The current American Diabetes Association (ADA) guidelines define prediabetes as having a fasting plasma glucose (FPG) of at least 100 mg/dL (5.6 mmol/L) but less than 126 mg/dL (7.0 mmol/L), or abnormal two-hour response to a 75-g oral glucose tolerance test (OGTT) of at least 140 mg/dL (7.8 mmol/L) and less than 200 mg/dL (11.1 mmol/L) (often termed IGT—impaired glucose tolerance).
1 The World Health Organization defers slightly by defining impaired fasting glucose (IFG) as a fasting glucose of at least 110 mg/dl (6.1 mm OL) with IGT similar to ADA Guidelines.
2
Looking at the prevalence of IFG levels according to race, Mexican American adolescents topped the list at 15.3% vs 11.3% of all non-Hispanic white and 7.4% of all non-Hispanic black adolescents.
3 This presents an enormous long-term risk for the potential development of type 2 diabetes mellitus (T2DM) in most patients. The etiology of T2DM is complex and multifactorial; it covers the gamut—from early development of oxidative stress leading to endothelial dysfunction, genetics, insulin resistance and cardiovascular risk factors.
The bodily processes of glucose regulation starts with the basic understanding that during normal homeostasis in a postabsorptive state, most glucose is taken up by the brain, splanchnic bed and erythrocytes.
4 Fasting glucose levels are determined primarily by hepatic production of glucose and are regulated by plasma insulin and glucagon concentrations.
5
Isolated IFG and isolated IGT are primarily insulin-resistant states. People with isolated IFG predominantly have hepatic insulin resistance and normal muscle insulin sensitivity, while individuals with isolated IGT have normal to slightly reduced hepatic insulin sensitivity and moderate to severe muscle insulin resistance. Subjects with both IFG and IGT manifest muscle and hepatic insulin resistance; over time, beta-cell dysfunction is precipitated causing frank diabetes. Not all patients develop diabetes; however, best estimates suggest approximately 70% will.
6,7
The purpose of this article is to evaluate the cardiovascular impact of IFG, with a focus on the mechanisms involved that contribute to the cardiovascular complications of T2DM. A better understanding and early identification of impaired fasting glucose will allow health care professionals to take a more comprehensive approach to multi-factorial diabetes management validated by published data and guidelines.
According to the federal Centers for Disease Control and Prevention (CDC), prediabetic individuals are five to 15 times more likely to develop type 2 diabetes when compared to people with normal blood glucose.
8 Among these individuals with IFG and/or IGT, those who are older, overweight and have a strong family history of diabetes or gestational diabetes are more likely to progress to diabetes.
9 In addition, those with both IFG and IGT are twice as likely to develop diabetes when compared to individuals with just one of the conditions.
9
Studies have shown that, in individuals with IGT, the annual incidence of development of type 2 diabetes is between 2% and 34% while for persons with IFG it is between 1.5% and 23%.
8 The Diabetes Prevention Program (DPP) and the Finnish Diabetes Prevention Study have shown the importance of weight loss and moderate physical activity. Among those individuals with IGT who lost weight and engaged in moderate physical activity, only 3% to 5% progressed to diabetes annually. Whereas, among individuals who did not lose weight and engaged in moderate physical activity, 11% progressed to diabetes annually.
10-11
Lifetime incidence of developing diabetes in prediabetic (IGT) individuals who neither lose weight nor engage in moderate physical activity is approximately 83%.
12 Surprisingly, even among those prediabetic individuals who lose weight and engage in moderate physical activity, 65% will still go on to develop diabetes.
12-13
Recent information from the Mexico City Diabetes Study found that the progression to diabetes is approximately 30% to 40% at seven years. In addition, the recently reported DREAM trial tested rosiglitazone and ramipril in a 2 x 2 factorial design in 5,269 individuals with IFG.
14 In this trial, at three months, the placebo arm showed approximately 25% of the cohort developed diabetes, about 50% continued to have IFG, and 20% to 30% of the group had their glucose levels returned to normal values.
