Search:
Home | Register or Login | Contact Us
 
  Screening &
Diagnosis Home
Prediabetic Conditions
  Type 1 Diabetes
  Type 2 Diabetes
  Pediatric Diabetes
  Gestational Diabetes
  Macrovascular Complications
  Microvascular Complications
  Diagnostic Tools and Techniques
 

Before Type 2 Diabetes: Screening, Diagnosis, and Treatment of Prediabetic Conditions

More than 16 million people in the United States are afflicted with type 2 diabetes, a chronic, degenerative disease that negatively affects life expectancy and quality of life.[1] The disease also imposes significant treatment obstacles and healthcare cost burdens.[2,3] The contemporary US lifestyle, which fosters obesity and other risk factors for prediabetes and metabolic syndrome (disease precursors), is closely correlated with type 2 diabetes.[4]

Prediabetes

Prediabetes, also referred to as impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG) (Table 1), is a major risk factor for the development of type 2 diabetes (Table 2).[5] Individuals with prediabetes and type 2 diabetes are also at increased risk for the development of cardiovascular disease.[6,7] It is estimated that nearly 12 million overweight individuals aged 45 to 74 years have prediabetes.[8] The predicted cumulative 5- to 6-year incidence of development of type 2 diabetes for patients with either IGT or IFG is 20% to 34%.[9] It is also estimated that nearly 60% of patients with type 2 diabetes had prediabetes at least 5 years prior to diagnosis.[10] The object of prediabetes treatment is to prevent or delay the onset of type 2 diabetes.

Table 1. American Diabetes Association's classification of prediabetes[11,12]

IFG = Fasting plasma glucose (FPG) 100 mg/dL (5.6 mmol/L) to 125 mg/dL (6.9 mmol/L)

IGT = 2-h plasma glucose 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L)

Table 2. Risk factors for type 2 diabetes mellitus[12,13]

Modifiable Risk Factors

Unmodifiable Risk Factors

Overweight (BMI ≥25 kg/m[2])

Age ≥45 years

Habitual physical inactivity

First-degree relative with diabetes

Previously-identified prediabetes (IGT or IFG)

Ethnicity (African American, Native American, Asian American, or Pacific Islander)

Hypertension (BP ≥140/90 mmHg)

History of gestational diabetes or delivery of a baby weighing >9 lbs

HDL ≤35 mg/dL (0.90 mmol/L)

History of polycystic ovary syndrome (PCOS)

Serum triglycerides ≥250 mg/dL (2.82 mmol/L)

History of vascular disease

Screening and diagnosis

The ADA recommends diabetes screening for men and women who are ≥45 years of age, particularly those with BMI ≥25 kg/m², in order to identify prediabetes patients.[9] Patients with either IGT or IFG should be screened every 1 to 2 years to check for development of type 2 diabetes; those with normal values should be screened again in 3 years.[14] A recent clinical study evaluated the effectiveness, costs, and efficiency of 5 strategies to identify people with prediabetes based on a one-time screening of the US population. Results are depicted in Table 3. Overall, hemoglobin A1C (A1C) testing was the most costly, followed by the oral glucose tolerance test (OGTT) and FPG testing. Capillary blood glucose (CBG) screening produced the lowest cost. Currently, the "gold standards" for defining prediabetes are FPG and OGTT.[14]

Table 3. Analysis of screening methods [14]

Identification Test

All Individuals Age 45-74 Years

Individuals Age 45-74 Years and BMI ≥25 kg/m²

Cost Per Case Identified (All Individuals) (US $/case)

Cases Identified (%)

Sensitivity (%)

Specificity (%)

Sensitivity (%)

Specificity (%)

2-h OGTT with cutoff value ≥140 mg/dL in the testing all with OGTT strategy

100

100

100

100

299

50

FPG test with cutoff value ≥110 mg/dL in the testing all with OGTT strategy

100

100

100

100

319

63

FPG test with cutoff value ≥95 mg/dL in the FPG testing strategy

87

47

91

37

    

A1C with cutoff values of ≥5.0%

91

19

92

17

332

46

CBG test with cutoff value of ≥100 mg/dL

70

67

70

67

247

35

Risk assessment questionnaire

69

54

69

54

263

35


Treatment

Treatment for prediabetes focuses on lifestyle interventions, as they have proven to be more effective than medications, do not cause any unwanted side effects, and confer additional benefits over and above the prevention or delay of type 2 diabetes, such as weight reduction and reduction of cardiovascular risk.[15,16] Although there are currently no approved pharmacologic treatments, research has investigated the efficacy of several glucose-lowering agents for the treatment of prediabetes.

