Treatment of Obesity Arne Astrup in International Textbook of Diabetes Mellitus, Third Edition Editors-in-Chief R A DeFronzo, E Ferrannini, H Keen and P Zimmet c John Wiley & Sons, Ltd., Chichester, 2004 36 Treatment of Obesity Arne Astrup The Royal Veterinary and Agricultural University, Frederiksberg, Denmark INTRODUCTION AND OVERVIEW The epidemic of type 2 diabetes is due to environmental factors, but the individuals developing the disease have a strong genetic predisposition. A number of recent observational surveys and intervention studies have shown that excess body fatness is the major environmental cause of type 2 diabetes, and that even a minor weight loss can prevent its development in high-risk subjects. Randomized trials using diet, weight loss agents, or surgical treatment of obesity have all clearly demonstrated that fat loss per se is crucial, whereas diet composition and physical activity play a minor role in improving insulin resistance and reducing the risk of overt diabetes. Weight loss improves glycemic control in type 2 diabetic patients and has a clinically relevant beneficial effect on all cardiovascular risk factors. Weight management programs are therefore a cornerstone in both the prevention and treatment of type 2 diabetes. A weight loss of 5–10% can be induced in almost all simple and diabetic obese patients, provided treatment is offered by a professional team consisting of a physician and dieticians or nurses trained to focus on weight loss and maintenance. Although increasing daily physical activity and regular exercise does not significantly affect the rate of weight loss in the induction phase, it plays an important role in the weight maintenance phase due to an important impact on daily energy expenditure and also to a direct enhancement of insulin sensitivity. Weight loss drugs have a role in patients in whom the lifestyle treatment is insufficient to produce the required weight control, and in obese subjects drugs like orlistat and sibutramine may both produce weight loss and reduce the risk of complications of obesity, such as type 2 diabetes. In obese individuals with impaired glucose tolerance (IGT), metformin and orlistat reduce the risk of developing type 2 diabetes, and in type 2 diabetic patients the drugs produce weight loss, improved glycemic control, and beneficial effects on cardiovascular risk factors. Bariatric surgery is a very effective means to produce a longer lasting weight loss, and may be an option in the severely obese patients who are difficult to treat with the other weight management tools. PRINCIPLES TO ACHIEVE DIET-INDUCED WEIGHT LOSS In almost every overweight and obese patient the diet must be adjusted to reduce energy intake. Dietary therapy consists of instructing patients on how to modify their dietary intake to achieve a decrease in energy intake while maintaining a nutritionally adequate diet. Obese patients have, because of their enlarged body size, higher energy requirements for a given level of physical activity than their normal-weight counterparts (Figure 1). Obese diabetic patients have slightly higher energy requirements than simple obese patients for a given body size and composition. Reducing the obese patient’s total energy intake compared to that of a normal-weight individual will inevitably cause weight loss, consisting of about 75% fat and 25% lean tissue, until weight normalization occurs at a new energy equilibrium [1, 2]. For patients with class I obesity this requires an energy deficit of 300–500 kcal/day, and for patients with class III obesity, 500–1000 kcal/day. There is no evidence to support that differences in diet composition exert clinically important effects on energy absorption and energy expenditure, and so the main mechanism of weight-reduction diets is to reduce total energy intake. This can be achieved by setting an upper limit for energy intake. The larger the daily deficit in energy balance, the more rapid the weight loss. A deficit of International Textbook of Diabetes Mellitus, Third Edition. Edited by R. A. DeFronzo, E. Ferrannini, H. Keen, and P. Zimmet. c 2004 John Wiley & Sons, Ltd. ISBN: 0-471-48655-8. 674 Obesity Figure 1 Energy expenditure (energy requirements) of normal weight, overweight, and obese subjects. Relationship between body weight and energy requirements assessed by measurement of energy expenditure or by apparent energy intake during weight stability. The growing underreporting with increasing body fatness makes the self-reported energy intake invalid for estimation of energy requirements in obese patients 300–500 kcal/day will produce a weight loss of 300– 500 g/week, and a deficit of 500–1000 kcal/day will produce a weight loss of 500–1000 g/week [1]. Greater initial energy deficits may produce even larger weight loss rates. Total energy expenditure declines and normalizes along with weight loss, and total energy intake should therefore gradually be further reduced to maintain the energy deficit. An alternative approach is to take advantage of the differences in the satiating power of the various dietary components in order to cause a spontaneous reduction in energy intake. This is the principle of the ad libitum lowfat diet. Choosing the Dietary Deficit Initially, the target of a weight loss program should be to decrease body weight by 10% [1–4]. Once this is achieved a new target can be set. Patients will generally want to lose more weight, but it should be remembered that even a 5% weight reduction improves risk factors and risk of comorbidities. However, several factors should be taken into consideration, e.g. the patient’s degree of obesity, previous weight loss attempts, risk factors, comorbidities, and personal and social capacity to undertake the necessary lifestyle changes. To prescribe a diet with a defined energy deficit, it is necessary to estimate the patient’s actual energy requirements. It would seem natural to estimate the patient’s habitual energy intake from self-reported diet registration over 3–7 days of weight stability, calculating the energy content of the diet by use of food table programs. However, these estimates are invalid because of systematic underreporting by obese individuals of energy intake amounting to 30–40%. Energy requirements should therefore be assessed indirectly by estimation of total energy expenditure. Resting metabolic rate (RMR) can be measured by indirect calorimetry, or be estimated with great accuracy using equations based on body weight, gender, and age [5] (Table 1) or, even better, estimated from information on the size of fat-free mass and fat mass [6]. Total energy expenditure (=energy requirement) is estimated by multiplication of RMR (kcal/day) by an activity factor (PAL, physical activity level) [5] (Table 1). The energy level of the prescribed diet is defined as the patient’s energy requirement minus the prescribed daily energy deficit. Theoretical Versus Clinical Outcome Translating the physiologically based considerations regarding energy balance and weight loss into clinical practice requires a high degree of compliance, which can be difficult to obtain. Weight loss results tend to be much better in clinical trials conducted in specialized clinics than in trials conducted by nonspecialists without sufficient resources and access to auxiliary therapists (dieticians, psychologists, etc.). Compliance and adherence to the diet are the cornerstones of successful weight loss, and are the most complicated part of the dietary treatment of obesity. To improve adherence, consideration should be given to Table 1 Estimating energy needs∗ Revised WHO equations for estimating basal metabolic rate (BMR) Men 18–30 years =(0.0630 × actual weight in kg + 2.8957) × 240 kcal/day 31–60 years =(0.0484 × actual weight in kg + 3.6534) × 240 kcal/day Women 18–30 years =(0.0621 × actual weight in kg + 2.0357) × 240 kcal/day 31–60 years =(0.342 × actual weight in kg + 3.5377) × 240 kcal/day Estimated total energy expenditure = BMR × activity factor Activity level Low (sedentary) Intermediate (some regular exercise) High (regular activity or demanding job) ∗ Reproduced by permission of Handbooks in Health Care Co. [5]. Activity factor 1.3 1.5 1.7 Treatment of Obesity the patient’s food preferences, as well as to personal, educational, and social factors. Great efforts should be made to see the patient frequently and regularly. Furthermore, long-term weight reduction is unlikely to succeed unless the patient acquires new eating and physical activity habits. These behavioral changes should be an integral part of the treatment program. 