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SYMPOSIUM |
From the Medical College of Georgia, Augusta.
Address for reprints: L. Michael Prisant, MD, 1120 Fifteenth Street, BI-5082, Hypertension and Clinical Pharmacology, Medical College of Georgia, Augusta, GA 30912.
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ABSTRACT |
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 TOP ABSTRACT PROSPECTIVE TRIALS OF DIABETES...TRIALS SHOWING A REDUCTION...TRIALS IN PROGRESSSUMMARYACKNOWLEDGEMENTSREFERENCES |
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Key Words: Diabetes mellitus • glucose intolerance • prevention • controlled trials • lifestyle • review
The metabolic syndrome is characterized by lipid abnormalities, increased blood pressure, increased waist circumference, a fasting glucose of 110 mg/dL or higher, and accelerated atherosclerosis.2 The prevalence of the metabolic syndrome is less than 10% for men and women ages 20 to 29 and as high as 40% for men and women 60 years or older.3 The prevalence for Caucasian, African American, and Mexican American men is 24.8%, 16.4%, and 28.3%, respectively. For women, the prevalence is 22.8% for Caucasians, 25.7% for African Americans, and 35.6% for Mexican Americans. The metabolic syndrome is associated with an increase in cardiovascular morbidity and mortality and overall mortality.4,5
Glucose intolerance is one component of the metabolic syndrome. All-cause mortality associated with impaired glucose tolerance is 1.96 times higher compared to a normal glucose tolerance.6 Mortality per 1000 person-years is 20.8 for impaired glucose tolerance compared to 40.9 with diabetes mellitus. Thus, impaired glucose tolerance represents an opportunity for intervention to prevent type II diabetes mellitus and avoid the long-term costly complications.7
The American Diabetic Association recommends screening overweight people age 45 or older for impaired glucose tolerance at regular visits.7 A fasting blood glucose or an oral glucose tolerance test can be used to identify these individuals. A fasting blood glucose from 110 to 125 mg/dL identifies patients with impaired fasting glucose, whereas a 2-hour glucose from 140 to 199 mg/dL after a 75-g glucose load identifies an impaired glucose tolerance. Testing should also be performed for adults younger than 45 years who are significantly overweight and have one or more risk factors (a family history of diabetes, low high-density lipoprotein [HDL] cholesterol and high triglycerides, high blood pressure, history of gestational diabetes or an infant birth weight greater than 9 lb, or belonging to a minority group).7
Once either impairment in fasting glucose or tolerance is confirmed, then what treatments are available? Epidemiologic studies suggest that obesity and lack of exercise are important predictors for the development of diabetes among women.8,9 Until recently, only a few studies examined patients with impaired glucose tolerance.10-13 Recent studies over the past 5 years prove that targeting impaired glucose tolerance can prevent or delay the occurrence of diabetes mellitus. In addition, several large studies are in progress that will address the issue of combination drugs in modifying outcome and assess cardiovascular events. The purpose of this article is to address these studies.
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PROSPECTIVE TRIALS OF DIABETES PREVENTION |
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TOPABSTRACTPROSPECTIVE TRIALS OF DIABETES...TRIALS SHOWING A REDUCTION...TRIALS IN PROGRESSSUMMARYACKNOWLEDGEMENTSREFERENCES |
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Treatment was stratified according to body mass index < 25 kg/m2 versus 
25 kg/m2. Follow-up of the subjects occurred at 3-month intervals with urine glucose dipsticks, followed by more testing if it was positive. Every 2 years for 6 years, subjects were tested for the development of diabetes.14 The development of diabetes mellitus was confirmed if the fasting glucose was 140 mg/dL or higher or the 2-hour postprandial glucose was 200 mg/dL or higher. The cumulative incidence of diabetes at 6 years for the 530 subjects who completed the study was 67.7% in the control group, 43.8% in the diet-only group, 41.1% in the exercise-only group, and 46.0% in the combined exercise and diet group. Although there were no differences among the intervention groups, each intervention significantly reduced the rate of diabetes compared to the control group (p < 0.05). The rate of diabetes was higher among obese subjects compared to lean subjects (Figure 1). For instance, the rate of diabetes among lean subjects in the exercise group was 26.3% compared to 51.1% in the overweight group. Among lean subjects, diet treatment alone was not superior to the control group in the rate of diabetes development after 6 years of follow-up.
