|Medical Crossfire October 1999|
Is It A Disease? If So, How Should It Be Treated?
Jeanine B. Albu, MD; George A. Bray, MD; M. Jean-Pierre Despres,
PhD; F. Xavier Pi-Sunyer, MD; Moderator:
Alan R. Shuldiner, MD
"For the better part of a billion years, nutrients have been scarce and nature selected for organisms with thrifty metabolism. Only in the last few hundred years, in the face of nutrient excess, have the tides turned such that, today, human obesity is an epidemic," said Alan R. Shuldiner, MD, Professor and Head of the Division of Endocrinology, Diabetes and Nutrition at the University of Maryland and Director of the Joslin Center for Diabetes, both in Baltimore. Dr. Shuldiner, who is also a member of the Editorial Advisory Board for Medical Crossfire, recently moderated a debate on the challenges that primary care physicians face concerning diagnosing and treating obesity.
"Physicians are inundated with obese patients who introduce very difficult management issues," said Dr. Shuldiner, opening the debate. Indeed, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health estimates that 97 million adults in the United States are overweight or obese, which increases their risk of mortality and morbidity associated with hypertension; dyslipidemia; type 2 diabetes; coronary heart disease; stroke; gallbladder disease; osteoarthritis;sleep apnea; respiratory problems; and cancer of the endometrium, breast, prostate, and colon.1
Obese individuals may also suffer from discrimination and social stigma.1 "Today were here todiscuss the scope of the problem, diagnostic guidelines, current therapeutic strategies, and futureprospects."
Is Obesity a Disease?
"I think obesity should be regarded as a disease. I believe its a disease of diseases," said F. XavierPi-Sunyer, MD, Professor and Chief of the Division of Endocrinology, Diabetes, and Nutrition at St.Lukes-Roosevelt Hospital at Columbia University, and Director of the Joselin Center for Diabetes in New York. Dr. Pi-Sunyer noted that obesity is often predictive of the development of "some of the biggest killers in America today." He pointed out that obesity contributes to the development of hypertension, diabetes, and abnormal lipid levels, which all contribute to cardiovascular disease.
"Ultimately, these conditions lead to high rates of morbidity and mortality from ischemic heart disease, other complications of diabetes and stroke, and peripheral vascular disease," he said. He added that obesity and excessive weight bearing cause increased risk of osteoarthritis, and that obesity is associated with pulmonary disease and sleep apnea, which can lead to congestive heart failure. "So I do believe it is a disease and we should treat it as a disease and not make it appear as something benign. Its actually quite serious," he emphasized.
"For a disease, you need a pathological basis," said George A. Bray, MD, Executive Director of Pennington Biomedical Research at Louisiana State University in Baton Rouge. "I think one can view the increased size of fat cells, which accompanies all obesity, and the increased number of fat cells, which accompanies many obese patients problems, as a pathological basis for their symptoms." He noted that many metabolic signals, such as leptin, cytokines, and fatty acids, fit the disease approach to obesity.
Diagnosing and Assessing Obese Patients
Guidelines from the NHLBI define an overweight individual to be any person with a body mass index (BMI) of 25 to 29.9 kg/m2. Obesity is defined as a BMI of 30 kg/m2 or greater. However, the NHLBI also encourages physicians to consider patients waist circumference, overall risk status, and motivation when assessing them as candidates for weight-loss therapy (see Figure 1).1
"We debated this for a long time, and there was some controversy, but in the end we came out with guidelines for defining obesity that have been accepted worldwide," said Dr. Pi-Sunyer, who chaired the panel that developed the NHLBI guidelines. Stressing the ease with which BMI is calculated, he said, "Its the weight in kilograms over the height in meters squared, and if you want to do weight in pounds and height in inches, then you have a correction factor where you multiply by 704.5."
Regarding waist circumference, he added, "we defined a circumference of greater than 100 centimeters in men and greater than 80 in womenwhich is greater than 35 inches in women and greater than 40 inches in menas being a risk factor in addition to BMI."
"Two additional things might be added," said Dr. Bray. "How much weight a person has gained and the rate at which it occurred, as people whove gained more than 10 kilograms after age 18 to 20 seem to be at higher risk. . . . So, I would add those to the BMI and waist measurement components of the physicians evaluation."
