A 12 Week, 3-Period Study to Evaluate the Effects of a Dietary Supplement on Lipid Metabolism

Hyperlipidemia Clinical Trial

Official title: A Randomized, Double-Blind, 3-Period Crossover Study to Evaluate the Effects of a Dietary Supplement Containing Botanical Extracts on Fasting and Postprandial Lipid Metabolism in Apparently Healthy, Overweight and Obese Individuals

Status Completed

Clinical Trial Summary

This study will evaluate the effects of encapsulated botanical extracts, previously shown to inhibit the enzyme diacylglycerol-acyltransferase-1 (DGAT-1) in vitro, on fasting and postprandial lipid metabolism during an oral fat tolerance test (OFTT) in apparently healthy, overweight and obese adult men and women.

Clinical Trial Description

Medications currently approved for the treatment of obesity act primarily to promote a state of energy balance - by either suppressing appetite or interfering with lipid absorption in the small intestine. Similarly, it may be possible to reduce or inhibit the synthesis of triglycerides (TG) from dietary fat by targeting the activity of diacylglycerol-acyltransferase-1 (DGAT-1) in the enterocytes of the small intestine.

DGAT-1 catalyzes the final step in the biosynthesis of TG and is most abundantly expressed in the small intestine and adipose tissue. DGAT-1 in enterocytes is critical for assembly of TG from fatty acids derived from food intake. Ingested dietary fat is cleaved to monoacylglycerol and free fatty acids by lipases in the gut lumen and these are next taken up by the enterocytes, where they are re-esterified to TG in the postprandial period. TG is eventually released into circulation, primarily transported by chylomicrons. Thus, DGAT-1 plays a critical role in the absorption of dietary fat and inhibition of DGAT-1 has been shown to delay and decrease re-esterification of dietary fats into circulating TG. It is hypothesized that this effect may lead to decreased deposition of excess dietary fat as adipose tissue, perhaps due to increased fatty acid oxidation in the enterocytes.

The potential physiological benefits of DGAT-1 inhibition lead to the development of the potent, selective DGAT-1 inhibitor, AZD7687. Human clinical trials of AZD7687 demonstrated attenuation of postprandial TG excursions, consistent with inhibition of gut DGAT-1. However, this compound has limited, if any, therapeutic potential due to profound gastrointestinal (GI) side effects, particularly diarrhea, nausea, and abdominal cramping which were deemed intolerable. Moreover, no consistent dose-related treatment effects on body weight, glucose or lipid metabolism were found in the small trials which were deemed to be non-representative of the target therapeutic population.

Both cell-free and cellular in vitro models have been used to identify botanical extracts that have potential to inhibit DGAT-1. In a follow-up 7-d parallel arm proof-of-mechanism human clinical trial, each of four lead ingredients (2 g/d) were evaluated for the ability to inhibit the intestinal release of dietary fat into circulation following a high-fat meal challenge using post-prandial TG response as a surrogate marker. Of the four lead botanical ingredients, whole grape extract (WGE) reduced fasting and postprandial TG levels (total area under the curve from 0 to 6 h) by ~ 7% to 8% following a high-fat meal challenge. This demonstration of efficacy, albeit modest, was sufficient to warrant continued exploration. Importantly, only a few subjects reported very mild GI side effects, primarily bloating, in this trial.

Combinations of WGE with other botanical extracts possessing biological activity against supportive secondary mechanisms that might strengthen the overall inhibition of dietary fat release into circulation and fat deposition were then explored. To examine potential synergistic interactions, WGE was combined with other ingredients known to act on complementary biological pathways that converge into a single efficacy outcome; in this case, cellular TG levels. Ingredients that had effects on both glucose and fatty acid metabolism that could ultimately synergize with the DGAT-1 pathway were chosen. The complementary pathway targets chosen for these experiments were Peroxisome-Proliferator-Activated Receptor-gamma Coactivator 1-alpha (PGC1-α) and Sterol Regulatory Element Binding Protein 1c (SREBP1c).

In the cellular DGAT-1 model, grape seed extract (GSE) resulted in a significant inhibition of DGAT-1 activity when combined with WGE. The combination index (CI), a quantitative measure of synergy, indicated a strong synergistic effect (CI = 0.61). Synergy occurred at a 1:1 ratio of WGE to GSE, and at ratios that induced no effect on DGAT-1 activity when either was used alone. The synergy data, together with the proof of mechanism clinical data, forms the basis for conducting the presently proposed clinical trial at a WGE level below that used in the previous study. ;

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Hyperlipidemia
• Hyperlipidemias

• NCT number: NCT02366156
• Study type: Interventional
• Source: Access Business Group
• Status: Completed
• Phase: N/A
• Start date: July 2014
• Completion date: March 2015