A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients

Protocol Merck 318-00: A Double-Blind, Placebo-Controlled, Randomized, Parallel, Clinical Trial To Study The Effect Of Losartan Potassium On Endothelial Dysfunction And Insulin Resistance In Obese Patients With Impaired Fasting Glucose

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00675987

Enrollment

Registered

2008-05-12

Start date

2007-05-31

Completion date

2008-12-31

Last updated

2018-09-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hyperglycemia, Hypertension, Obesity

Keywords

Impaired Fasting Glucose FPG >100-<126 mg/dL

Brief summary

The main purposes of this study are to find out if the study drug losartan (Cozaar) or placebo (sugar pill) has an effect on insulin sensitivity (how your body responds to insulin) and to measure the effect of the study drug losartan or placebo on how the arteries in your arm dilate (enlarge to carry more blood). We hope to learn if taking losartan changes the amount of certain proteins in the blood that effect blood vessel function. Losartan is approved by the US FDA to treat high blood pressure. It will take approximately 4 months for you to complete this study.

Interventions

DRUGlosartan

losartan 100 mg tablets 1 tab po QD

DRUGPlacebo control

Placebo 1 po QD

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

OTHER

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 75 Years

Healthy volunteers

Inclusion criteria

* Currently taking 1 or no antihypertensive medication * Male and female between 18 and 75 years of age * Mean trough sitting diastolic blood pressure (SiDBP) ≥80 and \< 100 mm Hg * Mean trough sitting systolic blood pressure (SiSBP) ≥120 and \<160 mm Hg * Non-diabetic patients with fasting plasma glucose ≥100 mg/dL and \<126 mg/dL * Body mass index (BMI) \>30 and \<40 * Waist circumference \>40 inches in males, \> 35 inches in females * A patient who is of reproductive potential and agrees to remain abstinent or use acceptable methods of birth control (intrauterine device (IUD), diaphragm with spermicide, contraceptive sponge, condom, hormonal contraception, vasectomy) within the projected duration of the study

Exclusion criteria

* Secondary hypertension of any etiology (renal artery stenosis, coarctation of the aorta or pheochromocytoma, hypertension induced by oral contraceptives) * History of malignant hypertension * Any clinically significant renal disease including single functioning kidney, and known history of anuria. Any severe renal impairment, as manifested by serum creatinine more than 1.5 mg/dL, or proteinuria \>2+ by urine dipstick * Known sensitivity or intolerance to angiotensin II receptor antagonists * Type I or II diabetes * Inability or unwillingness to abstain from taking prohibited medications during the study period * History of myocardial infarction (MI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), congestive heart failure (CHF), unstable angina, transient ischemic attack (TIA), or cerebrovascular accident (CVA) * Concomitant cardiac conditions that would make it unsafe to participate in the trial (e.g., clinically significant atrioventricular (AV) conduction disturbance, atrial flutter, atrial fibrillation, potentially life-threatening ventricular arrhythmias, decompensated valvular disease, presence of hemodynamically significant obstructive valvular disease, or cardiomyopathy) * History of angioedema and/or organ damage from hypertension * Serum potassium \< 3.5 or \> 5.5 mEq/L * Any clinically significant laboratory value which in the investigator's judgment could be clinically significant to the outcome of this study. * History of clinically important gastrointestinal resection or malabsorption * Patient with a history or current evident of any condition, therapy, lab abnormality, or other circumstance that might confound the results of the study, or interfere with the patient's participation for the full duration of the study, such that it is not in the best interest of the patient to participate. (Including but not limited to: recent or current alcoholism, drug abuse within the prior 2 years, mental or legal incapacitation, any disease which could reasonably be expected to be fatal or life-threatening, or a history of malignancy ≤ 5 years prior to signing informed consent.) * Currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent. * Inability to be taken off all current antihypertensive medication and placed on placebo for up to 12 weeks. * Unwillingness or unlikely to adhere to the study procedures, keep appointments, or is planning to relocate during the study. * Arm circumference great than 52 cm * Smokers or former smokers who have quite less than 1 year prior to Visit 1 * Anemia (Hemoglobin \< 11) * Allergy to latex * Deformed hands and/or fingers that would interfere with the collection of pulse volume amplitude measurements * History of Raynaud's disease or any other vascular condition * Bilateral mastectomy * Aortic stenosis * Patient is taking high doses of antioxidant supplements (vitamins, minerals, or other)

Design outcomes

Primary

Measure	Time frame	Description
Insulin Sensitivity Utilizing the Euglycemic Hyperinsulinemic Clamp	baseline, 8 weeks	Insulin clamp derived insulin sensitivity, as insulin stimulated glucose disposal corrected for steady state insulin level.
Insulin Sensitivity Utilizing Endothelial Function as Assessed by Pulse Volume Amplitude	baseline, 8 weeks	Endothelial function assessed as the ratio of pulse volume amplitude after compared with before a reactive hyperemia stimulus, measured by peripheral (fingertip) arterial tonometry. Reported values indicate the percentage change from Baseline in the ratio of pulse volume amplitude after compared to before the reactive hyperemia stimulus.

