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
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      1. SIGNIFICANCE

           Statins and the risk of T2D: Statin treatment is associated with an increase in incident
           T2D.1-4 5

           Mechanism of statin-induced T2D: It is unclear whether statins increase the risk of T2D
           by decreasing insulin action, secretion, or both. Several manuscripts have been
           published that substantially increase understanding of the link between statin use and
           incident T2D. Swerdlow, et al.2 based on evidence from genetic analysis and randomized
           trials, concluded that the increased risk of T2D noted with statins is at least
           "partially explained by HMG-coenzyme A reductase (HMGCR) inhibition." They also noted an
           association of weight gain with HMGCR variants in statin-treated patients, leading to
           the notion that decreases in insulin sensitivity contribute to statin-induced diabetes.
           In that context, Cederberg, at al.9 have shown in a large prospective study (n=8749 men)
           that participants treated with statins (n=2142) had a 46% increase in incident T2D,
           associated with a 24% decrease in insulin sensitivity and a 12% decrease in insulin
           secretion assessed by surrogate measures.

           Identifying those with at enhanced risk of statin-induced T2D: Studies of 3 randomized
           clinical trials with atorvastatin by David Waters' group 1,3,4 have demonstrated that
           "baseline fasting glucose, body mass index, hypertension, and fasting triglycerides were
           independent predictors of T2D." These abnormalities form a cluster attributed to insulin
           resistance.10 Since insulin resistance is a predictor of developing T2D, it seems likely
           that the more insulin resistant the individuals are before treatment, the greater is
           their risk to for statin-induced T2D.

           In that context, relatively little attention has been given to the role that metabolic
           heterogeneity in patients with elevated LDL-C concentrations might play in
           statin-induced T2D. Specifically, subjects with elevated LDL-C concentrations, whose
           plasma triglyceride (TG) concentrations are also elevated, are insulin resistant,
           hyperinsulinemic, and glucose intolerant as compared to those with isolated LDL-C
           levels. As such, this subset of patients with elevated LDL-C concentrations can be
           viewed as being at a "tipping point," and any adverse effect of statins on insulin
           action and/or secretion, irrespective of how mediated, places them at enhanced risk to
           develop statin-induced diabetes. Indeed, we have shown (Kohli et al)1 that patients with
           both insulin resistance (as estimated by high TGs) and prediabetes are at particularly
           high risk of statin-induced T2D.

           We seek to address 2 important unanswered questions: Do statins primarily affect insulin
           resistance or insulin secretion?; Are there subsets of individuals at highest risk of
           statin-induced T2D?

        2. RATIONALE, HYPOTHESIS

           Rationale:

           T2D develops when insulin resistant individuals cannot maintain the degree of
           compensatory hyperinsulinemia needed to maintain normal glucose tolerance. However,
           significant fundamental questions remain. For example, what is the cellular/molecular
           link between statin treatment and changes in insulin action and secretion?

           This proposal is based on the premise that studying the effect of statins on insulin
           action and insulin secretion using "gold standard" methods will help determine if
           statins adversely affect the risk of T2D by increasing insulin resistance or decreasing
           insulin secretion. We use the insulin suppression test (with the read-out of
           steady-state plasma glucose, SSPG) to ascertain insulin sensitivity and the graded
           glucose infusion test (with the readout of insulin secretion rate, ISR) to ascertain
           insulin secretion both before and after statin treatment in non-diabetic individuals.

