Sibutramine
Sibutramine helps control feelings of hunger and appetite by regulating neurotransmitters involved in energy intake and expenditure. Sibutramine increases signal transmission between nerves in the central nervous system (CNS).

Sibutramine has demonstrated energy-producing (thermogenetic) effects in animal studies (Connoley et al 1999). Obese Zucker rats treated with 10 mg/kg of sibutramine were found to consume smaller amounts of carbohydrates and fats (LeBlanc et al 2003), resulting in both increased energy expenditure and decreased body weight (Casado et al 2003). Most interestingly, sibutramine targets a type of fat known as "brown" fat. "Brown" fat activation is thought to allow more calories to be burned than stored (Giordano et al 2002).

In a 24-week clinical study consisting of 1047 patients treated with varying doses of sibutramine or a placebo, sibutramine demonstrated dose-responsive weight loss ( Weintraub et al 1991; Bray et al 1996; Hanotin et al 1998; Bray et al 1999). Even intermittent sibutramine treatment was found to reduce body weight (Wirth et al 2001).

A 2004 study of obese patients with type 2 diabetes found treatment with sibutramine was associated with significant reductions in body fat mass and weight. Significant improvements in plasma glucose control, plasma lipids, and markers of insulin resistance were also observed (Tankova et al 2004).

Another study of obese patients treated for 12 months with a combination of sibutramine and a low- calorie diet demonstrated significant improvements in glucose tolerance, insulin sensitivity, and some lipid levels (Sabuncu et al 2004). Further, sibutramine, when combined with metformin, was also shown to be a useful adjunctive treatment for obese individuals with type 2 diabetes mellitus (McNulty et al 2003).

Sibutramine is generally well tolerated. However, safety concerns have arisen regarding possible increased heart rate (5-6 beats per minute increase) and blood pressure (1-2 mm Hg increase) (de Simone et al 2005; Gaciong et al 2005; Faria et al 2005; Jordan et al 2005). Individual response to sibutramine may vary; therefore, blood pressure and heart rate should be monitored carefully.

Sibutramine should not be taken with other centrally acting antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, ergotamine derivatives, opiates, herbs such as St. John's wort, supplement precursors to serotonin (e.g., L-tryptophan), and certain other medications because of the very rare but potential risk of serotonin syndrome (Trakas et al 2000; Giese et al 2001).

Orlistat
Orlistat is an inhibitor of intestinal lipase, an enzyme involved in the breakdown of dietary fat. At a therapeutic dose of 120 mg three times daily with main meals, orlistat inhibits the absorption of approximately 30 percent of the dietary fat ingested.

Based on a weight-reduction diet of about 2200 calories a day, this would amount to a 200-calorie reduction in total caloric intake.

Animal studies have demonstrated orlistat'sability to inhibit absorption of fat regardless of the type of fat (e.g., saturated fat, polyunsaturated fat) (Porsgaard et al 2003), as well as the absorption of triglycerides (Isler et al 1995). Experiments in mice suggest that orlistat treatment also reduce interest in consuming dietary fat (Ackroff et al 1996). Further, in rats, the use of orlistat has demonstrated decreased atherosclerosis in the aorta (Ueshima et al 2004).

Clinical studies with orlistat have produced positive results. In double-blind, placebo-controlled, parallel-group randomized studies, a total of 171 subjects received oral daily doses that ranged from 30 to 1200 mg orlistat or a placebo three times a day for 9 to 10 days, resulting in a steep dose- response up to approximately 400 mg/day (Zhi et al 1994). Further, early dose-ranging trials showed that an additional weight loss of 1.75 kg with 360 mg a day of orlistat (120 mg three times daily) was observed in a 12-week period (Drent et al 1995).

A 2004 double-blind study showed that orlistat combined with a reduced-calorie diet produced weight loss and improvements in risk factors in overweight and obese patients with poorly controlled type 2 diabetes, hypertension, or hypercholesterolemia. (Guy-Grand et al 2004). A prospective, multicenter, open-label, randomized, controlled study showed that orlistat modified several cardiovascular risk factors in patients with both metabolic syndrome and type 2 diabetes (Didangelos et al 2004).

The Xenical in the Prevention of Diabetes in Obese Subjects trial (a four-year study involving more than 3000 patients randomized to either orlistat 120 mg three times daily or placebo) showed that orlistat treatment resulted in a greater reduction in the incidence of type 2 diabetes over four years and produced greater weight loss in a clinically representative obese population (Torgerson et al 2004).

Orlistat is generally well tolerated, although side effects can include flatulence and frequent loose stools but not frank diarrhea or intestinal malabsorption (Harp 1999). Consistent with orlistat's mechanism of action, malabsorption of fat-soluble vitamins is a potential risk (Cahill et al 1999).