675 Table 2 Adverse effects and complications of VLEDs Adverse effect Cold intolerence Dry skin Fatigue, dizzines, muscle cramps, headache, gastrointestinal distress Hair loss Gallstones Bad breath Occurrence ∼50% ∼50% 10–20% 10% 10–30% 20–30% OPTIONS FOR WEIGHT LOSS DIETS Therapeutic obesity diets distinguish between several recognized weight reduction regimens. Low-energy diets (LEDs) usually provide 800–1500 kcal/day and use fatreduced foods, though weight loss occurs independent of the diet composition. Diets providing 1200 kcal/day or more can be classified as balanced-deficits diets [4, 6], but this definition will not be used in this chapter. Very low energy diets (VLEDs) are “modified fasts”, providing 200–800 kcal/day that replace normal foods. Examples of weight loss on such diets are shown in Figure 2 Ad libitum low-fat diets do not restrict energy intake directly, but target a restriction of ad libitum fat intake to 20–30% of total energy intake. Energy intake is spontaneously reduced because of the higher satiating effect of this diet and a modest weight loss occurs. Very Low Energy Diets Starvation (diet providing less than 200 kcal/day) is the ultimate dietary treatment of obesity, but it is no longer used because of the numerous and serious medical complications associated with prolonged starvation [8]. Starvation has been replaced by VLEDs (200–800 kcal/day), which aims to supply very little energy but all essential nutrients. Reducing the energy content of a diet requires an increased nutrient density. This can be difficult to obtain with natural foods if the diet is to be acceptable once the energy content of the diet becomes lower than 800 kcal/day. This has led to the commercial production of VLEDs, supplemented with all nutrients in RDA (recommended dietary allowance) amounts. For decades, 250–400 kcal/day formula diets were extremely popular. The first VLEDs were clearly nutritionally insufficient, but reports of adverse effects and results from research have brought about a gradual increase in energy level. Today the 800 kcal/day VLED is the only version recognized as being both effective and safe [8]. A number of studies have shown that VLEDs with energy levels of less than 800 kcal/day do not produce a greater weight loss and are less well accepted than those comprising 800 kcal/day [9]. VLEDs usually provide a ketogenic diet with an energy content of around 800 kcal/day in the form of nutrition powders, or in the form of protein-, mineral-, trace-element-, and vitaminenriched meals or drinks. VLEDs can induce very rapid weight loss over a 2–3-month period (Figure 2), but do not seem to facilitate weight maintenance [9]. This is not because a rapid initial weight loss causes poorer long-term weight maintenance per se [10], as initial weight losses are positively, not negatively, associated with long-term weight loss [11]. However, VLEDs are not educational and do not facilitate the gradual modification of the patient’s eating behavior, nutritional knowledge, and skills, which seems to be required for long-term weight maintenance. Some concern has been raised about the cardiac safety of the use of VLEDs with less than 800 kcal/day [3], and patients using VLEDs have an increased risk of developing gallstones (Table 2). Their use without medical supervision has generally been abandoned and should not be recommended [1, 3, 4, 8]. Low-Energy Diets Figure 2 Weight loss in obese patients randomized to either an LED or a VLED. Initial mean body weight was nearly 100 kg and mean weight loss 12.6 kg in both groups. (Reproduced by permission of the British Medical Journal [7]) LEDs usually provide 800–1500 kcal/day and normally consist of natural normal foods. LEDs are also called traditional diets and calorie-counting diets, because previously more emphasis was put on restricting the total energy level of the diet and less on the macronutrient composition. Although macronutrient composition of the diet is of less importance for short-term weight loss, it is now usually modified in order to maximize the beneficial effect on cardiovascular risk factors and insulin resistance, and to prevent cancers, perhaps also promoting long-term weight 676 Obesity Table 3 Example of the composition of an LED Nutrient Calories Total fat Saturated fatty acids Monunsaturated fatty acids Polyunsaturated fatty acids Protein Carbohydrate Fiber Calcium Other vitamins, minerals, and trace elements maintenance. For practical reasons, LEDs are low-fat, carbohydrate-rich diets with a fixed energetic allowance. An example of an appropriate nutrient composition for an LED is given in Table 3. It should be supplemented with a daily vitamin and mineral tablet. A patient may choose an energy level of 1000–1200 kcal/day for women and 1200–1500 kcal/day for men. LEDs produce a lower rate of weight loss than VLEDs (Figure 2), but randomized clinical trials demonstrate that the long-term (>1 year) weight loss is not different from that of the LEDs [1]. Furthermore, using LEDs for weight loss induction introduces healthy eating habits early in the weight reduction program, giving a longer period in which to familiarize the patient with the dietary changes that are a central element in a weight maintenance program. Based on 34 randomized clinical trials examining the impact of LED in obese subjects, it was concluded that LED produces weight loss regardless of duration of treatment, and body weight was reduced by an average of 8% over 3–12 months [1]. In trials lasting 3–6 months, and 6–12 months, LED produced mean weight losses of approximately 8% compared to controls [1]. Although they targeted the same energy deficit there was a large variation in mean weight loss between the studies. The variation is less owing to differences in patient selection than to the differences in efforts to promote a low-fat intake as a practical way to reduce energy intake, and owing to differences in the skills and efforts of the therapeutic teams. The same large variation exists within each cohort of patients, and the mean weight loss of 8% corresponds to approximately 80% of the patients losing >5% and 15% losing >10%. It is difficult to separate the impact of the dietary therapy because all trials included some elements of behavior modification, which clearly contributed to the results. Prognostic Markers of Weight Loss Success and Reasons for Failure There is considerable variation in the weight loss and weight maintenance achieved by patients enrolled in dietary treatment programs. Some variation can be attributed Recommended intake 500–1000 kcal/day below energy requirements 20–30% of total calories <10% of total calories <15% of total calories <10% of total calories 15–20% of total calories >55% of total calories 20–30 g/day 1000–1500 mg/day RDA. Full coverage should be ensured by a vitamin/mineral supplement daily to physiological differences (RMR, age, gender, sympathetic activity) and some to differences in adherence (behavior), though combinations of and interactions between physiology and behavior may be the major factor. This variation is not seen from the mean weight loss of a group, which is difficult to translate into a clinically relevant success rate based on the intention-to-treat principle, i.e. how large a proportion of the patients entering a treatment achieve a certain weight loss, typically >5% and >10% of pretreatment body weight. It is difficult to identify clinically the patients who will benefit most before treatment is initiated. Positive predictors of weight loss are (1) high initial body weight, (2) high RMR and/or 24-h energy expenditure, (3) high fat oxidation rate, (4) high sympathetic activity, (5) high plasma dihydrotestosterone concentration, and (6) high perceived self-efficacy [4, 12]. However, these factors, separately or in combination, do not seem to explain enough of the variation to have a measurable clinical relevance. Ad Libitum Low-Fat Diets (<30% Energy from Fat) Efficacy Data from animal and experimental research, observational studies, and numerous randomized clinical trials have shown that a high dietary fat content plays an important role in the development of obesity [13–15]. A high-fat diet promotes weight gain and obesity in sedentary individuals with little self-restraint, who have a genetic predisposition to obesity in particular. The main mechanisms are the passive overconsumption of energy promoted by the high energy density of fatty foods and a reduced fat oxidation capacity in susceptible individuals. Low-fat diets are more satiating because of the high content of complex carbohydrates and protein. Restricting intake of dietary fat should be seen as a means to reducing the diet’s energy density and hence restricting the patient’s total energy intake. Unfortunately, while the effect of fat-rich foods on weight gain and obesity is substantial, the ability of Treatment of Obesity the ad libitum low-fat, carbohydrate-rich diet to induce weight loss is less pronounced. A systematic review of 28 ad libitum low-fat