           We hypothesize that treatment with atorvastatin 40 mg/day for approximately 10 weeks
           will impair insulin sensitivity and/or insulin secretion and that this effect may be
           exacerbated in those with underlying insulin resistance. Thus, we plan to look at the
           effect of atorvastatin not only in all participants but also in subsets of individuals
           with baseline insulin resistance (which will be enriched for by recruiting volunteers
           with elevated plasma TG levels (≥150 mg/dL) at baseline. The rationale for this is that
           plasma TGs are a surrogate measure for insulin resistance with a modest correlation with
           the direct measure of insulin resistance (steady-state plasma glucose) measured by the
           insulin suppression test. Clinically, subjects with elevated TGs prior to statin
           treatment would have substantial clinical benefit from statins, and one of
           investigators' secondary goals is to demonstrate that a simple measurement of plasma TG
           concentration (as a surrogate for insulin resistance) can help identify those most at
           risk of statin induced derangements in glycemic control. Consequently, we propose to
           enroll nondiabetic volunteers at high-risk for T2D, free of known atherosclerotic
           cardiovascular disease (ASCVD), not receiving statins, eligible for statin therapy
           according to ACC/AHA (American College for Cardiology/American Heart Association) 2013
           guidelines.11 We will also target recruitment efforts to enrich for subjects with plasma
           TG concentration ≥ 150 mg/dL to ensure that we enroll subjects across the range of
           insulin sensitivity.

           Hypothesis: We hypothesize that high intensity atorvastatin treatment for approximately
           10 weeks will impair insulin sensitivity and/or insulin secretion and that this effect
           may be exacerbated in those with underlying insulin resistance.

        3. STUDY DESIGN

           Sample Size

           • We aim to recruit and retain 75 total participants in this study.

           Study Location

           • Clinical and Translational Research Unit (CTRU) at 800 Welch Road, Palo Alto, CA
           94304.

           Duration

           • We anticipate that the entire study will take 4 - 5 years through the end of data
           analysis. Each eligible candidate who voluntarily consents to participate in the study
           will be active in the study for a total of 5 months from screening to the end of their
           last visit.

        4. STUDY PROCEDURES

           Recruitment

           Preliminary recruitment strategies will include:

           Volunteers will be recruited from the San Francisco Bay Area through advertisements in
           newspapers, posted flyers, and the social networking site NextDoor as well as from the
           Preventive Cardiology Clinics at Stanford Health Care. Our goal is to ensure recruitment
           across a broad range of insulin sensitivity. Prior work from our group and others has
           shown that high plasma TG concentrations are associated with increased insulin
           resistance as assessed by reference measures. Therefore, we will target advertisements
           to enrich for individuals with high TG levels (> 150 mg/dL) as a surrogate for increased
           insulin resistance.

           Participant Visits and Procedures

           Potential participants will be screened initially when they call or email in response to
           recruitment ads, or a letter from their MD, describing the study as follows:

           Preliminary intake will occur over the phone.

           Visit 1 Screening visit.

           Visit 2: Oral Glucose Tolerance Test (OGTT): This test will take approximately 3 hours.

           i) Glycemic status: Participants will be classified as having normal glucose tolerance
           (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance
           (IGT), or combined IFG/IGT12. In addition, the total integrated plasma glucose response
           during the OGTT will be calculated by the trapezoidal method (Glucose-AUC).

           ii) β-cell function: Calculations of the Insulin Secretion- Sensitivity Index-2 (ISSI-2)
           will be used to quantify insulin secretory function 13, if for some reason a graded
           glucose infusion study is not done. The ISSI-2 is a validated OGTT- derived method to
           measure of β-cell function, analogous to the disposition index obtained from the
           intravenous glucose tolerance test 14. It is calculated by multiplying the insulin
           secretory response during the OGTT (Insulin-AUC/Glucose-AUC) by insulin resistance
           (Matsuda index).

           The fasting and 2-hour glucose results will be discussed with the study participant and
           a copy of the results will be given to them.

           Visit 3. Graded Glucose Infusion, GGIT 15,16: This test will take approximately 6 hours.

           This test is designed to assess the ability of the pancreas to produce insulin in
           response to a graded glucose infusion. During this test, subjects will have two small IV
           catheters placed, one in each arm. One IV will be used for drawing samples and the other
           for the infusion of glucose. During the GGIT, continuous intravenous infusions of
           glucose will be given at progressively increasing rates: 1, 2, 3, 4, 5, 6, and 8 kg/min
           in six infusion periods of 40-min duration. Blood samples will be collected for
           measurements of glucose, insulin, and C-peptide concentrations at fasting and at 30 min
           and 40 min into each infusion period. The two values during the last 10 min of each
           infusion period will be averaged. The amount of blood taken for this test will 47.5 ml.