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Finnish Diabetes Prevention Study
The Finnish Diabetes Prevention Study screened high-risk individuals for the development of type II diabetes.15 Overweight subjects with a body mass index of 25 kg/m2 or greater who were between ages 40 and 65 years were included in the study. Impaired glucose tolerance for enrollment was documented by a 2-hour glucose of 140 to 200 mg/dL after 75 g of oral glucose.
There were 265 subjects randomized to the control group and 257 to the intervention group. The intervention group received individual counseling to reduce weight by 5% or more, to lower total fat intake less than 30% of energy intake, to decrease saturated fat less than 10% of energy intake, to increase fiber intake to 15 g per 1000 kcal or greater, and to exercise at least 30 minutes per day. Oral glucose tolerance tests were performed annually. If the test was positive, then it was confirmed by performing another test. Subjects were followed for a mean duration of 3.2 years.
At the end of year 1, the intervention group had significantly reduced each one of the following parameters compared to the control group: systolic and diastolic blood pressure, triglycerides, 2-hour serum insulin levels, 2-hour plasma glucose, fasting plasma glucose, waist circumference, and weight.15 The fasting serum insulin levels and the total and HDL cholesterol did not change significantly. After 4 years, the cumulative incidence of diabetes was 23% in the control group versus 11% in the intervention group.15
The Fasting Hyperglycemia Study
The Fasting Hyperglycemia Study (FHS) was a 6-year prospective, randomized, placebo-controlled study of 188 subjects with impaired glucose tolerance with two consecutive fasting plasma glucose levels in the range of 5.5 to 7.7 mmol/L.16-18 The goal of this study was to decide whether deterioration in glycemic tolerance toward diabetes could be delayed or prevented using the insulin secretagogue gliclazide or reinforced healthy-living advice. Using a 2-by-2 factorial design, gliclazide 160 mg twice daily or matching placebo was compared to reinforced versus basic healthy-living advice. Basic healthy-living advice included written dietary information and physician counseling for weight loss, if the body mass index exceeded 25 kg/m2, and increased physical activity. The reinforced healthy-living advice included the use of a dietician and a fitness instructor with tailored advice that was reinforced every 3 months.17 After 6 years, the intense lifestyle changes produced marginal benefits but did not delay progression to diabetes.19 There were more cases of overt diabetes in the placebo versus the gliclazide group (10.8% vs. 3.2%, p = 0.047).20 However, there was no difference in the proportion of subjects who were diabetic in the two groups; thus, gliclazide did not delay the progression of diabetes.
Diabetes Prevention Program
The Diabetes Prevention Program studied the effectiveness of lifestyle intervention and metformin in the prevention or retardation of the onset of diabetes at 27 centers.21,22 The study population included men and women age 25 years or older with impaired glucose tolerance, defined by a fasting glucose from 95 to 125 mg/dL and a 2-hour glucose from 140 to 199 mg/dL after a 75-g oral glucose load. Body mass index eligibility was 22 kg/m2 or higher for Asian Americans and 24 kg/m2 or higher for others.
Subjects were randomized to placebo (n = 1082), intense lifestyle modification (n = 1079), metformin 850 mg twice daily (n = 1073), or troglitazone (n = 585). The troglitazone treatment group was stopped in 1998 after troglitazone was withdrawn from the market. The goal of the intensive lifestyle intervention was to lose at least 7% of weight and maintain the weight loss by reducing less than 25% of the calories from fat and the total calorie intake between 1200 and 1800 kcal/day. Subjects were advised to engage in exercise of moderate intensity for 150 minutes per week. An annual oral glucose tolerance test or semiannual fasting glucose was performed to diagnose diabetes. The study population included 55% Caucasian, 20% African American, 16% Hispanic, 5% Indian, and 4% Asian.
