Editorials

Drug treatment for obesity

We need more studies in men at higher risk of coronary events

Although obesity, especially abdominal obesity, is the commonest cause of complications such as type 2 diabetes, hypertension, dyslipidaemia, and cardiovascular diseases, doctors most often use drugs to treat the complications rather than the underlying condition. This situation can be attributed to several factors, including lack of recognition of obesity as an important causal factor, doctors' ignorance about the potential contribution of drugs to managing obesity, and a lack of evidence that weight loss drugs can help maintain a reduced body weight while improving the patient's health profile. A recent trial has now provided some good evidence of the long term effectiveness of a weight loss drug.

The recently published STORM (sibutramine trial of obesity reduction and maintenance) study¹ differs from previous weight loss trials. Its objective was not to show that sibutramine, a drug acting on the central nervous system and increasing energy expenditure, could induce significant weight loss beyond that achieved by a reduced calorie diet or placeboan effect that already has been well documented.² Rather, it aimed to test whether sibutramine therapy for an additional period of 18 months could prevent weight regain among obese patients who had achieved a weight loss of over 5% over six months with an initial dose of 10 mg/day. Of the 467 patients who lost 5% of their body weight in the first phase and who were then randomised to sibutramine or placebo for the second phase, 43% of the sibutramine treated patients maintained at least 80% of their weight loss compared with only 16% in the placebo group. Furthermore, significant changes in cardiovascular disease risk factors were noted, including reduced triglyceride concentrations, increased high density lipoprotein (HDL) cholesterol concentrations, reduced cholesterol:HDL cholesterol ratio (an important index to predict the risk of coronary heart disease,³), reduced insulinaemia and C peptide levels, and decreased uric acid concentrations.

Only blood pressure did not fall significantly, a finding discordant with the expected effect of weight loss.⁴ This result will have to be re-examined carefully, but it is possible that sibutramine should be preferred for obese, insulin resistant dyslipidaemic patients who are not hypertensive. Indeed, these high risk but normotensive obese patients represent a substantial proportion of the obese population, because about half of all insulin resistant individuals do not have hypertension.⁵ Further studies are needed to identify the subgroup of patients likely to benefit most from sibutramine.

Though the results of the STORM study are important, they also raise several questions to address in future studies. Firstly, the study used specialised obesity clinics, often in academic settings, and a fairly sophisticated approach: assessment of resting metabolic rate for estimating daily energy needs; adjustment of the recommended energy intake over time to compensate for the body weight loss; dietary supervision every two weeks; and a visit to the treating physician every month. Thus, the results probably do not reflect what could be achieved by most family physicians in routine practice.

Secondly, only the successful weight losers (467/605) took part in the second part of the study. Thus, sibutramine was effective in maintaining reduced body weight so long as the patient had already "responded" to the drug. This result should again be interpreted in the context of routine practice. It may be argued that if a patient does not respond to a weight loss drug after a few months there is little chance that its continued use would be beneficial. Studies that have examined this issue suggest that a period of about three months may be sufficient to identify responders.^6-8

Finally, as in most weight loss trials, the vast majority of patients enrolled (over 80%) were women. Though this reflects the population of patients treated in most obesity clinics around the world, men are generally characterised by a more dangerous form of obesityvisceral, or abdominal, obesity.⁹ The current tragedy in medical practice is that neither obese men nor their doctors recognise the tremendous hazards of abdominal obesity. In the STORM study sibutramine therapy for two years reduced the waist circumference (the best crude index of abdominal fat accumulation) by more than 9 cm while also improving the cardiovascular risk profile. However, as the sample consisted largely of women with only moderate deterioration in their cardiovascular risk profile, even greater improvement in cardiovascular risk might have been observed in abdominally obese men.

What remains to be established from such a reduction in waist circumference is the impact on the risk of a first or recurrent coronary heart disease event in high risk abdominally obese patients. The VA-HIT study showed that increasing plasma HDL cholesterol concentrations with a fibrate was associated with a significant reduction (22%) in the risk of a recurrent coronary event among men with low HDL cholesterol and pre-existing coronary heart disease.¹⁰ As a large proportion of men in this study had abdominal obesity, combining a fibrate with a weight loss drug might be a good approach to managing the risk of coronary heart disease in abdominally obese patients.

Finally, the apparent lack of effect of sibutramine induced weight loss on plasma low density lipoprotein (LDL) cholesterol concentrations might mislead. We have reported that abdominally obese patients with high triglyceride and low HDL cholesterol concentrations have small, dense LDL particles.¹¹ It is known that pharmacotherapy leading to a significant reduction in triglyceridaemia could lead to the production of larger LDL particles, richer in cholesterol ester,¹² an alteration that might completely mask changes in LDL concentration resulting from weight loss. Studies on drug treatment of obesity and LDL size are therefore needed. Meanwhile, clinicians should not be misled by the lack of change in LDL cholesterol concentrations observed in some obese patients who have successfully reduced their body weight and their triglyceride concentrations.

In summary, the successful findings of the STORM study should pave the way to the design of long term randomised trials in high risk abdominally obese patients. Future trials should include proper evaluation of the impact of such drug treatment on the risk of developing prevalent chronic metabolic diseases such as type 2 diabetes and cardiovascular diseases.

Jean-Pierre Després, professor. 

Québec Heart Institute, Laval Hospital Research Center, Sainte-Foy (Québec), Canada G1V 4G5 (jean-pierre.despres{at}crchul.ulaval.ca)

Footnotes

   J-PD has received honorariums for consultancy and lectures and funding for his laboratory from Servier, Parke-Davis/Warner Lambert, Merck-Frosst, Fournier, Gatorade, DuPont-Merck, Knoll, Weight Watchers International, Roche, Eli Lilly, and Janssen-Ortho.

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