diet randomized clinical trials showed that a weight loss of 1.6 g/day was achieved per each percentage point reduction in energy from fat [14]. A realistic reduction in dietary fat can result in a weight loss of 20–100 g/week, which becomes clinically significant when the total exceeds 5% of body weight [14]. A meta-analysis of 34 ad libitum low-fat diet interventions lasting >2 months and 35 control groups found a statistically highly significant weight loss difference of 3.3 kg [16]. The size of the weight loss was mainly determined by the reduction in dietary fat energy, but pretreatment body weight was also positively associated with the weight loss. The analysis indicates that obese patients with a body weight of 95 kg who reduce dietary fat from 45 to 25 energy% under ad libitum conditions will reduce energy intake and will, on average, achieve a weight loss of 7.1 kg before a new equilibrium is reached. On the other hand, a normal-weight subject (60 kg) will loose only 0.5 kg with the same fat reduction. These weight loss predictions are probably underestimated because the analysis relies on the reductions in dietary fat as reported by the patients, which tend to be exaggerated. Moreover, patients with better adherence also achieved better weight loss than those with poorer adherence [17] (Figure 3). The systematic review [14] and the meta-analysis [16, 18] show that ad libitum low-fat, high-carbohydrate diet have a modest but predictable effect on weight loss. This is clinically relevant for obese patients habitually consuming a high-fat 677 diet, where an ad libitum low-fat, high-carbohydrate diet would be 15–20 percentage points lower in energy from fat than the habitual diet. Safety Under certain experimental conditions the change from a normal-fat to a low-fat, high-carbohydrate diet has been shown to induce hyperinsulinemia, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol concentrations [19, 20]. Such observations have prompted some researchers to advocate the implementation of healthier high-fat diets, i.e. emphasizing the replacement of saturated and trans-fats with unsaturated oils instead of with carbohydrates [20]. However, these studies replaced fat for carbohydrate under strictly isoenergetic conditions, not allowing the spontaneous weight loss with the accompanying beneficial changes in these risk factors to occur as in other studies [21–23]. This was stressed by Schaefer et al., who reduced dietary fat isoenergetically from 35 to 15% of total energy in hypercholesterolemic patients and found plasma reductions of 13% in total cholesterol and 17% in low-density lipoprotein (LDL) cholesterol, but a 23% decrease in HDL cholesterol. A rise of 47% in plasma triglycerides after 6 weeks was also seen [21]. The same diet was subsequently continued for 10–12 weeks under ad libitum conditions and it produced a mean weight loss of 3.6 kg, a further reduction in LDL cholesterol and a normalization of HDL cholesterol to total cholesterol ratio. Improvements in other risk factors, e.g. blood pressure [24], blood coagulation, and fibrinolysis, occurred independent of weight loss [18, 25]. Blood lipids should be monitored in obese patients with type 2 diabetes resistant to weight loss. This is the only precaution currently recommended. The use of ad libitum low-fat, high-carbohydrate diets in which carbohydrates are mainly of the complex and fiber-rich types have not given rise to safety concerns. LED Versus Ad Libitum Low-Fat Diets? Figure 3 A 5-year follow-up of a 1-year randomized controlled trial of a reduced-fat ad libitum diet versus a usual diet. Obese patients with IGT were randomized to a reduced-fat diet or control, and participated in monthly small-group education sessions on reduced-fat eating for 1 year. Weight decreased significantly in the reduced-fat-diet group; the greatest difference was noted at 1 year (−3.3 kg), best in the most compliant group, but diminished at subsequent follow-up (∗∗ denotes differences between low-fat and normal-fat diets). Glucose tolerance also improved in patients on the reduced-fat diet; a lower proportion had type 2 diabetes or IGT at 1 year (47% vs. 67%). This difference disappeared in subsequent years, but the more compliant 50% of the intervention group maintained lower fasting and 2-h glucose c 2001 at 5 years compared to control subjects. (Copyright American Diabetes Association. From Diabetes Care, Vol 24, 2001; 619–624. Reprinted with permission from The American Diabetes Association [17]) Ad libitum low-fat diets produce a rate of weight loss of 100–200 g/week in unselected obese patients, whereas LEDs induce weight losses of 300–700 g/week. Four randomized clinical trials have compared LEDs (using lowfat diets) with ad libitum low-fat diets. Taken together, these studies show that the impact of the ad libitum lowfat diets on weight loss is increased if total energy intake is restricted to some extent [26–29]. LEDs using low-fat diets are more effective in inducing weight loss than ad libitum low-fat diets, and they allow a better adjustment of the reduction in energy intake. LEDs are therefore the preferred dietary treatment for obesity. However, in an individually tailored treatment the first step could be to prescribe an ad libitum low-fat diet to 678 Obesity patients habitually consuming a high-fat diet, subsequently limiting energy intake if weight loss proves unsatisfactory. Ad Libitum Low-Carbohydrate Diets (<25 g/day Carbohydrate) Diets that promote very low-carbohydrate intakes have become very popular as part of a popular physiological concept that links surges in blood glucose and insulin to weight gain and obesity [30–32]. The Atkins’ New Diet Revolution is the most popular and recommends a daily intake of <25 g carbohydrates [33]. It is likely that such a “ketogenic” diet possesses anorectic properties and produces weight loss in the short term, but it may be very problematic in the weight maintenance phase because of side effects, adverse effects on risk factor profile, and an increased risk of developing type 2 diabetes in overweight and obese subjects. Very few controlled studies testing the low-carbohydrate diet have been published. Westman et al. found, in an uncontrolled study, that an ad libitum low-carbohydrate diet (<25 g/day) produced a weight loss of 10.3% over 6 months in 51 obese subjects [34]. They also found positive changes in blood lipids and blood pressure, but 68% of the participants experienced constipation, probably because of the low fiber intake. Other studies have shown that a fat-rich diet impairs the beneficial effects of training on insulin resistance [35]. When the weight loss has subsided it is likely that the low-carbohydrate (high-fat) diet will have very negative effects on most cardiovascular risk factors, and despite the weight loss, may increase insulin resistance and risk of type 2 diabetes. Low-carbohydrate diets cannot therefore be recommended. DIETARY WEIGHT MAINTENANCE PROGRAMS In professional weight loss programs LEDs induce a 5% weight loss in almost all patients, and frequent clinical encounters during the initial 6 months of weight reduction appear to facilitate achievement of the therapy goals. Larger success criteria (>10% weight loss) can be met by the majority of patients if the treatment program also includes group therapy and behavior modification. The real challenge is to maintain the reduced body weight and prevent subsequent relapse (Figure 4). In a systematic review of long-term (>3-year follow-up) efficacy of dietary treatment of obesity, success was defined as maintenance of all weight initially lost or maintenance of at least 9 kg of initial weight loss [36]. Initial weight loss was 4–28 kg, and 15% of the followed-up patients fulfilled one of the criteria for success, and the success rate was stable for up to 14 years of observation. Diet combined with group therapy led to better long-term success rates (27%) than did diet alone Figure 4 Weight loss outcomes for obese patients treated in weight management programs compared to predicted outcome of continued habitual lifestyle. It is noted that even weight stability may be a partial success and a goal in certain patients (15%), or diet combined with behavior modification and active follow-up, though active follow-up produced better weight maintenance than passive follow-up (19% vs. 10%). Although the principle of energy restriction (LED) is successful for weight loss induction independent of dietary composition, the low-fat, high-protein/carbohydrate diet seems to be more effective for long-term weight maintenance and preventing weight regain. In a study by Toubro and Astrup, patients were randomly assigned to two different weight maintenance groups, receiving either a low-fat diet ad libitum or a fixed-energy diet (LED) for 