Dirlotapide, a U.S. Food and Drug Administration-Approved First-in-Class Obesity Drug for Dogs—Will Humans Be Next?
J Diabetes Sci Technol. 2007 May; 1(3): 314–316.
Dirlotapide is the first FDA-approved product in a new class of drugs called selective microsomal triglyceride transfer protein (MTP) inhibitors. These types of agents block the assembly and release of lipoproteins into the bloodstream.6 The mechanism for the weight loss associated with dirlotapide is not completely understood but is thought to result from reduced fat absorption along with a satiety signal from lipid-filled cells lining the intestine. MTP is essential for the synthesis of both chylomicron in the intestine and very low-density lipoprotein (LDL) in the liver.
In another study,9 a different MTP inhibitor (EGR-773, previously BMS 201038, i.e. lomitapide) was administered to a cohort of six subjects with familial hypercholesterolemia to reduce LDL production and lower serum cholesterol levels. The subjects' initial mean BMI was high-normal at 24.8. After 4 weeks of therapy, the subjects' weights fell by a mean 4.4% (p = 0.06) and the weights returned to baseline following a 4-week washout period. This treatment reduced plasma LDL cholesterol levels by up to 50% and triglyceride levels by up to 65%, and had no clinically significant effects on high-density lipoprotein cholesterol levels. Steatorrhea was controlled by the restriction of dietary fat and dosage adjustments.9 Elevated aminotransferase levels occurred in four of six of the subjects, and magnetic resonance imaging-documented elevations of hepatic fat occurred in every subject. These enzyme and fat abnormalities returned to normal within 4 weeks of discontinuing the drug, except for one subject in whom the hepatic fat accumulation resolved after 14 weeks. The investigators expressed concern that the aminotransferase elevations and steatosis were potentially serious adverse events that should not be underestimated and recommended long-term studies of MTP inhibitors under carefully monitored conditions to fully determine safety of these agents.