Failure of Diet Drugs Tied to Leptin Resistance
By John Schieszer
TORONTO, Canada—Effective interventions to help obese patients lose weight and keep it off must include a multipronged approach with a behavioral component in addition to pharmacotherapy. New data presented at the annual meeting of the Endocrine Society have demonstrated that currently available medications for weight loss produce only marginal benefits in the long-term, and greater efforts are needed by physicians to target therapies to individual patients.
Robert Lustig, MD
Robert Lustig, MD, said that although lifestyle and drug interventions for obesity can induce weight loss, their acute efficacy is variable, and their ability to maintain weight loss is questionable. He added that only a handful of randomized controlled drug trials have lasted for ≥12 months, and their beneficial effects have been underwhelming.
A meta-analysis performed in 2003 of 16 randomized controlled trials (Cochrane Database Syst Rev. 2003; :CD004094) showed that sibutramine (Meridia) induced only a 4.6% weight loss and orlistat (Xenical) only a 2.9% weight loss compared with placebo over a 12-month study period. A subsequent meta-analysis of 4 randomized controlled trials (Cochrane Database Syst Rev. 2006;:CD006162) concluded that rimonabant (Acomplia) resulted in only a 4.9-kg greater weight loss than placebo at 1 year.
Dr Lustig, of the Division of Pediatric Endocrinology at the University of California, San Francisco, said that the efficacy of these medications attenuates after 4 months of continued use. This is not because of a lack of compliance, altered drug kinetics, or tachyphylaxis, but rather due to leptin resistance, which persists even in the face of pharmacotherapy.
Leptin resistance prevents exogenous leptin from inducing weight loss as it decreases sympathetic tone, which reduces energy expenditure (both resting and voluntary). Leptin resistance also increases vagal tone, which, in turn, increases appetite, insulin secretion, and energy storage. These 2 autonomic changes force the body's weight back to its starting point.
"Leptin is the hormone that goes from your fat to your brain to signal that you have enough energy on board to engage in normal metabolism," said Dr Lustig. "The phenomenon of leptin resistance is involved in the recidivism of obesity and the inability to further weight reduce. The problem is that we have not yet been able to solve the problem of leptin resistance."
In animal studies, when either standard pharmacotherapy or amylin alone is added to secondary exogenous leptin, animals lose more weight than with either agent alone. Clinically, 2 paradigms have resulted in improvement of leptin sensitivity: (1) caloric restriction with subsequent weight loss improves leptin sensitivity, allowing secondary exogenous leptin to effectively promote further weight loss; (2) insulin suppression using the somatostatin agonist octreotide effectively promotes continued weight loss, increased energy expenditure, and improved quality of life—indicators of improved leptin sensitivity. But these effects have been found only in patients with insulin hypersecretion.
Dr Lustig said these paradigms share at their core a reduction in systemic insulin concentrations, suggesting that hyperinsulinemia functions as an endogenous leptin antagonist that promotes leptin resistance. This hypothesis may help explain the meager efficacy of nontargeted obesity therapy and open the door for combination therapy in the future.
"Right now, pramlintide [Symlin] and exenatide [Byetta] are both treatments for diabetes that also appear to have weight-loss effects beyond their suppression of glucose. These effects are now being exploited in clinical trials," Dr Lustig told . "These would not be used as diet pills, but rather as shots. For now, primary care physicians need to view obesity as a chronic disease with numerous causes and etiologies, and they need targeted treatments. We have to target the treatments to the pathology, and until we do that we are probably not going to be successful."
Although many physicians believe that obesity is caused by eating too much and not exercising enough, he said, such thinking is too simplistic. Obesity is a chronic problem that needs to be managed like other chronic conditions.