20 Obesity and Its Treatment in Type 2 Diabetes Frank L. Greenway and William T. Cefalu CONTENTS Introduction Pharmacologic and Surgical Treatment Behavior Modification and Lifestyle Change Pharmacologic Treatment Diabetes Medications Obesity Surgery Conclusions References Summary The prevalence of obesity began rising about 1980, and one third of the US population is now obese. The medical risks of obesity are linked to insulin resistance, and diabetes prevalence follows that of obesity by a decade. This chapter approaches the treatment of obesity in the context of diabetes. The role of behavior modification, meal replacements and commercial weight loss programs are discussed. Medications that were approved before 1986 are approved for short-term use and are chemically related to amphetamine. Obesity medications approved after 1986 and are approved for long-term use, and include a lipase inhibitor and an inhibitor of norepinephrine and serotonin reuptake. All these drugs give modest weight losses of less than 5kg in excess of placebo. Rimonabant, a cannabanoid-1 receptor antagonist received an approvable letter from the FDA for the treatment of obesity, but its new drug application was ultimately rejected. Metformin and acarbose are 2 oral diabetes medications that give some degree of weight loss, as do the injectable diabetes medications, pramlintide and exenatide. Thiazoladinediones, sulfonylureas and insulin give weigh gain whereas the meglitinides and the DPP-4 inhibitors are weight neutral. Restrictive surgical procedures like the lap-band are one type of obesity surgery, and restrictive- malabsorptive procedures like gastric bypass is the other. Weight loss is more durable and the improvement in diabetes is more dramatic with the restrictive-malabsorptive procedures. Lifestyle change is the basis for all obesity treatments. Obesity medications and surgical procedures are useful adjuncts and all obesity treatments are best delivered by a team, as is the case with diabetes. Key Words: Behavior modification; gastric bypass; lap-band; orlistat; rimonabant; sibutramine. INTRODUCTION In very simple terms, obesity can be defined as an excessive amount of body fat, which increases the risk of medical illness and premature death, and obesity develops over time when an individual consumes more calories than he/she burns. In this regard, obesity can be viewed as developing secondary to an imbalance in energy balance. In general, the concept of an energy balance equation implies that food consumption, i.e., “energy intake,” needs to match energy output, i.e., “energy expenditure,” to maintain a stable body weight. As well described, the major determinants of energy expenditure are: 1) the thermogenic effect of food (TEF), which represents the amount of energy used by ingestion and digestion of food we consume; 2) physical activity; and 3) resting metabolic rate (RMR), determined in large measure by the amount of lean body mass. As research over the recent past has shown, however, obesity is not such a simple process, as insight into the mechanisms that contribute to its development have revealed systems that are complex and highly integrated. Over the recent past, as key regulators From: Contemporary Endocrinology: Type 2 Diabetes Mellitus: An Evidence-Based Approach to Practical Management Edited by: M. N. Feinglos and M. A. Bethel © Humana Press, Totowa, NJ 333 334 Greenway and Cefalu of energy balance and insulin signaling have been elucidated, there has been a rapid and substantive increase in our understanding of underlying physiologic systems and molecular pathways that contribute to the development of obesity. Although it is recognized that there have been many changes in our environment that promote obesity, it is also clear that many individuals manage to resist obesity. Thus, there appears to be evidence that the variable susceptibility to obesity in response to environmental factors is undoubtedly modulated by specific genes (1,2). It has also been determined that there is a dynamic interplay between adipose tissue and other key tissues in the body, such as liver, muscle and regulatory centers of the brain. Altered regulation of this integrated and coordinated system inevitably leads to accumulation of body fat, insulin resistance and development of associated cardiovasular risk factors. Clinically, assessments such as body weight and body mass index (BMI) have been used for years to define obesity. As well described, the BMI assessment represents the relationship between weight and height and is derived by: 1) calculating either the weight (in kg) and dividing by the height (in meters squared), or; 2) calculating weight (in pounds) times 704 divided by height in inches squared (3). The importance of the BMI assessment is that it allows classification of obesity into specific risk categories (Table 1). Such a risk classification is based on data collected from large population based studies that assessed the relationship