Effect of Pravastatin in the Subjects With Prediabetes or Early Diabetes

Study Overview
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Brief Summary
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An increased risk of incident diabetes with statin therapy have been reported in several studies. However, it is not recommended to limit the use of statin for this reason since the absolute risk increase was small, and the cardiovascular event rate reduction with statins overweighed the risk of new diabetes (Scatter N et al. Lancet, 2010). Moreover, each statin may have different effect on the development of incident diabetes. In the West of Scotland Coronary Prevention Study, pravastatin therapy reduced the hazard of becoming diabetic by 30%. Also, with pravastatin use, an increase in adiponectin level, which is related to the improvement in insulin sensitivity, has been reported. In this clinical trial, the investigators are aiming to evaluate the effect of pravastatin on insulin resistance, insulin secretion, glycemic control, and adiponectin level in participants with prediabetes or early diabetes by assigning them in a 24 weeks of pravastatin therapy group or in a placebo group.

Official Title
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Effect of Pravastatin in the Subjects With Prediabetes or Early Diabetes

Conditions
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Diabetes Mellitus, Prediabetic State

Intervention / Treatment
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* Drug: Pravastatin
* Drug: Placebo (for Pravastatin)
* Behavioral: Nutritional education only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects have early diabetes mellitus or prediabetes. Early diabetes mellitus or prediabetes are defined according to the following criteria; Subjects have two or more of the following three, or they have one of them at the initial test and the repeat test. hemoglobin A1C 5.7-9.0% fasting plasma glucose level 100mg/dL or more plasma glucose level 140mg/dL or more at 2 hours after 75g oral glucose tolerance test Subjects have one of the following three; Low-density lipoprotein cholesterol (LDL-cholesterol) 130mg/dL or more, and body mass index (BMI) > 23 kg/m2, 10 year atherosclerotic cardiovascular disease (ASCVD) risk of 7.5% or more, which is assessed by the ASCVD-Risk-Estimator (Circulation.2014;129:S1-S45) In diabetic patients, LDL-cholesterol 100mg/dL or more Exclusion Criteria: Hemoglobin A1C > 9.0% History of statin use in three months Use of oral antidiabetic drugs except for metformin in three months History of malignant diseases (cancers) History of coronary artery diseases, heart failure, arrhythmia, valvular heart diseases, or cerebrovascular diseases Pregnant serum creatinine level > 1.5 mg/dL aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels higher than 80 U/l Taking weight loss medications, corticosteroids, Angiotensin converting enzyme (ACE) inhibitors, or estrogen replacement therapy Chronic hepatitis B or chronic hepatitis C

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pravastatin<br>Pravastatin 40mg tablet by mouth, once daily for 24 weeks. Also, nutritional education was provided to participants in all arms by a nutritionist, and participants were instructed to follow the educated guideline. | Drug: Pravastatin<br>* Pravastatin 40mg once daily for 24 weeks and nutritional education by a nutritionist<br>|
| Placebo Comparator: Placebo<br>Placebo drug indistiguishable from pravastatin 40mg tablet, by mouth, once daily for 24 weeks. Also, nutritional education was provided to participants in all arms by a nutritionist, and participants were instructed to follow the educated guideline. | Drug: Placebo (for Pravastatin)<br>* Pill manufactured to mimic pravastatin 40mg tablet once daily for 24 weeks and nutritional education by a nutritionist<br>|
| Other: Open-label control<br>No medication. Only nutritional education was provided to participants by a nutritionist, and participants were instructed to follow the educated guideline. | Behavioral: Nutritional education only<br>* Only nutritional education by a nutritionist<br>* Other names: Open-label control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin resistance assessed by HOMA-IR (homeostatic model assessment index for insulin resistance) | compared to the HOMA-IR level calculated at the initial visit (at the beginning of the 24 weeks of medication period) | at the end of the 24 weeks of medication period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin resistance assessed by Matsuda index calculated through 75g oral glucose tolerance test | calculated according to a method described in a previous study (Matsuda M et al. Diabetes Care, 1999), compared to the results at the initial visit (at the beginning of the 24 weeks of medication period). It takes 120 minutes to perform 75g oral glucose tolerance test | at the end of the 24 weeks of medication period | 
| Insulin secretion capacity assessed by insulinogenic index (INS index) during 75g oral glucose tolerance test | the ratio relating enhancement of circulating insulin in 30min [in pmol/L] to magnitude of corresponding glycemic stimulus in 30min [in mmol/L] during the oral glucose tolerance test (H.S. Seltze et al. J. Clin. Investig., 1967), compared to the results at the initial visit (at the beginning of the 24 weeks of medication period) | at the end of the 24 weeks of medication period | 
| Insulin resistance assessed by the quantitative insulin sensitivity check index (QUICKI) | calculated using fasting insulin in uIU/mL and fasting plasma glucose in mg/dL according to the method described in a previous study (A. Katz et al. J. Clin. Endocrinol. Metab., 2000), compared to the results at the initial visit (at the beginning of the 24 weeks of medication period) | at the end of the 24 weeks of medication period | 
| Insulin secretory capacity relative to insulin resistance assessed by the oral disposition index | calculated according to a method described in a previous study (K.M. Utzschneider et al.Diabetes Care, 2008), compared to the results at the initial visit (at the beginning of the 24 weeks of medication period) | at the end of the 24 weeks of medication period | 
| Glycemic control evaluated by fasting glucose level (mg/dL) | compared to the values at the initial visit | at the end of the 24 weeks of medication period | 
| Glycemic control evaluated by hemoglobin A1C (%) | compared to the values at the initial visit | at the end of the 24 weeks of medication period | 
| Plasma adioponectin level (μg/ml), an adipocyte-derived insulin-sensitizing hormone level | compared to the values at the initial visit | at the end of the 24 weeks of medication period | 
| Biomarkers predicting cardiovascular diseases, assessed by high sensitive C-reactive protein (hsCRP) (mg/dL) | compared to the values at the initial visit | at the end of the 24 weeks of medication period | 
| Biomarkers predicting cardiovascular diseases, assessed by plasminogen activator inhibitor-1 (PAI-1) (ng/mL) | compared to the values at the initial visit | at the end of the 24 weeks of medication period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pravastatin, Insulin Resistance