The trial was terminated prematurely because of documented efficacy. The lifestyle intervention group achieved a sustained increase in leisure physical activity of 5 MET (metabolic equivalent)-hours per week during the 4 years following randomization.22 Weight loss was greatest among the lifestyle-intervention cohort. The greatest weight loss (6.75 kg) was observed at year 1 but declined to 3.46 kg four years after randomization. Diabetes development occurred significantly less frequently with lifestyle modification compared to metformin or the control group (Figure 2). Metformin was significantly better than placebo. The reduction in diabetes was 58% lower in the lifestyle intervention group and 31% lower in the metformin group.22 Intensive lifestyle intervention could prevent one case of diabetes for 6.9 patients treated for 3 years. Metformin could also prevent one case of diabetes for 13.9 patients treated for 3 years.
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Troglitazone in the Prevention of Diabetes Mellitus
Troglitazone in the Prevention of Diabetes Mellitus (TRIPOD) was a prospective, randomized, placebo-controlled, double-blind study examining Hispanic nondiabetic women with previous gestational diabetes.23,24 The purpose of the study was to determine if troglitazone 400 mg (n = 114) compared to placebo (n = 122) would reduce the incidence of type II diabetes and increase whole-body insulin sensitivity. All subjects were advised to exercise 30 minutes 3 days per week. In addition, dietary advice was provided. Fasting plasma glucose levels were taken every 3 months, and oral glucose tolerance tests were performed annually to determine the development of diabetes. This study was terminated once troglitazone was withdrawn from the market. The annual incidence of diabetes after 30 months was 12.1% in the placebo group and 5.4% in the troglitazone group (p < 0.01).24 The risk reduction of troglitazone was 56% after adjustment for baseline characteristics. Also, a protective effect of troglitazone was suggested because of a delay in the development of diabetes after the drug was stopped.
Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM)
The Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) was a double-blind, placebo-controlled, multicenter trial of 714 subjects.25,26 The purpose was to assess the effectiveness of acarbose, an alpha-glucosidase inhibitor that improves insulin sensitivity and decreases postprandial hyperglycemia, on the progression of impaired glucose tolerance to type II diabetes mellitus. Subjects were between ages 40 and 70 years, had a body mass index of 25 to 40 kg/m2, and were high risk for the development of diabetes. Enrollment required the subjects to have impaired glucose tolerance, which was defined as a 2-hour glucose between 140 and 200 mg/dL after a 75-g glucose load and a fasting plasma glucose between 101 and 140 mg/dL. Subjects were either treated with acarbose 100 mg or matching placebo three times daily with food.
Of the 14,742 patients assessed for eligibility in the trial, 1,429 were actually randomized, but only 682 in the acarbose group and 686 in the placebo group could be analyzed. Their mean age was 54 years, and most subjects were Caucasian. A large percentage of patients prematurely discontinued participation in the trial. The total number of discontinuations was 30% in the acarbose group and 18% in the placebo group. Of the subjects, 48% discontinued acarbose during the first year due to gastrointestinal side effects. Despite the dropouts, fewer subjects among acarbose-treated patients developed type II diabetes mellitus. The benefit was seen regardless of age, gender, or body mass index. Of subjects assigned to the acarbose group, 35% developed a normal glucose tolerance compared to 31% in the placebo group (Figure 3). Also, 42% developed diabetes mellitus in the placebo group compared to 32% in the acarbose group. Thus, the study showed that the progression of diabetes mellitus over 3.3 years was reduced to 25% with acarbose. Eleven patients with impaired glucose tolerance treated for 3.3 years with acarbose would prevent one case of diabetes mellitus.26 A separate analysis showed a 34% reduction in new cases of hypertension with acarbose.27
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Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS)
