Telmisartan-Induced Reduction in Intra-Myocellular Lipids Trial

• ClinicalTrials.gov Identifier: NCT00147264
• Recruitment Status: Completed
• First Posted: September 7, 2005
• Last Update Posted: December 14, 2016
• Sponsor: McMaster University
• Collaborators: Boehringer Ingelheim; Canadian Institutes of Health Research (CIHR); Heart and Stroke Foundation of Canada; Medtronic
• Information provided by: McMaster University

Tracking Information

• First Submitted Date: September 2, 2005
• First Posted Date: September 7, 2005
• Last Update Posted Date: December 14, 2016
• Study Start Date: April 2004
• Actual Primary Completion Date: January 2006 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: September 2, 2005): (for both interventions): change in IMCL content in the soleus muscle as assessed by 1H-MRI Spectroscopy at baseline and 6 months
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 22, 2006)

• Change in intra-hepatocellular lipid storage as assessed by 1H-MRI Spectroscopy
• Change in insulin sensitivity as determined by HOMA index
• Reversal of IFG to normal fasting glucose in participants with IFG
• Change in 72-hour subcutaneous glucose profile
• Change in fasting lipid profile (free fatty acids, triglyceride, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol)
• Change in serum/plasma levels of inflammatory markers (C-reactive protein, adiponectin, tumor necrosis factor a, interleukin 6, leptin, adhesion molecules, plasminogen-activation inhibitor-1, t-PA, global test of fibrinolysis, fibrinogen, homocysteine,
• Change in beta-cell function as assessed by the Insulin Secretion Index
• Other efficacy parameters of the AT1 blockade and LGI diet are:
• Change in waist circumference
• Change in body composition as assessed by bioelectrical impedance analysis
• Change in abdominal (visceral) adipose tissue as assessed by MRI
• Change in resting blood pressure
• Change in adipocytic cell size determined by grouped diameter distribution in subcutaneous abdominal adipose tissue biopsies
• Changes in mRNA expression of genes in adipose tissue for genes involved in adipose tissue differentiation, growth, metabolism, cardiovascular function and inflammation.
• Change in muscle triglyceride content (histochemical examination of muscle biopsies)
• Change in molecular markers of endoplasmic reticular stress in circulating blood cells
• Endothelial function as assessed by Doppler ultrasound of the forearm blood flow.
• Systolic and diastolic cardiac function as assessed by echocardiography

Original Secondary Outcome Measures (submitted: September 2, 2005)

• · Change in intra-hepatocellular lipid storage as assessed by 1H-MRI Spectroscopy
• · Change in insulin sensitivity as determined by HOMA index
• · Reversal of IFG to normal fasting glucose in participants with IFG
• · Change in 72-hour subcutaneous glucose profile
• · Change in fasting lipid profile (free fatty acids, triglyceride, total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol)
• · Change in serum/plasma levels of inflammatory markers (C-reactive protein, adiponectin, tumor necrosis factor a, interleukin 6, leptin, adhesion molecules, plasminogen-activation inhibitor-1, t-PA, global test of fibrinolysis, fibrinogen, homocysteine,
• · Change in beta-cell function as assessed by the Insulin Secretion Index
• Other efficacy parameters of the AT1 blockade and LGI diet are:
• · Change in waist circumference
• · Change in body composition as assessed by bioelectrical impedance analysis
• · Change in abdominal (visceral) adipose tissue as assessed by MRI
• · Change in resting blood pressure
• · Change in adipocytic cell size determined by grouped diameter distribution in subcutaneous abdominal adipose tissue biopsies
• · Changes in mRNA expression of genes in adipose tissue for genes involved in adipose tissue differentiation, growth, metabolism, cardiovascular function and inflammation.
• · Change in muscle triglyceride content (histochemical examination of muscle biopsies)
• · Change in molecular markers of endoplasmic reticular stress in circulating blood cells
• · Endothelial function as assessed by Doppler ultrasound of the forearm blood flow.
• · Systolic and diastolic cardiac function as assessed by echocardiography

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Telmisartan-Induced Reduction in Intra-Myocellular Lipids Trial
• Official Title: A Randomized, Double Blind, 2X2 Factorial Design Study to Evaluate the Effects of Telmisartan vs Placebo, and of a Low-Glycemic Diet vs Control Diet, in Reducing Intra-Myocellular Lipids In Individuals With Abdominal Obesity
• Brief Summary: The purpose of this study is to determine whether telmisartan and/or a low-glycemic index diet are effective in reducing intra-myocellular lipid (muscle fat) content.
• Detailed Description: The metabolic syndrome currently affects over 20% of the adult population in Canada. Patients with abdominal obesity are at markedly increased risk for diabetes and heart disease. Recent studies have shown that decreased sensitivity to insulin (insulin resistance), a hallmark of the metabolic syndrome, is related to increased storage of fat in muscle cells (muscle fat). Several recent studies indicate that blocking the renin-angiotensin system (RAS) may improve insulin sensitivity and prevent the development of type 2 diabetes. Other data suggests that this effect may be due to the effect of RAS blockade on the recruitment and growth of adipose tissue. The primary aim of this study is therefore to explore the role of angiotensin II in the development of insulin resistance. Specifically, we will examine the mechanisms underlying the putative anti-diabetic effect of RAS blockade by examining the effect of angiotensin receptor blockade on muscle fat content in individuals with the abdominal obesity. This study will therefore test the hypothesis that treatment with the angiotensin receptor blocker telmisartan (Micardis®) will reduce muscle fat, thereby improving insulin sensitivity in people with abdominal obesity, with or without additional features of the metabolic syndrome. A number of dietary factors can also affect insulin sensitivity and may influence muscle fat. Recent studies suggest that increasing the content of low-glycemic foods (carbohydrates which are less easily digested), can improve insulin sensitivity and lipid profile in patients with insulin resistance. A second aim of this study is therefore to test the hypothesis that a low-glycemic diet will reduce muscle fat, thereby improving insulin sensitivity in this population.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Factorial Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Metabolic Syndrome X