between body weight and mortality and provides the clinician a mechanism for identifying patients at high risk for complications associated with obesity (4,5). Although the body weight and BMI have served an important purpose in stratifying individuals at high risk, the assessment of the specific distribution of the body fat, e.g., central or abdominal obesity, has been suggested as an even more important assessment. In past studies, body fat distribution has been generally assessed by anthropometric measurements consisting of waist circumference, the waist/hip ratio (WHR), or skinfold thickness. Subsequently, more sophisticated techniques such as computed tomography (CT) scans or magnetic resonance imaging (MRI) scans have been used to assess central obesity. These techniques allow for the specific and precise quantification of abdominal fat depots. Using such methods, the relationship among specific adipose tissue depots, e.g., visceral fat depots, to peripheral muscle insulin sensitivity and other metabolic risk factors can be assessed. The prevalence of obesity has reached epidemic proportions around the world and the rate continues to increase; it is estimated that over 1 billion adults worldwide are overweight and at least 300 million are considered obese. There is no question that major contributors to this epidemic across the world include sedentary lifestyles, consumption of high fat, caloric-dense diets, and increased urbanization. Data from the National Health and Nutrition Examination Surveys in the United States have shown a dramatic shift in the percentage of the population considered overweight and obese. The most recent data demonstrate that 64% of the US adult population is classified as either overweight or obese (defined as BMI > 25). Whereas the prevalence of overweight adults increased slightly from data collected in 1960, from approx. 30.5% to 34.0 %, the prevalence of obesity (defined as a BMI > 30) has more than doubled, rising from approx. 13% in 1960 to over 30% in the year 2000 (6). The prevalence of individuals with extreme obesity, as defined by a BMI > 40, has changed even more dramatically, increasing over 6-fold in the 40-yr period (0.8% versus 4.7%). Thus, there are tremendous economic, medical and psycho-social consequences of this obesity epidemic, which will need to be addressed. Table 1 BMI associated disease risk Obesity class BMI (kg/m 2 ) Risk Underweight <18.5 Increased Normal 18.5–24 9 Normal Overweight 25.0–29 9 Increased Obesity I 30.0–34 9 High II 35.0–39 9 Very high Extreme obesity III ≥40 Extremely high Additional risks: (1)waist circumference >40 inches in men and >35 inches in women; (2) weight gain of≥5 kg since age 18–20 (3) poor aerobic fitness; and (4) Southeast Asian descent Chapter 20 / Obesity in Type 2 Diabetes 335 Table 2 Medical complications associated with obesity Gastrointestinal Gallstones, pancreatitis, abdominal hernia, NAFLD (steatosis, steatohepatitis, and cirrhosis), and possible GERD Endocrine/metabolic Metabolic syndrome, insulin resistance, imparied glucose tolerance, type 2 diabetes mellitus, dyslipidemia, polycystic ovary syndrome Cardiovascular Hypertension, coronary heart disease, congestive heart failure, dysrhythmias, pulmonary hypertension, ischemic stroke, venous stasis, deep vein thrombosis, pulmonary embolus Respiratory Abnormal pulmonary function, obstructive sleep apnea, obesity hypoventilation syndrome Musculoskeletal Osteoarthritis, gout, low back pain Gyneocologic Abnormal menses, infertility Genitourinary Urinary stress incontinence Ophthalmologic Cataracts Neurologic Idiopathic intracranial hypertension (pseudotumor cerebri) Cancer Esophagus, colon, gallbladder, prostate, breast, uterus, cervix, kidney Postoperative events Atelectasis, pneumonia, deep vein thrombosis, pulmonary embolus ∗ Adapted from reference 3. The major concern associated with the obesity epidemic is the expected increase in prevalence of the associated complications, which seem to affect every major organ system, and particularly the increase in cardiovascular risk factors (Table 2). Obesity has been suggested to increase an individual’s risk for cancer, gastrointestinal diseases, arthritis, diabetes, and cardiovascular disease. Specifically, obesity is significantly associated with both the traditional risk factors (i.e., hypertension, dyslipidemia, and diabetes) and the nontraditional Risk factors (i.e., fibrinogen and inflammatory markers) of cardiovascular disease. Furthermore, if one considers the presence of insulin resistance as the hallmark of the cardio-metabolic risk syndrome, it is clear that obesity and insulin resistance are integrally related. In addition to the significance of the relationship of obesity to medical complications, there is new understanding from research studies that adipose tissue is not merely a passive reservoir for energy storage, but is a very active endocrine organ. Specifically, adipose tissue has been shown to express and