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Editorials |
The National Institutes of Health–Centers for Disease Control and Prevention (NIH-CDC) workshop (1) on the need for and feasibility of a randomized clinical trial to estimate the long-term health effects of intentional weight loss in obese persons is timely. The Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults recently developed clinical guidelines for identifying, evaluating, and treating overweight and obesity in adults (2). The results of this large-scale initiative were reviewed by 115 health experts at major medical and professional societies and were endorsed by the coordinating committees of the National Cholesterol Education Program, the National High Blood Pressure Education Program, the North American Association for the Study of Obesity, the American Heart Association, and the National Institute of Diabetes and Digestive and Kidney Diseases' (NIDDK's) National Task Force on the Prevention and Treatment of Obesity. These groups represent 54 professional societies, government agencies, and consumer organizations.
The NIH-CDC workshop is also timely because the 1999 NIDDK budget provides funding for a multicenter clinical trial investigating the health effects of long-term, sustained weight loss in obese individuals, and a pending request for applications has suggested a study of 6000 obese patients with type 2 diabetes at 
15 clinical centers. An anticipated one-third of the subjects will be randomly assigned to community care, with the remainder randomly assigned to an intensive lifestyle intervention or intensive lifestyle intervention plus obesity medication for 4–7 y. Innovation in the intervention used and in the study design are priorities for the application.
Because most adverse events in obese patients with type 2 diabetes are cardiovascular in nature, one proposed primary outcome of the clinical trial will be slowing the progression of atherosclerosis as assessed by B-mode carotid ultrasound. Measuring coagulation factors will also be central to establishing a relation between obesity and the pathogenesis of myocardial infarction, stroke, and peripheral vascular disease. Additional outcomes will include cardiovascular and all-cause mortality, conventional cardiovascular disease risk factors, glycemic status, musculoskeletal outcomes, cost-effectiveness of interventions, quality of life, and changes in the use of medications. The trial is expected to build on the experience of the Diabetes Prevention Program (3) in developing diet, exercise, and lifestyle interventions suitable for a diverse population.
The UK Prospective Diabetes Study Group recently reported on the effectiveness of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (4). The median length of follow up in this study was 10.7 y. Cardiovascular disease accounted for 62% of the total mortality among overweight patients in the conventional treatment group. In contrast, subjects in the metformin group showed risk reductions of 32% for any diabetes-related endpoint, 42% for diabetes-related death (sudden death and death from hyper- or hypoglycemia, fatal or nonfatal myocardial infarction, angina, heart failure, stroke, renal failure, or peripheral vascular disease), and 36% for all-cause mortality. There was no significant difference between the treatment groups in risk reduction for microvascular disease. Subjects in the metformin and conventional therapy groups gained 1–2 kg over the study period, whereas those taking sulfonylureas or insulin had mean increases of 5 and 7 kg, respectively. The authors concluded that the decreased risk of diabetes-related endpoints, as well as the lower weight gain and fewer hypoglycemic attacks than with use of insulin or sulfonylureas, supports the use of metformin as a first-line drug therapy of choice in overweight, diabetic patients. Weight-loss therapy can be expected to simulate the effect of metformin, a biguanide that decreases blood glucose concentrations by reducing hepatic glucose output, enhancing insulin sensitivity, inducing greater peripheral uptake of glucose, and lowering fasting plasma insulin concentrations. Biguanides also decrease concentrations of plasminogen activator inhibitor 1 and may thus increase fibrinolytic activity.
The simultaneous occurrence of insulin resistance and impaired insulin secretion leads to hyperglycemia in type 2 diabetes. The combination of hyperinsulinemia, insulin resistance, and hyperlipidemia best describes the pathophysiology of macrovascular complications, whereas hyperglycemia per se is more closely linked to microvascular sequelae. Weight-loss therapy is expected to reverse these metabolic defects (2). Intensive therapy requires control of blood sugar to achieve a glycosylated hemoglobin concentration of 7–8%, ie, no >1% above the normal range. Clinical progression is reduced by 75% after 8–9 y of near-normal plasma glucose concentrations.
As for sample size, the UK study is instructive in the design of weight-loss therapy (4). The trial involved 1704 overweight patients [mean age: 53 y; mean body mass index (in kg/m2): 31.5]; 411 were assigned to conventional treatment and 342 to intensive treatment with metformin. At 10 y, 200 subjects were available for evaluation. The conventional treatment approach included 3 monthly clinical visits centered around dietary advice designed to help subjects attain normal body weights and fasting plasma glucose concentrations. Secondary randomization to additional nonintensive drug therapy took place if subjects developed marked hyperglycemia (>15 mmol/L or symptoms of hyperglycemia, polyuria, polydipsia, or polyphagia); this occurred in 44% of the person-years (number of persons studied times number of years of follow-up).
What can the NIH-CDC workshop group learn from such outcomes? First, only obese persons with new-onset type 2 diabetes should be recruited. By the time diabetes is diagnosed, it may have been present for up to 10 y, causing evidence of diabetic tissue damage in up to 50% of patients. Longer-term exposure to raised fasting plasma insulin concentrations may also be found to be damaging. Second, not all subjects will respond to intense intervention therapy. Most will require adjunctive medical treatment to achieve normal plasma glucose concentrations and control of elevated blood pressure to 
135/85 mm Hg. In a population with type 2 diabetes, coagulation factors VII and X are elevated and are involved with thrombosis and increased risk of myocardial infarction. Prophylactic aspirin therapy may also be required. Angiotensin-converting enzyme inhibitors effectively control blood pressure and slow the progression of diabetic nephropathy. Similarly, aggressive medical management of abnormal lipid concentrations (eg, plasma LDL concentrations 130 mg %) is the standard of care to retard macrovascular complications.
