Approaches to the Pharmacological Treatment of Obesity

Victoria Salem; Stephen R Bloom

Disclosures

Expert Rev Clin Pharmacol. 2010;3(1):73-88. 

In This Article

What are the Current Treatment Options?

Lifestyle

Although not yet matched by a robust evidence base, many government policy-makers support the introduction of societal interventions as a means of encouraging people away from obesogenic environments and behavior patterns. Such efforts are important, but seem largely impractical as an immediate means of tackling the obesity crisis as it stands. Dietary and exercise advice remains the mainstay of the medical management of obesity and should be encouraged alongside all other treatment adjuncts. Sustained caloric restriction (to 1500 kcal/day for women and 1800 for men), regardless of dietary macronutrient composition or regimen,[22] has fairly similar effects on weight loss, ranging from 3–5 kg over 2 years.[23] The addition of physical exercise facilitates weight loss by increasing energy expenditure and increasing basal metabolic rate through an increase in muscle mass. Unfortunately, lifestyle interventions alone rarely result in long-term weight loss and the majority of dieters return to baseline weight within 3–5 years. This even holds true for participants in weight-loss trials who are offered education and intensive support to help prevent weight regain,[24,25] and adds support to the concept that appetite may be consciously overridden in the short-term but in the longer term this is superseded by a biologically determined 'set-point'.

Pharmacotherapy

In the midst of the obesity-related health crisis, the case for safe and efficacious pharmacotherapies is clear. Unfortunately, drugs currently available for long-term weight management are limited in number and efficacy. There are many more examples of drugs used historically for weight loss that have been removed owing to significant side effects, including hypertension, severe mood disturbance, serious cardiac pathology and increased mortality. This has often been due to the use of centrally acting adrenergic stimulants, which suppress appetite and increase energy expenditure though generalized sympathetic activation. At present, there remain three sympathomimetic amphetamine-like drugs still approved by the US FDA as weight-loss adjuncts; phentermine, diethylpropion and phendimetrazine. This drug class has been associated with side effects including systemic and pulmonary hypertension, as well as the obvious potential for abuse and addiction. They are approved for short-term use only and so they have limited use in the long-term management of obesity.[26] FDA guidance for the approval of weight-loss therapies intended for long-term use recommends a 5% placebo-corrected weight reduction that should be maintained for at least 12 months after treatment initiation. Small, sustained reductions in weight can significantly improve cardiovascular risk factors, particularly glucose tolerance, in overweight and obese individuals. The target adult population for drug therapy is set at BMI above 30 (or >27 with comorbidities). This opens up a potentially huge market for weight-loss drugs. However, there are currently only two drugs licensed in the USA for the long-term treatment of obesity. The first is orlistat (Xenical; Roche) and the second sibutramine (Meridia/Reductil; Abbott). Orlistat irreversibly inhibits intestinal lipases by covalently binding to a serine residue on the active site. Lipases are required to hydrolyze dietary triglycerides into absorbable FFAs. With orlistat, up to 30% of ingested fat is not absorbed. This is the reason for the most common adverse events reported with the drug–gastrointestinal discomfort and fecal urgency. In fact, some claim that the benefit of the drug is best seen in patients who learn to switch to a low-fat diet in order to avoid such side effects. In the longer term, there is also the risk of deficiency of fat-soluble vitamins. Between 1999 and 2008, six cases of liver failure in patients taking orlistat were reported to the FDA's Adverse Event Reporting System. Analysis of these and other reports of liver injury associated with orlistat use is being undertaken by the agency, although as yet no clear link has been identified.[203] In terms of efficacy, meta-analysis of clinical trials indicate a mean weight loss for orlistat-treated patients of 2.89 kg compared with placebo-treated patients over 12 months.[27] This mix of modest weight loss and often intolerable side effects leads to high attrition rates in users. One survey of 17,000 orlistat users in Canada reported rates of ongoing use of less than 10% at 1 year and 2% at 2 years.[28] In 2007, GlaxoSmithKline (GSK) under licence from Roche released a low-dose, over-the-counter formulation of orlistat (Alli). Initial US sales in that year reached $119.6 million but fell to $76.7 million in 2008. European trends are following a similar pattern.[202] Sibutramine belongs to the class of selective serotonin and noradrenaline reuptake inhibitors that elevate synaptic concentrations of 5-hydroxytriptamine (5-HT).[29] It may also increase energy expenditure through sympathetic activation[30] and the elevated heart rate and blood pressure seen with the drug may be a cause for concern. Analysis from the ongoing Sibutramine Cardiovascular Outcomes (SCOUT) trial, which is a prospective randomized, double-blind, placebo controlled trial in cardiovascular high-risk, overweight and obese subjects, has raised some concerns about a possible increased incidence of cardiovascular events in such patients taking the drug. Further FDA guidance is awaited.[204] Meta-analysis of earlier clinical trials reveals that after 1 year, an average of 4.2 kg more weight is lost by patients taking sibutramine, with an associated 20–30% increased probability of losing at least 5% of their bodyweight.[27]

Surgery

At present, the most effective means of significant and sustained weight loss for obese patients is bariatric surgery. Gastric banding is a restrictive procedure that involves the insertion of an adjustable band around the upper portion of the stomach to limit the amount of food that can be ingested. Roux-en-Y gastric bypass involves the formation of a small stomach pouch and bypass of the proximal small bowel. Although malabsorption is not a major feature of modern gastric bypass surgery,[31] patients undergoing this type of procedure lose much more weight (in the order of 30%) than those undergoing gastric banding alone (20% loss).[32] They also experience a prompt reduction in appetite and improvement in glucose metabolism, well before the advantages of weight loss through restricted intake have had time to accrue. These added advantages of bypass surgery are thought to be due to an alteration in the release profile of gut hormones. Postprandial levels of glucagon-like peptide (GLP-)1 and peptide tyrosine tyrosine (PYY), which are appetite-inhibiting gut hormones, are elevated following gastric bypass surgery but not after gastric banding. GLP-1 also acts at pancreatic β-cells to augment glucose-dependent insulin release,[32–35] referred to as the incretin effect. However, bypass surgery is costly, in many cases irreversible and associated with significant risks, including a 0.5% mortality rate.[36] There is, therefore, a huge incentive to provide safe pharmacological alternatives.

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