Lifestyle treatments

Four research studies have demonstrated that type 2 diabetes can be prevented or delayed among people with prediabetes. The Malmo feasibility study showed that 50% of people with IGT who received a lifestyle intervention returned to normoglycemia. The Da Qing IGT and Diabetes Study, a large multicenter trial conducted in China in 1986, showed that either diet, exercise, or a combination of diet and exercise decreased the incidence of type 2 diabetes among people with IGT, as compared with a control group. The results demonstrated that the incidence of type 2 diabetes at follow-up was 43.8% for the diet group, 41.1% for the exercise group, and 46% for the combined group, as compared with an incidence of 67.7% in the control group.[17]

Similar findings were observed in the Finnish Diabetes Prevention (FDP) Study, which found that overweight participants with IGT who participated in intensive lifestyle intervention reduced their risk of type 2 diabetes by 58%. The lifestyle intervention consisted of individualized counseling designed to help participants lose weight, decrease dietary fat intake, and increase dietary fiber intake and physical activity.[18]

The results of these studies were replicated in the Diabetes Prevention Program (DPP), a large multicenter study conducted in the United States.[15] People with IGT or IFG were randomized either to receive a placebo, 850 mg of metformin, or lifestyle intervention. The lifestyle intervention consisted of a healthy low-fat diet and at least 150 minutes of physical activity (eg, brisk walking) per week. The incidence of diabetes was 58% lower in the lifestyle-intervention group and 31% lower in the metformin group than in the placebo group.

Pharmacologic treatments

Three different classes of glucose-lowering medications have been shown to be effective for the treatment of prediabetes and the prevention of type 2 diabetes. These classes include biguanides, α-glucosidase inhibitors, and thiazolidinediones (TZDs). Preliminary evidence suggests that statins and ACE inhibitors may also have beneficial effects for people with prediabetes.

Metformin, an insulin sensitizer that is not related to glucose-lowering medications, can reduce the likelihood of developing type 2 diabetes among people with IGT or IFG by 31%. The effectiveness of metformin was greater among younger people and people with a body mass index (BMI) of >35 kg/m².[15]

The ADA treatment of choice for patients with prediabetes is lifestyle modification consistent with a 5% to 10% weight reduction and increased physical activity (30 minutes per day, most days of week). At this time, the ADA does not recommend drug therapy for initial prevention of prediabetes based on the limited efficacy of treatment with oral agents versus lifestyle modifications, the potential for adverse drug reactions, the lack of data showing a reduction in the microvascular complications of diabetes in this patient population, and insufficient assessment of cost effectiveness of drug treatment.[9] More clinical studies are needed to determine the role of drug therapy (usually reserved for patients with clinically diagnosed diabetes) with lifestyle modifications to assess long-term safety, cost, and their potential to reduce cardiovascular risk. Several studies are currently underway to help provide more information regarding lifestyle modifications and drug therapy limiting progression from IGT to diabetes.[15,19-21]

Metabolic syndrome

Many individuals with prediabetes and diabetes have a constellation of risk factors for the development of cardiovascular disease now known as the metabolic syndrome. The most recent definition adapted from the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) includes the following [22]:

  • Abdominal obesity
  • Atherogenic dyslipidemia
  • Raised blood pressure
  • Insulin resistance with or without glucose intolerance
  • Proinflammatory state
  • Prothrombotic state

The diagnostic criteria proposed by the NCEP is illustrated in Table 4. It is estimated that more than 20% of adults have metabolic syndrome.[23] The metabolic syndrome can result from increased glucose intolerance and decreased insulin sensitivity, which is thought to precede the development of the metabolic syndrome.[24] The prevalence of metabolic syndrome appears to increase with increasing glucose intolerance. Insulin resistance subsequently leads to elevations in triglyceride and glucose levels and systolic and diastolic blood pressures and to reduced HDL cholesterol levels.[25] Furthermore, all 5 metabolic syndrome risk determinants are established cardiovascular risk factors which correlate with a 3-fold increased risk in coronary artery disease and stroke.[26,27]

Table 4. Clinical identification of the metabolic syndrome[28]

  • Abdominal obesity (waist circumference):
    • >102 cm (>40 in) in men
    • >88 cm (>35 in) in women
  • Blood pressure ≥130/≥85 mm Hg
  • Triglycerides ≥150 mg/dL
  • HDL cholesterol
    • <40 mg/dL in men
    • <50 mg/dL in women
  • Fasting plasma glucose ≥110 mg/dL

Metabolic syndrome = presence of ≥3 risk determinants

Screening and diagnosis

The evaluation of patients with 2 or more indications of metabolic syndrome should include measurement of vital signs and body weight, measurement of waist circumference, measurement of fasting blood glucose, and a complete lipid profile. Increased weight loss has a positive impact on all components of the metabolic syndrome. The DDP and FDP studies found that a mean weight loss of 7% reduces the risk of developing type 2 diabetes by 58%.[15,18] Thus, weight loss can prevent prediabetes from developing into type 2 diabetes, as well as aid in the prevention of metabolic syndrome.

