Type
Description
Average weight loss, kg (95 % CI)
Mediterranean diet
Fruits, nuts, red wine, fiber, whole grains, fish, and vegetable fat (extra virgin olive oil)
−4.4 kg (−5,9 to −2,9 kg)
Weight watchers
Moderate energy deficit
−2.8 kg (−5.9 to −0.7 kg)
Portion control
LEARN
Moderate energy deficit (lifestyle, exercise, attitude, intensive lifestyle, relationships, nutrition) modification
−2.6 kg (−3.8 to −1.3 kg)
Ornish
Vegetarian based
−2.2 kg (−3.6 to −0.8 kg)
Fat restricted (<10 % of total calories)
Zone
Low carbohydrate
−1.6 kg (−2.8 to −0.4 kg)
Carbohydrate/protein/fat 40/30/30
Atkins
Very low carbohydrate
−4.7 kg (−6.3 to −3.1 kg)
Minimal fat restriction
Changes in Total Calorie Intake
The Balanced Hypocaloric Diet
Evidence:
A caloric restriction between 500 and 1,000 kcal daily induces weight loss ranging between 0.5 and 1.0 kg/week, equivalent to a weight loss of 8 % for an average period of 6 months (evidence level 1+).
Measures such as reducing portion sizes or reducing the energy density of the diet can facilitate compliance with a reduced-calorie diet and weight loss in obese patients (evidence level 3).
Recommendations:
In obese adults, a caloric deficit of 500–1,000 kcal/day vs. caloric requirements is enough to induce a weight loss of 8 % in the first 6 months of therapy (grade A recommendation).
The reduction on the portion sizes of serving and the energy density of the diet are effective measures to reduce the weight via dietary management (grade D recommendation).
Dietary Modifications Based on Different Combinations of Macronutrients
Modified-Fat Diets Versus Modified-Carbohydrate Diets
Evidence:
Short term (6 months): a low-carbohydrate diet allows people to achieve greater weight loss than a low-fat diet (evidence level 1++).
Long term (12 months or more): a low-carbohydrate diet allows people to achieve similar weight loss than a low-fat diet (evidence level 1+).
Long term (12 months or more): a low-carbohydrate diet can help patients to achieve a further increase in the concentration of high-density cholesterol (HDL-Cl) and a greater reduction in the concentration of triglycerides than a low saturated fat diet (evidence level 1+).
Long term (12 months or more): a low saturated fat diet can help patients to achieve a further decrease in the concentration of low-density cholesterol (LDL-Cl) than a low-carbohydrate diet (evidence level 2+).
Low-carb diets cause more adverse effects than low-fat diets (evidence level 2++).
Low-carb diets can increase long-time mortality if the fat contained is, mostly, from animal origin.
Recommendations:
The reduction in the proportion of carbohydrates, with an increase in fats, is not helpful to enhance the effects of diet on weight loss (grade A recommendation).
In an obese patient, a low-fat diet is useful to control the levels of LDL cholesterol, whereas a low-carb diet allows to achieve better triglyceride and HDL cholesterol control (grade B recommendation).
Low-carb diets may not contain a high proportion of animal fats (grade D recommendation).
Modified-Carbohydrate Diets
Fiber-Enriched Diets
Evidence:
There are not enough data to establish evidence on the role of a diet enriched with dietary fiber or whole grains on weight loss.
Glucomannan supplements added to the diet may have a modest (satiating) effect, which encourages weight loss (level of evidence 1+).
Fiber supplements (different than glucomannan) added to the diet can contribute minimally to weight loss (level of evidence 2+).
The treatment of obesity with a diet enriched or supplemented with glucomannan, plantago ovata, and β-glucan lowers LDL cholesterol levels of obese patients (evidence level 1+).
Recommendations:
In the treatment of obesity, fiber supplements (mainly glucomannan) may increase the effectiveness of the diet on weight loss (grade C recommendation).
The prescription of diets enriched with fiber or fiber supplements (mainly glucomannan) may benefit obese people with lipid abnormalities (grade B recommendation).
