Acarbose

Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002; 359:2072-7.

* BACKGROUND Patients who develop type 2 diabetes initially pass through a state of impaired glucose tolerance. Therapies that reduce resistance to insulin or protect [beta] cells could prevent or delay the progression to diabetes.

* POPULATION STUDIED This multinational study was conducted in Canada, Israel, and Western Europe. Investigators recruited high-risk patients through newspaper advertising. They screened 14,742 individuals with a body mass index (BMI) between 25 and 40 kg/[m.sup.2] (mean 31.0 kg/[m.sup.2]) with a 2-hour glucose tolerance test. Eligible subjects had impaired glucose tolerance, defined as a 2-hour plasma glucose concentration of [greater than or equal to] 140 mg/dL (7.8 mmol/L) and <200 mg/dL (11.1 mmol/L). Investigators excluded subjects who had a serum creatinine concentration [greater than or equal to] 1.5 mg/dL, or who had taken thiazide diuretics, [beta]-blockers or nicotinic acid within the past 3 months. (1) Ninety-seven percent of the 1429 randomized patients were white and 48% were men. The average age was 54.3 years.

* STUDY DESIGN AND VALIDITY This was a randomized, double blind, placebo-controlled trial. Randomization was done at each center in a sequential manner in blocks of 4 and 6 patients, using a centrally generated random allocation sequence and numbered drug containers. Allocation was appropriately concealed. Treatment groups were comparable at baseline. To minimize gastrointestinal side effects, patients randomized to acarbose were started at 50 mg/day and gradually increased to a maximum of 100 mg 3 times a day with meals or to the maximum tolerated dose. The mean daily dose was 197 mg. All patients met with a dietitian before randomization and then yearly, were instructed in a weight reduction or maintenance program, and were encouraged to exercise. Patients saw a nurse every 3 months for a pill count and fasting plasma glucose measurement. Patients with abnormal fasting plasma glucose levels had a 2-hour oral glucose tolerance test, and all patients had a yearly glucose tolerance test. Patients were followed for a mean of 3.3 years. Ninety-six percent of patients were accounted for at the end of the trial. All patients at the end of the trial who were not diagnosed with diabetes were placed on placebo and followed for an additional 3 months. An intention-to-treat analysis was performed using appropriate statistical methods.

This well-done trial had no threats to internal validity. The homogeneity of the study population could limit generalizability, as ethnic groups more frequently encountered in the United States, for example African Americans or Hispanic Americans, might have dietary habits that could affect the tolerability, and thus the effectiveness, of acarbose.

* OUTCOMES MEASURED The primary outcome measured was time to development of type 2 diabetes, defined by a plasma glucose concentration of >200 mg/dL (11.1 mmol/L) after a 2-hour glucose tolerance test.

* RESULT Patients treated with acarbose were less likely to develop type 2 diabetes after 3.3 years (17% vs 26%, numbers needed to treat = 11, P = .0003). The effectiveness of acarbose became apparent at 1 year. More patients taking acarbose dropped out of the trial secondary to gastrointestinal side effects (31% vs 18%, numbers needed to harm = 8, P < .0001). When acarbose was stopped at the end of the study period, more patients who had been treated with acarbose developed diabetes in the next 3 months than did patients who were treated with placebo (15% vs 11%).

RECOMMENDATIONS FOR CLINICAL PRACTICE Treating patients with impaired glucose tolerance with acarbose will delay the onset of type 2 diabetes for at least 3.3 years. It is unclear whether acarbose actually prevents diabetes or just delays its onset, and whether acarbose reduces morbidity or mortality secondary to diabetes. One third of patients who take acarbose will not tolerate the medication, which must probably be continued indefinitely to remain effective. Lifestyle modification, including dietary changes and regular moderate physical activity, should be the first-line therapy to prevent diabetes in patients with impaired glucose tolerance. (2) Acarbose can be used for patients who are not willing or able to change behavior.

REFERENCES

(1.) Chiasson JL, Gomis R, Hanefeld M. Josse RG, Karasik A, Laakso M. The STOP-NIDDM Trial: an international study on the efficacy of an alpha-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Study to Prevent Non-Insulin-Dependent Diabetes Mellitus. Diabetes Cam 1998: 21:1720-5.

(2.) Knowler WC, Barrett-Connor E, Fowler SE, et al Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393-403.

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