Treatment

First-line therapy for treating metabolic syndrome is lifestyle modification that targets the root causes by reducing weight and obesity, improving the amount of physical activity, and modifying the diet.[29] Overweight and obesity are defined as body mass indexes of 25 to 29.9 kg/m² and greater than 30 kg/m², respectively.[30,31] Abdominal obesity apart from general obesity presents a particular risk factor for metabolic syndrome (see Table 4).[22] Through behavior modification (increased physical activity and dietary modification), patients should expect to reduce their weight by 5% to 13% over 6 to 12 months.[30]

Dietary modification also plays an important role in the treatment of metabolic syndrome. Dietary recommendations are the same as those for managing diabetes. Carbohydrate intake should include whole grains, fruits, vegetables, and low-fat milk. The total amount of carbohydrate consumed, rather than the type or source of the carbohydrate, determines the glycemic effect; sucrose does not increase glycemia any more than isocaloric amounts of starch. Saturated fats should be reduced.[32]

A second treatment approach addresses the metabolic risk factors-- insulin resistance, dyslipidemia, hypertension, and prothrombotic state—individually through nonpharmacologic and pharmacologic therapies.[22]

Insulin resistance

Insulin resistance is believed to be the main factor of metabolic syndrome, which is why metabolic syndrome is sometimes referred to as the insulin resistance syndrome.[29] Weight loss and increased physical activity lower insulin resistance.[33,34] Diets with a lower glycemic load and increased dietary fiber are also associated with lower insulin resistance. If insulin resistance does not improve with lifestyle changes, it can be treated with pharmacotherapy. Drugs commonly used to treat insulin resistance include metformin, pioglitazone and rosiglitazone.

Dyslipidemia

Dyslipidemia often responds to lifestyle changes. If NCEP ATP III goals for LDL cholesterol (the primary target of lipid-lowering therapy) cannot be reached by using diet and exercise, drug alternatives may be used. Statins and fibrates are commonly prescribed for dyslipidemia. Clinical trials have shown the efficacy of various statin medications, such as lovastatin, atorvastatin, pravastatin, fluvastatin, and simvastatin, in lowering LDL cholesterol and reducing the risk of coronary heart disease (CHD). No clinical trials have conclusively shown the benefit of one statin over another.[35] The fibrate medications gemfibrozil and fenofibrate have also been shown to be effective in improving dyslipidemia and are sometimes used in combination with statins.[18]

Hypertension

Hypertension that does not respond to weight loss and dietary modification can be treated with antihypertensive agents. β-blockers and diuretics are appropriate at low doses. Some clinical trials have suggested that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may offer advantages over other medications for patients with diabetes, but this has not been proven.

Prothrombosis

Elevated blood serum levels of fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and other coagulation factors indicate a prothrombotic state, but these blood tests are not routine. Aspirin therapy can reduce the risk for thrombotic events. The American Heart Association recommends aspirin therapy for patients whose 10-year risk for CHD is ≥10%, and this guideline would apply to patients with metabolic syndrome. Treatment of insulin resistance with thiazolidinediones improves PAI-1 and fibrinolytic activity.[36,37]

Inflammatory markers

Markers of inflammation accompany metabolic syndrome. Such markers include elevated plasma C-reactive protein and elevated white blood cell counts and metalloproteinase-9.[38] Thiazolidinedione treatment improves the proinflammatory state in the patient with metabolic syndrome.[39]