Low Glycemic Index Diets
The glycemic index (GI) is a system for quantifying the glycemic response of a food containing the same amount of carbohydrates with that of a reference food [37]. The glycemic load (GL) is the product of the GI and the amount of ingested carbohydrates and provides an indication of the amount of glucose available to metabolize or store after ingestion of food containing carbohydrates [38].
Evidence:
In the treatment of obesity, dietary modifications in GI or GL have no persistent effect on weight loss (evidence level 1+).
There are not enough data to establish evidence on the role of low-GI diets or low GL on maintenance of weight loss after a low-calorie diet.
Recommendations:
As a specific strategy for the dietary management of obesity, the decrease in GL and GI, can’t be recommended (grade A recommendation).
High-Protein Diets
Evidence:
A high-protein diet can induce greater weight loss in the short term (less than 6 months) than a conventional diet, rich in carbohydrates (evidence level 2+).
A high-protein diet does not induce greater weight loss in the long term (over 12 months) than conventional diet, rich in carbohydrates (evidence level 1+).
There are insufficient data to establish the effectiveness of high-protein diets in the maintenance of weight loss after an initial phase of weight loss with other diets.
A high-protein diet helps to preserve lean mass, better than a diet rich in carbohydrates (evidence level 2+).
A high-protein diet can increase (in the long term) the risk of total mortality and cardiovascular mortality, mainly when the protein is of animal origin (evidence level 2+).
Recommendations:
In the treatment of obesity, it is not recommended to induce changes in the proportion of dietary protein (grade A recommendation).
To ensure the maintenance or the increase of the lean mass during a low-calorie diet, it is effective to increase the protein content of the diet above 1.05 g/kg (grade B recommendation).
When a high protein is prescribed, the intake of animal protein in the diet should be limited, to prevent an increased risk of mortality in the very long term (grade C recommendation).
Meal Replacement Diets
Evidence:
The use of commercial meal replacements for one or more meals a day may facilitate the monitoring of a hypocaloric diet more effectively, promoting, in this case, both weight loss and maintenance of weight loss (evidence level 1−).
This benefit is greater when those meal replacements are used in the context of structured treatments that include physical activity, education, and food behavior modification (evidence level 3).
There have not been clinically significant adverse effects associated with the use of meal replacements in the context of low-calorie diets (evidence level 3).
Recommendations:
In obese or overweight adults, replacing some meals for meal replacements (in the context of low-calorie diets) can be useful for weight loss and its maintenance (grade D recommendation).
Very-Low-Calorie Diets
Evidence:
In the short term (less than 3 months), very-low-calorie diets (VLCD) (400–800 kcal/day) result in a greater weight loss than low-calorie diets (>800 to <1,200 kcal/day) (evidence level 1+).
In the long term (over 1 year), these diets do not result in a greater weight loss than low-calorie diets (evidence level 1+).
The use of a VLCD before bariatric surgery, in patients with hepatic steatosis and increased surgical risk, can reduce surgical risk (evidence level 1+).
At the moment, there are no data available to establish whether VLCD with commercial products help patients to reach an adequate protein intake.
The VLCD presents a higher risk of adverse effects than the low-calorie diet (evidence level 1−).
The evidence available does not support that the VLCD are associated with a greater lean mass loss in relation to fat mass loss, compared to less restrictive calorie diets.
Recommendations:
The VLCD can be used in the treatment of obese patients, following a specific clinical indication and a close medical monitoring (grade D recommendation).
The VLCD can’t be used in patients who don’t meet the guidelines, requirements, and criteria (grade A recommendation).
Under medical supervision, and considering the possible adverse effects that can be observed, the use of VLCD can be justified in the preoperative bariatric surgery in patients with hepatic steatosis and increased surgical risk (grade B recommendation).
Using VLCD with commercial products could be justified in the immediate postoperative of bariatric surgery to help the patient reach an adequate protein intake (grade D recommendation).