Secondary

Measure	Time frame	Description
Change in VCAM-1(Vascular Cell-adhesion Molecule-1)	baseline, 8 weeks	VCAM-1 is an immunoglobulin-like adhesion molecule expressed on activated endothelial cells.
Change in MCP-1 (Monocyte Chemoattractant Protein-1)	baseline, 8 weeks	MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages.
Change in Urine Albumin/Creatine	baseline, 8 weeks	Urine was obtained to assess for the presence of microalbuminuria.
Change in F2-isoprostanes	baseline, 8 weeks	F2-isoprostanes is a marker of oxidative stress.
Change in E-selectin	baseline, 8 weeks	E-selectin is expressed on inflamed endothelial cells in response to treatment with inflammatory cytokines.
Change in Ox-LDL (Oxidized Low-density Lipoprotein)	baseline, 8 weeks	ox-LDL measures protein damage due to the oxidative modification of the ApoB subunit on LDL cholesterol.
Change in hsCRP (High-sensitivity C-reactive Protein)	baseline, 8 weeks	hsCRP (high-sensitivity C-reactive protein) is a marker of inflammation

Countries

United States

Participant flow

Participants by arm

Arm	Count
Losartan 100 mg 1 Tab po QD Losartan 100 mg 1 tab po QD	26
Placebo 1 Tab po QD Placebo 1 tab po QD	27
Total	53

Baseline characteristics

Characteristic	Placebo 1 Tab po QD	Losartan 100 mg 1 Tab po QD	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	27 Participants	26 Participants	53 Participants
Age, Continuous	53.8 years STANDARD_DEVIATION 8.3	51.1 years STANDARD_DEVIATION 10.5	52.5 years STANDARD_DEVIATION 9.5
Region of Enrollment United States	27 participants	26 participants	53 participants
Sex: Female, Male Female	12 Participants	14 Participants	26 Participants
Sex: Female, Male Male	15 Participants	12 Participants	27 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 26	0 / 27
serious Total, serious adverse events	0 / 26	0 / 27

Outcome results

Primary

Insulin Sensitivity Utilizing Endothelial Function as Assessed by Pulse Volume Amplitude

Endothelial function assessed as the ratio of pulse volume amplitude after compared with before a reactive hyperemia stimulus, measured by peripheral (fingertip) arterial tonometry. Reported values indicate the percentage change from Baseline in the ratio of pulse volume amplitude after compared to before the reactive hyperemia stimulus.

Time frame: baseline, 8 weeks

Population: analysis was ITT, but limited to those with interpretable data (3 clamp studies were excluded)

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Insulin Sensitivity Utilizing Endothelial Function as Assessed by Pulse Volume Amplitude	1.76 percentage change	Standard Deviation 0.7
Losartan	Insulin Sensitivity Utilizing Endothelial Function as Assessed by Pulse Volume Amplitude	2.11 percentage change	Standard Deviation 0.7

Primary

Insulin Sensitivity Utilizing the Euglycemic Hyperinsulinemic Clamp

Insulin clamp derived insulin sensitivity, as insulin stimulated glucose disposal corrected for steady state insulin level.

Time frame: baseline, 8 weeks

Population: analysis was ITT, but limited to those with interpretable data (3 clamp studies were excluded)

Arm	Measure	Value (MEAN)	Dispersion
Placebo	Insulin Sensitivity Utilizing the Euglycemic Hyperinsulinemic Clamp	5.3 mg/kg/min	Standard Deviation 4.5
Losartan	Insulin Sensitivity Utilizing the Euglycemic Hyperinsulinemic Clamp	2.8 mg/kg/min	Standard Deviation 1.7

Secondary

Change in E-selectin

E-selectin is expressed on inflamed endothelial cells in response to treatment with inflammatory cytokines.

Time frame: baseline, 8 weeks