The Xenical (orlistat) in the Prevention of Diabetes in Obese Subjects (XENDOS) study randomized 3305 patients in a double-blind, placebo-controlled, multicenter trial.28,29 The purpose of this trial was to assess the effectiveness of orlistat, an oral inhibitor of gastrointestinal lipase activity, dosed 120 mg three times daily with food versus placebo on the progression of diabetes mellitus. Swedish subjects with a body mass index of 30 kg/m2 or greater and either a normal (79%) or an impaired (21%) glucose tolerance were enrolled into the study and instructed to follow an intense calorie restriction of 800 kcal/day and moderate exercise. A 75-g oral glucose tolerance test was performed at baseline and every 6 months. After 4 years, the orlistat group had a greater reduction in weight (-5.8 kg vs. -3.0 kg, p < 0.001), low-density lipoprotein (LDL) cholesterol, and systolic and diastolic blood pressure compared to the placebo group. The risk of developing diabetes was 37% lower among all subjects treated with orlistat versus placebo (p = 0.0032) and 45% among subjects with impaired glucose tolerance (p = 0.0024).29 These results are consistent with a previous post hoc analysis that showed that orlistat was more effective than placebo on conversion to normal glucose tolerance (71.6% vs. 49.1%, p = 0.04) and progression to diabetes mellitus (3.0% vs. 7.6%, p = 0.04) among 675 obese adults with impaired glucose tolerance treated for a mean follow-up of 582 days.30
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TRIALS SHOWING A REDUCTION IN THE DEVELOPMENT OF DIABETES |
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TOPABSTRACTPROSPECTIVE TRIALS OF DIABETES...TRIALS SHOWING A REDUCTION...TRIALS IN PROGRESSSUMMARYACKNOWLEDGEMENTSREFERENCES |
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A total of 5270 subjects who were not diabetic or randomized to a substudy were also included.33 The nondiabetic subjects were evaluated as to the rate of new-onset diabetes by a history of self-reported diabetes, hemoglobin A1c > 110% of the upper limits of normal, or the use of hypoglycemic agents. The rate of diabetes development was significantly lower among ramipril-treated patients using each of the criteria or all three criteria in combination (Figure 4). Ramipril was associated with a 34% (p < 0.001) lower rate of new diagnosis of diabetes mellitus in this post hoc analysis.33
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Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension Study
The Losartan Intervention for Endpoint (LIFE) reduction in hypertension study compared losartan or atenolol in its ability to reduce the incidence of cardiovascular morbidity and mortality (stroke, myocardial infarction, and cardiovascular death).34,35 Subjects (n = 9193) between the ages of 55 and 80 with hypertension and electrocardiographic left ventricular hypertrophy were enrolled in this trial. The entry systolic blood pressure was between 160 and 200 mmHg, and the diastolic blood pressure was between 95 and 115 mmHg. Subjects were randomized to atenolol or losartan 50 mg daily. The dose of each agent could be doubled, and hydrochlorothiazide 12.5 to 25 mg could be added. Other drugs, except converting enzyme inhibitors, angiotensin receptors, or beta-blockers, could be added. There was a 13% risk reduction (p = 0.021) in the primary composite endpoint favoring losartan, driven by a 25% reduction in stroke (p = 0.001).34 The diabetic cohort (n = 1195) enjoyed a 37% reduction (p = 0.028) in cardiovascular mortality and a 39% reduction (p = 0.002) in total mortality.35 During the study, there were 560 cases of new-onset diabetes in patients without diabetes at randomization: 13.0 per 1000 patient-years for losartan versus 17.4 per 1000 patient-years for atenolol.34 Compared to atenolol, losartan reduced the new diagnosis of diabetes mellitus by 25% (p = 0.001).
West of Scotland Coronary Prevention Study
The West of Scotland Coronary Prevention Study (WOSCOPS) studied men between the ages of 45 and 65 without a prior myocardial infarction (n = 5974) with pravastatin 40 mg daily compared to the placebo group to assess cardiovascular events.36 The actual number of patients who developed diabetes was 139. Predictors of the development of diabetes included body mass index, triglyceride levels, glucose, and the use of pravastatin. There was a 30% reduction in the development diabetes with pravastatin compared to placebo.
The Heart and Estrogen/Progestin Replacement Study (HERS)
The Heart and Estrogen/Progestin Replacement Study (HERS) was a randomized, placebo-controlled, double-blind trial of 2763 postmenopausal women followed for 4.1 years.37 Patients received placebo or the combination of conjugated estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg daily. The primary outcome was the occurrence of nonfatal myocardial infarction or coronary heart disease (CHD) death, which was not reduced. During the trial, three fasting glucose measurements were performed. Of the 2029 women without diabetes at baseline, 7.9% developed diabetes mellitus.38,39 The rate of development was 30% with impaired fasting glucose at baseline and 5% with a normal fasting glucose. The cumulative incidence was 9.5% for placebo-assigned participants and 6.2% (p = 0.006) for women who received hormone replacement therapy. There was risk reduction of 35% for the development of diabetes. Treating 30 women with hormone replacement therapy for 4 years could prevent one case of diabetes.
