Type I hyperlipoproteinemia is a rare, autosomal recessive metabolic disorder characterized by extreme hypertriglyceridemia due to a deficiency in lipoprotein lipase or related proteins. Treatment of these patients is challenging as triglyceride-lowering medications are ineffective. A low fat diet is helpful, however, despite good dietary compliance, some patients continue to have severe hypertriglyceridemia and recurrent pancreatitis which can be life threatening. Therefore, this study will investigate whether inducing dietary fat malabsorption or inhibiting chylomicron formation will cause further lowering of serum TG beyond the effect of limiting dietary fat intake. The investigators will assess the efficacy and safety of an inhibitor of intestinal lipase (Orlistat) and an intestinal-specific inhibitor of microsomal triglyceride transport protein (MTP) involved in the assembly and secretion of chylomicrons (SLx-4090), alone and in combination, for reducing serum triglyceride levels in patients with type I hyperlipoproteinemia. This study will enroll 20 patients with type I hyperlipoproteinemia in a randomized, double-blind, placebo-controlled, cross-over trial. After a baseline evaluation, the subjects will be randomly assigned to placebo/placebo, Orlistat/placebo, SLx-4090/placebo or Orlistat/SLx-4090 for the duration of four weeks followed by a one week wash out period. During the last week of each study period, fasting blood samples will be drawn for three consecutive days for serum lipids and chemistry panel. The primary endpoint will be serum triglycerides;the secondary endpoint variables will be fasting and postprandial serum chylomicron-TG levels, postprandial serum TG levels during a meal tolerance test and retinyl palmitate levels during a meal tolerance test, and episodes of acute pancreatitis. Repeated measures analysis of variance will be used for statistical comparisons.
Treatment of type I hyperlipoproteinemia is challenging as currently available triglyceride-lowering medications are ineffective. A low fat diet is the only option, however, despite good dietary compliance, some patients do not respond. Therefore, we wish to investigate whether inhibiting dietary fat absorption and chylomicron formation using pharmacological agents will cause further lowering of serum triglycerides beyond the effect of limiting dietary fat intake.