           Visit 4.Insulin Suppression test, IST 17,18: This test will take approximately 6 hours.

           This test is designed to determine whole body insulin sensitivity. Following an
           overnight fast, subjects will have an IV placed in each arm. One for collection of blood
           and the other for infusion with octreotide (0.27 μg/m2/min), insulin (32 mU/m2/min), and
           glucose (267 mg/m2/min) for 180 minutes. During the test, endogenous insulin is
           suppressed and all individuals are given the same concentration of insulin, based on
           their body surface area. Blood is drawn every 30 minutes for 150 minutes and then at
           10-minute intervals from 150 to 180 minutes of the infusion to measure plasma glucose
           and insulin concentrations. The mean of the last four values is used as the steady-state
           plasma insulin (SSPI) and glucose (SSPG) concentrations for each individual. As SSPI
           concentrations are similar in all subjects during the IST, the SSPG concentration
           provides a direct measure of the ability of insulin to mediate disposal of an infused
           glucose load; the higher the SSPG concentration, the more insulin resistant the
           individual. Labs to check kidney and liver function plus a lipid panel and a urine
           pregnancy test (if appropriate) will be done at this visit. Blood drawn or IST will be
           58.5 ml and 5 ml for SHC labs.

           Labs for iPOP will be drawn at this time and additional samples will be obtained for
           transcriptome, microbiome, metabolome, and proteome analysis in blood; nasal, tongue,
           skin surface swabs; urine; and stool.

           The study drug, atorvastatin 40 mg will be given to study participants, once all labs
           have been reviewed and participant qualifies.

           Visit 5-7: Visits will be every 2 weeks for a total of 10 weeks on study medication
           (statin). Participants will be assessed for any side effects or adverse events (AE) on
           the statin. Adherence to study medication will be assessed at each visit.

           Visit 8: Weight, vital signs, and OGTT described above.

           Visit 9: Repeat GGIT as described above.

           Visit 10: Repeat IST and iPOP lab testing and samples as described above. At the end of
           this visit, the statin will be stopped and the study participant would be scheduled for
           4- and 8-week follow up visits.

           Visit 11: One month off statin study visit - weight, vital signs, and iPOP laboratory
           testing and samples will be done as described above.

           Visit 12: Last study visit - weight, vital signs, and iPOP laboratory testing and
           samples will be done as described above.

           Participants will be asked to fill out questionnaire about her/his physical activity
           status, food and eating habits, and stress at the time of each iPOP.

        5. STATISTICAL CONSIDERATIONS

      Based on our prior work19, we calculated that with 60 subjects, we would be able to detect an
      8% change in SSPG concentration and an 8% change in ISRAUC after atorvastatin therapy with
      80% power and two-side significance level of 5% using a paired samples t test. Thus, we
      estimated needing to enroll 75 subjects with an anticipated a dropout rate of 20%.

      Summary statistics will be reported as median (interquartile range) or number (percent) of
      participants unless otherwise specified. Shapiro-Wilk tests will be used to assess normality
      of data, and variables that are not normally distributed will be log-transformed. Percent
      changes in variables will be calculated by the formula: [(end-of study value) - (baseline
      value) / baseline value] x 100. Paired samples t tests will be used to compare baseline and
      end-of-study means. One sample t tests will be employed to evaluate whether percent changes
      in variables are significantly different from zero (no change). Pearson correlation
      coefficients will be calculated to determine the strength of association between variables of
      interest. Prespecified subgroup analyses will be carried out by stratifying for insulin
      resistant versus insulin sensitive subjects. The SSPG concentration median will be used to
      define subjects as being insulin resistant or insulin sensitive. Insulin resistant and
      insulin sensitive group means will be compared by independent sample t tests and proportions
      by chi-square tests or Fisher's exact tests. Statistical analyses will be performed by using
      statistical software IBM SPSS version 26.0.
    

Intervention name(s): Atorvastatin
Intervention type(s): Drug
Intervention description(s): Study subjects will receive atorvastatin 40 mg for 10 weeks.
Other intervention name(s): Lipitor
Intervention MeSH terms: Atorvastatin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: statin; diabetes; insulin resistance; insulin secretion