Orlistat for the Treatment of Type I Hyperlipoproteinemia (T1HLP)

Patients with Type I Hyperlipoproteinemia (T1HLP) have a rare form of hypertriglyceridemia marked by significant chylomicronemia and recurrent episodes of acute pancreatitis. T1HLP is caused by a deficiency of lipoprotein lipase or one of its cofactors. Many patients are a challenge to treat, as the only effective therapy available is an extremely low fat diet. This diet is exceedingly difficult to follow, and despite adherence, many patients still have chylomicronemia and develop acute pancreatitis. Specific Aim: To determine the efficacy of a gastric and pancreatic lipase inhibitor, Orlistat, in reducing serum triglyceride levels in patients with T1HLP.

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, Investigator wish to investigate whether inducing dietary fat malabsorption or inhibiting chylomicron formation will cause further lowering of serum triglycerides (TG) beyond the effect of limiting dietary fat intake. Investigator will study the efficacy and safety of an inhibitor of intestinal lipase (Orlistat) for reducing serum triglyceride levels in patients with Type I hyperlipoproteinemia. Investigator plan to enroll 20 patients with Type I hyperlipoproteinemia in a randomized, double-blind, placebo-controlled, cross-over trial. 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. Repeated measures analysis of variance will be used for statistical comparisons. These results may help in designing novel therapeutic approaches for patients with Type 1 hyperlipoproteinemia.

120 mg of Orlistat will be given 3 times to patients weighing greater than 50 kg and patients weighing less than 40 kg will be given 60 mg of Orlistat 3 times a day for 3 months.

Orlistat is a gastric and pancreatic lipase inhibitor that is approved by the FDA for weight loss. It is available over-the-counter as 60 mg tablets under the trade name Alli, and available by prescription as 120 mg capsules under the trade name Xenical.

Fasting blood samples were collected on three consequetive days at the end of each three month period. Mean values of the three days were calculated.

Inclusion Criteria: Type I hyperlipoproteinemia Fasting serum triglyceride levels of greater than 1000 mg/dL Age > 8 years Exclusion Criteria: Secondary hypertriglyceridemias due to diabetes, renal disease, hypothyroidism, alcoholism and drug therapy such as estrogens and estrogen analogues, steroids, HIVprotease inhibitors, retinoic acid derivatives and interferons Pregnant or lactating women Significant liver disease (elevated transaminases > 2 times upper limit of normal) Alcohol abuse (> 7 drinks or 84 g per week for women and > 14 drinks or 168 g per week for men) Severe anemia (hematocrit < 24%) Drug use (cocaine, marijuana, LSD, etc.) Major surgery in the past three months Congestive heart failure Serum creatinine greater than 2.5 mg/dL Cancer within the past five years Gastrointestinal surgery in the past Current therapy with anti-coagulants, digoxin, and anti-arrhythmics Current therapy with cyclosporine Chronic malabsorption syndromes Cholestasis Acute illnesses such as acute pancreatitis in the last 8 weeks

Patni N, Quittner C, Garg A. Orlistat Therapy for Children With Type 1 Hyperlipoproteinemia: A Randomized Clinical Trial. J Clin Endocrinol Metab. 2018 Jun 1;103(6):2403-2407. doi: 10.1210/jc.2018-00369.