Volume 2, Issue 1, Pages 43-46 (April 2010)

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ABSTRACT

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The challenge of undiagnosed pre-diabetes, diabetes and associated cardiovascular disease

Received 7 August 2009; accepted 24 October 2009. published online 26 November 2009.

Abstract

Objective

To present the challenges of undiagnosed pre-diabetes, diabetes and associated cardiovascular disease.

Results

A substantial number of people with diabetes and pre-diabetes remain undiagnosed worldwide. Without preventive measures, pre-diabetes progresses to overt diabetes at the rate of approximately 5% per year. Both diabetes and pre-diabetes are associated with vascular complications.

Conclusion

Undiagnosed pre-diabetes and diabetes is a major health problem, and we recommend widespread screening for diabetes. An international expert committee has recommended that HbA1c be used for the diagnosis of diabetes. Further studies are needed before HbA1c can be used as a diagnostic test for gestational diabetes.

Keywords: Diabetes, Pre-diabetes, Undiagnosed diabetes, HbA1c, Cardiovascular disease

Article Outline

• Abstract

• 1. Introduction

• 2. Diagnosis of diabetes and pre-diabetes

• 2.1. Progression and prevention of pre-diabetes to diabetes

• 2.2. Vascular complications of pre-diabetes and diabetes

• 3. Screening for diabetes

• 4. Conclusion

• Acknowledgment

• References

• Copyright

1. Introduction

The prevalence of diabetes and pre-diabetes has reached epidemic proportions. It is estimated that currently, approximately 7.8% of the US population or 23.6 million Americans have diabetes [1]. Of these, 17.9 million people are diagnosed and 5.7 million people have diabetes that has not been diagnosed. In addition, there are an estimated 57 million people who have “pre-diabetes” [1]. In 2005–2006, the crude prevalence of total diabetes in the US among people aged ⩾20 years was 12.9%, of which approximately 40% (of cases) were undiagnosed. In addition 29.5% had pre-diabetes [2]. In the UK, the overall weighted prevalence of diabetes was 9.1% and 1.7% had undiagnosed diabetes. Of the cases of diabetes, 18.5% were undiagnosed [3]. It is projected that the global prevalence of diabetes will approximately double by the year 2030 [4]. Worldwide, the number of people with pre-diabetes (impaired glucose tolerance) in the age group 20–79 was 308 million in 2007, and is expected to increase to 418 million by the year 2025 [5].

Pre-diabetes, as diagnosed by impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), progresses to overt diabetes at the rate of approximately 5% per year [6] unless some interventions are introduced [7]. Diabetes is associated with an increased risk of microvascular (diabetic retinopathy, nephropathy, and neuropathy) [8], as well as macrovascular complications such as myocardial infarction, stroke or peripheral vascular disease [9]. The majority of patients with type 2 diabetes mellitus die due to cardiovascular complications [10]. Thus, a missed diagnosis of diabetes amounts to a missed diagnosis of cardiovascular disease [11].

2. Diagnosis of diabetes and pre-diabetes

Since both fasting and postprandial glucose levels in the population are distributed in a unimodal fashion, the diagnosis of diabetes and more recently pre-diabetes has been made by somewhat arbitrary criteria. Prior to the criteria for diagnosis of diabetes promulgated by the National Diabetes Data Group [12], there was no agreement about the levels of plasma glucose at which a diagnosis of diabetes mellitus could be made. These criteria were revised in 1997 [13], and are still used widely to make a diagnosis of diabetes mellitus. At that time, the glycemic threshold for making a diagnosis of diabetes was lowered from a fasting plasma glucose of 140 mg/dl to a plasma glucose level of 126 mg/dl. Also at that time, pre-diabetes was defined as either an impaired fasting glucose (IFG), i.e., FPG 110–125 mg/dl, or impaired glucose tolerance ([IGT), i.e., 2h post glucose load plasma glucose 140–199mg/dl. The criteria for impaired IFG were subsequently revised to FPG 100–125mg/dl [14]. The reasons for this decision by the expert committee were several, and are discussed in detail in their report [14].

2.1. Progression and prevention of pre-diabetes to diabetes

It is well known that people with pre-diabetes have an increased risk of progression to type 2 diabetes mellitus [6], [15]. Several studies have followed the progression of IFG and IGT to the development of overt diabetes. An evaluation of these studies reveals that although there are some differences among studies, it appears that IFG or IGT progresses to overt diabetes at the rate of approximately 5% per year. The risk appears to be similar with isolated IFG or IGT, and is highest for those who have combined IFG and IGT [6].

