The incidence of obesity is increasing dramatically worldwide. In North America alone,
approximately 60% of the population is either overweight or obese. Obese individuals are at high
risk for the development of metabolic disorders, including insulin resistance, type II diabetes
mellitus and cardiovascular diseases (CVD). In terms of CVD, in particular, obese individuals are at
increased risk for heart diseases and stroke. Dyslipidemia in obesity is a major cause of obesityrelated
CVD. More specifically, the characteristic dyslipidemia of obesity is elevated plasma
triglycerides and low plasma levels of high-density lipoprotein (HDL) particles. Since HDL
particles carry the “good cholesterol” and are highly anti-atherogenic particles, the lowering of
plasma HDL levels in obesity, is of particular concern. Moreover, with every 1% increase in plasma
HDL levels, there is a 1-3% decline in CVD risk. Thus, HDL rising in obesity is an attractive
therapeutic target. However, because of its complex metabolism, developing safe and potent HDL
raising therapies has been a challege. In terms of nonpharmacological therapies, diet and exercise
interventions only raise plasma HDL levels modestly at best (10-15%). Of the current anti-obesity
therapies, orlistat and sibutramine do not raise plasma HDL levels, while rimonabant does directly
increase HDL concentrations. There is concern, however, over the serious central nervous system
side-effects of rimonabant. Furthermore, in terms of HDL raising pharmaceutical therapies, the
most widely used are niacin and fibrates. Fibrates only achieve a modest rise (10-15%) in plasma
HDL, while niacin produces a larger increase (25%); however, due to the induction of flushing with
niacin, it’s use is limited. More recently, non-flushing niacin has been developed which is a
promising therapy. There is currently wide interest in developing new more potent HDL raising
therapies that can induce greater reductions in CVD risk than current therapies. Foremost, the
initially promising cholesteryl ester transfer protein (CETP) inhibitors proved to paradoxically
increase CVD risk. In contrast, infusion of HDL or its protein apolipoprotein A-I has been more
effective at reducing CVD risk. Overall, there are multiple points in the HDL metabolic pathway
that may be targets for future HDL drug therapies and the future in HDL drug therapy holds great
promise as we understand more about HDL’s complex physiology.
Keywords: HDL, cholesterol, obesity, cardiovascular disease.
