Clinical trial NCT01942291: Short-term Effect of Extended-release Niacin on Endothelial Function.
Official title: Short-term Effect of Extended-release Niacin With and Without the Addition of Laropiprant on Endothelial Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypoalphalipoproteinemia
Keywords: Niacin
Endothelial function
Laropiprant
HDL
Lead sponsor: University of Campinas, Brazil
Sponsor class: OTHER
First posted: 2013-09-13
Enrollment: 18
Sex: ALL
Minimum age (years): 20
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Individuals with reduced plasma concentration of high-density lipoprotein (HDL) cholesterol are more susceptible to oxidative stress and often present reduced endothelial function, which has been mainly related to this susceptibility. Studies in animal and cell models have demonstrated that niacin activates both GPR-109A in leukocytes and heme oxygenase-1 (HO-1) pathway promoting strong anti-inflammatory and anti-oxidative effects. . In this context, the aim of this study was to investigate the short-term effect of niacin on endothelial function and verify the existence of interaction of PGD2 receptor antagonist, i.e. laropiprant (LRPT), in subjects with low HDL-cholesterol (HDL -C).

Detailed description: Study design and treatments The study was randomized, double-blind, controlled, using a 2-way crossover design with both treatment periods and washout time lasting 7 days. Subjects were allocated by simple randomization to extended-release niacin 1g/day alone (ERN, Metri, Libbs Farmacêutica, São Paulo, Brazil) or niacin associated with LRPT 1g/20mg (ERN/LRPT, Cordaptive, Merck, São Paulo, Brazil). Medications were kindly supplied by Libbs and Merck. Plasma samples and brachial artery reactivity were obtained at baseline, 7th day of treatment 1, 7th day after washout and 7th day of treatment 2.

Study Measurements The following blood measurements were performed using the Modular Hitachi system and Roche Diagnostics (Mannheim, Germany) reagents: glucose (GOD-PAP), triglycerides (TG)(GPO-PAP), HDL-C (HDL-C plus 3rd generation) and C-reactive protein (CRP) (high-sensitivity CRP, Cardiophase, Dade Behring, Marburg, Germany). LDL cholesterol was calculated by the Friedewald formula. HDL size was measured by laser scattering (Zetasizer - Nanoseries DTS 1060, Malvern Instruments, Worcestershire, UK). Total and direct bilirrubin was measured by the Jendrassik-Grof method (Roche/Hitachi analyzer).

The cholesteryl ester transfer protein activity was measured by an endogenous assay. Aliquots of the whole plasma (in which LCAT activity was inhibited by DTNB 9 μL/mL) were added to HDL-\[3H\]cholesteryl ester fractions and simultaneously incubated at 4°C and 37°C for 4h. Apo-B containing lipoproteins, present in the incubation mixture, were then precipitated; the CE radioactivity in the supernatant represented the net rate at which CE mass was transferred and values expressed as percent of \[3H\] cholesteryl ester transferred/4 hours depended upon the plasma concentrations of HDL, TG-rich lipoproteins and CETP simultaneously.

Endothelial-dependent vasodilation was assessed by ischemia-induced reactive hyperemia. Briefly, after 12-hour overnight fasting patients were examined at 8 a.m. in a quiet room at 22ºC by using a ultrasound equipment Vivid i (GE Healthcare, Wauwatosa, WI, USA) with a high-resolution (up to 13 MHz) vascular probe (12l-RS, GE Healthcare, Wauwatosa, WI, USA) in B-mode. The cardiac cycles were monitored simultaneously by electrocardiography coupled to the equipment. Flow-mediated dilation (FMD) was assessed after 5-minutes inflation of a cuff placed below the transducer, 50 mm Hg above the systolic blood pressure. Two-dimensional images of the brachial artery were obtained during 5 minutes from the longitudinal axis approximately 5-10 cm above the antecubital fossa. The maximum expansion of the diameter of the brachial artery was measured in triplicate at the peak of the T wave of the cardiac cycle before the interruption of the flow and post deflation.

Eligibility criteria: Inclusion Criteria:

* asymptomatic individuals
* plasma HDL-C levels \<40 mg/dL

Exclusion Criteria:

* symptomatic atherosclerotic disease
* diabetes
* liver disease
* renal disease
* thyroid dysfunction
* indication for or use of lipid-lowering treatment in the last six months
* use of anti-inflammatory treatment in the last 30 days
* current or previous diagnosis of cancer or immune inflammatory diseases
* chronic obstructive pulmonary disease
* infectious disease manifested in the last 3 months
* body mass index ≥ 26 kg/m2

Primary outcomes:
measure: The short-term effect of niacin on endothelial function.
timeFrame: 7 days
Secondary outcomes:
measure: Plasma C-reactive protein levels
timeFrame: 7 days
measure: HDL-C and HDL size
timeFrame: 7 days
Other outcomes:
Locations:
city: Campinas
country: Brazil
facility: University of Campinas
state: SP
Study officials:
affiliation: University of Campinas
name: Andrei C Sposito, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nasser Figueiredo V, Vendrame F, Colontoni BA, Quinaglia T, Roberto Matos-Souza J, Azevedo Moura F, Coelho OR, de Faria EC, Sposito AC. Short-term effects of extended-release niacin with and without the addition of laropiprant on endothelial function in individuals with low HDL-C: a randomized, controlled crossover trial. Clin Ther. 2014 Jun 1;36(6):961-6. doi: 10.1016/j.clinthera.2014.03.012. Epub 2014 Apr 24.