Dr. Shuldiner asked the group about the value of measuring the waist-to-hip ratio.
"Waist-to-hip ratio was found to be a risk factor for development of diseases such as diabetes, cardiovascular disease, and stroke in populations in Northern Europe, " answered Jeanine B. Albu, MD, Assistant Professor in the Department of Medicine at Columbia University College of Physicians and Surgeons in New York. For example, in a study from Paris, France, persons whose waist-to-hip ratios were in the top quintile (>0.98 for men and >0.91 for women) had significantly higher rates of cardiovascular complications, including coronary heart disease, death, myocardial infarction, and stroke, compared with those with waist-to-hip ratios in the lower quintiles.2 Dr. Albu noted, however, when cutoffs defined in these trials were applied to other ethnic populations, particularly African-American women, they were not as predictive of risk.3
"There has been a lot of confusion unfortunately in medical practice regarding the waist-to-hip ratio," noted M. Jean-Pierre Després, PhD of the Lipid Disorder Research Center at Center Hospital, Laval University in Quebec City. "You have to keep in mind that the waist-to-hip ratio is an index of the relative accumulation of abdominal fat because it is a ratio. It means that you could have, for example, a woman with a BMI of 25, a waist circumference, lets say, of 80 cm, and a hip circumference of 100 cm, which would mean a waist-to-hip ratio of 0.8, and you would compare this woman with an obese woman with a BMI of 35, a waist circumference of 100 cm, and a hip girth of 125 cm, and both women would have the same waist-to-hip ratio. . . . Would you conclude that they are at the same risk of developing diabetes? Of course not, because the absolute amount of abdominal fat would be much greater in the obese woman. So, its a very simple example of how there could be a misinterpretation of the waist-to-hip ratio." He added, "You dont have that problem if you use the waist circumference, per se."
Dr. Albu agreed that "the waist circumference is a much better predictor of the amount of visceral fat that seems to work quite well in different populations, in both sexes, and across age and BMI ranges." However, she said, "waist circumference is best applied to individuals with a BMI below 35."
She explained that "once your BMI goes over a certain degree of overweight, the amount of visceral fat will be enlarged to a degree of being unhealthy, so, it may not be necessary to apply another criteria for risk besides the BMI."
"I think this is an excellent rationale for why the NHLBI uses both an absolute BMI cutoff as well as that of the waist measurement to be used in conjunction with each other," noted Dr. Shuldiner.
Selecting a Target: Obesity or Its Complications?
"Should we be treating obesity or simply its comorbid conditions?" asked Dr. Shuldiner.
"I think both," answered Dr. Pi-Sunyer. For example, he said, "about 90% of those patients who have diabetes also have obesity, so obesity makes the diabetes worse. Now, nobody would say you wouldnt treat the blood sugar, the abnormal lipids or the potentially abnormal blood pressure that would come in these diabetic individuals, but the first way to treat this is by trying to get these patients to lose weightand if they cant lose weight, at least to maintain their weight so they dont gain more weight." Extrapolating further, he added, "So clearly, the way to hit at hypertension, diabetes, and hyperlipidemia, initially, is to try to reduce the weight of an overweight individual, and you will benefit all those conditions and therefore benefit the outcomes, primarily ischemic heart disease and stroke."
Dr. Bray agreed, noting that, at the clinic at Pennington Center, "about 10% of our patients were on treatment for diabetes and, when they lost weight, 100% of them got off of either their insulin or their oral agents with a mean interval of about eight weeks." Thus, he said, "if you could get diabetic patients to lose weight, the reduction in diabetic medications would be very substantial and their diabetes markedly improved."
"I think there is overwhelming evidence that we need to treat the complications in these obese patients," cautioned Dr. Després. That should be, obviously, a major concern for a general physician, if the patient has hypertension, type 2 diabetes, or dyslipidemia." However, he agreed that "if you dont attack the cause of the complications, . . . the excess weight, . . . it is a suboptimal management of risk."
Regarding cardiovascular disease and dyslipidemia specifically, Dr. Shuldiner questioned, "Are all obese patients at equal risk of heart disease?"
