to DM compared to placebo [83]. Several thiazolidinediones also have proven efficacy in reducing the progression to DM, including pioglitazone, rosiglitazone, and troglitazone [84–86]. Additionally, combined hormone replacement therapy in post‐menopausal women, glipizide, valsartan, orlistat, and acarbose also significantly reduced the progression to DM compared to placebo [87–92]. Interestingly, during the Study to Prevent Non‐Insulin Dependent Diabetes Mellitus (STOP‐NIDDM), acarbose was associated with a 49% relative risk reduction in cardiovascular events compared to placebo with a HR 0.51 (95% CI 0.28–0.95). However, the methodology of STOP‐NIDDM has been heavily criticized and the validity of the results has been questioned [93]. Many pharmacologic therapies have also been studied and shown to be ineffective in preventing progression to DM, including vitamin D, nateglinide, glimepiride, and ramipril [94–97].
Bariatric surgery for the prevention or delay of diabetes mellitus
A Swedish study enrolled a large cohort of adult nondiabetic subjects who had already chosen to undergo various bariatric surgeries including banding (19%), vertical banded gastroplasty (69%), or gastric bypass (12%), and matched them with a nonrandomized control group [98]. At the time of enrollment, 17.2% of the control group had IFG, compared to 16% of the surgical group. After a median follow‐up time of 10 years, bariatric surgery compared with usual care reduced progression to DM by 87% among subjects with IFG. Another study reported that 98.6% of subjects with prediabetic range dysglycemia had normal FPG following gastric bypass [99].
Exercise and diet for the prevention or delay of diabetes mellitus
A systematic review and meta‐analysis included 28 studies with 1 261 991 subjects and investigated the role of physical activity in reducing progression to DM [100]. Overall, for those who achieved 11.25 metabolic equivalent of task (MET) hours/week (equivalent to 150 minutes/week of moderate activity) there was a risk reduction of 26% for DM. Further risk reductions occurred at greater MET hours/week. The Health Professionals Follow‐up Study showed that engaging in weight training or aerobic exercise for at least 150 minutes/week was independently associated with a lower risk of DM of 34% and 52%, respectively [101]. The greatest reduction in DM risk was seen in men who engaged in both aerobic exercise and weight training for at least 150 minutes/week, with a risk reduction of 59%.
The Prevención con Dieta Mediterránea (PREDIMED) study enrolled older adult subjects at high risk for but without baseline CVD and randomized participants to either a Mediterranean diet supplemented with extra‐virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet based on general advice to reduce fat intake [102]. Compared to the control group, the Mediterranean diet supplemented with extra‐virgin olive oil group had significantly lower progression to DM with a HR of 0.60 (95% CI 0.54–0.85). The beneficial effect seen in this study was thought to be due to dietary composition itself and not attributed to calorie restriction, increased physical activity, or weight loss.
American diabetes association 2020 guideline recommendations for the management of prediabetes
The 2020 ADA guidelines recommend that patients with prediabetes participate in an intensive behavioral lifestyle intervention program modeled on the DPP to achieve and maintain 7% weight loss and to achieve ≥ 150 minutes/week of moderate intensity physical activity (such as brisk walking) [103]. Additionally, the ADA recommends that a variety of eating patterns are acceptable for patients with prediabetes including the Mediterranean diet and a low‐calorie, low‐fat diet. Regarding pharmacologic therapy, the 2020 ADA guidelines state that metformin for prevention of DM should be considered in patients with prediabetes, especially those with BMI ≥ 35 kg/m2, those aged < 60 years, and women with prior GDM.
Conclusion
In summary, patients with prediabetes have abnormal glucose regulation mediated by impaired insulin secretion and reduced insulin action, as well as an increased risk of progression to DM [18, 25, 26]. Many clinicians screen for diabetes and prediabetes using the combination of FPG and HbA1c. However, even when used together, the combined sensitivity for diagnosing DM and prediabetes is poor [41]. Therefore, omission of a 75‐g OGTT results in both misclassification and under‐diagnosis of DM and prediabetes. The following question then arises: are there clinical consequences to misclassifying diabetes as only prediabetes or prediabetes as normal glucose metabolism?
We conclude that the answer is yes. There is a clear association of increasing microvascular complications with rising glucose concentrations, and patients with prediabetes have an increased prevalence of retinopathy, nephropathy, and neuropathy compared to individuals with normal glucose metabolism [13, 14, 55, 57,59–61, 63,104–106]. There is also an increased prevalence of CVD, cardiovascular mortality, and all‐cause mortality in patients with prediabetes compared to those with normal glucose metabolism [66–68, 70].
Therefore, recognition and treatment of prediabetes is essential to minimize morbidity and mortality. Intensive lifestyle changes emphasizing weight loss and physical activity have been shown to prevent or delay progression to DM, potentially decrease microvascular complications, potentially reduce macrovascular complications, improve comorbidities, improve quality of life, reduce medical costs, and decrease mortality [1875–80]. In addition to lifestyle changes, numerous medications are also effective in preventing or delaying progression to DM including metformin, glipizide, liraglutide, insulin glargine, several thiazolidinediones, orlistat, acarbose, valsartan, and estrogen/progestin [18,82–85,87–92, 107].
The totality of available evidence suggests that prediabetes is not only a risk factor, it is in fact a disease. Perhaps the term “prediabetes” should be changed to “early diabetes” and managed as such clinically.
References
1 1. American Diabetes Association, 2. Classification and diagnosis of diabetes: standards of medical care in diabetes – 2020. Diabetes Care. 2020; 43(Suppl 1):S14–S31.
2 2. World Health Organization, Global Report on Diabetes. 2016.
3 3. Diabetes Mellitus. Report of a WHO expert committee. World Health Organ Tech Rep Ser. 1965; 310:1–44.
4 4. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997; 20(7):1183–1197.
5 5. Genuth S et al. Follow‐up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003; 26(11):3160–3167.
6 6. American Diabetes Association, Standards of medical care in diabetes – 2010. Diabetes Care. 2010; 33(Suppl 1):S11–61.
7 7. Bennett PH et al. Epidemiologic studies of diabetes in the Pima Indians. Recent Prog Horm Res. 1976; 32:333–376.
8 8. Zimmet P and Whitehouse S. Bimodality of fasting and two‐hour glucose tolerance distributions in a Micronesian population. Diabetes. 1978; 27(8):793–800.
9 9. Rosenthal M et al. Evidence of bimodality of two hour plasma glucose concentrations in Mexican Americans: results from the San Antonio Heart study. J Chronic Dis. 1985; 38(1):5–16.
10 10. Omar MA et al. South African Indians show a high prevalence of NIDDM and bimodality in plasma glucose distribution patterns. Diabetes Care. 1994; 17(1):70–73.
11 11. Fan J et al. Bimodality of 2‐h plasma glucose distributions in whites: the Rancho Bernardo study. Diabetes Care. 2005; 28(6):1451–1456.
12 12. McCance DR et al. Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes. BMJ. 1994; 308(6940):1323–1328.
13 13. Davidson MB et al. Relationship between fasting plasma glucose and glycosylated hemoglobin: potential for false‐positive diagnoses of type 2 diabetes using new diagnostic criteria. JAMA. 1999; 281(13):1203–1210.
14 14. Engelgau MM et al. Comparison of fasting and 2‐hour glucose and HbA1c levels for diagnosing diabetes. Diagnostic criteria and performance revisited.