Biomedical subjects
L J Aronne
Publications and source records attributed to L J Aronne.
Obesity surgery: pros and cons.
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Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats.
Tachyphylaxis to the effects of anorexigenic agents, such as sibutramine (S), may be due, in part, to counterregulatory decreases in energy expenditure (EE) and increases in hunger that result from reduced circulating leptin (L) due to loss of body fat and lowered L production/adipocyte. The present study was conducted to test the hypothesis that L administered at low doses sufficient to restore ambient L to preweight loss concentrations would enhance the intercurrent efficacy of S by reducing the strength of physiologic counterregulation to weight loss. Forty male Sprague-Dawley rats were fed a high-fat (HF) diet (45% energy) to induce obesity. After 8 weeks, the obese rats (600 +/- 58 g) were weight-matched into 4 groups (N = 8/group) and implanted subcutaneously (SC) with 2 mL, 7-day Alzet mini-pumps that provided: vehicle (V, saline), L (0.5 mg/kg/d), S (3 mg/kg/d), or L+S. Food intake (FI) on the HF diet was measured daily. On day 7, 24-hour EE was measured by indirect calorimetry, and the animals then killed for body composition analysis. Compared with vehicle, treatment with S alone, but not L alone, produced significant weight loss (-23 +/- 26 v -6 +/- 16 g, P <.01). L alone, or with S, increased fat oxidation (decreased respiratory quotient [RQ]) compared with V (P <.05). The lack of decline in EE with S may be due to its documented effect to stimulate thermogenesis. Administration of L with S synergistically decreased FI and increased weight loss and fractional fat loss. A reduction in plasma L concentration may contribute to the "plateau phenomenon" observed in studies of weight loss therapies. Replacement doses of L during S administration increased weight loss and fractional fat loss by (1) decreasing food intake and (2) by increasing fat oxidation. Such drug combinations may be useful in the treatment of human obesity.
Treating obesity: a new target for prevention of coronary heart disease.
Recognition by the American Heart Association that obesity is a major modifiable risk factor for coronary heart disease has prompted health providers to take a more active role in obesity management. Obesity has long been known to accompany a host of chronic diseases, e.g., type II diabetes, hypertension, and dyslipidemia. We now recognize that obesity is itself a chronic disease with a complex etiology; like diabetes and hypertension, it is treatable with a similar chronic disease treatment model. Relatively modest weight loss confers disproportionate health benefits, improving a roster of risk factors. Diet, exercise, and behavior modification still compose the gold standard of treatment. If these measures fail, medication and surgery should be considered for appropriate patients. With current techniques, many patients can achieve realistic weight goals that can be maintained over the long term. Published management guidelines can now assist in integrating the practical applications of obesity-related research findings into everyday clinical practice.
Epidemiology, morbidity, and treatment of overweight and obesity.
Although still considered more of a cosmetic problem by both the general public and some areas of the medical community, overweight and obesity have reached epidemic proportions worldwide. Overweight and obesity have not only a significant psychological impact but also result in an increased risk for development of numerous chronic and sometimes fatal diseases. The morbidity from obesity-associated disorders increases with higher body mass index and begins within the normal weight range. The costs (direct and indirect) associated with treating obesity and its comorbid conditions are notable and increasing. Obesity rates in patients with schizophrenia are at least as high, if not higher, than in the general population. This article reviews the epidemiology and burden of obesity and its associated comorbid disorders. The guidelines from the National Heart, Lung, and Blood Institute of the National Institutes of Health for diagnosing and treating obesity are also discussed.
The effects of drugs used to treat obesity on the autonomic nervous system.
