MEDICAL ASPECTS OF OBESITY

by Russell Ellison M.D., M.Sc., Vice President Drug Development, Head of the Global Xenical Development Program, Hofftmann-La Roche Ltd., Mississauga, Canada

Obesity has recently become recognised as a major public health problem, of epidemic proportions, in Europe and North America. In the US in 1990, there were 300 thousand diet- or activity-related deaths (primarily due to obesity), or 15% of the total deaths, second only to tobacco related deaths. Obesity is also a major component of direct and indirect health costs, estimated at up to 8% in Sweden and the US.

This is due to two factors. There is an extremely high and increasing prevalence of overweight and obese individuals in industrialised countries (more than 40% in the US, Germany, and the UK, for example). Also, an increasing risk of mortality from heart disease, diabetes and cancer, as well as increasing risks of morbidity from hypercholesteremia, diabetes hypertension, gallstones and sleep apnea etc., are associated with increasing Body Mass Index (BMI) and weight gain.

Up to a two-fold increase in mortality from all causes is associated with progressive increases in BMI, as seen in the Boston Women's Health Study data. Mortality from coronary artery disease similarly increases with BMI and weight gain (up to three-fold), as does the incidence of diabetes in both men (seven-fold) and women.

Key risk factors, which individually and together increase mortality, are frequent comorbid conditions in the overweight, such as diabetes (8%), hypertension (up to 60%), and hypercholesteremia (up to 40%), as well as hyperinsulinemia, which is associated with an increased risk of diabetes hyperlipidemia and (independently of these) with heart disease. Visceral adiposity appears to increase these risks for a given weight.

Numerous prospective observational epidemiological studies have examined the question of whether weight loss will reduce the risk of mortality and morbidity from obesity. Some studies have observed no benefit or even somewhat increased risk. However, in those studies (usually either smoking is not controlled for, or eliminated), there was little information on the intentionality of the weight loss, and/or patients with comorbidities who would benefit most were not evaluated. A recent re-analysis of the US Cancer Prevention Study demonstrated that intentional weight loss was associated with a profound reduction in mortality from cancer (30%), diabetes (30%), heart disease (9%), and all causes (20%) in women with pre-existing illness. However there was little protective effect, and some suggestion of increased risk in otherwise healthy overweight women, perhaps due to the limitations of weight change reporting, and the limits of observational studies in general.

Preliminary data from a prospective intervention study, SOS (Swedish Obese Subjects) have recently been published. 4,000 patients are to be randomised to either gastric surgery or normal care, and followed for ten years. Early data indicates that, after only two years, a considerable reduction in the incidence of diabetes (fourteen-fold), hypertension, and hyperlipidemia (between three- and four-fold), as well as resolution of these diseases in 43 to 68% of the cases, was achieved by the weight loss from surgery.

Over the last 15 years, a large body of literature has developed which consistently demonstrates the effect of even modest weight loss (e.g. 5 to 10% of body weight) on the reduction of blood pressure, improvement of metabolic control of diabetes, and improvement in lipid and insulin levels.

However, long term weight reduction with currently available dietary programmes appears to be inadequate, whereby individuals losing 10% of their body weight by non-surgical means, gain two-thirds of it back in two years, and almost all of it back in five. Addition of behaviour modification modalities does not seem to affect the long-term picture, and even with the addition of exercise, 58% of lost weight is regained in two years.

Given the morbidity and mortality of obesity, the goal of any new approaches to treatment (and especially pharmacotherapy) should be weight management, aimed at achieving the best possible weight in the context of overall health, rather than being limited to the narrower objective of weight loss, which is more related to appearance.

If pharmacotherapy is seen in this context (i.e. of weight management), then in addition to weight loss, efficacy in terms of weight maintenance while on diet (one year), and the prevention of weight regain when the diet is liberalised (two years), becomes as important. If positive effects on risk factors such as insulin, blood glucose levels, or lipid levels, as well as blood pressure, are observed above the effect of diet alone, over the maintenance and regain periods, then our degree of certainty about a positive health impact will increase, with an overall public health goal of the prevention and resolution of comorbidities such as diabetes and hypertension (two to five years), and the reduction of mortality (ten years).

Inasmuch as current treatments have not progressed substantially beyond the chemical targets and approaches known and exploited over twenty years ago, clearly there is a need for novel and innovative approaches to weight management. These approaches would include those which have a wide safety margin, are well tolerated, and can achieve sustained reasonable weight reduction in long-term use, sufficient to reduce the risk factors associated with morbidity and mortality.

In view of the increasing deaths, suffering and costs associated with obesity, this need is urgent if we are to adequately address one of the major public health challenges facing us today.