secrete a number of bioactive proteins referred to as adipocytokines in addition to expressing numerous receptors that allow it to respond to different Table 3 Adipocyte derived Proteins and receptor Adapted from reference 7 336 Greenway and Cefalu Table 4 Levels of evidence for diabetes prevention Recommendation Level of evidence (reference #) Lifestyle intervention causes weight loss of 5-10% and reduces the incidence of diabetes in people with impaired glucose tolerance 1A (10) Calorie controlled portions are an important dietary tool to aid in a weight loss program 1-B (13) Commercial weight loss programs like Weight Watchers and Jenny Craig give a clinically significant weight loss that is greater than self-help weight loss 1A (14,18) Sibutramine causes a mean weight loss of less than 5kg in excess of placebo in diabetic subjects 1A (27) Orlistat causes a mean weight loss of less than 5 kg in excess of placebo in diabetic subjects 1A (30) Orlistat and sibutramine give statistically similar weight losses in diabetic subjects 1B (32) Rimonabant causes weight loss similar to sibutramine, but gives greater improvements in insulin resistance 1A (43) Metformin gives a weight loss of approx 2 kg and reduces the risk of converting from impaired glucose tolerance to type II diabetes 1A (10) Pramlintide use in diabetic subjects is associated with weight loss 1A (47) Exenatide use in diabetic subjects is associated with weight loss 1A (54) Acarbose use in diabetic subjects is associated with a small weight loss 1A (56) Restrictive surgical procedures for weight loss like the lap-band regain about half the lost weight between 1 and 10 yr postoperatively 1C Restrictive-malabsorptive surgical procedures for weight loss cause a greater improvement in diabetes than purely restrictive procedures 1C hormonal signals (Table 3 ). Thus, in addition to its function to store and release energy, adipose tissue is able to metabolically communicate with other organ systems, and, in this way, contributes greatly to biological processes that include energy metabolism, neuroendocrine and immune function. PHARMACOLOGIC AND SURGICAL TREATMENT The treatment of obesity and diabetes share common ground beyond the fact that the 2 diseases often coexist in the same patient. Both diabetes and obesity are chronic diseases for which a team approach is required if treatment is to be optimally safe and effective. The medical treatment of obesity with pharmaceuticals should be accompanied by a lifestyle program to be optimally effective, and the surgical treatment of obesity should employ a team approach involving medical and surgical disciplines to deliver treatment with optimal safety. The need for a team approach presents a challenge, which the presence of diabetes may make both easier and harder to surmount. On one hand, weight loss is more difficult and more complicated in the presence of diabetes. However, third party reimbursement for obesity treatment is better in the presence of diabetes, and monetary resources often determine the treatments that it is possible to deliver. In discussing the pharmacologic and surgical treatment of obesity in the diabetic patient, we will discuss the role of behavior modification or lifestyle change programs and strategies to deliver them in the context of a diabetes practice. We will discuss the medications approved for the treatment of obesity and the most efficient manner to employ them. We will also discuss the impact of diabetes medications on body weight. Finally, we will discuss the role of obesity surgery in the treatment of diabetes, the reasons for the greater efficacy of restrictive-malabsorptive procedures, and the health care team needed to deliver surgical treatment of obesity with optimal safety. Chapter 20 / Obesity in Type 2 Diabetes 337 BEHAVIOR MODIFICATION AND LIFESTYLE CHANGE A major challenge to the delivery of a lifestyle change program is the lack of preparation and lack of interest of most physicians in providing behavior modification to their patients. The argument has been made that the physician, by virtue of his or her authority, is the most appropriate person to advise the patient on behavior changes that can result in weight loss. The medical treatment paradigm, however, is not designed to allow time for this activity and an argument can be offered that doing so would violate the law of comparative advantage. Physicians usually see patients every 15 min, and diabetic subjects often have multiple medical problems to be addressed in that short period of time. It is, therefore, not surprising that the typical physician’s advice consists of telling patients who need to lose weight that their diabetes would improve with weight loss and increased physical activity. If patients are to get the behavior modification and lifestyle counseling they need, a referral is generally required. The insulin requiring diabetic patient in poor control represents a special challenge, but it is a challenge that most