1 year after having lost a mean of 13.6 kg on energy restricted diets [7]. There was only a small weight regain during the weight maintenance program. However, 2 years after the weight loss the LED group had regained 11.3 kg whereas the low-fat group had regained only 5.4 kg. Forty percent of the patients in the LED group and 65% of the patients in the low-fat group had maintained a weight loss of >5 kg [7]. This and other studies show that the success rate may be improved by using the ad libitum low-fat diet for prevention of relapse, although it is not effective in all patients [1]. Whether long-term weight maintenance failure is due to lack of treatment efficacy or lack of compliance is unknown. Notably, the amount of time spent with the patient and frequent contact between the professional counselors and patients favorably affect weight maintenance. DOES DIET COMPOSITION MATTER? Numerous popular diet books promote changing diet compositions in accordance with principles that are claimed to have a particularly favorable impact on weight loss and maintenance. Generally these claims are unsubstantiated and scientifically improbable, and some may even promote nutritionally insufficient diets (for review see references 4 and 37). For LEDs there is little evidence to support that weight loss may be improved by diets different from Treatment of Obesity that given in Table 2. For ad libitum diets, and for weight maintenance diets particularly, differences in the satiating effects of different macronutrients may have some importance. Carbohydrate Types The high carbohydrate content of low-fat diets stems mainly from the complex carbohydrates of different vegetables, fruits, and whole grains, which are more satiating for fewer calories than fatty foods and are a good source of vitamins, minerals, trace elements, and fiber. A high fiber content may further improve the satiating effect of the diet and a diet rich in soluble fiber, including oat bran, legumes, barley, and most fruits and vegetables, may be effective in reducing blood cholesterol and blood pressure levels. The recommended intake is 20–30 g of fiber daily. The role of simple carbohydrates in low-fat diets remains controversial, mainly because of the lack of proper randomized clinical trials. One large European multicenter trial has compared two different ad libitum low-fat diets, high in either complex or simple carbohydrates, with a normal-fat diet. The two low-fat diets induced similar fat loss in overweight and obese subjects over 6 months, and the diet high in simple carbohydrates had no detrimental effects on blood lipids [38]. However, more recent studies suggest that a high intake of sugar from soft drinks may have a special fattening property [39, 40]. Glycemic Index Some scientists have warned against the fattening properties of high-GI (glycemic index) foods such as potatoes, white bread, bagels, and rice—foods that people are otherwise advised to eat more of as part of the currently recommended low-fat diet. Instead, the public is advised to eat more whole grain products, and types of rice and potatoes characterized by a low GI. Although low-GI foods are beneficial for glycemic control in diabetic patients [41] and have a modest beneficial effect on cardiovascular risk factors, its effect on body weight regulation is controversial [42]. The proponents of the GI hypothesis suggest that high-GI foods produce rapid and transient surges in blood glucose and insulin, which are in turn followed by rapidly returning hunger sensations and excessive caloric intake [31]. However, a recent systematic review of the different types of studies found that of the 31 studies that measured appetite sensations following low-GI vs. high-GI meals, low-GI meals produced greater satiety and reduced hunger in 15 studies, no difference was found in 14 studies, and in 2 studies the high-GI meals produced greatest satiety. Similarly, among the 20 longer term intervention studies identified, 4 studies found larger weight loss and 2 studies less weight loss on the low-GI diets, and 14 studies found no difference [32]. It was concluded that most of the stud- 679 ies were statistically underpowered to pick up clinically relevant differences in weight loss. The lack of robust evidence prohibits issuing general dietary advice that low-GI foods are preferable to highGI foods in preventing weight gain, although it appears likely that this dietary change will have beneficial effects on risk factors of cardiovascular disease and diabetes, and unlikely that it will exert any adverse effects. However, the GI concept is complicated for the patients and comprehensive tables are required in order to calculate the diet [43]. Newer research shows that GI of meals cannot accurately be calculated by the carbohydrate source alone, but requires information about the energy, fat, and protein contents as well [44]. There is a need for well-powered, randomized, long-term trials to show the potential for low-GI vs. high-GI diets to produce weight loss or maintenance, and for a more patient-friendly classification of carbohydrate foods (Figure 5). Protein Content A large body of experimental human data suggests that protein possesses a higher satiating power per calorie than do carbohydrate and fat [45]. The impact on weight loss of replacing carbohydrate with protein in ad libitum low-fat diets has been addressed in only one randomized clinical trials. Two fat-reduced diets (30% of energy) with either normal protein (12% of energy) or high protein content (25%) were compared with a normal fat diet in 65 obese patients. Weight loss after 6 months was 5.1 kg in the low-protein group and 8.9 kg in the high-protein group, and more subjects lost >10 kg in the high-protein group (35%) than in the low-protein group (9%). The proteinrich diet had no adverse effect on blood lipids, renal function, or bone mineral density, and seems to have a positive influence on the atherogenic risk factor profile in abdominally obese men [46]. Replacement of some dietary carbohydrate by protein in ad libitum low-fat diets may improve weight loss. More freedom to choose between protein-rich and complex-carbohydrate-rich foods may encourage obese subjects to choose more lean meat and dairy products and hence improve adherence to lowfat diets in weight reduction programs. Increased protein allowances in weight reduction diets should await confirmation of these results by other studies. The study results do not endorse the dietary principles promoted in recent popular diet books advocating high-protein, lowcarbohydrate diets [47]. Fat Quality and High-Monounsaturated-Fat Diets Although similar amounts of different fats contain nearly the same amount of energy, differences may exist in their satiating effects, which could influence total energy intake of ad libitum low-fat diets and weight maintenance diets. 680 From a biochemical and physiological view saturated fatty acids behave very differently from monounsaturated fats (MUFA), which seem to be more neutral than other fats in relation to cardiovascular disease, insulin resistance, and cancer. However, animal studies suggest that MUFA increase body weight more than polyunsaturated fatty acids (PUFA) do [48]. In a cross-sectional, observational study in 128 males the highest positive correlation was found between the intake of MUFA and body fat mass, whereas no significant association was found between PUFA and body fat, and only a weak association to saturated fat was seen [49]. Two experimental appetite studies have concordantly shown that meals/infusions with MUFA produce lower satiety, and that they suppress energy intake for the remainder of the day less than PUFA [50, 51]. These preliminary reports suggest that a high MUFA content in the diet may promote passive overconsumption and obesity. Two randomized trials have compared diets moderate in fat, high MUFA, with low-fat diet. The first trial failed to find any difference in weight loss after 18 months [52]. However, in this study, both groups were on energy restriction, the study was small, and it had a large dropout rate in the low-fat group. The other study randomized 257 obese subjects with IGT to ad libitum diets of reducedfat, high-carbohydrate with either high- or low-GI, or a third normal-fat (35% energy from fat), high-MUFA, lowcarbohydrate diet for 16 weeks [53] (Figure 5). The highMUFA group gained more weight, increased insulin resistance and HbA1c , and the high-carbohydrate, low-GI diet had the most positive effect on -cell function and body weight. The ad libitum normal-fat, high-MUFA diets might therefore have adverse effects on body weight, insulin sensitivity, and other risk factors as compared to fat-reduced, high-carbohydrate diets with low GI [53, 54]. Some caution should be exercised before