A review of several studies of prevention of diabetes from pre-diabetes revealed that with life style interventions the relative risk reduction ranged from 28% to 67% while with the use of some drugs the relative risk reduction was 26–60% [16]. A larger meta-analysis to quantify the effectiveness of pharmacologic and lifestyle interventions to prevent or delay type 2 diabetes in people with IGT determined that the pooled hazard ratios were 0.51 (95% confidence interval 0.44–0.60) for life style interventions vs. standard advice, 0.70 (0.62–0.79) for oral diabetes drugs vs. controls, 0.44 (0.28–0.69) for Orlistat vs. controls and 0.32 (0.03–3.07) for herbal remedy Jiangtang recipe vs. standard advice. The authors concluded that life style and pharmacologic interventions reduce the rate of progression to type 2 diabetes in people with IGT, and that the lifestyle interventions seem to be at least as effective as drug treatment [7]. It should be mentioned that at the present time no drugs are approved by the Federal Drug Administration in the USA for the treatment of pre-diabetes.

Although either IFG and/or IGT can be used to make a diagnosis of pre-diabetes, their significance in terms of progression of disease and the cardiovascular complications may not be the same. For example, a study from Mauritius [17] demonstrated that for predicting progression to type 2 diabetes, the sensitivity, specificity, and positive predictive values were 26%, 94% and 29% for IFG and 50%, 84% and 24% for IGT, respectively. The authors concluded that IGT had higher sensitivity over IFG for predicting progression to type 2 diabetes [17].

Similarly in the Fungata study, it was observed that IGT was a risk factor for cardiovascular disease, but IFG was not [18]. An international workshop on impaired glucose tolerance and impaired fasting glycemia [6] concluded that: (i) in the majority of populations studied, IGT is more prevalent than IFG, (ii) IFG is substantially more common amongst men, and IGT slightly more common amongst women, (iii) the prevalence of IFG tends to plateau in middle age, whereas prevalence of IGT rises in old age, (iv) because IGT is more common than IFG in most populations, it is more sensitive (but slightly less specific) for identifying people who will develop diabetes, (v) both IFG and IGT are associated with cardiovascular disease risk factors including hypertension, dyslipidemia and other features of the metabolic syndrome, and finally (vi) in unadjusted analysis, both IFG and IGT are associated with cardiovascular disease and total mortality.

2.2. Vascular complications of pre-diabetes and diabetes

Pre-diabetes has been associated with microvascular [15], [19] and macrovascular complications [15], [20], [21]. Several studies have demonstrated that IGT is associated with an increased risk of cardiovascular mortality [22], [23], [24]. Once pre-diabetes progresses to overt diabetes, the risk of cardiovascular disease greatly increases [10], [25], [26]. It has also been demonstrated that HbA1c levels are continuously and positively associated with cardiovascular and total mortality independent of other risk factors (27–30). In the EPIC study [27], an increase in HbA1c of 1% points was associated with a relative risk of death from any cause of 1.24 (95% CI, 1.14–1.34). Danaei et al. [28] in a global study to assess the relationship of mortality from ischemic heart study and glucose concentration, concluded that higher than optimum blood glucose is a leading cause of cardiovascular mortality in most world regions. Finally, in the studies of Saydah et al. [29], based on the NHANES data, and that of Dale et al. [30], based on a 20 years follow up of newly diagnosed diabetes patients demonstrated that poor long term glycemic control as indicated by increased HbA1c levels is associated with higher cardiovascular and all cause mortality.

In recent years, the controversy, whether the control of hyperglycemia is beneficial to reduce cardiovascular complication risk has been settled. The Diabetes Control and Complications Trial (DCCT) in type 1 [31] and UK prospective diabetes study [32] in type 2 diabetes demonstrated that control of hyperglycemia reduces the risk of microvascular complications of diabetes. In the UKPDS study, there was a 16% reduction in the risk of myocardial infarction, but this difference was not statistically significant. However, there was a correlation between the risk of MI and HbA1c level [33]. In a recent follow up of the UKPDS, it was demonstrated that despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction or death from any cause were observed during 10 years of post trial follow up [34]. Based on studies like these [31], [34] and the observations that HbA1c levels are continuously and positively associated with cardiovascular disease and total mortality independent of other cardiovascular risk factors [27], [28], [29], [30], the American Diabetes Association (ADA) recommended that a HbA1c <7% for microvascular disease prevention, and the general goal of <7% appeared reasonable for many adults for macrovascular risk reduction. In selected individuals, a HbA1c goal lower than <7% might be reasonable if this can be achieved without significant hypoglycemia or other adverse effects of treatment [35]. This leads to the concept that perhaps the lower the HbA1c, the better it was [36]. However, the results of the recent studies, Action to Control Cardiovascular Risk in Diabetes (ACCORD) [37] and Action in Diabetes and Vascular Disease (ADVANCE) study [38] have led to re-examination of the “lower is better” role of hyperglycemia in cardiovascular disease. Neither of these two studies showed any benefit of lowering the HbA1c to 6.4% and 6.3%, respectively; compared with the standard intervention, which achieved a HbA1c level of 7.5% and 7.0%, respectively. Moreover, in the ACCORD study, intensive therapy was associated with increased mortality [37].

