Type 1 hyperlipoproteinemia (T1HLP) is a rare genetic disorder charecterized by extremely high serum triglycerides and chylomicronemia, and often leads to recurrent acute pancreatitis. Traditionally, the only effective therapy has been an extremely low-fat diet. But following this diet can be challenging and adherence doesn’t guarantee success.
Patients may soon have a more effective option, thanks to research from Nivedita Patni, M.D., Pediatric Endocrinologist at Children’s Health℠ and Assistant Professor of Pediatrics at UT Southwestern, and Abhimanyu Garg, M.D., Division Chief of Nutrition and Metabolic Diseases at UT Southwestern.
In a small pilot trial, they found that an FDA-approved weight loss drug called orlistat reduced participants’ triglyceride levels by more than 50%. Now they’re planning to build on these findings through a larger clinical study.
A Breakthrough Hyperlipoproteinemia Study
Orlistat is a gastric and pancreatic lipase inhibitor that works by blocking dietary fat absorption by about 33%. Dr. Patni and the research team reasoned that blocking dietary fat absorption would also help reduce blood triglyceride levels by reducing chylomicron production in the intestine.
To test this, they recruited two unrelated boys (9 and 11 years old with T1HLP). A randomized, open-label, crossover trial with four periods and two sequences (“orlistat” and “off” for 3 months each) was conducted.
The results were impressive — orlistat reduced triglyceride levels by 53.3% and 53.0% in patient 1, and by 45.8% and 62.2% in patient 2, compared with the two “off” periods. Height and weight were not affected, and metabolic markers stayed safe throughout the trial.
What’s more, the boys did not experience the typical side effects of orlistat (oily and loose stools, abdominal pain) because they maintained an extremely low-fat diet (~15% of the total energy from fat) throughout the study.
Searching for the Genetic Basis of Pediatric Hypertriglyceridemia
A separate study by Drs. Patni and Garg aims to identify novel genes and variants involved in lipid metabolism that contribute to severe hypertriglyceridemia (sHTG) in children.
In adults, sHTG (serum triglycerides ≥ 500 mg/dL) is often caused or exacerbated by uncontrolled diabetes mellitus, alcohol abuse or obesity. But in children, the condition is more likely to be tied to genetic causes. Yet, the molecular basis of pediatric sHTG has not been studied systematically.
The research team aims to enroll 200 children with sHTG (excluding those with secondary sHTG) and their first-degree relatives. The researchers will perform whole exome sequencing on participants’ DNA samples to pinpoint disease-causing mutations. The researchers will also study genotype-phenotype relationships, correlating genotypes with clinical features, body fat distribution, height, weight and serum metabolites.
“While there are medicines that can be helpful for patients with secondary causes, like diabetes, there is no specific therapy for genetic causes of sHTG,” Dr. Patni says. “If we can identify these genes, we can start working on specific therapies to help patients decrease their blood triglyceride levels.”
The Children’s Health Difference
Children’s Health is home to the region’s most advanced lipid disorder clinic, offering access to the latest treatments and clinical trials. Dr. Patni is currently recruiting for both the orlistat and sHTG trials. Learn more about the innovative research and discoveries being made in pediatric endocrinology at Children’s Health.