recommending replacement of low-fat diets with higher-fat, MUFA-based diets for both simple obese and diabetic obese patients until Figure 5 The only randomized trial compared ad libitum diets with either a low-carbohydrate, high-MUFA diet; highcarbohydrate, high-GI diet; or high-carbohydrate, low-GI diet. There was a statistically significant difference in weight loss between all three diets. Low-carbohydrate, high-MUFA diet also adversely influenced glucose homoestasis. (Reproduced by permission of The Nutrition Society [53]) Obesity more and better randomized clinical trials have been conducted. Alcohol Alcohol provides energy that displaces more nutritious foods. Alcohol suppresses fat oxidation, thereby allowing more dietary fat to be stored. The satiating effect of alcohol energy may be low and alcohol consumption has been shown to promote passive overconsumption of fat [55]. Alcohol has also been associated with obesity in epidemiological studies [56]. High alcohol consumption also increases the risk of losing control over otherwise restrained behavior. Consequently, energy from alcohol should be limited and needs to be assessed and appropriately controlled. WEIGHT MANAGEMENT PROGRAMS FOR THE PREVENTION OF TYPE 2 DIABETES The potential of intensive lifestyle treatment to induce and maintain weight loss has been evaluated in two recent major studies on the prevention of type 2 diabetes in obese subjects with IGT [57, 58]. In the Finnish Diabetes Prevention study, 522 overweight individuals with IGT were randomized to an intensive lifestyle intervention or to a control group [58]. The intervention aimed at a weight loss of >5% achieved by reduction of total fat to <30% of calories from fat (<10% from saturated fat), >15 g/1000 kcal fiber, and >30 min of exercise per day (walking, jogging, etc.). The subjects were instructed to have a frequent intake of whole grain products, vegetables, fruits, low-fat milk and meat products, and soft margarines, and vegetables oils rich in monounsaturated fatty acids. Subjects attended seven counseling sessions with nutritionists during the first year of the intervention, and one session every 3 months in the subsequent years. The weight loss after 1 year was 5%, and after 5 years the weight loss maintained was still 3 kg. This intervention produced a 58% reduction in the incidence of type 2 diabetes. In a subsequent analysis weight loss was the strongest predictor of the diabetes preventive effect, and a weight reduction of 5% was associated with a reduction in relative risk of 61%. Every 3 kg of additional weight loss doubled this effect. In the much larger, but very similar, American Diabetes Prevention Program, 3234 obese individuals (mean BMI, 34 kg/m2 ) with IGT were randomized to intensive lifestyle, metformin, or a control group [57]. The goals of the lifestyle intervention were >7% weight loss, achieved by a diet providing <25% energy from fat and restricted to 1200–1800 kcal/day, and >150-min brisk walking per week [57]. The participants in the intervention group had 16 sessions with a nutritionist over the first 6 months, and subsequently one session per month for the remaining 2.5 years. After 1 year the weight loss was 7%, and 5% was maintained throughout Treatment of Obesity the trial as compared to the placebo group. The relative risk reduction of diabetes was the same as in the Finnish study, 58% [57, 58]. These studies strengthen the evidence to support the low-fat diet in combination with physical activity as the superior strategy for diabetes prevention. Achieving and maintaining a desirable body weight is a major goal in management of type 2 diabetes. Weight loss dramatically improves glycemic control, lipid profile, and blood pressure in obese individuals with type 2 diabetes (ADA recommendations). Although it is more difficult to produce and maintain weight loss in type 2 diabetic patients than in simple obese patients, it is possible, and the health benefits are more substantial [59]. In overweight and obese type 2 diabetic patients who have difficulty in losing weight on a conventional diet, a liquidformula 800 kcal/day diet may be a safe alternative. Irrespective of whether an intensive 800 kcal/day diet consists of normal foods or of a liquid-formula diet, weight loss after 3 months is 14–15% of initial body weight. This also produces substantial improvements in glycemic control, blood lipids, and blood pressure [60]. Most of the weight loss is maintained after 1 year. These studies show that it is possible to obtain substantial benefits in the treatment of type 2 diabetic patients through intensive diet therapy and lifestyle modification. The major problem in the execution of this treatment is that most diabetologists do not give it the priority it deserves, and resources are not allocated to staff with the necessary skills. Physical Activity in Type 2 Diabetes Physical activity alone may have a modest, but nevertheless important, effect on glycemic control. Favorable changes in glucose tolerance and insulin sensitivity usually deteriorate within 72 h of the last exercise session. Consequently, regular physical activity is imperative to sustain glucose-lowering effects and improved insulin sensitivity [61]. According to a meta-analysis of intervention studies (>8 weeks) addressing the effect of exercise on glycemic control and body weight in type 2 diabetic patients, aerobic and resistance training produced a beneficial effect on HbA1c of −0.66%, whereas they failed to find any effect on body weight [62]. However, training may reduce body fat and increase lean tissue mass, so that body mass index (BMI) is unchanged. In addition, physical activity has other important beneficial effects in type 2 diabetes, such as those on cardiovascular risk factors and general well-being. CURRENT DRUGS FOR TREATMENT OF OBESITY This section focuses solely on drugs currently available for the treatment of obesity, or drugs with weight-reducing 681 properties used for the treatment of type 2 diabetes or for smoking cessation. These will be grouped within each of the following three categories: those that shift nutrient metabolism; those that reduce food intake; and those that increase energy expenditure. For more recent reviews covering most of the current drugs, including new potential compounds, the reader is referred to references 63 and 64. Amylase Inhibitors (Acarbose) Inhibition of digestion of starch and disaccharides reduces absorption of di- and monosaccharides and may produce a negative energy balance, providing that energy intake is not increased because of counterregulatory mechanisms. Theoretically, the efficacy with respect to body weight regulation is modest, as starch that is not digested in the small intestine is fermented in the colon and finally absorbed as short-chain fatty acids. It is estimated that fermentation of carbohydrates in the colon is associated with a 50% reduction of energy content available for the body, thus reducing the energetic value of carbohydrates from 4 to 2 kcal/g. Acarbose is an antidiabetic drug that lowers blood glucose by inhibition of -glucosidase in the gastrointestinal tract, thereby delaying the hydrolysis of ingested disaccharides and complex carbohydrates. However, the effect of acarbose on glycemic control in diabetic patients is modest, and the effect on body weight is negligible in simple obese [65], obese with IGT [66], and in type 2 diabetic [67] patients. In a weight maintenance study in obese subjects, Hauner et al. failed to find any effect of 6-month acarbose treatment on body weight after an initial diet-induced weight loss of 10 kg [65]. About 50% more patients reported side effects on treatment with acarbose than with placebo, these being mainly flatulence, abdominal pain, and diarrhea. In the STOP-NIDDM trial, 1429 overweight and obese patients with IGT were randomized to a 3-year treatment with acarbose or placebo [66]. After 3 years acarbose produced a weight loss of 0.8 kg compared to placebo, and the risk of progression to diabetes over 3.3 years was reduced by 25%. The risk reduction was partially attributable to the weight loss [66]. However, 31% of the patients in the acarbose group, compared to 19% in placebo group, discontinued treatment early, mainly owing to gastrointestinal side effects [66]. The effects of acarbose in type 2 diabetes are equally unpromising. In the UK Prospective Diabetes Study (UKPDS), 1946 type 2 diabetic patients randomized to acarbose or placebo were followed for 3 years [67]. Fifty-eight percent of the included patients discontinued acarbose versus 39% dropouts in the placebo group. In an intentionto-treat analysis acarbose produced only a 0.2% lower HbA1c than did placebo, while in those who remained on the allocated therapy HbA1c was 0.5% lower. Mean body weight