Treatment of Prediabetes

Prediabetes refers to the subclinical states during which glucose levels are too high to be considered normal but not high enough to meet the diagnostic criteria for type 2 diabetes.[1] Prediabetes encompasses both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG). IGT is diagnosed through the use of a 2-hour, 75 g glucose tolerance test, and IFG is diagnosed by testing fasting plasma glucose levels. Diagnostic criteria for IFG and IGT appear in Table 1.

Table 1. American Diabetes Association’s diagnostic criteria for IFG and IGT[2]

Diabetes is known to have a long preclinical phase of approximately 10 to 12 years,[3] during which time metabolic changes may already be causing microvascular and macrovascular complications.[4,5,6] The subclinical phase, known as prediabetes, represents an ideal time to intervene for the prevention of diabetes. Currently, lifestyle treatment is the first line of defense, although research is being conducted to test the safety and efficacy of pharmacologic treatment of prediabetes.

Lifestyle treatments

Four major research trials have demonstrated that type 2 diabetes can be prevented or delayed among people with prediabetes. The Da Qing IGT and Diabetes Study[7] was a large multicenter trial conducted in China in 1986. This study showed that either diet, exercise, or a combination of diet and exercise decreased the incidence of type 2 diabetes among people with impaired glucose tolerance, as compared with a usual-care control group. The diet intervention consisted of reduced-calorie meals (25-30 kcal per kg of body weight), with approximately one half to two thirds of caloric intake coming from carbohydrates. The exercise group was encouraged to increase their leisure physical activity. The combined intervention simply received both the dietary and the exercise intervention. 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.

Similar results were obtained in the Malmo study.[8] Among people with impaired glucose tolerance, even a modest weight loss of approximately 2% to 4% of body weight was associated with improvement in glucose tolerance, with approximately 50% of participants in the lifestyle intervention condition returning to normoglycemia. Finnish Diabetes Prevention Study[9]demonstrated that overweight participants with IGT who participated in an intensive lifestyle intervention reduced their risk of type 2 diabetes by 58%.

The results of these 3 studies were replicated in the Diabetes Prevention Program, a large multicenter study conducted in the US.[6] 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. At 6-month follow-up, 50% of the lifestyle participants had met their dietary goals and 75% had met their activity goals. In spite of the less-than-perfect adherence, participants in the lifestyle condition group demonstrated a 58% reduction in type 2 diabetes, as compared with the group receiving placebo.

Pharmacologic therapy

Although no pharmacologic therapies are currently approved for the treatment of prediabetes, several different classes of glucose-lowering medications have been investigated as potential therapeutic options, including biguanides, á-glucosidase inhibitors, and thiazolidinediones (TZDs).

In addition to the demonstrated lifestyle effects, the DPP study also showed that metformin 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 greater than 35 kg/m[2,6]

There is some evidence to suggest that á-glucosidase inhibitors are also beneficial for the treatment of prediabetes and prevention of type 2 diabetes. In a randomized trial comparing the effects of the á-glucosidase inhibitor acarbose with placebo in patients with IGT, 32% of the acarbose-treated patients developed diabetes, as compared with 42% of the placebo patients. Further, patients treated with acarbose were significantly more likely to return to normal glucose tolerance than were placebo patients.[10]

The third class of medications that may be beneficial for people with prediabetes is the TZDs. One study demonstrated that the TZD troglitazone (no longer available due to the occurrence of adverse liver effects) was an effective way to reduce the incidence of type 2 diabetes among high-risk women with a history of gestational diabetes.[11] Incidence of type 2 diabetes in the placebo group was 12.1% as compared with 5.4% in the troglitazone group. A small preliminary study showed similar effectiveness using rosiglitazone.[12]

In cardiovascular studies, the incidence of diabetes was shown to be lowered by the ACE inhibitor ramipril (3.6% incidence as compared with 5.4% in the placebo group).[13] Pravastatin also has been associated with a reduction in diabetes incidence.[14]

References

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004;27 (suppl 1):S5-S10.
2. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2004;27(suppl 1):S15-S35.
3. Harris R, Donahue K, Rathore SS, Frame P, Woolf SH. Screening adults for type 2 diabetes: a review of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2003;138:215-234.
4. Wang WQ, Ip TP, Lam KS. Changing prevalence of retinopathy in newly diagnosed non-insulin-dependent diabetes mellitus patients in Hong Kong. Diabetes Res Clin Pract.1998; 39:185-191.
5. Klein R, Klein BEK, Moss SE. Prevalence of microalbuminuria in older-onset diabetes. Diabetes Care. 1993; 16:1325-1330.
6. Eastman RC. Neuropathy in diabetes. National Diabetes Data Group, eds. In: Diabetes in America. 2nd ed. Bethesda, Md: National Institutes of Health, National Institutes of Diabetes and Digestive and Kidney Diseases;1996:339-348.
7. 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.
8. Erikson KF, Lindgarde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia. 1991;34:891-898.
9. 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:S108-S113.
10. Chiasson LJ, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M for the STOP-NIDDM Trial Research Group. Acarbose for the prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet. 2002;359:2072-2077.
11. Buchanan TA, Xiang AH, Peters, et al. Preservation of pancreatic â-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:2796-2803.
12. Bennett SMA, Agrawal A, Elasha, et al. Rosiglitazone improves insulin sensitivity, glucose tolerance and ambulatory blood pressure in subjects with impaired glucose tolerance. Diabetic Med. 2004;21:415-422.
13. Yusef S, Gertstein H, Hoogwerf B, et al. Ramipril and the development of diabetes. JAMA. 2001;286:1882-1885.
14. Freeman DJ, Norie J, Sattar, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103:357-362.