"For the general physician in daily practice, one has to emphasize the notion that all obese patients are not equally at high risk for complications," said Dr. Després. He cited studies conducted over the last 15 years that have emphasized the heterogeneity of obesity, highlighting variations in the metabolic risk profiles of these patients and making distinctions in risk based on the anatomical area in which the fat is concentrated.4,5 "If you have too much abdominal fat, theres a great likelihood of hypertension, dyslipidemia, and type 2 diabetes." However, he added, "Im not saying that peripheral obesity is benign. . . . It is a common conception that obesity, excess fatness, is associated with hypercholesterolemia, and I want to strongly emphasize that it is not the case," stressed Dr. Després. He noted that most obese patients with or without type 2 diabetes have normal cholesterol levels or only marginal elevations. "The typical dyslipidemia that you will find in an obese patient with or without type 2 diabetes is hypertriglyceridemia," often in the range of 150 to 200 mg/dl. In addition, such patients often have low high-density lipoprotein (HDL) cholesterol levels of approximately 30 or 35 mg/dl. "So, thus, the clinician will frequently see a marked elevation in the cholesterol-to-HDL cholesterol ratio in the ballpark of 6, 6.5, and even 7," which is a good predictor of ischemic heart disease, he said.
Dr. Bray pointed out that research conducted by Dr. Després and colleagues,5 as well as a Swedish study,6 have shown that with graded weight loss comes graded improvement in HDL and triglyceride levels. However, he noted, it took a very large change in weight (20 to 40 kg) to have any effect on cholesterol.
Can Obesity Be Managed Safely and Effectively?
Considerable controversy has surrounded the management of obesity, with critics claiming that the risks of the typical weight cycling seen among obese patients seeking to lose weight may be greater than the risks of the obesity. The NHLBI argues that strong evidence exists that weight loss in the overweight and obese can reduce risk factors for diabetes and cardiovascular disease. The NHLBI recommends treatment for those who are overweight (BMI 25 to 29.9 kg/m2 ) only if at least two risk factors or a high waist circumference is present. For such patients, treatment should consist of lifestyle changes (i.e., diet and exercise) intended to produce moderate weight loss. All obese patients should be offered treatment to produce "substantial weight loss over a prolonged period [see Page 43]."1
The initial goal should be a 10% weight loss over the first six months of treatment, after which the rate of weight loss usually declines and weight loss plateaus. A plan for weight maintenance after the first six months is essential, as weight is otherwise usually regained. Strategies for weight loss/maintenance include dietary therapy (a low-fat, reduced carbohydrate diet designed to produce a deficit of 500 to 1000 kcal/day), increased physical activity, behavior therapy, pharmacotherapy (with sibutramine or orlistat), and surgery (gastric restriction or gastric bypass).1
"I have a little bit of a problem with recommending treatment according to the degree that one is overweight," commented Dr. Albu. Rather, she said, for the patient in whom weight loss is medically indicated, she recommends a stepped-care approach that begins with diet and exercise. "The patient has to be compliant with a decrease in the amount of calories, . . . and then, if the weight loss doesnt happen, we could move up to a stricter calorie restriction by a liquid diet. Medication may then be the next step."
Dr. Després said he fully supported Dr. Albus approach, but noted, "There are instances when it is very, very important that the patient loses weight rapidly. . . . Therefore, there are instances where you need to be a little more aggressive."
Two agents are currently approved by the FDA for pharmacological management of overweight: sibutramine and orlistat.
Sibutramine, an orally-administered, centrally-acting, weight management agent, induces the natural processes leading to enhancement of satiety and thermogenesis by inhibiting serotonin and noradrenaline reuptake, thereby reducing food intake. Weight loss was examined in 11 double-blind, placebo-controlled obesity trials with study durations of 12 to 52 weeks, at doses ranging from 1 to 30 mg/day. Weight was significantly reduced in sibutramine-treated patients compared with placebo over the dose range of 5 to 20 mg/day.7 Those who completed therapy lost an average of 8.1 to 29.7 pounds compared with an average of 2.9 to 16.7 pounds among those given placebo. Significant dose-related reductions in waist circumference were also observed over six and 12 months in placebo-controlled clinical trials. Analysis of the data in three long-term (six months or longer) obesity trials indicated that patients who lose at least four pounds in the first four weeks of therapy were most likely to achieve significant long-term weight loss. Unlike amphetamines and related antiobesity agents, sibutramine does not have high potential for abuse. Side effects of sibutramine include dry mouth, anorexia, insomnia, constipation, and a small increase in pulse rate and blood pressure7. Sibutramine is contraindicated in patients receiving monoamine oxidase inhibitors and those receiving other centrally-acting appetite-suppressant drugs.