was lower by 0.4 kg in the acarbose group 682 after 1 year, but no difference was seen after 2 or 3 years [66]. In conclusion, acarbose produces only a very modest weight loss (<1 kg), if any, and taken together with its low tolerability due to prevalent gastrointestinal side effects, has no place in the treatment of obesity. Acarbose may, however, have some role in type 2 diabetic patients with a capacity to tolerate the compound [63]. Lipase Inhibitors (Orlistat) Mechanism of Action and Use Malabsorption of dietary fat is an obvious drug target as high dietary fat intake plays a special role in promoting weight gain and obesity. A number of compounds that act as intestinal lipase inhibitors are currently being investigated for use in the treatment of obesity and related disorders, but only orlistat is currently approved and freely available. Orlistat is a specific inhibitor of intestinal lipase, the enzyme secreted from the exocrine pancreas and responsible for enzymatic fat digestion [68, 69]. Within the small intestine, lipase and colipase hydrolyze ingested triglyceride, and produce fatty acids and mono- and diglycerides that interact with bile to form micelles, enabling absorption of ingested fat. Orlistat inhibits lipase activity through formation of a covalent bond with serine within the catalytic site of gastric and pancreatic lipase. At the recommended therapeutic dose (120 mg) taken immediately prior to or within 1 h of each of the three daily main meals, the absorption of dietary fat is reduced by ∼30%. Fecal energy loss is not fully compensated by an increased total caloric intake, and so orlistat produces a negative energy balance resulting in weight loss. Moreover, the reduced absorption of saturated fatty acids and trans-fatty acids has, independent of weight loss, a beneficial effect on plasma total and LDL cholesterol and triglycerides. Furthermore, there is some evidence to support that the reduction in total fat uptake exerts a similar positive effect on thrombotic factors. Orlistat is recommended for use as the pharmacological support for a nutritional strategy of a modest caloric restriction and a diet providing less than 30% of energy from fat. An obese patient with a typical energy requirement of 2600 kcal/day will, on a 600 kcal deficit diet with 30% of calories from fat, experience an extra loss of 220 kcal fat in fecal energy. Systemic absorption of orlistat and its metabolites is negligible, and so adverse effects of orlistat are a consequence of the partial reduction of fat absorption, leading to an increased proportion of undigested fat in the bowel. The most frequent adverse effects of orlistat are flatulence, flatulence with discharge, oily spotting, fecal urgency and incontinence, oily stools, and steatorrhea. In the majority of patients these adverse effects are self-limiting and mostly transient, generally Obesity occurring within the first months of treatment and often triggered by the ingestion of high-fat meals. The unabsorbed fat binds some fat-soluble vitamins (A, D, and E) and secondary nutrients (-carotene, lycopene, flavanoids, etc.). A simple vitamin supplement and increased intake of fruit and vegetables counteracts this effect. Pharmacodynamic studies suggest that orlistat does not affect the pharmacokinetic properties of lipid-soluble drugs such as digoxin, phenytoin, warfarin, glyburide, furosemide, captopril, nifedipine, atenolol, or oral contraceptives [64]. Efficacy and safety in adolescents have so far only been examined in an open-labeled pilot study [70], and remain to be demonstrated in pregnant women. Treatment in Simple Obese Subjects The efficacy and safety of orlistat have been documented in several short- and long-term double-blind trials lasting for up to 4 years, involving a total of more than 30 000 patients, making orlistat the most well-investigated drug for the treatment of obesity. In most trials, orlistat induces a dose-dependent reduction in body weight, and the recommended dose induces a mean weight loss that typically exceeds that of the placebo group by 3–5 kg, to some extent independent of the degree of dietary energy restriction or other ancillary treatment (Figure 6). The weight loss typically continues for the first 3–6 months of treatment and then plateaus, and the patients may subsequently remain weight stable or regain some weight, depending on the intensity of the dietary treatment. However, the weight difference between the orlistat and placebo groups is sustained over 1–4 years, which indicates that efficacy is maintained. The weight loss may not seem large viewed in relation to the patients’ excessive body fat, but it has important clinical implications. Typically, orlistat doubles the proportion of patients achieving >5% and >10% weight loss, and it also doubles the proportion maintaining this goal after 1 and 2 years. The immediate weight regain Figure 6 Weight loss and maintenance of simple obese patients treated with energy-restricted diet and randomized to orlistat or placebo. ∗ P < 0001; least-squares mean difference from placebo. (Reproduced by permission of Elsevier [71]) Treatment of Obesity 683 Table 4 Changes in body weight and HbA1C in overweight type 2 diabetes during long-term orlistat treatment∗ Medication Sulfonylurea Insulin Metformin Baseline HbA1C (%) 7.5 9.0 8.9 Change in HbA1C † (%) −0.46 −0.35 −0.29 Change in Body weight† (%) −1.9 −2.6 −2.9 ∗ c 2001 American Diabetes Association. From Diabetes Care, Vol 25, 2002; 1033–1041. Reprinted with permission from The Copyright American Diabetes Association [74]. † Placebo subtracted. is greater in orlistat-treated patients after discontinuation of treatment than in placebo-treated patients which indicates that orlistat maintains its pharmacological efficacy. However, the total weight loss and maintenance is greater after orlistat than after placebo. In obese subjects with metabolic syndrome (insulinresistance syndrome) orlistat produces weight loss of the same magnitude as in simple obese subjects, and the weight loss is associated with significant decreases in fasting insulin, triglycerides, and the LDL/HDL cholesterol ratio and increase in HDL cholesterol [72]. Treatment in Obese Subjects with IGT Treatment of obese subjects with IGT by orlistat as an adjuvant to diet and lifestyle modification has been shown to decrease the incidence of conversion to type 2 diabetes. In a retrospective analysis of obese adults with IGT treated with orlistat, the additional weight loss produced by orlistat reduced the 1-year incidence of type 2 diabetes from 7.6% in the placebo group to 3.0% [73]. Moreover, while 49% converted from IGT to normal glucose tolerance in the lifestyle (plus placebo) group, 72% did so in the orlistat group [73]. In a recent multicenter trial, 3304 nondiabetic obese subjects underwent intensive lifestyle modification with a dietary energy deficit of 800 kcal/day, and were randomized to either orlistat or placebo for 4 years [71]. They attended reinforcement sessions every fortnight for the first 6 months, and subsequently every month for the following 3.5 years. More orlistat-treated than placebotreated patients completed the trial (52% vs. 34%). The mean weight loss was greater by 4 kg in the orlistat group after 1 year, and most of this weight loss was maintained throughout the rest of the study period. The weight loss was 6.9 kg in the orlistat group and 4.1 kg in the placebo group after 4 years. About 50% more patients treated with orlistat achieved and maintained >5% and >10% weight loss after 1 and 4 years. Nine percent in the placebo group and only 6.2% in the orlistat group had developed type 2 diabetes after 4 years (relative risk reduction = 37%, P = 0.003). In addition, orlistat patients obtained greater reductions in waist circumference, LDL cholesterol, and systolic and diastolic blood pressures than did placebo patients. The study clearly shows that the additional weight loss achieved by orlistat is sufficient to reduce the incidence of diabetes, even among more nonselected obese subjects where 80% had normal glucose tolerance. In the 20% of patients with IGT, at enrollment the intensive lifestyle change alone resulted in a similar absolute diabetes incidence as the lifestyle treatment in the Diabetes Prevention Program [57]. The addition of orlistat further improved the preventive effect. Treatment in Obese Diabetic Patients One-year multicenter trials have been conducted with the use of orlistat in addition to each of the treatments of type 2 diabetic patients: sulfonylurea, insulin, and metformin. Whatever medication the diabetic patients received at baseline, orlistat produced weight loss above that produced by diet and placebo (of 2–5 kg) [68], and reductions in HbA1c of 0.46% (sulfonylurea), 0.35% (insulin) [63, 74], and 