Prediabetes: What Is it? Why Is It Important to Identify and Treat?

Diabetes Q&A:

Q: How are glucose intolerance and impaired fasting glucose or “prediabetes” defined?

A: According to the definitions established by the American Diabetes Association (ADA) Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, impaired fasting glucose is defined as fasting plasma glucose levels between 100 mg/dL (5.6 mmol/L) and 125 mg/dL (6.9 mmol/L).¹ Other organizations, including the World Health Organization, define the lower cutoff as 110 mg/dL (6.1 mmol/L).²

Impaired glucose tolerance isdefined as a blood glucose level of 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0 mmol/L) after a 2-hour oral 75-g glucose tolerance test.²

In light of epidemiologic data that show an association of increased hemoglobin A_1c (HbA_1c) levels with heightened risk of diabetes and cardiovascular disease, a category of prediabetes has been defined, which includes patients with HbA_1c values between 5.7% and 6.4%.^3,4

Q: What is the importance of identifying patients with impaired fasting glucose, impaired glucose tolerance, or prediabetes?

A: Although patients in these groups do not have high enough blood glucose levels to meet criteria for diabetes, their above-normal blood glucose values put them at high risk for the development of diabetes in the future.

In addition, impaired glucose tolerance and impaired fasting glucose are independent risk factors for the development of cardiovascular disease, obesity, and lipid abnormalities.²

Q: What is the estimated prevalence of prediabetes/impaired fasting glucose/impaired glucose tolerance in the United States?

A: An estimated fifty-seven million people in the United States have prediabetes.⁵

Q: Are all patients with impaired fasting glucose, impaired glucose tolerance, or prediabetes at the same risk for the development of diabetes in the future?

A: A review of multiple cohort studies revealed that among patients with HbA_1c levels between 5.5% and 6.0% the risk of developing diabetes during the next 5 years is 9% to 25%. Those with an HbA_1c level in the 6.0% to 6.5% range are at even higher risk (25% to 50%) for the development of diabetes during the same 5-year period. Patients with an HbA_1c level in the 6.0% to 6.5% range are 20 times more likely to develop diabetes than those with an HbA_1c level of 5%.⁴

Q: Between fasting plasma glucose and HbA_1c, which one is the most predictive of future diabetes and cardiovascular risk?

A: A community-based study initially prospectively followed a cohort of 11,092 nondiabetic African-American and Caucasian patients who had no history of diabetes or cardiovascular disease. The investigators then retrospectively assayed these patients’ HbA_1c levels during the 5-year follow-up period and concluded that compared to fasting glucose, HbA_1c is a stronger predictor of diabetes, cardiovascular events, and death.⁶

Q: What are the current treatment options and recommendations for patients at risk (impaired fasting glucose, impaired glucose tolerance, prediabetes) for developing diabetes?

A: Nonpharmacologic interventions. According to the ADA, the following steps (grade B recommendations)² should be taken to decrease at-risk patients’ likelihood of developing diabetes:

• Referral to a program that can help the patient achieve a target loss of 7% of body weight. (This results in at least a 58% reduction of progression to diabetes at 3 years with lifestyle modification; up to 43% reduction at 20 years)^.7

• Increasing physical activity to at least 150 minutes per week.

• Follow-up counseling.

• At least annual follow-up with monitoring for the development of overt diabetes.

A Finnish study looked at the effect of a 4-year intervention on the development of overt diabetes in patients at high risk for type 2 diabetes during long-term follow-up. The authors found that the group receiving intensive lifestyle modification focusing on weight reduction, dietary changes, and increased physical activity showed a significant decrease in the development of diabetes compared with controls, who received general lifestyle counseling.⁸

Analysis of 10-year data from the Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) found lifestyle changes and metformin to be cost-effective in preventing diabetes in high-risk adults.⁹

Pharmacologic interventions. A meta-analysis of randomized, controlled trials totaling 11,600 participants showed that the use of oral agents such as thiazolidinediones and α-glucosidase inhibitors more than doubled the odds of achieving normoglycemia in patients with prediabetes (odds ratio 2.33, 95% CI 1.93 - 2.81; odds ratio 2.02, 95%, CI 1.26 - 3.24, respectively). Biguanides and sulfonylureas, on the other hand, did not significantly increase the likelihood of reversing elevated glucose levels to normoglycemia.¹⁰