Mediterranean Diet (MedDiet)
Evidence:
Studies point to a possible role of MedDiet in the prevention of overweight and obesity, although there are inconsistent results (evidence level 2−).
The available evidence suggests that greater adherence to the MedDiet could prevent the increase of the abdominal circumference (evidence level 2+).
Recommendations:
Increased adherence to the MedDiet could prevent overweight and obesity and prevent the increase of the abdominal circumference (grade C recommendation).
Benefits of the Mediterranean Diet:
Most prospective studies researching the association between dietary quality and risk of obesity found that an overall dietary pattern based on the traditional Mediterranean diet was inversely associated with the risk of obesity or weight gain [39–42]. The inverse association between the MedDiet and adiposity indices has also been reported in some studies [43–47]. Some clinical trials have added support for this association [48–50].
Nutrigenetic studies [51–53] have analyzed the biological and statistical interactions between the Mediterranean diet and its components and variations in key genes in lipid metabolism, inflammation, adipocytokines, obesity, diabetes, and cardiovascular disease (APOA1, APOA2, ABCA1, LIPC, COX-2, FTO, TCF7L2, PRKAG3, PRKAA2, ADIPOQ, CD36, NR1H3, etc.). There have been many statistically significant interactions in which greater adherence to the MedDiet, or some of its typical foods, is able to reverse the adverse effects that have risk allelic variants in these genes on their specific phenotypes, being able to modulate the adverse effects of certain genetic variants, dyslipidemia, hyperglycemia, and/or obesity.
This evidence suggests that the typical MedDiet pattern, based on whole foods, minimally processed, which includes fruits, nuts (walnuts), vegetables, legumes, whole grains, red wine, fiber, fish, vegetable protein, and vegetable fat (from extra virgin olive oil), has qualitative elements that promote weight loss and glycemic control and enhances the management of the metabolic syndrome [54]. It has recently been demonstrated a further reduction in the incidence of cardiovascular events in people at high risk who consumed a Mediterranean diet supplemented with extra virgin olive oil or nuts [55].
Physical Activity
Increased physical activity is an important component in the medical treatment of obesity; it represents an increase in energy expenditure. A class A evidence indicates that, with or without diet associated, the impact of physical activity has good results for weight loss and its maintenance [56, 57]. However, subsequent recommendations of the American College of Sports Medicine indicate that physical activity in itself has a limited effect on weight loss [58].
Since the publication in 1999 of the report “A one year follow-up to Physical Activity and Health: A report of the Surgeon General” [59] in the USA, a large amount of evidence-based knowledge has been accumulated on the benefits of physical activity in overweight and obese individuals, although not so much in the morbidly obese.
In order to update the scientific knowledge, an Experts Committee reviewed new research and classified the degree of evidence of the benefits of physical activity on health. The results of this review were published in the report Physical Activity Advisory Committee Report, 2008 [60]. These guidelines suggest that the health benefits of physical activity include the prevention of disease and the reduction of multiple risk factors associated with many diseases and chronic conditions, becoming part of the treatment recommendations of some of these, as in the case of obesity.
Benefits of Physical Activity
The benefits of physical activity include reduced risk of premature death of any cause, CVD, T2DM, some cancers (breast cancer and colon cancer), depression, prevention of weight gain, weight loss (in combination with caloric restriction), and improvement of physical fitness and musculoskeletal fitness [61, 62]. Inactivity and low cardiorespiratory fitness are as important as overweight and obesity as mortality predictors [63].
In elderly people there is strong evidence supporting the improvement of cognitive function in people who are physically active and moderate evidence in regard to overall improvement in well-being [64] and functional health, reduction of abdominal obesity, reduced risk of developing hip fracture, risk reduction of lung cancer, and weight loss maintenance. In a recent systematic review and meta-analysis, Hobbs et al. [65] found that interventions in adults aged 55–70 years led to long-term improvements in physical fitness at 12 months; however, maintenance beyond this is unclear. Interventions which involved individually tailoring with personalized activity goals or provision of information about local physical activity opportunities in the community may be more effective in this population [65], and the benefits associated with regular exercise and physical activity contribute to a more healthy, independent lifestyle, greatly improving the functional capacity and quality of life in this population [66].
