What complicates this process considerably is the heterogeneity in defining and diagnosing glucose disorders-the subject of this monograph. Accurately defining prediabetes is challenging as glucose and HbA1c are relatively insensitive for diagnosing subtle metabolic conditions and may identify different populations. Categorical definitions applied to a continuous process may therefore considerably underestimate those at risk for progression to diabetes; the overwhelming number of individuals at risk is therefore undiagnosed.

Differences in the definitions of prediabetes and diabetes by the ADA and WHO, pertaining to glucose and HbA1c parameters, have recently been reviewed. Defining glucose disorders is nevertheless imprecise whether HbA1c or glucose criteria are utilized. Individuals with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) have relatively little overlap and demonstrate distinctive underlying biological mechanisms and pathophysiological abnormalities based on fasting glucose, 2-hour glucose or HbA1c levels .Those with an increase in both fasting and 2-hour post-load glucose levels do not represent a mixture of each phenotype but rather a distinctive entity. Individuals with both IFG and IGT experience the steepest rise in the development of diabetes. The importance of early identification of those at risk goes beyond the potential for developing diabetes per se as individuals with elevated fasting and 2-hour glucose concentrations also have a higher risk of cardiovascular disease warranting intervention with aggressive modifications in lifestyle.

Determining the optimal method to identify individuals at high-risk for developing diabetes is challenging as no single modality is likely to be uniformly applicable. HbA1c as a diagnostic tool identifies those with a mixture of abnormalities found when applying glucose criteria. The latter, furthermore, can be affected by a variety of clinical circumstances which need to be taken into consideration. In addition, HbA1c and the OGTT do not relate uniformly across all ethnic groups in those with normal, intermediate glucose tolerance or with diabetes. For example, in the US, African Americans have higher HbA1c than both Mexican Americans and non-Hispanic Whites.

Overall, results of all diabetes prevention studies were remarkably similar: a carefully followed diet–exercise combination seemed to be superior in preventing or delaying the development of diabetes compared with metformin. Although lifestyle intervention has clearly been shown to be beneficial in reducing progression to diabetes in those with prediabetes (largely IGT), considerable reduction in efficacy occurred subsequently.

Even though the diabetes prevention studies have been uniformly positive in those with prediabetes, nonetheless, diagnosis of dysglycemic states at an even earlier state before the development of prediabetes is likely delayed as current diagnostic criteria apply absolute threshold values to a continuous process. Raised glucose levels, even within the so-called normal range, occur considerably late in the evolution to diabetes thereby overlooking an opportunity for earlier diagnosis and intervention when prevention is more likely to be effective. Regression from prediabetes to normal glucose regulation was associated with long-term reduction in diabetes risk in the US Diabetes Prevention Program (DPP). In addition, those who did not develop diabetes had a lower prevalence of microvascular complications.

Therefore, it is entirely plausible that with earlier detection of individuals at high-risk, at a stage when β-cell function is more substantially intact, lifestyle intervention should be considerably more effective in thwarting progression to diabetes. This earlier stage is herein termed "pre-prediabetes" representing a prolonged phase of relative stability, a harbinger of prediabetes, subsequent to which a more rapid deterioration in β-cell function occurs leading to a relatively rapid decline in glucose tolerance as demonstrated in the Whitehall II Study. In diagnosing prediabetes employing absolute criteria, which by definition cannot define an incremental disease process, individuals at risk may inadvertently be diagnosed relatively late in the continuous progression to diabetes obviating the possible benefit inherent with earlier intervention. Physiologic studies have consistently demonstrated that β-cell function is significantly reduced at glucose levels below established cut points for impaired fasting glucose (IFG) or IGT.

Aside from increased risk for progression to T2DM, prediabetes also portends increased risk for cardiovascular disease and other complications. As intervention in the prediabetic population during the DPP appears to have limited ability to reduce vascular disease (except for those becoming normoglycemic during the study period), it is plausible that in targeting the “pre-prediabetic” phase, the development of complications may be more favorably impacted.

Newer approaches for early diagnosis of glucose disorders may have the greatest benefit in preserving β-cell function and preventing the potential evolution to worsening dysglycemia. Although defining the optimal strategy for identifying high-risk individuals before progressing to prediabetes or diabetes remains an area of active investigation, an elevated 1-h postprandial glucose level > 155 mg/dl (8.6 mmol/l) during the OGTT may represent an opportunity for early diagnosis and intervention based on several epidemiologic publications including the Texas Heart Study, Botnia Study and Malmö Prevention Project. The 1-hour post-load glucose level during the OGTT was shown to be continuously associated with increasing HbA1 concentrations and therefore could serve as an early marker for abnormalities in glucose tolerance potentially identify at-risk individuals well before the traditional 2-hour glucose value.

Whether lifestyle intervention in those with “pre-prediabetes” having a1-h glucose > 155 mg/dl (8.6 mmol/l) – before developing prediabetes- further reduces progression to T2DM and risk of complications should be evaluated. Consideration should be given as well to redefining the OGTT based on published data regarding interim glucose values. Finally, new staging categories of dysglycemic conditions could be established recognizing the continuous process by which glucose disorders insidiously evolve thereby facilitating prevention. To avoid relying on laboratory testing as a first-line approach to identifying those at high-risk, screening tools have been developed based on known risk factors for diabetes. Established tools developed in one population, though, need to be calibrated to assess specific diabetes risk in other ethnic groups. The latter can be applied for purposes of public screening and glucose testing can be incorporated subsequently to definitively stratify those at risk.

Eradicating diabetes will require increased attention to prevention on a worldwide basis. Indeed, global initiatives in this effort have been the subject of a recent text. Government, food and agriculture stakeholders, in conjunction with public health authorities, community and medical institutions, play a vital and integrative role in thwarting the “diabesity” epidemic.


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About the Author

Michael Bergman, MD, FACP
NYU School of Medicine
Clinical Professor of Medicine
Director, NYU Diabetes Prevention Program
Section Chief, Endocrinology,Diabetes, Metabolism
VA New York Harbor Healthcare System
Manhattan Campus

Dr. Bergman completed his fellowship training in Endocrinology, Diabetes and Metabolism at Yale University and the Albert Einstein College of Medicine. He is a Clinical Professor in the Department of Medicine at New York University School of Medicine, Director of the NYU Langone Diabetes Prevention Program and Section Chief of Endocrinology at the Manhattan Veterans Administration Medical Center.. His research interests have focused on the intensive management of diabetes, pre-diabetes and diabetes prevention. He has lectured and written widely including having served as an editor of the text “Global Health Perspectives in Prediabetes and Diabetes Prevention” published by World Scientific.

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