Relationship Between Insulin Resistance and Statin Induced Type 2 Diabetes, and Integrative Personal Omics Profiling
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 115
- 试验地点
- 1
- 主要终点
- Steady-state Plasma Glucose (SSPG)
研究概览
简要总结
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:
- 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);
- compare a number of cardio-metabolic characteristics (e.g. weight, lipids) before, during, and after administration of atorvastatin;
- 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);
- 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.
详细描述
- 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 30 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adults 30 - 70 years old
- •BMI: 20 - 37 kg/m2
- •Without diabetes as defined by fasting plasma glucose <126 mg/dL and not taking glucose lowering medications
- •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
排除标准
- •Younger than 30 or older than 70 years
- •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%).
- •Individuals taking any medications for weight loss or known to influence insulin sensitivity.
- •Pregnant or lactating
- •Women unwilling to use an effective birth control method
- •History of statin intolerance
研究组 & 干预措施
Individuals without diabetes eligible to receive statin therapy
Eligible participants will receive 40 mg of atorvastatin
干预措施: Atorvastatin (Drug)
结局指标
主要结局
Steady-state Plasma Glucose (SSPG)
时间窗: baseline, week 9 or 10
Insulin sensitivity measured by SSPG concentration (mg/dL) during the insulin suppression test.
Insulin Secretion Rate Area Under the Curve (ISR-AUC)
时间窗: baseline, week 9 or 10
Insulin secretion measured by ISR-AUC (pmol/min x 4 h) during the graded glucose infusion test.
次要结局
- Fasting Plasma Glucose(10 weeks)
- Fasting Plasma Insulin(10 weeks)
- OGTT Glucose AUC(baseline, week 8)
- OGTT Insulin AUC(baseline, week 8)
研究者
Joshua Knowles
Assistant Professor
Stanford University