Relationship Between Insulin Resistance and Statin Induced Type 2 Diabetes, and Integrative Personal Omics Profiling
Condition: Hyperlipidemia; Insulin Resistance; Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Hyperlipidemias
Intervention: Atorvastatin
Intervention description: Study subjects will receive atorvastatin 40 mg for 10 weeks.
Intervention MeSH terms: Atorvastatin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 115.0
Sex: All
Minimum age: 30 Years
Maximum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: statin; diabetes; insulin resistance; insulin secretion

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.
    

Eligibility 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