third party payers are prepared to address. The team effort of a diabetic educator, dietitian, and physician working together can address the needs for a lifestyle change program while, at the same time, addressing the challenges of dietary regulation and glycemic control. Obesity treatment alone is more problematic, because it is often not covered by third party payers, leaving patients to seek out lifestyle change programs on their own. Behavior modification results in loss of approx 10% of initial body weight over 16–26 wk (8). A 5-10% loss of initial body weight has been demonstrated to produce clinically important benefits (9). Continued contact with the therapist can help maintain the major proportion of that weight loss. In the Diabetes Prevention Program, subjects in the lifestyle change program lost an initial 7% of body weight and at 3 yr maintained a 4% body weight loss accompanied by a 58% reduction in the conversion from impaired glucose tolerance to diabetes (10). Weight loss in patients with diabetes represents a particular challenge. Patients with diabetes lose approximately half the weight of nondiabetic patients (11). Because newly diagnosed diabetic patients seem to lose as much weight as nondiabetic individuals, the reduced weight loss in diabetic patients may be owing to chronic dietary restraint related to physicians admonishing diabetic patients to lose weight (12). Regardless of the reason, diabetic subjects, who have greater medical reasons to lose weight, do so at a reduced rate compared to their nondiabetic counterparts. Diabetes Education and Dietitian Counseling As previously mentioned, many third party payers will cover behavior modification and weight loss for patients with diabetes through diabetic education programs and coverage for dietitian consultations. As the diabetes becomes less difficult to manage and is controlled with diet or oral agents, the likelihood of third party coverage for lifestyle programs to induce weight loss diminishes. Because physicians do not have the time or inclination to administer lifestyle counseling themselves, other methods to deliver a lifestyle modification program must be sought. This usually means some type of commercial weight loss program. Calorie-Controlled Portions Calorie-controlled portions like SlimFast® once or twice daily have been compared to diets of comparable caloric content that use an exchange system. A 1-yr long study compared a group taking 2 meal replacements per day for 3 mo followed by 1 meal replacement/d with a group following an exchange diet of similar calories for 3 mo followed by 1 meal replacement daily. The group starting with meal replacements lost 11.3 ± 6.8% of initial body weight at 1 yr compared to the group initially using an exchange diet, which lost 5.9 ± 5.0% (13). Thus, calorie-controlled portions can be a powerful tool in delivering a weight loss program (Fig. 1). Commercial Weight Loss Programs Weight Watcher’s is a commercial program that delivers a lifestyle change program using counselors who are successful graduates of the program. The program uses a balanced diet constructed from food lists, is conducted in a group context and is relatively inexpensive. A 6-mo controlled trial comparing Weight Watcher’s to a self-help 338 Greenway and Cefalu Fig. 1. Mean (+ SEM) percentage change from initial body weight in obese patients during 27 mo of treatment with an energy- restricted diet containing 5.2-6.3 MJ/d. Data were analyzed on an available case basis. During the first 3 mo (phase 1), patients were randomly assigned to receive the energy-restricted diet only (group A, ) or to receive the energy-restricted diet with 2 meals and 2 snacks replaced by energy-controlled, nutrient-dense meal-replacement products (group B, •). During the next 24 mo (phase 2), all patients received the energy-restricted diet and 1 meal and 1 snack were replaced by energy-controlled, nutrient-dense meal-replacements products. Am J Clin Nutrition 1999;69:198–204. weight loss group resulted in a 4.8 ± 5.6 kg weight loss in the Weight Watcher’s group compared to a 1.4 + 4.7 kg weight loss in the self-help group (14). This weight loss was greater than 5% of initial body weight and clinically significant. At 2 yr, subjects in the Weight Watcher’s group maintained more than a 3% weight loss while weight in the self-help group returned to baseline (15). A recent review of commercial weight loss programs concluded that the only well controlled trial was the study of the Weight Watcher’s program, but called for “naturalistic studies” of program results (16). The Jenny Craig program, which combines calorie-controlled portions with individual behavior and lifestyle counseling, recently published such a study of their program (17) (Fig. 1). Those subjects who remained in the program for a year lost 15.6 ± 7.5% of their initial body weight. Rock et al published a 1 year study comparing the Jenny Craig program with a self-help control group (18). The Jenny