Orlistat, which was more recently approved for the long-term pharmacological management of obesity, is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%. A randomized, multi center, controlled trial to assess weight control and risk-factor reduction in 1187 obese subjects (BMI 30 to 42 kg/m2) showed that two-year treatment with orlistat plus reduction in diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors, particularly low-density lipoprotein (LDL) cholesterol. In this trial, during the first year, orlistat-treated patients lost an average of 8.76 kg versus 5.81 kg in the placebo group (P<0.001). During the second year, the orlistat group regained an average of 3.2 to 4.26 kg (depending on dose) versus 5.63 kg with placebo. Orlistat was also associated with decreased LDL and insulin levels.8 A similar European multi center study of 743 patients (BMI 28 to 47 kg/m2) showed that the orlistat group lost an average of 10.3 kg (10.2% of bodyweight) versus 6.1 kg (6.1% of bodyweight) in the placebo group. During the second year, the patients who continued on orlistat regained half as much weight as did those who were switched to placebo at the end of the first year. Orlistat was also associated with improvements in LDL cholesterol, LDL-to-HDL ratio, and glucose and insulin levels. Gastrointestinal effects were the only adverse events that were more common with orlistat than with placebo.9
Dr. Pi-Sunyer noted that in the NHLBI guidelines, he and the rest of the panel had recommended consideration of medication for weight loss for individuals with BMI of 30 or greater, or a BMI of 27 to 30 in the presence of two or more associated risk factors (e.g., central obesity hypertension, abdominal obesity, hyperlipidemia, elevated blood sugar). He added that this guideline is in accordance with the product labeling on the available pharmacological therapies.
"There are some patients who request pharmacological treatment immediately," said Dr. Albu. "I think it is very important to emphasize the point to all primary care physicians and to all physicians who treat obesity that that is not what should be done and that one should start with a program of diet and exercise." She continued, "I mean, its not necessarily true that if your BMI is over 40 youre going to lose weight only if you take drugs. . . . A severely obese patient could come in and lose 100 pounds in our weight loss center just using a low-fat diet and increased physical activity." She stressed again that pharmacological therapy should be reserved for patients who have decreased caloric intake and still cannot lose weight.
When she does prescribe pharmacological therapy, Dr. Albu may start with sibutramine. However, she added, if there are contraindications, the patient does not tolerate sibutramine, or the patient fails to lose weight on sibutramine, she prescribes orlistat. The effectiveness and the potential for side effects of these medications in an individual patient may help decide which one would be the first line of treatment.
"I think one of the problems with [sibutramine] that doctors have to keep in mind is that in some people there is an increase in heart rate and an increase in blood pressure. . . . So this has to be monitored carefully in the first three weeks or so," said Dr. Pi-Sunyer. He recommended that the drug be discontinued if the patient has an increase in blood pressure or heart rate that is alarming. Orlistat may then be tried in such patients, he suggested.
Dr. Bray cited reports suggesting that sibutramine can also serve as maintenance therapy in patients who have already lost weight. In one such report, Apfelbaum et al10 randomized patients (initial BMIs of ³ 30 kg/m2) who had lost 6 kg or more on a very-low-calorie diet to either one year of sibutramine (10 mg; n = 81) or placebo (n = 78). After one year of treatment, mean absolute weight change was 5.2 kg in the sibutramine group versus +0.5 kg in the placebo group (P = 0.004). The Sibutramine Trial of Obese Weight Reduction and Maintenance (STORM) showed similar findings.11 "Weight losses in these two trials are up to about 15%, which is better than the use of the drug in the trials [where it] was the initial treatment," he said, adding that "it may be a better drug for maintaining a weight loss once achievedor inducing a little morethan for an initial weight loss agent."