0.29% (metformin) (Table 4). Greater reductions were also seen in LDL cholesterol and blood pressure in the orlistat groups. Consequently, orlistat can be used as first drug of choice in type 2 diabetic patients when diet and lifestyle is not sufficient to achieve glycemic control, and it can be used safely in combination with the second drug of choice, metformin. Metformin Metformin is a biguanide that is approved for the treatment of type 2 diabetes. It lowers plasma glucose by reducing the intestinal absorption of glucose, suppressing hepatic glucose production and increasing peripheral insulin sensitivity. It has long been known to induce a slight weight loss not only in diabetic patients but also in obese subjects with metabolic syndrome or IGT. The size of the placebosubtracted weight loss induced by metformin in diabetic patients varies from 0.5 to 8 kg, probably depending on BMI, age, and glycemic control [63]. In the Diabetes Prevention Program of obese subjects with IGT, metformin produced a 2 kg weight loss and reduced the incidence of diabetes by 31% above placebo after 3 years [57]. A subgroup analysis revealed no difference in efficacy across gender and ethnicity, but the effect was mainly seen in subjects aged 25–59 years with a BMI above 30 kg/m2 , whereas it was largely ineffective in nonobese (BMI < 30 kg/m2 ) and those above 60 years [57]. In this trial, more than 1000 patients entered each treatment arm and the resulting high statistical power gives more credit to the outcome than to that of smaller trials. 684 Obesity It is not known how metformin produces weight loss, but it is possible that the improvement in insulin sensitivity increases the central effect of insulin where it acts as a satiety hormone [75]. Another possibility is that reduced food intake is caused by nausea and other gastrointestinal effects. There are no indications of any thermogenic effect of metformin. Sibutramine Sibutramine is a serotonin and norepinephrine reuptake inhibitor with only a weak inhibitory action on dopamine reuptake. Unlike amphetamine, sibutramine does not stimulate locomotor activity, and unlike dexfenfluramine and fenfluramine, it does not induce serotonin release, and has not been implicated in the development of valvular disease [76]. Sibutramine decreases food intake in humans by increasing meal-induced satiety [77, 78]. It also exerts a weak thermogenic effect both acutely and during longterm use [78, 79]. Controlled trials in simple obesity have consistently shown dose-related weight loss, and optimal weight loss with a dose of 10–15 mg sibutramine once daily. Typically, weight loss was 3–5 kg greater than with placebo at 24 weeks, and weight loss was sustained for 2 years. The proportion of patients losing at least 5% of body weight over 12 months was 29% with placebo, 56% with sibutramine 10 mg, and 65% with sibutramine 15 mg/day [80]. Intermittent and continuous sibutramine therapies are similar in regard to effectiveness and safety [81]. Wadden et al. found that patients treated with sibutramine alone achieved a weight loss of 4% after 12 months, but the drug plus lifestyle intervention produced a weight loss of 11% and better outcomes in terms of risk factor reductions [82]. In the STORM trial, sibutramine was assessed for the potential to both induce and maintain weight loss [83]. Six-hundred five obese individuals were treated with a 600 kcal/day deficit diet and sibutramine 10 mg daily for 6 months (Figure 7). The 467 participants who lost more than 5% were randomly assigned to continue to receive sibutramine or placebo for 18 months. The mean weight loss after 6 months was 12 kg, and whereas weight was gradually regained in the placebo group during the second year of follow-up, the sibutramine group essentially maintained the weight lost during the initial 6 months [83]. Although sibutramine had positive effects on blood lipids as expected from the weight loss, it seems to have an HDLcholesterol increasing effect that is independent of weight loss [83], and it has been shown to be appropriate for correction of lipid abnormalities in obese patients having high-serum triglyceride levels and low HDL-cholesterol levels [84]. Sibutramine also increases weight loss and improves maintenance of reduced weight in obese patients Figure 7 The STORM trial. Mean body weight changes during weigh-loss and weight-maintenance phases. During the first 6 months all patients received −600 kcal/day diet and sibutramine. Those who lost >5% were randomized to continue on sibutramine or placebo. (Reprinted with permission from Elsevier Science (The Lancet, 2000, 356; 2119–2125) [83]) who have previously lost weight on a very low calorie diet [85]. Sibutramine is generally well tolerated and has few side effects. These include dry mouth, headache, insomnia, and constipation. The adverse effects of sibutramine include increase in blood pressure and heart rate. Although these increases are generally mild and without clinical relevance, blood pressure should be monitored on a regular basis. Increases in blood pressure may lead to discontinuation of treatment in about 5% of patients. Obese patients with well-controlled hypertension (calcium-channel blockers, -blocking agents, angiotensin-converting enzyme inhibitors, thiazide diuretics) do not experience any rise in blood pressure with sibutramine therapy, and their overall risk factor profile will benefit from the induced weight loss [86–88]. Sibutramine has been shown to produce a substantial weight loss above that of placebo (∼9 kg) and a 2% decrease in HbA1c over 6 months in type 2 diabetic patients with poor glycemic control despite maximum doses of sulfonylureas and metformin [89]. In a 12-month study Rissanan et al. found sibutramine to produce a weight loss of 7.1 kg in diet-treated type 2 diabetic patients vs. 2.6 kg in the placebo group. Overall, there was no benefit of sibutramine therapy on glycemic control (−0.3% vs. −0.2%), but in a subgroup with HbA1c >8% the improvement was superior in the sibutramine group (−1.4% vs. −0.6%). Longer term studies and studies in other groups of diabetic patients have not been published. Bupropion Bupropion has dual neurotransmitter properties working as norepinephrine and dopamine reuptake inhibitors, which may both have relevance for body weight regulation. Sustained-release bupropion is approved for the Treatment of Obesity treatment of smoking cessation and for major depression. In depressed patients with normal weight, bupropion seems to have a weight neutral profile, whereas there are suggestions of weight-reducing properties in overweight and obese depressed patients [90, 91]. Moreover, weight gain after smoking cessation is less in bupropion-treated subjects than in placebo-treated subjects [92, 93]. Two randomized, placebo-controlled trials have been conducted in nondiabetic obese subjects. Both found that bupropion was superior to placebo in reducing body weight when given together with an energy-restricted diet [94, 95]. In the largest trial, 327 simple obese patients were treated with diet and lifestyle modification and randomized to bupropion SR 300 mg/day, SR 400 mg/day, or placebo for 24 weeks. In completers, weight loss was greater than with placebo by 2.2 kg in the SR 300 mg/day group, and by 5.1 kg in the SR 400 mg/day group [95]. In a 24-week extension of the study, weight loss was essentially maintained. Bupropion has little, if any, effect on heart rate and blood pressure, but should be used with caution in patients with a history of seizures. These studies suggest that bupropion may be of particular relevance for smoking cessation in obese and diabetic patients, and perhaps even for weight reduction in nonsmoking obese individuals. Nicotine Cigarette smoking is recognized as one of the most important preventable causes of premature death, but still 20–35% of the population in the affluent world continue to smoke. One of the most important barriers to quit smoking is the subsequent weight gain, and the weight control properties of smoking reinforce the decision to continue smoking. Anorectic and thermogenic properties produced by nicotine are considered to be factors responsible for the lower body weight of smokers compared with nonsmokers. Nicotine gum has been shown to relieve withdrawal symptoms and to double the success rates over placebo in trials of smoking cessation, and has been shown to diminish weight gain after smoking cessation. The use of nicotine gum is therefore an accepted tool to treat withdrawal symptoms and prevent weight gain in a vulnerable phase after smoking cessation. Dale et al. [96] demonstrated that 100% replacement does not completely prevent weight gain. To determine whether attempts to prevent weight gain will increase success rates for stopping smoking, 287 female weight-concerned smokers were enrolled into a combination of a standard smoking cessation program with nicotine gum and a behavioral weight control program including a low-energy diet [97]. A control group was treated with the identical program but without the diet. After 16 weeks, 50% of the women had stopped smoking in the diet group versus 35% in the control group. 