Craig group lost 7.8 ± 11.1 of initial body weight compared to 0.7 ± 6.2% in the control group (Fig. 2). The Jenny Craig program is more expensive than the Weight Watcher’s program, in addition to being more effective. These studies give the physician some basis upon which to make a referral to a commercial weight loss program. Jenny Craig N = 70, p < 0.01 by Intent to Treat –10 –8 –6 –4 –2 0 06 12 Months Percent Body Weight Lost Self Help Jenny Craig Fig. 2. A randomized study comparing the Jenny Craig program to self-help weight loss. The Jenny Craig group lost significantly more weight at 6 and 12 months than the self-help group (ref 18). Chapter 20 / Obesity in Type 2 Diabetes 339 PHARMACOLOGIC TREATMENT There are 2 medications presently approved for the long-term treatment of obesity, sibutramine and orlistat. Medications approved before 1985, the year the NIH conference declared that obesity is a chronic disease, were approved and tested for up to 12 wk as an adjunct to diet and lifestyle change (19). There is one medication, remonabant, which was issued an approvable letter for long-term weight loss by the Food and Drug Administration (FDA) but the New Drug Application (NDA) was rejected by the Food and Drug Administration due to concerns of depression, anxiety and neurological adverse events. Rimonabant is approved in Europe and some other countries throughout the world for the treatment of obesity. Medicines used to treat diabetes can have an impact on body weight in both directions but most diabetes drugs cause weight gain. We will review drugs approved for the treatment of obesity and describe rimonabant, since it is approved in countries outside the United States. Obesity Medication Approved for Short-Term Use Drugs approved before 1985 for the treatment of obesity are chemically related to amphetamine, and all are associated with some degree of CNS stimulation. Phentermine and diethylpropion are in DEA class IV and are felt to have a lower abuse potential than phendimetrazine and benzphetamine (class III) or phenmetrazine (class II). One might logically ask if these drugs can be useful in a chronic disease when they are all approved for up to 12 wk of use. There is a study comparing phentermine given continuously to phentermine given every other month and to a placebo in a 36-wk trial (20). The intermittent use of phentermine gave equivalent weight loss to continuous use. The intermittent regimen gave lower drug exposure, was less expensive and allowed phentermine to be used in a way that is consistent with its package insert. Although the long-term studies of these drugs are limited, phentermine gave a 7.9 kg greater weight loss than placebo in a 1-yr trial (21) (Fig 3). Sibutramine Sibutramine is a reuptake inhibitor of norepinephrine and serotonin. Its use results in 2.8 kg more weight loss than a placebo at 3 mo and 4.5 kg more weight loss than placebo at 1 yr (22). The adverse events associated with the use of sibutramine are associated with its adrenergic mechanism of action and include dry mouth, insomnia, and nausea. Sibutramine treatment is associated with the improvement in glucose and lipids expected with weight loss. However, sibutramine use is associated with an average increase in pulse rate of 4 beats per min, and the expected improvement in blood pressure is not seen, probably owing to noradrenergic stimulation. In a 6-mo dose-ranging study of 1,047 patients, there was a clear dose-response effect, and patients regained weight when the drug was stopped (23). In a trial in patients who initially lost weight eating a very-low-calorie diet Phentermine: Continuous and Intermittent Treatment -30 -25 -20 -15 -10 -5 0 0 4 wk 8 wk 12 wk 16 wk 20 wk 24 wk 28 wk 32 wk 36 wk lb. Placebo Q O Mo. Continued Munro JF et al. Br Med J 1968 Feb 10;1(5588):352 -4 Fig. 3. Intermittent treatment versus continuous phentermine. 340 Greenway and Cefalu before being randomized to sibutramine (10 mg/d) or placebo, sibutramine produced additional weight loss, while the placebo-treated patients regained weight (24) The Sibutramine Trial of Obesity Reduction and Maintenance lasted 2 yr and provided evidence for weight maintenance (25). Patients were initially enrolled in an open-label phase and treated with 10 mg/d of sibutramine for 6 mo. Of the patients who lost more than 8 kg, two-thirds were then randomized to sibutramine and one-third to placebo. During the 18-mo double-blind phase of this trial, the placebo-treated patients steadily regained weight, maintaining only 20% of their initial weight loss at the end of the trial. In contrast, the subjects treated with sibutramine maintained their weight for 12 mo and then regained an average of only 2 kg, thus maintaining 80% of their initial weight loss after 2 yr (26). Despite the higher weight loss with sibutramine at the end of the 18 mo of controlled observation, the blood pressure levels of the sibutramine-treated patients were still higher than in the patients treated