References

  1. Centers for Disease Control and Prevalence. Diabetes Surveillance, 1997. Geiss LS, ed. Atlanta, Ga; US Department of Health and Human Services; 1997.
  2. Hogan P, Dall T, Nikolov P. American Diabetes Association. Economic costs of diabetes in the US in 2002. Diabetes Care. 2003;26:917-932.
  3. Knowler WC, Narayan KM, Hanson RL, et al. Preventing non-insulin-dependent diabetes. Diabetes. 1995;44:483-488.
  4. Narayan KM, Bowman BA, Engelgau ME. Prevention of type 2 diabetes. BMJ. 2001;323:63-64.
  5. Irons BK, Mazzolini TA, Greene RS. Delaying the onset of type 2 diabetes mellitus in patients with prediabetes. Pharmacotherapy. 2004;24:362-371.
  6. DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;161:397-405.
  7. Smith NL, Barzilay JI, Shaffer D, et al. Fasting and 2-hour postchallenge serum glucose measures and risk of incident cardiovascular events in the elderly: the Cardiovascular Health Study. Arch Intern Med. 2002;162:209-216.
  8. Benjamin SM, Valdez R, Geiss LS, Rolka DB, Narayan KM. Estimated number of adults with prediabetes in the US in 2000: opportunities for prevention. Diabetes Care. 2003;26:645-649.
  9. American Diabetes Association; National Institute of Diabetes, Digestive and Kidney Disease. The prevention or delay of type 2 diabetes. Diabetes Care. 2002;25:742-749.
  10. Unwin N, Shaw J, Zimmet P, Alberti K. Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabet Med. 2002;19:708-723.
  11. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004;27(suppl 1):S15-S35.
  12. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36.
  13. American Diabetes Association. Screening for type 2 diabetes. Diabetes Care. 2003;26(suppl 1):S21-S24.
  14. Zhang P, Engelgau MM, Valdez R, Benjamin SM, Cadwell B, Narayan KM. Costs of screening for prediabetes among US adults: a comparison of different screening strategies. Diabetes Care. 2003;26:2536-2542.
  15. Knowler WC, Barrett-Connor E, Fowler SE, et al, and the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New Engl J Med. 2002;346:393-403.
  16. Dunn AL, Marcus BH, Kampert JB, Garcia ME, Kohl HW III, Blair SN. Reduction in cardiovascular disease risk factors: 6-month results from Project Active. Prev Med. 1997;26:883-892.
  17. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537-544.
  18. Lindstrom J, Eriksson JG, Valle TT, et al. Prevention of diabetes mellitus in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study: results from a randomized clinical trial. J Am Soc Nephrol. 2003;14(7 suppl 2):S108-S113.
  19. Tuomilehto J, Lindstrom J, Eriksson JG, et al, and the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.
  20. Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic β-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796-2803.
  21. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Lansko M; STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077.
  22. US Department of Health and Human Services. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. National Cholesterol Education Program National Heart, Lung, and Blood Institute National Institutes of Health. NIH Publication No. 02-5215. September 2002. II-26.
  23. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287:356-359.
  24. Kendall DM, Harmel AP. The metabolic syndrome, type 2 diabetes, and cardiovascular disease: understanding the role of insulin resistance. Am J Manag Care. 2002;8(20 suppl):S635-S653.
  25. Palaniappan L, Carnethon MR, Wang Y; and the Insulin Resistance Atherosclerosis Study. Predictor of the incident metabolic syndrome in adults. Diabetes Care. 2004;27:788-793.
  26. Alexander CM, Landsman PB, Teutsch SM, Haffner SM; the Third National Health and Nutrition Examination Survey (NHANES III); and the National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214.
  27. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683-689.
  28. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
  29. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; American Heart Association; National Heart, Lung, and Blood Institute. Definition of metabolic syndrome. Report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-438.
  30. National Heart, Lung, and Blood Institute in cooperation with the National Institute of Diabetes and Digestive and Kidney Disease. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Bethesda, Md: National Institutes of Health, National Heart, Lung, and Blood Institute; 1998. NIH publication 98-4083.
  31. National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults - The Evidence Report. Obes Res. 1998;6(suppl 2):51S-209S.
  32. American Diabetes Association Task Force for Writing Nutrition Principles and Recommendations for the Management of Diabetes and Related Complications. American Diabetes Association position statement: evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. J Am Diet Assoc. 2002;102:109-118.
  33. Ahmad F, Considine RV, Bauer TL, Ohannesian JP, Marco CC, Goldstein BJ. Improved sensitivity to insulin in obese subjects following weight loss is accompanied by reduced protein-tyrosine phosphatases in adipose tissue. Metabolism. 1997;46:1140-1145.
  34. Perseghin G, Price TB, Petersen KF, et al. Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med. 1996;335:1357-1362.
  35. Snow V, Aronson MD, Hornbake ER, Mottur-Pilson C, Weiss KB; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Lipid control in the management of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2004;140:644-649.
  36. Kruszynska YT, Yu JG, Olefsky JM, Sobel BE. Effects of troglitazone on blood concentrations of plasminogen activator inhibitor 1 in patients with type 2 diabetes and in lean and obese normal subjects. Diabetes. 2000;49:633-639.
  37. Harte AL, McTernan PG, McTernan CL, Smith SA, Barnett AH, Kumar S. Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes. Diabetes Obes Metab. 2003;5:302-310.
  38. Lebovitz HE, Banerji MA. Treatment of insulin resistance in diabetes mellitus. Eur J Pharmacol. 2004;490:135-146.
  39. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002;106:679-684.
 



About Us | Terms of Use | Privacy Statement | Disclaimer