The third lesson concerns statistical analysis. Generalized estimating equations, a method for analyzing longitudinal data, do not rely on distributional assumptions (5). They give robust estimates of parameters and their SEs. In addition, generalized estimating equation models can use variables that include sex, ethnicity, smoking and cardiovascular disease, and comorbidities, particularly hypertension and dyslipidemia (low HDL cholesterol and high triacylglycerol and LDL cholesterol) (3, 4). In the proposed NIDDK trial, 15 sites would recruit and manage 400 subjects each. Certain geographic areas may be specified to recruit necessary ethnic groups, particularly blacks and Hispanics. Subjects in these groups will require ethnic-specific interventions and can be expected to have ethnic-specific outcomes. The generalized estimating equation method of analysis will facilitate hypothesis testing.
Dietary variables and physical activity patterns are considered the major modifiable factors in weight control. Powerful societal and environmental forces, however, influence energy intake and energy expenditure, whereas genetics, sex, age, and hormonal activity influence individual response to treatment (6). Interventions, in turn, must consider the social, cultural, political, physical, and structural environments that affect the weight status of the population at large. Innovations in diet, exercise, and the behaviors needed for motivation and promotion of long-term compliance are priorities for success (2).
The fourth lesson deals with innovations in diet. Stamler (7) proposes a diet for all stages of life based on the DASH (Dietary Approaches to Stop Hypertension) diet and the US Dietary Guidelines. This diet not only puts the focus on foods with high ratios of nutrients to energy content, it is also delicious—high in fruit and vegetables, high in legumes and whole grains, and high in fat-free and low-fat dairy products, poultry, fish, shellfish, and low-fat meats. Heber's (8) Resolution Diet proposes a California cuisine and provides a food guide pyramid to illustrate healthful eating goals. A relapse intervention diet designed by the Diabetes Prevention Program (3) uses meal-replacement foods for special dietary purposes (9).
The fifth lesson involves innovations in exercise. All interventions require exercise components. Jeffery et al (10) describe an intense exercise intervention that increases cues for activity, makes use of a personal trainer, and heightens reinforcement by providing small financial incentives for attending exercise sessions. The top quartile of subjects in this study reported an exercise level averaging >10.5 MJ/wk (>2500 kcal/wk) and had excellent long-term weight loss.
The sixth lesson pertains to safety concerns. Treatment interventions, including weight-control medications approved by the Food and Drug Administration, offer reasonable expectations of safety as well as mild, transient, and easily-monitored adverse events (2, 6). Favorable safety profiles relative to alternative treatment options protect subject well-being, and adjunctive therapy addresses ethical and safety concerns related to comorbidities and nonresponders.
The NIH-CDC workshop succeeds in making the argument for a randomized clinical trial that will supply needed guidance on the risks and benefits of long-term weight loss to health care providers and insurers as well as millions of obese Americans. Sufficient scientific evidence shows that benefits are reasonably probable and adverse outcomes unlikely. Sampling persons with newly diagnosed type 2 diabetes will allow the research findings to be generalized to patients with all aspects of the metabolic syndrome (3, 4, 11). A correlation between the magnitude of weight loss, the degree of plasma glucose control, and diabetes-related morbidity and mortality will provide strong support for diet and exercise therapy.
In response to the emerging body of scientific, medical, and behavioral data linking excess adiposity to coronary artery disease, the American Heart Association recently classified obesity as a major, modifiable risk factor for coronary artery disease. It also issued a 9-point "call to action" that urges legislators, insurers, health care providers, and the public to sharply escalate the war against obesity (12).
Obesity research today is still in its infancy. Innovations are needed in the ways we address the major modifiable factors in weight control, ie, dietary factors and physical activity patterns. Areas of particular interest include assessment methods; behavioral and psychosocial tools and techniques that restrain energy intake and increase energy expenditure; the design of novel diet and exercise programs, particularly for nonresponders; and the development of strategies that reduce relapse rates and strengthen motivation for compliance. There is a great need to address the social factors that contribute to obesity and to initiate efforts on a broad scale to modify these factors (2, 6). Community and environmental resources, which can be mobilized as part of the trial, are required to reduce food portion sizes, decrease exposure to high-fat foods, and increase opportunities to pursue physical activities during leisure time.
FOOTNOTES
1 From the Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
2 Address reprint requests to GL Blackburn, Beth Israel Deaconess Medical Center, One Deaconess Road, Boston, MA 02215. E-mail: gblackbu{at}bidmc.harvard.edu.
REFERENCES
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  J. O. Hill Understanding and Addressing the Epidemic of Obesity: An Energy Balance Perspective Endocr. Rev., December 1, 2006; 27(7): 750 - 761. [Abstract] [Full Text] [PDF]
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 K. M. Gadde, D. M. Franciscy, H. R. Wagner II, and K. R. R. Krishnan Zonisamide for Weight Loss in Obese Adults: A Randomized Controlled Trial JAMA, April 9, 2003; 289(14): 1820 - 1825. [Abstract] [Full Text] [PDF]
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