OBJECTIVE: Body fatness is partly under hypothalamic control with effector limbs, which include the endocrine system and the autonomic nervous system (ANS). In previous studies we have shown, in both obese and never-obese subjects, that weight increase leads to increased sympathetic and decreased parasympathetic activity, whereas weight decrease leads to decreased sympathetic and increased parasympathetic activity. We now report on the involvement of such ANS mechanisms in the action of anti-obesity drugs, independent of change in weight. RESEARCH METHODS AND PROCEDURES: Normal weight males (ages 22 to 38 years) were fed a solid food diet, carefully measured to maintain body weight, for at least 2 weeks, as inpatients at the Rockefeller University General Clinical Research Center. In a single-blind, placebo/drug/placebo design, eight subjects received dexfenfluramine, seven phentermine (PHE), and seven sibutramine (SIB). ANS measures of parasympathetic and sympathetic activity included: determination of amount of parasympathetic control (PC) and sympathetic control (SC) of heart period (interbeat interval), using sequential pharmacological blockade by intravenous administration of atropine and esmolol. These autonomic controls of heart period are used to estimate the overall level of parasympathetic and sympathetic activities. Norepinephrine, dopamine, and epinephrine levels in 24-hour urine collections were measured and also resting metabolic rate (RMR). RESULTS: Sufficient food intake maintained constant body weight in all groups. PHE and SIB produced significant increases in SC but no change in PC or in RMR. In contrast, dexfenfluramine produced marked decreases in SC, PC, and RMR. For all three drugs, the effects on urine catecholamines directly paralleled changes in cardiac measures of SC. DISCUSSION: ANS responses to PHE and SIB were anticipated. The large, and unanticipated, response to dexfenfluramine suggests further study to determine whether there could be any relation of these ANS changes to the adverse cardiovascular effects of treatment with dexfenfluramine.
Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study.
BACKGROUND: Long-term maintenance of weight loss remains a therapeutic challenge in obesity treatment. OBJECTIVE: This multicenter, double-blind, placebo-controlled study was designed to test the hypothesis that orlistat, a gastrointestinal lipase inhibitor, is significantly more effective than a placebo in preventing weight regain. DESIGN: Obese subjects who lost > or = 8% of their initial body weight during a 6-mo lead-in of a prescribed hypoenergetic diet (4180-kJ/d deficit) with no adjunctive pharmacotherapy were randomly assigned to receive placebo, 30 mg orlistat, 60 mg orlistat, or 120 mg orlistat 3 times daily for 1 y in combination with a maintenance diet to help prevent weight regain. Of 1313 recruited subjects [body mass index (in kg/m2): 28-43], 729 subjects lost > or =8% of their initial body weight during the 6-mo weight-loss lead-in period and were enrolled in the double-blind phase. RESULTS: After 1 y, subjects treated with 120 mg orlistat 3 times daily regained less weight than did placebo-treated subjects (32.8 +/- 4.5% compared with 58.7 +/- 5.8% regain of lost weight; P < 0.001). Moreover, more subjects in the 120-mg orlistat group than in the placebo group regained < or = 25% of lost weight (47.5% of subjects compared with 29.9%). In addition, orlistat treatment (120 mg 3 times daily) was associated with significantly greater reductions in total and LDL-cholesterol concentrations than was placebo (P < 0.001). CONCLUSION: The use of orlistat during periods of attempted weight maintenance minimizes weight readjustment and facilitates long-term improvement in obesity-related disease risk factors.
Therapeutic controversy: Obesity--a modern-day epidemic.
While the hyperleptinemia of obesity is likely to be associated with the metabolic complications of obesity/hyperinsulinemia/insulin resistance, it is not associated with diabetes, with the relative hypercortisolism of upper body obesity, with hypertension in women, (it is in men), or with dyslipidemia. Overall, the correlations between leptin and the metabolic diseases associated with obesity are weak. The equivocal results of an association of leptin with components of the metabolic syndrome make it unlikely that leptin affects these directly. (On the other hand, these correlations, when found, preclude any causal relationship between leptin and metabolic diseases.) There are experimental data showing a definite role for insulin and glucocorticoids in the regulation of leptin, and of leptin in the regulation of insulin. More data are required on the effects of leptin, but it is likely that leptin will not be a major link between obesity and the metabolic syndrome. Certainly, however, when leptin is available for clinical use, its effect on different aspects of the metabolic syndrome will be worth studying.
Modern medical management of obesity: the role of pharmaceutical intervention.