Recommendations for Physical Activity
Best practices:
1.
All adults should avoid inactivity and all those who participate in physical activity should obtain some health benefits.
2.
In order to obtain significant benefits of physical activity in adults, its duration should be at least 2.5 h/week (150 min) of moderate-intensity activity or 75 min of vigorous activity or a combination of both (category: “active”).
The guidelines also recommend that adults should get involved in physical activity, increasing gradually its duration, frequency, and intensity, with the aim of minimizing the risk of injury.
As for the type of exercise recommended, muscle-strengthening activities involve all muscle groups 2 or more days a week. The elderly at risk of falling should also practice exercises to maintain and/or improve their balance.
There appears to be a linear relation between physical activity and health status, such that a further increase in physical activity and fitness will lead to additional improvements in health status. In addition to the recommendations from the guidelines, different studies provided data underlying the importance of avoiding a sedentary lifestyle as a key tool in health promotion [68, 69]. These recommendations are mainly addressed to obese people who are fairly inactive, encouraging them to reach gradually higher levels of physical activity in order to obtain the maximum benefit from its protective effects.
Some studies have focused attention on the sedentary profile of patients, in order to observe the benefit that certain dose of physical activity (in intensity and duration) would produce greater benefit in terms of weight loss and cardiovascular function. These studies concluded that the duration of exercise (150 min) is more important than the intensity (moderate vs. vigorous), but these studies did not include patients with BMI > 40 kg/m2 [70].
The rise of new technologies on the development and marketing of instruments to measure the amount of physical activity (pedometers, accelerometers) will undoubtedly help to better determine the amount of physical activity needed to optimize the dose–response results on physical activity-based interventions [71].
There are few randomized controlled clinical trials evaluating the impact of physical activity in a lifestyle intervention in morbidly obese patients. Goodpaster et al. [22] conducted a trial designed specifically to evaluate the effects of an intensive lifestyle intervention on weight loss, abdominal fat, hepatic steatosis, and other cardiovascular risk factors in people with obesity (degrees II and III, BMI >35 and >40 kg/m2, respectively) without T2DM. They concluded that, among patients with severe obesity, a lifestyle intervention involving diet combined with initial or delayed initiation of physical activity resulted in clinically significant weight loss and favorable changes in cardiometabolic risk factors.
In summary, the available evidence suggests that physically active people live longer than sedentary people and do so with a greater quality of life by improving their rest, reducing the risk of cardiovascular disease, type 2 diabetes, hypertension, dyslipidemia, and colon cancer. In relation to obesity, physical activity appears to help weight loss (although not induce weight loss by itself) and, in a dose sufficient, help in the maintenance of weight loss [57, 72–74].
Behavioral Therapy
Behavioral therapy is a key tool to help overweight and obese patients make long-term changes in their behavior by modifying and monitoring their food intake, increasing their physical activity, and controlling cues and environmental stimuli that trigger overeating [56, 57, 75–78].
Different eligibility criteria, target population, and inclusion criteria (T2DM and BMI) have been used in the most important clinical trials (Table 2). Two of the most cited studies involving behavioral therapy in the context of a lifestyle modification targeted diabetic and/or nondiabetic persons with elevated fasting and post-load plasma glucose concentrations: the Diabetes Prevention Program (DPP) [79] and the Action for Health in Diabetes (Look AHEAD) [80–82]. DPP participants (overweight, sedentary, and nondiabetic persons with elevated fasting and post-load plasma glucose concentrations) were randomly assigned to a metformin group, a lifestyle modification group, and a placebo group. The research team hypothesized that modifying these risk factors with a lifestyle intervention program or the administration of metformin would prevent or delay the development of diabetes. This program was based on 16 individual education sessions during the first 24 weeks and bimonthly the rest of the period. A low-fat, hypocaloric diet was prescribed (1,200–2,000 kcal/day depending on the degree of overweight), composed of conventional foods, and 150 min/week of physical activity (generally brisk walking), with a goal of losing 7 % of their initial body weight.
