Recent Advances in the Use of Orlistat in the Treatment of Abdominal Obesity and Associated Cardiometabolic Risk Factors

INTRODUCTION

A large proportion of the population in western society today has a sedentary lifestyle and easy access to energy-dense food that can be consumed in large amounts. This environment leads to a positive energy balance and an increased risk for the development of obesity. Obesity (defined as a body mass index (BMI) above 30 kg/m) has become a major health problem in several parts of the world and has overtaken smoking as the leading preventable cause of premature death []. Even though BMI has been a useful measurement in defining obesity, it has become increasingly obvious that it is insufficiently precise in identifying the cardiovascular risk of obese patients. Recent large epidemiological studies in the US and Europe have pointed out the importance of body composition measurements, and specifically the evaluation of abdominal obesity. In these studies, measurements of obesity, such as waist circumference, have been more strongly associated with cardiovascular events and death than BMI [, ]. Furthermore, intra-abdominal obesity is more closely associated with major metabolic complications including the key components of the metabolic syndrome: dyslipidemia, hypertriglyceridemia, and hypertension. When the International Diabetes Foundation presented their revised definition of the metabolic syndrome, abdominal obesity was included as a prominent component [].

Three different mechanisms have been proposed to explain how increased intra-abdominal fat is related to an increased risk for metabolic abnormalities []. (1) The insulin-resistant, hypertrophic fat in the visceral region could increase the exposure of the liver to free fatty acids, leading to hyperinsulinemia, glucose intolerance, and hypertriglyceridemia. (2) Intra-abdominal fat could function as an endocrine organ that produces several factors to generate an insulin-resistant, pro-inflammatory, pro-thrombotic, and pro-hypertensive milieu. (3) Intra-abdominal fat could be a marker of dysfunctional or absent subcutaneous fat, indicating an increase in ectopic fat deposition in several locations.

In the clinical evaluation of obese patients with an increased risk for cardiovascular disease, it is important to aim to reduce intra-abdominal fat. Lifestyle interventions, including diet and physical activity, should be first-line treatments; however, weight-loss drugs might also be considered as valuable additional treatment options. Orlistat (tetrahydrolipstatin) is a pharmacological agent available for the long-term treatment of obesity. It is a derivative of lipstatin and inhibits gastric and pancreatic lipase degradation of triglycerides in the intestine. Due to this inhibition, triglycerides cannot be hydrolyzed and absorbed as free fatty acids, causing them to be excreted unmetabolized through the gastrointestinal channel. The effect of the drug, therefore, is to both reduce the uptake and increase the excretion of fat. Orlistat is prescribed at a dose of 120 mg tid (blocking approximately 30% of ingested fat from being absorbed) or sold over-the-counter at a dose of 60 mg tid (blocking approximately 25% of ingested fat from being absorbed). Orlistat has been investigated in several large studies that have demonstrated its efficacy and safety, and it is currently available in more than 120 countries, with more than 20 million doses having been distributed worldwide (, May 2010). The purpose of the present report is to provide a short review of the available data regarding the effects of orlistat on abdominal obesity and associated metabolic disturbances.

Keywords

abdominal obesity, orlistat, hyperglycemia, dyslipidemia, hypertension, atherosclerosis, cardiovascular disease,