In one study, 105 patients with impaired glucose tolerance or impaired fasting glucose were treated with pioglitazone with metformin (PM), PM plus exenatide, or lifestyle modification alone. The lifestyle modification group did not show significant improvement in any of the glucose/insulin sensitivity parameters measured at a mean of 8.9 months into follow-up. Both of the groups receiving pharmacologic agents had a significant improvement in their glucose and insulin sensitivity parameters; 14.3% in the PM group and 59.1% in the PM plus exenatide group reverted to normoglycemia, and no patients in either group developed diabetes.¹¹

Not all studies have shown an added benefit for medication therapy, however. A meta-analysis of randomized, controlled trials involving patients with prediabetes revealed that those treated with nonpharmacologic interventions were significantly less likely to progress to overt diabetes than those who received pharmacologic therapy. Among both of the groups, the only decrease in macrovascular endpoints was a trend in reduction of nonfatal stroke.¹²

The latest ADA guidelines and a consensus panel recommend that metformin should be the only drug considered for treating prediabetes, given its relatively safe side-effect profile, low cost, and long-term effectiveness in preventing diabetes.¹³ Metformin should especially be considered in patients with a history of gestational diabetes, obesity (body mass index greater than 35 kg/m²), or progressive hyperglycemia. The consensus panel cautions that other medications may have a washout effect after their use is discontinued.^13,14

Finally, cardiovascular risk factors (dyslipidemia, hypertension, obesity, physical inactivity, pro-coagulative state, and endothelial dysfunction) should be treated as aggressively in persons with prediabetes as in those with diabetes.¹⁵ 

REFERENCES:

1.Genuth S, Alberti KG, Bennett P, et al. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003:26:3160-3167.

2.Standards of Medical Care in Diabetes - 2012. Diabetes Care. 2012;35(S1):S11-S63.

3.American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012;35(suppl 1):S64-S71.

4.Zhang X, Gregg EW, Williamson DF, et al. A1C level and future risk of diabetes: a systematic review. Diabetes Care. 2010;33:1665-1673.

5.Pour OR, Dagogo-Jack S. Prediabetes as a therapeutic target. Clin Chem. 2011;57(2):215-220.

6.Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362:800-811.

7.Li G, Zhang P, Wang J. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet. 2008;371:1783-1789.

8.Lindström J, Peltonen M, Eriksson JG, et al. Improved lifestyle and decreased diabetes risk over 13 years: long-term follow-up of the randomised Finnish Diabetes Prevention Study (DPS). Diabetologia. 2013;56(2):284-293. Epub 2012 Oct 24.

9.Diabetes Prevention Research Study Group. Diabetes The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care. 2012;35(4):723-730.

10.Phung OJ, Baker WL, Tongbram V, Bhardwaj A, Coleman CL. Oral antidiabetic drugs and regression from prediabetes to normoglycemia: a meta-analysis. Ann Pharmacother. 2012;46(4):469-476.

11.Armato J, DeFronzo RA, Abdul-Ghani M, Ruby R. Successful treatment of prediabetes in clinical practice: targeting insulin resistance and ß-cell dysfunction. Endocr Practice. 2012;18(3):342-350.

12.Hopper I, Billah B, Skiba M, Krum H. Prevention of diabetes and reduction in major cardiovascular event s in studies of subjects with prediabetes: meta-analysis of randomized controlled clinical trials. Eur J Cardiovasc Prev Rehabil. 2011;18(6):813-823.

13.DREAM Trial Investigators. Incidence of diabetes following ramipril or rosiglitazone withdrawal. Diabetes Care. 2011;34:1265-1269.

14.Nathan DM, Davidson MB, DeFronzo RA, et al. American Diabetes Association. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007;30:753-759.

15.DeFronzo RA, Abdul-Ghani M. Assessment and treatment of cardiovascular risk in prediabetes: impaired glucose tolerance and impaired fasting glucose. Am J Cardiol. 2011;108(3 suppl):3B-24B.