A 12 Week, 3-Period Study to Evaluate the Effects of a Dietary Supplement on Lipid Metabolism
Condition: Hyperlipidemia
MeSH terms: Hyperlipidemias
Study type: Interventional

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.
    

Detailed 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.
    

Intervention name(s): Placebo; Low Dose Grape Blend; High Dose Grape Blend
Intervention type(s): Dietary Supplement; Dietary Supplement; Dietary Supplement
Intervention description(s): Three placebo capsules consumed prior to breakfast each day for 4 weeks; Three low dose grape blend capsules consumed prior to breakfast each day for 4 weeks.; Three high dose grape blend capsules consumed prior to breakfast each day for 4 weeks.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science