Relationship Between Insulin Resistance and Statin Induced Type 2 Diabetes, and Integrative Personal Omics Profiling

• Status: Completed
• Trial end date: 2020-04-01
• Target enrollment: 0
• Participant gender: All

Summary

Background:

There is general agreement that statin-treatment of patients to lower plasma cholesterol levels can increase the incidence of type 2 diabetes mellitus (T2D) in some individuals1-5. The physiologic mechanism for the increased risk for T2D from statin treatment is unknown but could result from effects on insulin sensitivity or insulin secretion. This study will evaluate how the medication atorvastatin (trade name Lipitor) works in non-diabetic individuals in regards to its effect on insulin sensitivity and insulin secretion to help further understand the possible cause of the increased occurrence of T2D in people who are at risk for T2D. This research study will also examine what metabolic characteristics and variables (for example insulin resistance, high triglycerides, or both) will identify those people at highest risk of statin-induced T2D.

The goals of this study are to:

1. determine the effect of high-intensity atorvastatin (40 mg/day) for ~ 10 weeks on insulin sensitivity and insulin secretion (defined with gold standard methods) (PRIMARY OUTCOMES) as well as other glycemic traits (SECONDARY OUTCOMES);

2. compare a number of cardio-metabolic characteristics (e.g. weight, lipids) before, during, and after administration of atorvastatin;

3. determine if significant deterioration of insulin action and/or secretion following statin treatment will be confined to those with baseline insulin resistance (PRE-SPECIFIED SUBGROUP ANALYSES);

4. perform Personal Omics Profiling (iPOP) 6,7 before and after taking atorvastatin to examine treatment-associated changes in all baseline variables and to analyze not only previously-known drug efficacy but also untargeted drug efficacy (EXPLORATORY ANALYSES).

General approach:

This will be an open-label study to evaluate the diabetogenic effect of atorvastatin (40 mg/day for 10 weeks) on both insulin action and insulin secretion in nondiabetic individuals. To ensure we recruit individuals across a broad range of insulin sensitivity, we will target recruitment to enrich for those with combined increases in LDL-C and TG concentrations (see SIGNIFICANCE and RATIONALE). The experimental population will consist of ~75 apparently healthy, non-diabetic volunteers eligible for statin therapy but without pre-existing atherosclerotic cardiovascular disease. Following baseline assessments of co-primary outcome measures: insulin sensitivity (by insulin suppression test, IST) and insulin secretion (by graded glucose infusion test, GGIT), participants will be placed on a weight maintenance diet and treated with 40 mg/day of atorvastatin. All baseline measurements will be repeated ~10 weeks later with iPOP8 measurements done at baseline, at weeks 2, 4, and 10 on atorvastatin, and at weeks 4 and 8 off atorvastatin.

• Phase: Phase 4
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Stanford University
• Collaborator: Doris Duke Charitable Foundation
• Treatments: Atorvastatin; Atorvastatin Calcium

Criteria

Inclusion Criteria:

1. Healthy adults 30 - 70 years old

2. BMI: 20 - 37 kg/m2

3. Without diabetes as defined by fasting plasma glucose <126 mg/dL and not taking glucose lowering medications

4. Eligible for statin therapy for primary prevention of ASCVD based on LDL-C ≥ 130 mg/dL, > 5% ASCVD risk over 10 years, or hs-CRP ≥ 2.0 mg/L

Exclusion Criteria:

1. Younger than 30 or older than 70 years

2. Persons with any significant co-morbidities, such as diabetes (fasting glucose ≥ 126 mg/dL or use of glucose lowering medications), active coronary artery disease, heart failure, accelerated or malignant hypertension, kidney disease (creatinine ≥ 1.5 mg/dL), liver disease (alanine aminotransferase > 2 times upper limit of normal), or severe anemia (hematocrit < 30%).

3. Individuals taking any medications for weight loss or known to influence insulin sensitivity.

4. Pregnant or lactating

5. Women unwilling to use an effective birth control method

6. History of statin intolerance