with placebo. Studies with diabetic patients treated with sibutramine have also been published. In one such trial, sibutramine 20 mg/d was studied in 175 subjects with poorly controlled diabetes. The sibutramine group lost 4.5% of initial body weight compared to 0.5% in the placebo group. Fasting insulin, glycemic control, triglycerides, HDL cholesterol, and quality-of-life assessment improved commensurate with the weight loss, but blood pressure and pulse increased except in those that lost more than 5% of initial body weight (27). Sibutramine is available in 5-, 10-, and 15-mg doses; 10 mg/d as a single dose is the recommended starting level, with titration up or down depending on the response. Doses higher than 15 mg/d are not recommended. Of the patients who lost 2 kg (4 lb) in the first 4 wk of treatment, 60% achieved a weight loss of more than 5%, compared with less than 10% of those who did not lose 2 kg (4 lb) in 4 wk. Combined data from 11 studies of sibutramine showed a reduction in triglyceride, total cholesterol, LDL cholesterol levels and an increase in HDL cholesterol levels that were related to the magnitude of the weight loss. Orlistat Orlistat is an inhibitor of pancreatic lipase and causes one-third of dietary fat to be lost in the stool (27). Orlistat is designed for use with a 30% fat diet. Its use is associated with approx 3.2 kg more weight loss than placebo at 6 mo and 3.2 kg more weight loss than placebo at 1 yr (28). The adverse events associated with the use of orlistat can be predicted from its mechanism of action. There is an increased incidence of diarrhea, flatulence and dyspepsia. Orlistat use results in the expected decrease in blood glucose and blood pressure with weight loss, but gives a reduction in lipids in excess of that expected for the degree of weight loss, probably because it enforces a low-fat diet. Orlistat is available in 120 mg doses; and 120 mg 3 times per day with meals is the recommended dose. An over-the-counter dose of 60 mg 3 times a day is expected to be available shortly. Orlistat has also been studied in diabetic patients. In a 1-yr study of 391 subjects taking a sulfonylurea, the orlistat group lost 6.2 ± 0.45% of initial body weight compared to 4.3 + 0.49% in the placebo group, and diabetic control improved to a greater degree in the orlistat group commensurate with the weight loss (29). A 4-yr trial randomized 3,305 subjects, 79% with normal glucose tolerance and 21% with impaired glucose tolerance to orlistat 120 mg 3 times a day or a placebo. At the end of 4 yr, 52% remained in the orlistat group compared to 34% in the placebo group. The orlistat patients not only lost more weight, 3.6 kg versus 1.4 kg, but the conversion to diabetes was reduced by one-third, to 6.2%, in the orlistat group, compared to 9% in the placebo group (30). Comparing and Combining Orlistat and Sibutramine Orlistat and sibutramine were compared in a double-blind randomized clinical trial of 113 subjects over 1 yr . Both medications induced significant weight loss, but there was no statistically significant difference among them (31). A similar trial in 144 type 2 diabetic subjects confirmed these results (32). Because orlistat and sibutramine work by different mechanisms, it is logical to ask whether using them in combination might give additive weight loss. The first trial addressing this question treated subjects with sibutramine for 1 yr and added orlistat during weight maintenance. No further weight was lost by the addition of orlistat (33). Three studies compared sibutamine, orlistat and the combination. The first trial of 80 subjects showed more weight loss in the combination and sibutramine 10 mg/d groups than either the orlistat 120 mg 3 times per day or the diet alone groups, but the sibutramine group and the combination group did not differ from each other (34). This finding was confirmed by a second study using a similar design (35). The third trial compared orlistat 120 mg 3 times daily to sibutramine 10 mg/d and the combination in 89 obese subjects. The sibutramine and the Chapter 20 / Obesity in Type 2 Diabetes 341 Weight Loss with Orlistat, Metformin and Sibutramine n = 150, p < 0.0001 –12 –10 –8 –6 –4 –2 0 06 Months Percent Weight Loss Orlistat 120 mg tid Metformin 850 mg bid Sibutramine 10 mg/d Gokcel A et al. Diab Obes Metab. 