Commenting on orlistat, Dr. Després pointed out that it has been associated with reductions in total and LDL cholesterol levels.7,8 However, he noted, "once again, obese patients are not characterized by hypercholesterolemia and raised major elevation in LDL cholesterol levels." In fact, he pointed out that 80% of the patients in these two major trials were women with fairly normal lipid profiles. However, Dr. Després said he recently presented at the American Diabetes Association meeting a subgroup analysis of the use of orlistat in patients with abdominal obesity and elevated triglyceride levels, which showed the cholesterol-lowering, triglyceride-lowering, and HDL-raising effects of orlistat in this group are much greater than what was reported in full patient populations in the two large orlistat trials. He noted, "I think that from the published evidence with [orlistat] theres clearly an effect on cholesterol and LDL cholesterol levels that is independent from the loss of body weight, body fat, which makes sense, since this drug partly blocks the absorption of fat by roughly one third."
Dr. Bray expressed surprise that Dr. Després had observed an increase in HDL level in this subgroup of high-risk patients. "Thats very interesting. There arent many medications that do that with weight loss," he pointed out.
Dr. Després agreed, adding that it is actually not uncommon to see a decrease in HDL during active weight loss. He cautioned physicians not to be too concerned if they observe such a decrease "because once the patient is stabilized at the lower body weight in energy balance, then the physician will note an increase in HDL cholesterol levels."
"Dr. Pi-Sunyer, what is your experience in managing gastrointestinal adverse effects with orlistat?" asked Dr. Bray.
"In the trials that were done here at St. Lukes . . . we warned patients very explicitly about the fact that if they ate too much fat they would have more symptoms." He noted that patients who did not heed the warning did, indeed, have significant gastrointestinal effects including loose stools, steatorrhea, discomfort, and soiling. "In a sense, it taught them the lesson and so, as the trial went on, there was less and less of that . . . and it did tend to control the amount of fat that they took into their diet."
"Is anyone recommending both medications together as the final step [in a stepped-care approach]?" asked Dr. Shuldiner.
"You cant recommend it because its against the package insert strategies," said Dr. Bray. "It may be a very good combination, but theres no data."
"We desperately need clinical studies to look at that," agreed Dr. Albu.
"Drugs are only one form of treatment," stressed Dr. Bray. "Diet and exercise advice might be appropriate for almost anybody whose BMI is over 25, and, indeed, some whose BMIs are below 25, particularly if theyre in settings where theres a family history of diabetes or a woman whos had large babies, or where theres a family risk of dyslipidemia."
"We dont give diets below 800 calories," noted Dr. Albu, "but weve had a good experience with a liquid diet and some patients better maintain their low-calorie intake with that."
"It is also important to caution patients and physicians against switching from a high-fat diet to a diet low in fat but high in refined sugar," stressed Dr. Després. He also recommended brisk walking three or four times per week for obese patients with complications. Using such a program at Laval University, his patients showed a weight loss of only 5%; however, "we were able to induce a loss of abdominal fat of 25% and substantially improve the metabolic risk profile to a greater extent than what could be predicted by this weight loss of only 5%."
"Quite a small amount of weight loss will produce quite a large improvement in the risk factors and metabolic abnormalities," agreed Dr. Albu. She added that a small reduction in dietary fat consumption might produce improvement in metabolic risk profile, even in the absence of fat mass reduction. "If you dont decrease the fat mass, however, some patients may have a big problem with the ability to increase physical activity," she said.
"I really do think that American physicians are too timid about physical activity," emphasized Dr. Pi-Sunyer. "Many of them have this fear that obese patients have heart disease and are at risk for myocardial infarction and therefore theyre loathe to tell them to begin exercising. . . . I do believe its a mistake because these people are extraordinarily sedentary. If one starts carefully with walkingjust plain walkingand then moves that plain walking gradually to brisk walking, I think its very difficult to get into trouble with these patients and it can be extraordinarily helpful to them. So I think were too conservative regarding the recommending of exercise to many of these patients."
Dr. Shuldiner asked the group whether it was necessary for patients to undergo a stress test before embarking on an exercise regimen.