Thus, although it is not clear what the ‘ideal’ target for HbA1c should be, it is apparent from the above discussion that many cases of pre-diabetes and diabetes remain undiagnosed, pre-diabetes increases the risk of progression to overt diabetes, and both pre-diabetes and diabetes are associated with an increased risk of cardiovascular disease morbidity and mortality.

3. Screening for diabetes

Effective treatments are now available to retard the progression of pre-diabetes to diabetes [7], [16] and to reduce the cardiovascular risk in diabetes mellitus [31], [32], [33], [34], [39]. It, therefore, appears reasonable to undertake aggressive screening for pre-diabetes and diabetes to reduce the overall disease burden. However, whether to screen for diabetes or not, and how to screen, remains controversial. The ADA recommends screening for all adults who are overweight and have one of the following additional risk factors: physical inactivity, first degree relative with diabetes, members of high risk ethnic populations, women who have delivered a baby weighing more than 4.1 kg or were diagnosed as having gestational diabetes mellitus, hypertension, HDL – cholesterol level <35 mg/dl or triglyceride level >250mg/dl, women with polycystic ovarian syndrome, IGT or IFT on previous testing, other clinical conditions associated with insulin resistance and history of cardiovascular disease [35]. In the absence of above criteria, testing for diabetes and pre-diabetes should begin at age 45 years. If results for diabetes and pre-diabetes are normal, testing should be repeated at least at 3 years intervals with consideration of more frequent testing depending on initial results and risk status [35]. The US Preventive Services Task Force (USPTF) recently updated its guidelines for screening adults for type 2 diabetes mellitus [40]. This report was based on a literature review of existing data in both MEDLINE and Cochrane Library database. Based on their review the USPTF concluded that screening for diabetes in asymptomatic individuals with hypertension (blood pressure ⩾135/80) was indicated. On the other hand, the National Screening Committee (NSC) of UK, after an extensive literature review, concluded that the case for screening for undiagnosed diabetes is probably somewhat stronger than it was at the time of their last review [41]. They also noted that there is a good case for screening for IGT with the aim of preventing some future diabetes and reducing cardiovascular disease. An interesting discussion about whether to screen for diabetes or not has been recently published in the Mayo Clinic Proceedings [42], [43], [44].

In the aforementioned discussion, we agreed [44] with the broader screening recommendations of the ADA [35] and Sheehy et al. [42] in supporting more aggressive screening for diabetes, as compared to the USPSTF more restrictive recommendations [40]. Assuming that one is going to undertake screening, the optimal methods for screening are also somewhat controversial. The ADA recommends using FPG and OGTT and presently these are used widely [35]. Both of these tests require measurement of plasma glucose and also require at least an overnight fast. However, the sensitivity of FPG is not very high and fails to detect 30–50% of individuals with diabetes [45], [46]. OGTT is inconvenient, costly, time consuming, labor intensive, and has low reproducibility that can add to confusion and uncertainty to confirmation of the diagnosis of diabetes [45], [46]. We have suggested in the past that HbA1c may be a reasonable alternative for screening for diabetes [47], possibly including GDM [48]. In recent years, there has been an increasing support for the use of HbA1c for screening purposes [45], [46].

