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Cholesterol and Statin in Healthy Adults

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Marielle PKJ Engelen, PhD, Texas A&M University
ClinicalTrials.gov Identifier:
NCT02908425
First received: September 15, 2016
Last updated: September 7, 2017
Last verified: September 2017
  Purpose

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.


Condition Intervention
Elevated HMB Excretion Other: Statin user

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Human Metabolism of HMB

Resource links provided by NLM:


Further study details as provided by Marielle PKJ Engelen, PhD, Texas A&M University:

Primary Outcome Measures:
  • Beta Hydroxymethyl butyrate turnover [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 minutes ]
    Measures the rate that Beta Hydroxymethyl butyrate is appears in blood


Secondary Outcome Measures:
  • Ketoisocapric acid turnover [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Measures the rate that Ketoisocapric acid is appears in blood

  • Leucine turnover [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Measures the rate that Leucine is appears in blood

  • Isoleucine turnover [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Measures the rate that Isoleucine is appears in blood

  • Ketomethylvalerate turnover [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Measures the rate that Ketomethylvalerate is appears in blood

  • Valine turnover [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Measures the rate that Valine is appears in blood

  • Ketoisovalerate turnover [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Measures the rate that Ketoisovalerate is appears in blood

  • Beta Hydroxymethyl butyrate concentration [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Blood Beta Hydroxymethyl butyrate concentration

  • Ketoisocapric acid concentration [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Blood Ketoisocapric acid concentration

  • Leucine concentration [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Blood Leucine concentration

  • Isoleucine concentration [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Blood Isoleucine concentration

  • Ketomethylvalerate concentration [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Blood Ketomethylvalerate concentration

  • Valine concentration [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Blood Valine concentration

  • Ketoisovalerate concentration [ Time Frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240 min ]
    Blood Ketoisovalerate concentration

  • Beta Hydroxymethyl butyrate concentration [ Time Frame: 0 and 240 min ]
    Urinary Beta Hydroxymethyl butyrate concentration


Enrollment: 13
Study Start Date: July 2016
Estimated Study Completion Date: July 2018
Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Healthy taking statin
healthy subjects currently taking cholesterol lowering statin
Other: Statin user
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.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   65 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02908425

Locations
United States, Texas
Texas A&M University CTRAL
College Station, Texas, United States, 77845-4253
Sponsors and Collaborators
Texas A&M University
Investigators
Principal Investigator: Marielle Engelen, PHD Texas A&M University
  More Information

Publications:
Nissen SL, Abumrad NN. Nutritional role of the leucine metabolite β-hydroxy β-methylbutyrate (HMB). The Journal of nutritional biochemistry. 1997;8(6):300-11.

Responsible Party: Marielle PKJ Engelen, PhD, Associate Professor, Texas A&M University
ClinicalTrials.gov Identifier: NCT02908425     History of Changes
Other Study ID Numbers: 2015-0767
Study First Received: September 15, 2016
Last Updated: September 7, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Lipid Regulating Agents

ClinicalTrials.gov processed this record on September 19, 2017