"I think if your exercise is walking, which people do every day, and theres no evidence of cardiovascular disease on their resting cardiogram, [it is unnecessary to] put them through a lot of expense for a stress test if all theyre going to do is walk a little bit more," said Dr. Bray. He also added that "its easier to get people to walk for exercise after theyve lost a little bit of weight. . . . So I tend to use it a little later rather than right at the beginning [of a weight loss program]."
Dr. Després argued, "It depends what type of patient youre dealing with. Indeed, if youre dealing with a very obese patient, I think your point is well taken, but there will be several obese patients, the majority of them, who can walk a little more quite easily." He encouraged primary care physicians to write out prescriptions for exercise, saying that the opinions and advice of physicians have more influence over patients than most doctors believe.
Dr. Shuldiner added that physicians should encourage patients to increase their activity level in their daily activities "such as taking the steps instead of waiting for the elevator and parking maybe a block or two away from the mall rather than the closest spot they can find."
"You can hardly find a staircase in most buildings," said Dr. Bray. "For fire reasons . . . theyve got doors in front of them."
"So, we need to make opportunities for our kids to play safely outside, to be more active, and it goes way beyond the medical system," said Dr. Després. "It will involveit has to involveevery related expertise: urban planners, politicians, and so on."
"I think we need to re-engineer a lot of things," agreed Dr. Bray. "Preventions clearly what we have to do but thats going to be a challenge."
Patience Is Key
"I would like to stress the point that the idea that you can cure obesity in a program that will last eight weeks, 12 weeks, 24 weeks, or whatever, is clearly wrong," said Dr. Pi-Sunyer. "Obesity is a chronic disease. It goes on forever and a person has to change lifestyle and habits life-long, so what were talking about in a weight control program or an exercise program is to develop habits that will not stop at 12 weeks or 24 weeks, but will essentially continue for the lifetime of the individual."
Dr Bray agreed. "We cant cure obesity, but we can treat it. With a few exceptions, obesity is like hypertension." He added, "There are some outcome studies in the behavioral areas suggesting that a few things that patients can do make a difference. One is monitoring the kinds of things they do, like where they eat, what they eat, with whom, and how much. A second is changing their dietary patterns to eat less fat, more fruits and vegetables and whole grains. A third thing they need to do is be more active."
"If I may add, I think for the perspective of general physicians, patience is the key," said Dr. Després, "and they have to provide patients with realistic expectations. . . . Theres a lot of energy stored in every kilogram of adipose tissue or fat tissueits about 7000 caloriesand if you are very successful, lets say, in increasing daily physical activity in your patient or implementing an exercise program, you can expect maybe to burn an extra thousand calories per week. . . . So, the physician should not expect . . . that the patient will lose 30 pounds in a month." However, he did note, "if there is a steady, moderate weight loss . . . long-term, this could be associated with a substantial improvement in the metabolic risk profile."
"Clearly, obesity is an important risk factor for cardiovascular disease. . . . I think weve determined that obesity is a chronic disease and, as such, it should be treated," said Dr. Shuldiner. The panelists provided an excellent perspective into the correct use of the BMI and waist measurement when assessing risk in overweight patients. "To summarize regarding therapy, we are all in agreement that a stepped approach is quite reasonable in most patients. There are some that may need more dramatic and more rapid weight loss, in which case maybe a stepped approach is less indicated. But for the most part, a stepped approach is indicated in which diet and exercise are clearly the very most important," followed by pharmacotherapy if additional therapy is needed to accomplish weight loss goals. Surgery should be reserved for severely obese individuals with risk factors in which more conservative approaches have failed repeatedly. Since obesity is a chronic disease, life-long lifestyle modifications are key.
Dr. Pi-Sunyer is Professor and Chief of the Division of Endocrinology, Diabetes, and Nutrition at St. Lukes-Roosevelt Hospital at Columbia University College of Physicians and Surgeons, and Director of the Joselin Center for Diabetes in New York.
Dr. Shuldiner is Professor and Head of the Division of Endocrinology, Diabetes, and Nutrition and Director of the Joslin Center for Diabetes at the University of Maryland, Baltimore in Baltimore, Maryland.