Intervention

• Drug: Telmisartan (Micardis®) vs. Placebo
• Behavioral: Low-Glycemic Index Diet vs. Control Diet

• Study Arms: Not Provided

Publications *

• Chetty VT, Damjanovic S, Gerstein H, Singh N, Yusuf S, Anand SS, Sharma AM. Metabolic effects of telmisartan in subjects with abdominal obesity: a prospective randomized controlled trial. Blood Press. 2014 Feb;23(1):54-60. doi: 10.3109/08037051.2013.791411. Epub 2013 Jun 3.
• Kochan AM, Wolever TM, Chetty VT, Anand SS, Gerstein HC, Sharma AM. Glycemic index predicts individual glucose responses after self-selected breakfasts in free-living, abdominally obese adults. J Nutr. 2012 Jan;142(1):27-32. doi: 10.3945/jn.111.146571. Epub 2011 Nov 16.

Recruitment Information

• Recruitment Status: Completed
• Enrollment (submitted: September 2, 2005): 120
• Original Enrollment: Same as current
• Actual Study Completion Date: November 2006
• Actual Primary Completion Date: January 2006 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Written informed consent
• Between 30 and 70 years of age
• Abdominal obesity defined as increased waist circumference (Men >102cm (>40in), Women >88cm (>35in)), with or without any of the following additional criteria of the metabolic syndrome:
• Triglycerides >=1.7mmol/L (>=150 mg/dL and/or on prescribed lipid lowering medication for > 3 months)
• HDL cholesterol
• Men <1.0 mmol/L (<40 mg/dL)
• Women <1.3 mmol/L (<50 mg/dL)
• Blood pressure >=130 and/or >=85 mmHg and/or on anti-hypertensive therapy (except ACE-I or ARB)
• Fasting glucose >=6.1 mmol/L (>=110 mg/dL)
• Ability and willingness to complete dietary and activity diaries and questionnaires.

Exclusion Criteria:

• Participant has taken ACE inhibitor or ARB in the last 3 months, or in the opinion of the study physician currently has indication for either of these medications
• Concurrent antidiabetic medication
• Use of systemic glucocorticosteroids (topical and inhaled are acceptable)
• On lipid-lowering medication and NOT on stable dose for the last three months

• If the participant has any one or more of the following medical disorders:

  1. diabetes mellitus and/or FBG >=7.0 mmol/L on two separate occasions within the screening period
  2. uncontrolled hypertension (SBP >=160 mmHg and/or DBP >=100 mmHg) or known participants with secondary causes of hypertension
  3. biliary obstruction
  4. hepatic dysfunction as defined by SGPT (ALT) > 3 times the upper limit of normal range
  5. renal dysfunction as defined by serum creatinine > 130umol/L AND/OR proteinuria 1+ or greater (dipstick)
  6. serum triglycerides >10 mmol/L
  7. history of hypertrophic obstructive cardiomyopathy, hemodynamically relevant stenosis of the aortic or mitral valve
  8. sodium depletion or hyperkalemia.
  9. uncorrected volume depletion
  10. endocrine disorder (e.g. hyperthyroidism, Cushing's syndrome, acromegaly, etc.) Participants on thyroid-replacement therapy and TSH < 5.0 mU/L may be enrolled in the study.
  11. contraindications to study diet
  12. any major surgery that is, at the time of screening, planned to take place during the study period.
  13. previously angioedema with ACE Inhibitor or ARB or known hypersensitivity to any component of the study drug formulations (e.g. hereditary fructose intolerance)
  14. history of drug or alcohol dependency within six months prior to signing the informed consent form.
  15. history of active malignancy, chronic inflammatory disorder, or chronic infections which would interfere with protocol completion.
  16. any other medical, social or geographic condition, which, in the opinion of the investigator would not allow safe completion of the protocol and/or safe administration of trial medication
• If the participant has any contraindications to MRI

• Pre-menopausal women (last menstruation >=1 year prior to consent) who:

  1. are not surgically sterile or
  2. are nursing, or pregnant, or
  3. are of child-bearing potential and are NOT practicing acceptable methods of birth control, or do NOT plan to continue practicing an acceptable method throughout the study, AND do not agree to periodic pregnancy testing during participation in the study.
• Intention to go on weight - reducing medications or weight-loss diets during the study period
• Significant fluctuations in weight over past 3 months(e.g. >10%)
• Household member currently in study
• Any investigational drug therapy within one month of signing the informed consent form.
• Participant has knowledge that he/she will be unable to consume study foods for >2 weeks during treatment phase of study
• <70% compliant during run-in
• Unable to reduce total fat consumption to <40% and/or reduce saturated fat consumption to <15% during run-in

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 30 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT00147264
• Other Study ID Numbers: 502.433; BI Pharmaceuticals - 502.433; CIHR - 116099
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Not Provided
• Original Responsible Party: Same as current
• Current Study Sponsor: McMaster University
• Original Study Sponsor: Hamilton Health Sciences Corporation

Collaborators

• Boehringer Ingelheim
• Canadian Institutes of Health Research (CIHR)
• Heart and Stroke Foundation of Canada
• Medtronic

Investigators

• Principal Investigator: Arya M Sharma, MD, FRCPC; McMaster University

• PRS Account: McMaster University
• Verification Date: December 2016