685 Among these women, weight fell by mean 2.1 kg in the diet group but increased by 1.6 kg in the control group (P < 0.001). After 1 year the success rates in the diet and control groups were 28 and 16% respectively (P < 0.05), but there was no statistical difference in weight gain. Combining the smoking cessation program with an intervention to control body weight helped women to stop smoking and control weight; nicotine replacement alone is insufficient to prevent weight gain when quitting smoking. No weight loss trials have been conducted with the use of nicotine. Ephedrine/Caffeine Ephedrine is both an indirect sympathomimetic, causing release of norepinephrine from the sympathetic nerve endings, and a direct agonist on -receptors. Numerous studies have shown that ephedrine (E) as monotheraphy decreases body fat in obese subjects by a combined action of suppression of appetite and stimulation of energy expenditure. Adenosine antagonists such as caffeine (C) potentiate the thermogenic and clinical effects. Combinations of E+C have been shown to be effective for treatment of obesity for up to 50 weeks. In a study including 180 obese patients it was found that E+C (20 mg/200 mg t.i.d.) produced a larger weight loss than did placebo, C, or E, in combination with a hypoenergetic diet over 24 weeks [98]. After 24 weeks the placebo group had lost 13.2 kg, and E+C further increased the weight loss by 3.4 kg to a total of 16.6 kg. Also, more patients in the E+C group than in the placebo group lost more than 5% and 10% of initial body weight. Breum et al. tested E+C against dexfenfluramine in a double-blind, placebo-controlled trial, and found that E+C produced a greater weight loss than did dexfenfluramine in subjects with a BMI of more than 30 kg/m2 [99]. The reductions in pulse rate and blood pressure were similar with the two treatments. E+C has also been evaluated for prevention of weight gain after smoking cessation. The double-blind, placebo-controlled trial included 225 subjects and after 12 weeks weight gain was less in the E+C group than in placebo group [100]. However, after 1 year there was no difference in the proportion of subjects not smoking. Molnar reported a 20-week, randomized double-blind, placebo-controlled trial of E+C in adolescents aged 16 years and in Tanner stage III–V, and found that E+C produced more substantial weight loss than did placebo (14.4 vs. 2.2%) [101]. Subjects dropped out only in the placebo group, and adverse effects were mild and not different from those in the placebo group after 4 weeks. Notably, E+C increases blood pressure and heart rate slightly with the first exposure [102]. However, during chronic treatment tachyphylaxis develops to the cardiovascular effects of the compound, but not to the anorectic and thermogenic [98]. In the largest trial of E+C, only a slight increase in blood pressure and heart rate could be 686 detected when the treatment was initiated, but after 12 weeks of dietary treatment, the reductions in blood pressure were similar in the E+C group to those in the placebo group [98]. A hypothetical cardiovascular safety concern could be raised by the combination of E+C and exercise. With more extensive measurement of cardiovascular function by thoracic impedance, automatic sphygmomanometry, and continuous electrocardiographic recording, Waluga et al. concluded that E+C had no undesirable effects on cardiovascular function in obese subjects [103]. E+C has also been tested in overweight subjects with controlled hypertension [104]. Treatment with E+C produced a larger weight loss and a greater reduction in systolic blood pressure (5.5 mmHg) than did treatment with placebo; moreover the antihypertensive effect of -blockers was not reduced by E+C [104]. E+C does not seem to have any long-term effect on glucose and lipid metabolism apart from the beneficial changes in risk factors secondary to weight loss. Buemann et al. reported that E+C prevented the decline in HDL cholesterol associated with weight loss, and it increased the ratio of HDL cholesterol to total cholesterol, whereas no effect on fasting glucose metabolism was observed [105]. The clinical studies of E+C clearly show that the compound is effective in the treatment of obesity for up to 1 year [10]. However, because of the limited number of patients treated in the trials, the total evidence does not meet the efficacy and safety requirements of the American FDA or the European CPMP for licensing E+C as a prescription compound. Various herbal combinations of E+C based on Ma Huang, guarana, and aspirin are sold over the counter in the United States and the total sales reached about 950 million dollars in 1999. The pharmacokinetics of these herbal preparations may vary, and they contain many other ingredients such as minerals and herbs that might alter or interact with E or C [106]. As concluded by Greenway [106], These herbal products containing ephedrine and caffeine should be tested in controlled clinical trials to confirm their presumed efficacy and safety which cannot truly be extrapolated from the peer-reviewed scientific literature using pharmaceutical grade caffeine and ephedrine in isolation. No studies exist in obese subjects with IGT or type 2 diabetes, and the use of E/C compounds in these conditions is not substantiated. SURGICAL TREATMENT OF OBESITY Weight management programs fail in a substantial proportion of the severely obese patients, and to ensure a better long-term outcome, bariatric surgery is the treatment of choice for well-informed and well-motivated obese Obesity patients with acceptable operative risks [107]. Patients should be obese for at least 5 years and have a strong desire for a substantial weight loss, or have severe impairments because of their obesity. Surgery is indicated for patients with a BMI greater than 40 kg/m2 , or for those with serious medical comorbidities and a BMI greater than 35 kg/m2 . A number of different procedures are available: (1) adjustable silicone gastric banding, (2) vertical gastric banding, and (3) gastric bypass, which should be reserved for the heavier patients. The malabsorptive intestinal bypass ( jejuno-ileal) has a high rate of complications and cannot be recommended. Effect in Simple Obesity In a series of 100 obese patients gastric bypass was shown to prevent the progression of IGT to frank type 2 diabetes [108]. In the Swedish Obese Subjects (SOS) study, 2000 matched morbidly, but simple obese patient pairs will be followed for 10 years each, one pair member is surgically treated, while the other serves as a control group [109]. The 2-year mean weight reduction was 28 kg in the operated patients and 0.5 kg in the controls. After 8 years the weight loss was 20 kg in the surgical group, while the controls had gained 0.7 kg. The average weight loss for gastric bypass and vertical banded gastroplasty was 16% after 10 years. These weight reductions were sufficient to reduce the 2-year incidence of type 2 diabetes 32 times as compared to the controls. After 5 years the relative risk reduction was 80%, and after 10 years, 67%. However, while the incidence of hypertension was markedly reduced the first years, after 8 years the incidence of hypertension was almost equal in the two study groups. The weight loss achieved by surgery has pronounced effects on cardiac structure and function, quality of life, rates of employment, and health care costs. Gastric Surgery in Type 2 Diabetes The weight loss achieved by surgical procedures in obese type 2 diabetic patients has marked effects on glycemic control, cardiovascular risk factors, progression of the disease, and mortality [110, 111]. In a study of 154 type 2 diabetic patients followed for up to 10 years, the proportion of control subjects being treated with oral hypoglycemics or insulin increased from 56.4% at initial contact to 87.5% at last contact, whereas the percentage of surgical patients requiring medical management fell from 31.8% preoperatively to 8.6% at last contact. The mortality rate in the control group was 28% compared to 9% in the surgical group. The improvement in the mortality rate in the surgical group was primarily due to a decrease in the number of cardiovascular deaths. Laparoscopic adjustable gastric banding is a minimally invasive and reversible surgical procedure that yields a Treatment of Obesity significant reduction in gastric volume and hunger sensation. 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