Bennett et al. [46], in a systemic review, concluded that HbA1c and FPG are equally effective screening tools for the detection of type 2 diabetes. In a study by McCane et al. [49] it was reported that FPG, OGTT and HbA1c all three significantly predicted the development of retinopathy and nephropathy [49]. A recent consensus statement published by a panel of experts in the area of diagnosis, monitoring and management of diabetes, led by Saudek et al. [50], recommended that: (1) screening standards should be established that prompt further testing and closer follow up including FPG 100 mg/dl or greater, random plasma glucose of 130 mg/dl or greater or HbA1c greater than 6.0%, (2) HbA1c 6.5–6.9% or greater, confirmed by a specific test (FPG or OGTT) should establish the diagnosis of diabetes, (3) HbA1c of 7% or greater confirmed by another HbA1c or a specific test (FPG or OGTT) should establish the diagnosis of diabetes. Although so far, ADA has not endorsed using HbA1c as a diagnostic test, with the consensus of several leading diabetes organizations, ADA’s Expert Committee on the Diagnosis and Classification of Diabetes plans to publish guidelines recommending the HbA1c test as a diagnostic tool for type 2 diabetes [51]. The reasons given for this change are that both FPG and OGTT show thresholds for the diabetes specific complications of retinopathy; the variability of glucose measures is actually much larger than that of standardized A1c measurements. While to date there are no criteria for using HbA1c in diagnosing diabetes, A1c has a threshold for retinopathy, can be measured anytime of day without regard to meal status and has less variability [51].

Although it appears that the community of diabetes experts may be close to an agreement about the use of HbA1c for the screening or diagnosis of diabetes, the issue of using HbA1c for similar purposes is more controversial in gestational diabetes mellitus (GDM). Currently, the ADA recommends screening for GDM using risk factor analysis and if appropriate, use of OGTT. A two-step approach, using an initial screening by measuring plasma or serum glucose 1h after 50gm oral glucose load and performing diagnostic 100gm glucose load on a separate day in women who exceed the chosen threshold on 50 gm screening, is recommended [35]. All the disadvantages of using an oral glucose load mentioned above apply even more strongly to pregnant women who already may have reduced tolerance to foods and drinks. Moreover, the glucose load used is even greater [100gm] compared to the glucose load used in nonpregnant state (75gm). Anecdotally, the drink has been described as nauseating or even obnoxious by patients, and up to 4% women have reported vomiting following ingestion of oral glucose load [52].

There are, however, few studies supporting the diagnostic utility of HbA1c in GDM. This may be a result of the fact that most of the studies were done in the 1980’s [53], [54], [55], [56], [57] when HbA1c assays were diverse, and the test was not standardized [47]. Furthermore, these studies were small and the diagnostic criteria used in these studies were not uniform. Thus the conclusions drawn from these studies were not clear.

The results of two recent larger studies from UAE addressing HbA1c in GDM screening and diagnosis are also conflicting regarding the sensitivity and specificity of the test [58], [59]. Interestingly both of these studies were performed by the same group. In their earlier study [58], Agarwal et al. observed that HbA1c may have potential as a screening test for GDM but they were not able to confirm that in the subsequent study [59]. In a retrospective study in a Saudi population of 145 women in the third trimester of pregnancy, we observed that the sensitivity of HbA1c in predicting GDM was 87%. The study design did not allow us to calculate specificity [48]. In a recent review by the New Zealand GDM Technical Working Party, this group recommended HbAlc as a practical initial screening test but noted that further research was needed [60]. It is, therefore, apparent that further studies are needed to determine the role of HbA1c in screening and diagnosis of GDM.

4. Conclusion

The prevalence of diabetes continues to increase on a world wide basis. A substantial proportion of subjects with pre-diabetes and diabetes remain undiagnosed. Pre-diabetes progresses to overt diabetes at the rate of approximately 5% unless appropriate interventions are introduced. Both pre-diabetes, and diabetes are associated with an increased risk of cardiovascular complications. Effective modalities to prevent the progression of pre-diabetes to diabetes and to reduce the CV risk of diabetes are now available. Therefore, we believe that aggressive screening of diabetes should be undertaken. However, this issue remains controversial. Although FPG and OGTT are widely used for screening, there is increased recognition of the role of HbA1c for screening purposes. It appears that we will be using HbA1c, not only for monitoring the glycemic control of diabetes, but also for recognition of diabetes in the near future. However, the role of HbA1c in screening for GDM remains uncertain, and further studies are needed to clarify its role for this purpose

Acknowledgement

We would like to thank Jinie Shirey, Division of Endocrinology, Department of Medicine, College of Human Medicine, Michigan State University, East Lansing for assistance in manuscript preparation.

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Division of Endocrinology, Department of Medicine, Michigan State University, East Lansing, MI, USA

Corresponding author. Address: Division of Endocrinology, Department of Medicine, B323, Clinical Center, Michigan State University, East Lansing, MI 48824, USA. Tel.: +1 517 353 3730; fax: +1 517 432 1326.

1 Present address: Cape Diabetes and Endocrinology and Cape Thyroid Center, Saint Francis Diabetes Center, 17 Doctors Park, Cape Girardeau, MO 63703, USA.

PII: S1877-5934(09)00056-3

doi:10.1016/j.ijdm.2009.10.004

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