Steven Heymsfield, MD, Obesity Research Center, St. Luke's-Roosevelt Hospital, New York, NY, discussed pharmacologic agents that may play a role in modifying fat mass at a Diabetes Conference at the Mount Sinai Medical Center, New York, NY.
Weight is proportional to energy stores and reflects "cumulative lifetime energy balance," stated Dr. Heymsfield. Energy balance is a highly regulated system that we are beginning to appreciate is controlled by leptin and a number of other hormones. Obesity is increasing in prevalence, and it is not easily treated.
Nongenetic determinants of obesity include hormonal abnormalities such as hypothyroidism and glucocorticoid excess; psychiatric illnesses and treatments, particularly the atypical antipsychotic drugs; cigarette discontinuation; and lack of physical exercise. Obesity is strongly associated with the metabolic syndrome, with features including upper-body obesity, abnormal lipid metabolism, abnormal glucose metabolism, and hypertension. The metabolic syndrome affects 20% of the overall US adult population and approximately 40% of those over age 60. Sixty percent of the US population has BMI > 25 kg/m2, and there is a striking increase in prevalence of the metabolic syndrome as BMI increases from 25 to 30. Dr. Heymsfield also noted that as BMI exceeds 25, three quarters of the increase is in fat mass. Mortality is lowest for persons with BMI between 20 and 25 kg/m2 among whites, and at lower levels in persons of Asian ethnicity. A BMI > 36 is associated with a 50% increase in mortality.
Sixty-five percent of individuals with BMI > 27 have at least 1 comorbidity such as hypertension, dyslipidemia, or type 2 diabetes, so pharmacologic treatment is appropriate for many individuals in this group. The average weight loss with most drugs available today is between 5% and 7%. This degree of weight loss may be sufficient to produce clinical benefit. The Diabetes Prevention Program and Diabetes Prevention Study both showed the efficacy of lifestyle modification with modest weight loss in decreasing conversion from impaired glucose tolerance to diabetes.
Several long-term clinical trials are being conducted. Xendos (Xenical in the prevention of diabetes in obese subjects), a Scandinavian study with orlistat, is projected to cost $40 million. Look AHEAD (Action for Health in Diabetes), with a projected cost of $100-200 million, and the SOS (Swedish Obesity Study) of obesity surgery, now in the fifth of a projected 10 years, are additional upcoming studies.
Dr. Heymsfield presented the ABC model of behavioral modification for obesity management. This model is based on patient understanding of the:
Antecedent causes of obesity,
Behaviors of overeating and lack of exercise that lead to obesity, and the
Consequences of obesity.
With pharmacologic management, one cannot overlook the components of cognitive/behavioral therapy, stimulus control, cognitive restructuring, self-monitoring, stress management, and social support. Virtually all of the studies that have been conducted include lifestyle management, but the "challenging question" is whether behavioral approaches will still be required when more potent pharmacologic agents are available. For example, behavior modification has become less crucial in the management of hypertension and dyslipidemia with the introduction of new drug therapies. Will this be true for obesity management too? Furthermore, the pattern seen in most studies of weight loss is relapse during the 1- to 5-year period following a dietary intervention, further suggesting that behavioral management is not sufficiently effective.
"The stronger the intervention, the better the weight loss," stated Dr. Heymsfield, and medication alone is less effective than medication combined with lifestyle modification.
"Meal replacement" products show independent effects in leading to greater weight loss, perhaps because "many obese individuals have trouble managing regular food," stated Dr. Heymsfield. The extreme of this approach is the very-low-calorie liquid diets such as Optifast, in which liquid meal replacement is the sole source of nutrition. These approaches are less widely used today than they were a decade ago.
As yet, there have essentially been no systematic studies of the very popular non-"food pyramid" approaches, such as the Atkins, grapefruit, Last-Chance, Rotation, Stillman, Scarsdale, T-Factor, and Zone diets.