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TRIALS IN PROGRESS |
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TOPABSTRACTPROSPECTIVE TRIALS OF DIABETES...TRIALS SHOWING A REDUCTION...TRIALS IN PROGRESSSUMMARYACKNOWLEDGEMENTSREFERENCES |
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Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM)
Since the HOPE study observed a 34% reduction in new-onset diabetes and the TRIPOD study observed a 56% reduction, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial was designed prospectively to test the same outcome using converting enzyme inhibitor ramipril and the thiazolidinedione rosiglitazone in 4000 subjects with impaired glucose tolerance.24,33,42 DREAM is a double-blind, placebo-controlled, multicenter trial using a 2-by-2 factorial design. Impaired glucose tolerance will be determined as a 2-hour glucose of 140 to 199 mg/dL after a 75-g glucose load. The primary outcome is new-onset diabetes mellitus or all-cause mortality. Follow-up will be for 3 years after randomization.
Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR)
The Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a double-blind, placebo-controlled, multicenter trial examining about 7500 patients with impaired glucose tolerance to determine if treatment with either valsartan 160 mg once daily and/or nateglinide 60 mg before meals will lower the incidence of diabetes and cardiovascular events.43 Nateglinide increases early insulin secretion and lowers postprandial hyperglycemia. This is a 2-by-2 factorial design trial with forced titration. There will be 600 or more centers from 40 countries participating in this trial. Subjects will be age 50 years or older with cardiovascular disease or 55 years or older with risk factors for cardiovascular disease. New-onset diabetes mellitus over a minimum of 3 years will be assessed by fasting plasma glucose levels every 6 months and an annual 2-hour oral glucose tolerance test. The effect of the drugs on all-cause mortality and cardiovascular events will be assessed after the accrual of 1000 patient events, estimated to be between 5 and 6 years.
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SUMMARY |
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TOPABSTRACTPROSPECTIVE TRIALS OF DIABETES...TRIALS SHOWING A REDUCTION...TRIALS IN PROGRESSSUMMARYACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTPROSPECTIVE TRIALS OF DIABETES...TRIALS SHOWING A REDUCTION...TRIALS IN PROGRESSSUMMARYACKNOWLEDGEMENTSREFERENCES |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTPROSPECTIVE TRIALS OF DIABETES...TRIALS SHOWING A REDUCTION...TRIALS IN PROGRESSSUMMARYACKNOWLEDGEMENTSREFERENCES |
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1. Mokdad AH, Ford ES, Bowman BA, et al: Diabetes trends in the U.S.: 1990-1998. Diabetes Care 2000;23: 1278-1283.
2. 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.
3. 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.
4. Isomaa B, Almgren P, Tuomi T, et al: Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24: 683-699.
5. Henry P, Thomas F, Benetos A, Guize L: Impaired fasting glucose, blood pressure and cardiovascular disease mortality. Hypertension 2002;40: 458-463.
6. Saydah SH, Loria CM, Eberhardt MS, Brancati FL: Subclinical states of glucose intolerance and risk of death in the U.S. Diabetes Care 2001;24: 447-453.
7. The prevention or delay of type 2 diabetes. Diabetes Care 2002;25: 742-749.
8. Hu FB, Sigal RJ, Rich-Edwards JW, et al: Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA 1999;282: 1433-1439.
9. Hu FB, Manson JE, Stampfer MJ, et al: Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med 2001;345: 790-797.
10. Jarrett RJ, Keen H, Fuller JH, McCartney M: Worsening to diabetes in men with impaired glucose tolerance ("borderline diabetes"). Diabetologia 1979;16: 25-30.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
11. Sartor G, Schersten B, Carlstrom S, Melander A, Norden A, Persson G: Ten-year follow-up of subjects with impaired glucose tolerance: prevention of diabetes by tolbutamide and diet regulation. Diabetes 1980;29: 41-49.[Abstract]
12. Keen H, Jarrett RJ, McCartney P: The ten-year follow-up of the Bedford survey (1962-1972): glucose tolerance and diabetes. Diabetologia 1982;22: 73-78.[Web of Science][Medline] [Order article via Infotrieve]
13. Eriksson 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.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
14. 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.[Abstract]