2002 Jan;4(1):49–55 Fig. 4. Sibutramine, metformin, and orlistat in diabetes. combination groups lost 10.2% and 10.6 % of initial body weight, respectively, which was not different but was greater than the 5.5% weight loss in the orlistat group (36). A trial in obese type 2 diabetic subjects compared metformin 850 mg twice per day to sibutramine 10 mg twice per day and orlistat 120 mg 3 times per day. The sibutramine group lost more weight (10.4%) than the orlistat group (6.6%) or the metformin group (8.1%) (37). In summary, sibutramine use appears to result in superior weight loss and is better tolerated than orlistat, but orlistat use is associated with the expected decrease in blood pressure not seen with sibutramine (Fig. 4). Combining Sibutramine with Behavior Therapy Although there does not seem to be an advantage of combining sibutramine and orlistat, advantage of combining sibutraminewithbehaviortherapyhasbeenwelldemonstrated.Inonestudy,224subjectswererandomizedto4groups: 1) Sibutramine 15mg/d, delivered by a primary care provider in 8 visits of 10–15 min each, 2) Lifestyle-modification counseling alone, delivered in 30 group sessions, 3) Sibutramine plus 30 group sessions of lifestyle-modification counseling (i.e., combined therapy), 4) Sibutramine plus brief lifestyle-modification counseling, delivered by a primary care provider in 8visits of 10–15 min each.At 1 yr , subjectswho received combined therapylost a mean 12.1 kg, subjects using sibutramine alone lost 5.0 kg, the lifestyle modification alone group lost 6.7kg, andthose receiving sibutramine plus brief therapy lost 7.5 kg (38) (Fig. 5) (subjects who received combined therapy ost significantly more weight at all times than subjects in the other three groups. Subjects treated with lifestyle modification alone and those treated with sibutramine plus brief therapy lost significantly more weight at week 18 than those who received sibutramine alone, with no other significant differences at any other time. Panel B shows that a last-observation- carried-forward analysis yielded the same statistical conclusions). The importance of lifestyle modification has been demonstrated in diabetic subjects as well. Obese type 2 diabetic subjects were randomized to a standard lifestyle program or a combination program using calorie-controlled portions and sibutramine, in addition to the lifestyle change program. At 1 yr , the lifestyle group lost 0.8 kg compared to 7.3 kg in the combined group and the combined group had statistically better glycemic control (39) (Fig. 5). Rimonabant Rimonabant is approved for the treatment of obesity in Europe and some other countries, but although it received an approvable letter from the FDA, its approval was denied by the United States Food and Drug Administration due to safety concerns about depression, anxiety and neurological adverse events. The mechanism by which rimonabant causes weight loss is thought to be through inhibition of the cannabinoid-1 receptor. There are 2 cannabinoid receptors, CB-1 (470 amino acids in length) and CB-2 (360 amino acids in length). The CB-1 receptor has almost all the amino acids that comprise the CB-2 receptor and additional amino acids at both ends. CB-1 receptors are distributed throughout the brain in the areas related to feeding, on fat cells, in the gastrointestinal tract and on immune cells. Marijuana and tetrahydrocannabinol stimulate the CB-1 receptor, 342 Greenway and Cefalu 0 2 4 6 8 A B 10 Weight Loss (kg)Weight Loss (kg) 12 52 40 Weeks Sibutramine alone Sibutramine+brief therapy Combined therapy Lifestyle modification alone Sibutramine alone Sibutramine+brief therapy Combined therapy Lifestyle modification alone 1810630 5240 Weeks 18106 3 0 14 16 0 2 4 6 8 10 12 14 16 Fig. 5. Mean (+ SE) weight loss in the 4 groups as determined by an intention-to-treat analysis (panel A) and a last-observation- carried-forward analysis (panel B). Subjects who received combined therapy lost significantly more weight at all times than subjects in the other three groups. Subjects treated with lifestyle modification alone and those treated with sibutramine plus brief therapy lost significantly more weight at week 18 than those who received sibutramine alone, with no other significant differences at any other time. Panel B shows that a last-observation-carried-forward analysis yielded the same statistical conclusions. (From Wadden et al. NEJM 353: 20, 2005). increase high-fat and high-sweet food intake, and increase fasting levels of endocannabinoids such as anandamide and 2-arachidonyl-glycerol. The rewarding properties of cannabinoid agonists are mediated through the meso- limbic dopaminergic system. Rimonabant, being a specific antagonist of the CB-1 receptor, inhibits sweet food intake in marmosets as well as high-fat food intake in rats, but not food intake in rats fed standard chow. In addition to being specific in inhibiting highly palatable food intake, pair feeding experiments in diet-induced obese rats show that the rimonabant treated animals lost 21% of their body weight compared to 14% in the pair-fed controls. This suggests, at least in rodents, that rimonabant increases energy expenditure in addition to reducing food intake. CB-1 knockout mice are lean and resistant to diet-induced obesity, but have an accelerated cognitive decline with aging (40). CB-1 receptors are up-regulated on adipocytes in diet-induced obese mice, and rimonabant increases adiponectin, a fat cell hormone associated with insulin sensitivity (41). The results of 3 phase III trials of rimonabant for the treatment of obesity have been published. The first trial to be announced was called the Rio-Lipids trial. This was a 1-yr trial that randomized 1,018 obese subjects equally to placebo, rimonabant 5 mg/d, or rimonabant 20 mg/d. The subjects in this trial had untreated dyslipidemia, a BMI between 27 and 40 kg/m 2 and a mean weight of 96kg. Weight loss was 2% in the placebo group and 8.5% in the 20 mg rimonabant group. In the 20 mg/d rimonabant group, waist circumference was reduced 9cm, triglycerides [...]