The caloric expenditure of most mammals is approximately twice their resting energy expenditure, while the activity level of the average sedentary person leads to expenditure of approximately one quarter this amount of energy. "That requires a tremendous change" in food intake, Dr. Heymsfield commented. The compensatory adaptation to reduction in energy intake with reduction in energy expenditure and increased drive to food intake limits the effectiveness of pharmacologic treatment. Energy intake-output interrelationships led to the paradigm for pharmacotherapy, which is now empirical and mainly addressed to limiting intake. However, future forms of treatment may be based on changing fuel partitioning and adipocyte metabolism.
Current pharmacologic approaches involve appetite suppression with sibutramine or phentermine and induction of food malabsorption with orlistat.
Phentermine stimulates norepinephrine and dopamine release and is given at doses of 8 to 30 mg daily. Phentermine is the most commonly prescribed antiobesity agent, although no long-term studies are available on the use of this agent alone.
Sibutramine, a tertiary amine, is a selective serotonin-norepinephrine reuptake inhibitor that was originally introduced as an antidepressant. It is administered at a dose of 5-15 mg daily. In clinical trials, 60% of subjects receiving sibutramine showed a 5% weight loss and 30% showed a 10% weight loss, compared with 30% and 10% of subjects receiving placebo. The STORM trial assessed the effectiveness of sibutramine at maintaining weight loss over 2 years. Forty-three percent of the sibutramine-treated subjects who completed the trial maintained 80% or more of their original weight loss, compared with 16% of subjects in the placebo group.
Blood pressure increases on average by 2-3 mm Hg with sibutramine treatment. However, there is a marked blood pressure increase in some patients, and the agent is contraindicated in persons with severe cardiovascular disease. Headache and dry mouth are other side effects. The combination of sibutramine with monoamine oxidase inhibitors is contraindicated, and the combination of sibutramine and other serotonergic drugs should be avoided because of the risk of the serotonin syndrome.
Orlistat inhibits intestinal lipase activity and was originally developed as a lipid-lowering replacement for cholestyramine. The drug blocks absorption of approximately 30% of dietary fat, about 300 calories per day in the average American diet. Most patients do not compensate for this, and weight is lost. The drug causes oily spotting, flatus with discharge, and fecal urgency, so, Dr. Heymsfield stated, "It has been difficult to get patients to take this." He also pointed out that the gastrointestinal effects are "relatively mild and short-lived." When used with diet, orlistat is of similar efficacy to sibutramine. Over a 2-year period, placebo led to 6-kg and orlistat to 10-kg weight loss in studies using a "weight maintenance" diet after the first year, which may have lessened the apparent efficacy. Over the course of 2 years, the risk of progression from impaired glucose tolerance to diabetes was 7.5% with diet alone, and 3.0% with orlistat, suggesting clinical benefit.
Leptin has not shown benefit in the majority of obese persons, although it is beneficial in the lipodystrophy syndromes, including those caused by protease inhibitors for HIV infection and in the rare patients with leptin deficiency. Leptin leads to greater decrease in fat mass than is seen with other agents. Leptin causes injection-site reactions, but leptin molecule analogs may be effective and have fewer side effects.
Axokine, or ciliary neurotrophic factor, is a cytokine-like agent that appears to act at pathways distal to those activated by leptin. Significant weight loss in the 5% to 8% range has been seen at 3 to 6 months, and there is some evidence of weight loss maintenance following discontinuation of treatment.
The antidepressant bupropion appears to be associated with weight loss, as does the anticonvulsant topiramate, although the latter causes paresthesias and some cognitive defects, so it has been withdrawn from development. Additional studies are being carried out with cannabinoid receptor antagonists; cholecystokinin and thyroxin agonists; P57, a cactus component; MLN4760, a carboxypeptidase inhibitor; and HMR1426, a gastric emptying inhibitor. So-called alternative treatment approaches (eg, acupuncture, hypnosis, and aromatherapy) are either ineffective or unsafe (eg, ephedra).
Medscape Diabetes. 2002;4(2) © 2002 Medscape
Cite this: Diabetes in New York: Topics in Obesity - Medscape - Dec 23, 2002.