Based on the 1997 and 2003 IFG definitions, the odds of developing coronary heart disease (CHD) among women with IFG in the 110 to 125 mg/dl (6.1 to 6.9 mmol/l) range approach the risk conferred by having diabetes. The 1997 IFG definition was associated with a statistically significant increased odds of developing cardiovascular disease (CVD) among women, whereas no increased odds were observed in men for either IFG definition. For diabetes, the 1997 IFG definition is associated with a greater risk of developing diabetes compared with the 2003 IFG definition. In a study conducted by Levitsky et al, women with FPG 110 to 125 mg/dl (6.1 to 6.9 mmol/l) are at significantly increased risk of both CHD and CVD.
15
According to Levitsky et al, there are conflicting data regarding the effect of impaired fasting glucose on cardiovascular risk. Several studies have found that the 1997 IFG definition is associated with significantly increased risk for CVD, while some have shown no significantly increased risk. To date, very few studies exist which have evaluated the 2003 IFG cut-point and its ability to predict CVD, and none have demonstrated an increased risk.
15
Data from the Heart and Estrogen/Progestin Replacement Study enrolled women with known coronary disease based on their fasting glucose status. The study followed them for CVD events, stroke, transient ischemic attacks and congestive heart failure hospitalization for an average of 6.8 years.
16 Kanaya et al reviewed this data and found that women with FPG 100 to 125 mg/dl (5.6 to 6.9 mmol/l) were at no increased risk for any end point as compared with women with normal levels of fasting glucose.
16
Similarly, Levitzky et al found that women categorized by the 2003 IFG definition did not have a statistically significant increased risk of CVD (OR 1.4, 95% CI 0.9 to 2.1). However, they did have significantly increased odds of CHD (OR 1.7, 95% CI 1.0 to 3.0, p = 0.048). This difference could have been due to the differences between the study samples. Only individuals free of CVD at baseline were included in the study by Levitsky et al. Whereas, Kanaya et al used a sample of women with pre-existing CVD, and followed their participants for new events.
Finally, a recent study by Kim et al examined CVD risk factor prevalence and prevalent CVD events among individuals based on the 1997 and the 2003 IFG definition. The study found that the 2003 definition was not associated with an elevated level of CVD risk factors or CVD as compared to the 1997 definition.
17
Several of these studies have found that women had greater odds of CHD and CVD as compared with men. However, men have greater absolute event rates for cardiovascular disease. A recent meta-analysis that included approximately 33,000 women and 172,000 men, examined the potential of IFG as a risk factor for CVD. Once again, results demonstrated that the risk of CVD events was markedly greater in cohorts that included women.
18
Current ADA 2010 guidelines for prediabetes patients suggest that testing to detect prediabetes in asymptomatic people should be considered in adults of any age who are overweight or obese (BMI >25 kg/m
2) and who have one or more additional risk factors for diabetes.
19 In those without these risk factors, testing should begin at 45 years of age. If tests are normal, repeat testing should be carried out at least at three-year intervals. Many experts feel that a two-hour OGTT (75-g glucose load) probably better defines the risk for diabetes than FPG.
The DIAD study is a randomized controlled trial evaluating the role of cardiovascular screening in asymptomatic diabetes patients.
20 This trial enrolled 1,123 type 2 diabetic patients without symptoms of coronary artery disease into two groups. The first group was screened with a myocardial perfusion scan and the second group was not screened. And, 4.8 years later, the cumulative cardiac event rate was 2.7% in the screened group and 3.0% (P <0.73) in the unscreened group. Hence, in asymptomatic patients with prediabetes, it becomes even more difficult to recommend cardiovascular screening because of even lower cardiac event rates.
Prediabetes diagnosis can be made by:
There continues to be the issue of conflicting data regarding the effect of impaired fasting glucose on cardiovascular risk. However, there are good data to suggest that risk of CVD in women may occur at lower glucose thresholds as compared with men. At the same time, it is also important to understand that men have higher CVD event rates as compared to women. This raises an important question whether there should be a lower glycemic threshold to diagnose IFG or diabetes in women. Finally, diagnosing individuals with IFG and IGT can result in aggressive lifestyle and CVD risk factor modification, which in turn may result in better outcomes.