The medical model of obesity treatment--combining diet, exercise, and behavior modification with antiobesity agents--suffered a setback when fenfluramine and dexfenfluramine were withdrawn from the market because of an association between these medications and valvular regurgitation. The Food and Drug Administration has recently approved sibutramine (Meridia), a norepinephrine and serotonin reuptake inhibitor that was originally developed as an antidepressant, but which has also been shown to reduce weight. In a 1-year placebo-controlled trial, 65% of patients receiving 15 mg sibutramine daily lost more than 5% of their body weight, compared with 29% of patients receiving a placebo; 39% of patients in the sibutramine group lost more than 10% of their body weight, compared with 8% of patients in the placebo group. Health benefits observed in patients receiving sibutramine include reductions in levels of triglycerides, uric acid, total cholesterol, and low-density lipoprotein (LDL) cholesterol and an increase in high-density lipoprotein (HDL) cholesterol levels. Another antiobesity drug currently under review by the Food and Drug Administration is orlistat (Xenical), a pancreatic lipase inhibitor that reduces the absorption of dietary fat by approximately 30%, thus reducing energy intake. In a 1-year placebo-controlled trial, 55% of patients receiving orlistat lost more than 5% of their body weight, and 25% lost more than 10% of their body weight, compared with 33% and 15%, respectively, of patients in the placebo group. In addition, orlistat slowed the rate of weight regain in the second year of treatment. Health benefits demonstrated in clinical trials of orlistat include reduced LDL cholesterol levels and increased levels of HDL cholesterol, reduced blood pressure and fasting insulin levels, improved oral glucose tolerance test outcomes, and improved glycemic control in obese patients with diabetes. The future of the pharmacologic treatment of obesity is promising. Many new antiobesity agents are in the early stages of development, and our understanding of the body's weight-regulating mechanisms is advancing steadily. Human trials of recombinant leptin are underway. Other promising compounds include those that block the Neuropeptide Y5 and Y1 (NY5, NY1) and Melanocortin-4 (MC4) receptors, stimulate uncoupling proteins, and unbind corticotrophin-releasing factor from its binding protein. As better medical treatments for obesity become available, the focus in dietary prescription may shift away from reducing energy intake toward healthier eating for disease prevention. At present, a comprehensive approach, which, in some patients, may include medical therapy as an adjunct, is necessary to treat obesity effectively.
The therapeutic efficacy of critical care units. Identifying subgroups of patients who benefit.
The majority of patients are admitted to critical care units for observation and to facilitate intervention if deterioration occurs or complications develop. We attempted to determine if a reduction in mortality in a subgroup of these patients admitted directly to the critical care units could be identified. A new method using the scientific principles of a randomized trial applied to the case-control design was employed. All 1905 patients admitted to the medical service over a three-month period were prospectively evaluated for illness severity and stability. Patients who would not have been eligible for a randomized clinical trial were excluded. Based on the prospective evaluations, four prognostically distinct subgroups of patients were formed. An odds ratio for each of the prognostic groups was calculated, a ratio of greater than 1 indicating a protective effect of direct critical care admission. Only one subgroup of patients, the unstable moderately ill, had an odds ratio greater than 1 (13.3). These results, in association with the results of our previous study, suggest that at the time of admission to the hospital, direct admission to the critical care unit reduced mortality among the unstable moderately ill subgroup of patients.
Cost-effectiveness of extracorporeal shock-wave lithotripsy.
A study was done comparing the charges and outcomes for extracorporeal shock-wave lithotripsy (ESWL) with those for percutaneous nephrostolithotomy (PCN), which was the treatment of choice at our hospital for stones of the upper urinary tract when ESWL was introduced. Using a retrospective cohort design, patients were matched for age, sex, physical status index (American Society of Anesthesiologists), stone size, and urinary tract obstruction. Twenty-nine pairs of PCN and ESWL patients with complete data were matched. The groups were not significantly different in the matching parameters. Seventy-two per cent of patients in each group (21/29) were stone-free after the initial hospitalization. PCN patients required more auxiliary procedures per patient than did the ESWL patients; in addition, 5 (17%) of the PCN patients had perforation of the renal pelvis and 5 (17%) required transfusions. On discharge, 48 per cent (14/29) of the PCN patients had nephrostomies compared with none of the ESWL patients. The ESWL group had a shorter mean length of stay (2.9 vs 8.7 days, p less than 0.0005) and lower charges in all categories. Total charges were significantly less for ESWL ($9,290 vs $11,796 for PCN, p less than 0.005) as were physicians' fees ($3,391 vs $5,607, p less than 0.0005), room and board charges ($825 vs $2,164, p less than 0.0005), and operating room fees ($313 vs $1,452, p less than 0.0005). We conclude that ESWL is a cost-effective means for treating stones of the kidney and upper urinary tract.