Cholesterol and Statin in Healthy Adults

Study Overview
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Brief Summary
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Statins are a class of drugs that are the most commonly prescribed medications in developing countries. Statins act on the enzyme HMG-CoA reductase to inhibit its conversion to mevalonate, a precursor for cholesterol synthesis. Subsequently statins are prescribed to patients with relatively high blood cholesterol levels. However, taking statins does not come without side effects. Most notably, the effects of statins on muscle wasting have been studied extensively. This includes up-regulation of the ubiquitin proteasome system, muscle cell damage and rhabdomyolysis, elevated creatine kinase, and mitochondrial dysfunction. Due to the negative side effects of statin therapy, additional therapies are warranted to help offset the effects on muscle wasting. Loss of muscle mass is a significant concern as it is associated with a reduction in muscle strength and power (Ferrando et al., 1996; Creditor, 1993). This condition is observed in aging, disease states, and long periods of unloading such as hospital admission and can lead to disability, increased falls, loss of independence, and mortality. Subsequently, there is a critical need to develop interventions to counteract this loss of muscle mass and strength. Exercise is one such intervention, however, in some cases may not be a feasible option. For instance, exercise has been demonstrated to exacerbate the muscle side of effects of statins. Subjects complain of increased muscle soreness and have elevated creatine kinase levels and they also do not want to take statins anymore (Kearns et al., 2008; Parker et al., 2012; Sinzinger et al., 2004). Because of this limitation, there is a critical need to develop other interventions that can prevent the loss of muscle mass during statin use.

Detailed Description
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The use of nutritional interventions have gained much attention and are being explored for their ability to increase muscle mass and/or attenuate loss of muscle mass. Leucine, isoleucine, and valine are branched chain amino acids that have been studied extensively and have been shown to stimulate muscle anabolism. Beta-hydroxy-beta-methylbutyrate (HMB), a metabolite of leucine, has been suggested to play a significant role in preserving muscle mass in situations that favor muscle mass loss. This is thought to occur through stabilizing sarcolemma integrity, reduced proteasome activity and expression of the proteasome 20S subunit, inhibition of apoptosis, and by activation of skeletal muscle satellite cells. Furthermore, in a catabolic-induced myotube and a murine adenocarcinoma cell line, HMB (50µM) was more potent in reversing the increased protein degradation and decreased protein synthesis compared to a higher dose of leucine (1mM). Similar findings were reported in a rodent cancer model. These data suggests that HMB plays a significant role in preventing muscle wasting. Understanding the metabolic fate of HMB is crucial to developing strategies to increase HMB concentrations in populations that are subjected to muscle wasting. The objective of this application is to determine if a cholesterol lowering statin alters HMB metabolism in healthy adults. The Researchers will test the hypotheses that with statin administration, HMB metabolism and urinary excretion is affected and that this will have an unknown effect on the production of HMB and the response to intake of HMB precursors like leucine.

Official Title
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Human Metabolism of HMB

Conditions
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Elevated HMB Excretion

Intervention / Treatment
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* Other: Statin user


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and Female, Age ≥ 65 y to 80 y BMI >20 but less than or equal to 35 Currently taking a cholesterol lowering statin Stable body-weight (± 5%) for the past 3 months Subject is judged to be in satisfactory health based on medical history, physical examination, and laboratory screening evaluations. Ability to walk, sit down and stand up independently Ability to lie in supine or elevated position for up to 8 hours Willingness and ability to comply with the protocol Exclusion criteria: Metabolic diseases including diabetes, hepatic or renal disorder Subject has malignant disease or autoimmune disease Subject has impaired liver function Subject has had a significant cardiovascular event (e.g. myocardial infarction, stroke) ≤ 6 months prior to screening visit; or stated history of congestive heart failure Subject has current significantly impaired liver function in the opinion of the study PI (mild asymptomatic fatty liver is acceptable), or hepatic enzyme tests are ≥2.5 times normal limit Subject has a chronic, contagious, infectious disease, such as active tuberculosis, hepatitis B or C, or HIV Subject has chronic disease such as COPD Subject is expected to have surgery within one-month of screening Subject is currently participating or has participated in a study with an investigational compound or device within 30 days of signing the informed consent. Presence of acute illness or metabolically unstable chronic illness (unrelated to the primary disease) Unwilling to stop taking nutritional protein supplements within 5 days of first study day Any other condition according to the PI or nurse that would interfere with the study or safety of the subject or influence the results Presence of fever within the last 3 days Untreated metabolic diseases including hepatic or renal disorder unrelated to the primary disease Active dependence of alcohol or drugs Medication: Use of substances known to influence amino acid metabolism: antibiotics within 3 weeks prior to the study visit, current use of corticosteroids, growth hormone, testosterone, estrogen, immunosuppressant, blood thinners, or insulin. Subject cannot refrain from taking dietary supplements/substances that could modulate metabolism or weight in the opinion of the principal investigator or physician, starting four weeks prior to enrollment and over the entire course of the study such as b-hydroxy-b-methyl butyrate (HMB) or products containing HMB Adherence to a weight loss diet. Currently taking any drugs that impact liver function Subject having elevated blood CK/CPK levels (3-10X above normal range)

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 80 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy taking statin<br>healthy subjects currently taking cholesterol lowering statin | Other: Statin user<br>* Subjects will be studied on 2 occasions with both being identical. One will be after 7 days or more of cholesterol lowering statin administration and the other occasion will be after at least 4 weeks of cholesterol lowering statin discontinuation. All study visits include (but are not limited to) blood draws, urine collection, and stable isotope infusions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beta Hydroxymethyl butyrate turnover | Measures the rate that Beta Hydroxymethyl butyrate is appears in blood | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ketoisocapric acid turnover | Measures the rate that Ketoisocapric acid is appears in blood | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Leucine turnover | Measures the rate that Leucine is appears in blood | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Isoleucine turnover | Measures the rate that Isoleucine is appears in blood | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Ketomethylvalerate turnover | Measures the rate that Ketomethylvalerate is appears in blood | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Valine turnover | Measures the rate that Valine is appears in blood | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Ketoisovalerate turnover | Measures the rate that Ketoisovalerate is appears in blood | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Beta Hydroxymethyl butyrate concentration | Blood Beta Hydroxymethyl butyrate concentration | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Ketoisocapric acid concentration | Blood Ketoisocapric acid concentration | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Leucine concentration | Blood Leucine concentration | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Isoleucine concentration | Blood Isoleucine concentration | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Ketomethylvalerate concentration | Blood Ketomethylvalerate concentration | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Valine concentration | Blood Valine concentration | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Ketoisovalerate concentration | Blood Ketoisovalerate concentration | 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min | 
| Beta Hydroxymethyl butyrate concentration | Urinary Beta Hydroxymethyl butyrate concentration | 0 and 240 min |