... systematic review of the clinical effectiveness of orlistat used for the management of obesity Obes Rev 2004;5:51– 68 29 Hollander PA, Elbein SC, Hirsch IB, et al Role of orlistat in the treatment of obese patients with type 2 diabetes A 1-year randomized double-blind study Diabetes Care 19 98; 21:1 288 –1294 30 Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L XENical in the prevention of diabetes in obese... significant, and even the lack of weight gain can be a victory in treating the obese type 2 diabetic individual DPP-4 Inhibitors Sitagliptin, an inhibitor of DPP-4, is a recently approved class of medications for the treatment of diabetes, and there are other DPP-4 inhibitors in development DPP-4 is the enzyme that breaks down the incretin hormones from the gut, like glucagon-like peptide-1 (GLP-1) Clinical... prospective study of the influence of intensive dietary therapy Q J Med 1 986 ;59:579–5 98 13 Ditschuneit HH, Flechtner-Mors M, Johnson TD, Adler G Metabolic and weight-loss effects of a long-term dietary intervention in obese patients Am J Clin Nutr 1999;69:1 98 204 14 Heshka S, Greenway F, Anderson JW, et al Self-help weight loss versus a structured commercial program after 26 weeks: a randomized controlled... Exendin-4 (exenatide) is a 39-amino-acid peptide that is produced in the salivary gland of the Gila monster lizard and has been approved for the treatment of type 2 diabetes It has 53% homology with GLP-1 but has a much longer half-life Exenatide decreases food intake and body weight gain in Zucker rats while lowering HbA1c ( 48) , inducing satiety and weight loss with peripheral administration and crossing... Gastroenterol 2003; 98: 2042–2047 Chapter 21 / Liver in Type 2 Diabetes 363 46 McCullough AJ The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease Clin Liver Dis 2004 ;8: 521–533, viii 47 Grant BF, Dufour MC, Harford TC Epidemiology of alcoholic liver disease Semin Liver Dis 1 988 ;8: 21–25 48 Mofrad P, Contos MJ, Haque M, et al Clinical and histologic spectrum of nonalcoholic... Karakose H, et al Evaluation of the safety and efficacy of sibutramine, orlistat and metformin in the treatment of obesity Diabetes Obes Metab 2002;4:49–55 38 Wadden TA, Berkowitz RI, Womble LG, et al Randomized trial of lifestyle modification and pharmacotherapy for obesity N Engl J Med 2005;353:2111–2120 39 Redmon JB, Raatz SK, Reck KP, et al One-year outcome of a combination of weight loss therapies... loss, and improve metabolic parameters Ann Surg 2006;243:1 08 114 68 Mason EE Ileal [correction of ilial] transposition and enteroglucagon/GLP-1 in obesity (and diabetic?) surgery Obes Surg 1999;9: 223–2 28 69 Gallwitz B Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus Treat Endocrinol 2005;4:361–370 350 Greenway and Cefalu 70 Pories WJ, Swanson MS, MacDonald KG, et al... McGraw-Hill, 2004 21 The Liver in Type 2 Diabetes Mellitus Anna Mae Diehl and Steve S Choi CONTENTS Etiology of Liver Disease in Type 2 Diabetes Prevalence of NAFLD Pathogenesis of Diabetes-Related Liver Disease Diagnosis of NAFLD Natural History and Prognosis of NAFLD Associated with Type 2 Diabetes Management of Diabetes-Associated Liver Disease Future Directions References Summary Type 2 diabetes... C, Thomas F, Leutenegger E Long-term maintenance of weight loss after a very-lowcalorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine Am J Med 1999;106:179– 184 25 James WP, Astrup A, Finer N, et al Effect of sibutramine on weight maintenance after weight loss: a randomised trial STORM Study Group Sibutramine Trial of Obesity Reduction and Maintenance Lancet 2000;356:2119–2125... Hepatology 2003;37:1 286 –1292 49 Cohen JA, Kaplan MM The SGOT/SGPT ratio: an indicator of alcoholic liver disease Dig Dis Sci 1979;24 :83 5 83 8 50 Poynard T, Imbert-Bismut F, Munteanu M, et al Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C Comp Hepatol 2004;3 :8 51 Poynard T, Imbert-Bismut F, Munteanu . and Intermittent Treatment -3 0 -2 5 -2 0 -1 5 -1 0 -5 0 0 4 wk 8 wk 12 wk 16 wk 20 wk 24 wk 28 wk 32 wk 36 wk lb. Placebo Q O Mo. Continued Munro JF et al. Br Med J 19 68 Feb 10;1(5 588 ):352 -4 Fig. 3. Intermittent. for 6 mo. Of the patients who lost more than 8 kg, two-thirds were then randomized to sibutramine and one-third to placebo. During the 1 8- mo double-blind phase of this trial, the placebo-treated. 2006;243:1 08 114. 68. Mason EE. Ileal [correction of ilial] transposition and enteroglucagon/GLP-1 in obesity (and diabetic?) surgery. Obes Surg 1999;9: 223–2 28. 69. Gallwitz B. Glucagon-like peptide-1-based