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Published on 1 March 2002

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Treating obesity in the 21st century

Greet Vansant
PhD
Professor of Nutrition
Department of Endocrinology, Metabolism and Nutrition
University Hospital Gasthuisberg
Catholic University Leuven, Belgium

Obesity is one of the most common medical problems in industrialised countries and a risk factor for illnesses such as diabetes, hypertension, cardiovascular diseases and degenerative arthritis. It is a cause of significant morbidity and mortality and generates great social and financial costs. In addition, the obese patient often faces social discrimination.

Weight loss has been shown to reduce the risk for many of the comorbid conditions of obesity.
A multidisciplinary approach to the obese patient should include:

  • Identifying potential causes of weight gain.
  • Outlining medical conditions that could ­benefit by weight loss.
  • Tailoring a weight loss programme that is safe and effective for the individual in the long term.

A successful weight loss programme includes:

  • Dietary intervention.
  • Recommendations for physical activity.
  • Behaviour modifications.
  • In a selected group of patients, ­pharmacological or surgical intervention.

Pharmacological intervention

Orlistat
Today, in several European countries, both orlistat and sibutramine are approved for the pharmacological therapy of obesity. Orlistat produces a dose-dependent reduction in dietary fat absorption by inhibiting both gastric and pancreatic lipases. In several studies of up to two years’ duration, the weight loss achieved with orlistat (9%) has been greater than that seen with placebo (6.5%).

Along with weight loss, orlistat also has favourable effects on blood pressure and glucose and insulin levels, both in obese individuals and in obese type 2 diabetic patients.(1) Increased fat losses via the stools are associated with side-effects that may result in withdrawal from treatment.

Recently, in a randomised, double-blind, placebo-controlled multicentre study, the effects of orlistat on weight and on serum lipids were studied in 294 obese patients with hypercholesterolaemia – low-density lipoprotein cholesterol (LDL-C) 4.1–4.7mmol/l.(2)

As in previous studies, orlistat-treated patients lost significantly more weight than those on placebo. Treatment with orlistat was associated with significantly greater changes in total cholesterol and LDL-C levels. For any category of weight loss during the double-blind treatment period, change in LDL-C was more pronounced in orlistat-treated patients than in placebo recipients, indicating that orlistat had a direct cholesterol-lowering effect that was independent of weight reduction.

Adjunction of orlistat during the extension phase in patients who initially received placebo induced a further decrease in weight, total cholesterol and LDL-C. These results confirm previous findings from the Swedish Multimorbidity Study. Again, treatment with orlistat in conjunction with diet promoted significantly greater weight loss and cardiovascular risk factor reduction than diet alone among obese patients at high risk for coronary events.(3)

The efficacy and safety of orlistat have been comprehensively studied. Because orlistat reduces dietary fat absorption, treatment with orlistat can be associated with certain gastrointestinal events, such as oily stools. In general, these effects are mild and transient.

Sibutramine
In most European countries, sibutramine was launched in 2001. Sibutramine is a selective serotonin and noradrenaline reuptake inhibitor. It exerts a weight-reducing effect partly via its anorectic properties. In addition, it may have a moderate thermogenic effect through stimulation of peripheral noradrenergic receptors.

The effects of sibutramine on weight reduction are similar to those of orlistat. Clinical trials indicate that sibutramine given for six months induces a significant dosage-dependent reduction in body weight, which for dosages ranging from 10 to 20mg/day is 3–5kg greater than the weight loss with placebo.(4)

The most common side-effects of sibutramine are dry mouth, headache, fatigue and insomnia. They are generally mild, reversible and diminish over time. The effects of sibutramine have been extensively studied in specific groups of patients, such as obese patients with hypertension or diabetes mellitus. Sibutramine-induced weight loss resulted in improvements in serum levels of triglycerides, high-density lipoprotein cholesterol, uric acid and glucose, and in waist circumference and ­quality-of-life measures.(5) Also, in type 2 diabetic patients, ­sibutramine has been shown to improve glycaemic control.(6) Blood pressure and heart rate increased by a small amount.

In obese patients with controlled hypertension, sibutramine is an effective and well-tolerated ­treatment for weight loss and maintenance. Nevertheless, accurate monitoring of patients’ blood pressure is recommended.

A randomised controlled trial is being planned to start soon to demonstrate the long-term health benefits of weight management with sibutramine plus lifestyle interventions (diet and exercise). Primary outcomes will be cardiovascular morbidity and mortality and progression to type 2 diabetes.

Drugs for the 21st century
Although important progress has been made in the pharmacological treatment of obesity, no “magic bullet” exists as yet. Future targets for pharmacotherapy include:

  • The OB protein leptin.
  • Neuropeptide Y.
  • beta(3)-adrenergic receptors (aiming to increase energy expenditure).
  • Uncoupling proteins 2 and 3.
  • Glucagon-like-peptide 1 (GLP-1).
  • Protein kinase A.
  • Drugs interfering with tumour necrosis factor-alpha or free fatty acid release from the adipose tissue.
  • Agents that slow gastric ­emptying.

However, results so far in terms of efficacy and safety of several of these approaches have been disappointing or preliminary in humans.(6)

The clinical relevance of leptin in the therapy of obesity is probably limited, but cannot be fully evaluated at the moment.

To develop new, perhaps even more specific pharmacological agents, further research is needed to understand the individually different genetic and physiological aetiologies of obesity.

Over the next few years, results of long-term trials (longer than two years) with sibutramine and orlistat will become available. The use of orlistat in children is also under investigation.

Despite the availability of drugs, they should be seen only as adjuvant therapeutic options. The cornerstone of obesity therapy remains permanent lifestyle changes.

References

  1. Uusitupa MI. New aspects in the management of obesity: operation and the impact of lipase inhibitors. Curr Opin Lipidol 1999;10:3-7.
  2. Muls E, et al. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterol- aemia: a randomized, double-blind, placebo-controlled, multicentre study. Int J Obesity 2001;25:1713-21.
  3. Lindgarde F. The effect of orlistat on body weight and coronary heart disease risk profile in obese patients: the Swedish Multimorbidity Study. J Intern Med 2000;248:245-54.
  4. Kolanowski J. A risk-benefit ­assessment of anti-obesity drugs. Drug Safety 1999;20:119-31.
  5.  McMahon FG, et al. Efficacy and safety of sibutramine in obese white and African American patients with hypertension: a 1-year, double-blind, placebo-controlled, multicenter trial. Arch Intern Med 2000;160:2185-91.
  6. Scheen AJ, Lefebvre PJ. Antiobesity pharmacotherapy in the management of type 2 diabetes. Diabetes Metab Res Rev2000;16:114-24.

Resources
International Obesity Task Force
W:www.iotf.org
European Association for the Study of Obesity
President: Dr Xavier Formiguera Sala
T:+34 93 4978912
F:+34 93 4978843
North American Association for the Study of Obesity
W:www.naaso.org

Forthcoming event
9th International Congress on Obesity
24–29 August 2002
Sao Paula, Brazil



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