15. Tuomilehto J, Lindstrom J, Eriksson JG, et al: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344: 1343-1350.
16. Hammersley MS, Meyer LC, Morris RJ, Manley SE, Turner RC, Holman RR: The Fasting Hyperglycaemia Study: I. Subject identification and recruitment for a non-insulin-dependent diabetes prevention trial. Metabolism 1997;46: 44-49.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
17. Dyson PA, Hammersley MS, Morris RJ, Holman RR, Turner RC: The Fasting Hyperglycaemia Study: II. Randomized controlled trial of reinforced healthy-living advice in subjects with increased but not diabetic fasting plasma glucose. Metabolism 1997;46: 50-55.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
18. Karunakaran S, Hammersley MS, Morris RJ, Turner RC, Holman RR: The Fasting Hyperglycaemia Study: III. Randomized controlled trial of sulfonylurea therapy in subjects with increased but not diabetic fasting plasma glucose. Metabolism 1997;46: 56-60.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
19. Dyson PA, Mehta Z, Hammersley M, Holman RR: Reinforced healthy living advice over six years does not delay progression to diabetes. Diabetologia 2000;43(Suppl. 1): A114.
20. Herlihy OM, Morris RJ, Holman RR: Sulphonylurea therapy over six years does not delay progression to diabetes. Diabetologia 2000;43(Suppl. 1): A73.
21. The Diabetes Prevention Program: baseline characteristics of the randomized cohort. The Diabetes Prevention Program Research Group. Diabetes Care 2000;23: 1619-1629.
22. 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.
23. Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang A, Buchanan TA: TRIPOD (Troglitazone in the Prevention of Diabetes): a randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus. Control Clin Trials 1998;19: 217-231.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
24. Buchanan TA, Xiang AH, Peters RK, et al: Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51: 2796-2803.
25. 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 Care 1998;21: 1720-1725.[Abstract]
26. 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: 2072-2077.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
27. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003;290: 486-494.
28. Torgerson JS, Arlinger K, Kappi M, Sjostrom L: Principles for enhanced recruitment of subjects in a large clinical trial: the XENDOS (XENical in the Prevention of Diabetes in Obese Subjects) study experience. Control Clin Trials 2001;22: 515-525.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
29. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L: XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27: 155-161.
30. Heymsfield SB, Segal KR, Hauptman J, et al: Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med 2000;160: 1321-1326.
31. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: 145-153.
32. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355: 253-259.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
33. Yusuf S, Gerstein H, Hoogwerf B, et al: Ramipril and the development of diabetes. JAMA 2001;286: 1882-1885.
34. Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359: 995-1003.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
35. Lindholm LH, Ibsen H, Dahlof B, et al: Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359: 1004-1010.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
36. Freeman DJ, Norrie J, Sattar N, 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.
37. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. JAMA 1998;280: 605-613.
38. Kanaya AM, Herrington D, Vittinghoff E, et al: Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/Progestin Replacement Study: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138: 1-9.
39. Wilson PW: Lower diabetes risk with hormone replacement therapy: an encore for estrogen? Ann Intern Med 2003;138: 69-70.
40. Holman RR: Assessing the potential for alpha-glucosidase inhibitors in prediabetic states. Diabetes Res Clin Pract 1998;40(Suppl.): S21-S25.
41. Holman RR, North BV, Tunbridge FK: Possible prevention of type 2 diabetes with acarbose or metformin. Diabetes 2000;49(Suppl. 1): A111.
42. Gerstein HC: Reduction of cardiovascular events and microvascular complications in diabetes with ACE inhibitor treatment: HOPE and MICRO-HOPE. Diabetes Metab Res Rev 2002;18(Suppl. 3): S82-S85.
43. Nateglinide and valsartan in impaired glucose tolerance outcomes research: rationale and design of the NAVIGATOR trial. Diabetes 2002;51(Suppl. 2): A116.
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