Table 2.
Eligibility criteria, population targeted, and inclusion criteria (T2DM and BMI) in the clinical trials Look AHEAD, DPP, LOSS, and TRAMOMTANA
Ages eligible for study | Ethnically diverse population | Inclusion criteria: T2DM | Inclusion criteria: BMI | |
|---|---|---|---|---|
Look AHEAD | 45–74 | Yes | Yes | 25 or higher (27 or higher if on insulin) |
DPP | 25 at least | Yes | No (ADA 1997 criteria) | 24 or higher (22 or higher in Asians) |
Impaired glucose tolerance (WHO 1985 criteria) | ||||
LOSS | 20–60 | Yes | No | 40 or higher |
TRAMOMTANA | 18–65 | No | No | 40 or higher |
In the Look AHEAD study, more than 5,100 overweight participants with DM2 were randomized to a Diabetes Support and Education group (DSE) or an Intensive Lifestyle Intervention (ILI) with a weight loss goal of 7 % of their baseline weight and an increase of the time spent in physical activity to an average of 175 min a week. In the first 6 months, the patients attended to three group sessions and one individual visit. They used two meal replacement products a day, with a 1,200–1,800 kcal/day caloric intake goal. Between months 7–12, patients had a single and a group session per month, using one meal replacement product every day. From years 2–4, participants attended a single visit to the hospital and received a telephone call or an e-mail every month, with regular group sessions to help maintain a 7 % initial weight loss and/or neutralize possible weight regain.
These two examples illustrate the wide range of approaches (Table 3) in regard to the number and configuration of individual visits, group sessions, dietary changes, exercise programs as well as patterns in weight loss and weight loss maintenance through these changes in lifestyle. The literature suggests that the current weight loss programs usually achieve a reduction of 7–10 % of the initial body weight [75, 83] after 6–9 months of intervention, and the combination of diet, physical activity, and behavioral changes can obtain even better results if anti-obesity agents are added to the therapy [84].
Table 3.
Comparison of different lifestyle interventions: (1) Look AHEAD vs. DPP
Frequency of sessions/visits | Format | Weight loss goal | Physical activity goal | Special features | Weight loss drugs | Meal replacements | |
|---|---|---|---|---|---|---|---|
Look AHEAD phase 1.1 (months 1–6) | Weekly | Three groups, one individual | Lose 7 % of initial weight | Exercise #175 min/week by month 6 | Treatment toolbox | No | Two meal replacement products, one portion-controlled snack, and a self-selected meal each day |
Look AHEAD phase 1.2 (months 7–12) | Three per month | Two groups, one individual | Increase minutes per week of activity; 10,000 steps/day goal | One meal replacement per day and two meals of self-selected foods are allowed | |||
Look AHEAD phase 2 (months 13–48) | Two per month | One on site, one by mail or telephone | Continued weight loss or weight maintenance | Advanced treatment toolbox orlistat | One meal replacement per day | ||
Additional: refresher groups are offered three times a year | |||||||
Look AHEAD phase 3 (month 49+) | Two per year | On site. Additional phone calls and/or e-mail contacts. Participants may also join refresher groups | Additional support through newsletters, phone, or e-mail contact | ||||
Diabetes Prevention Program (DPP), initial structured core curriculum (months 1–6) | 16 in 24 weeks + 4 supervised phisic physical activity. Supervised sessions | Individual and group sessions | Lose 7 % of initial weight | 150 min/week | Toolbox: adherence strategies, local and national network of training, feedback, and clinical support | No | Structured meal plans and meal replacement products were provided as an option for participants |
Diabetes Prevention Program (DPP), maintenance program (months 7–12) | Face to face at least once every 2 months and by phone at least once between visits | Motivational campaigns | |||||
Small incentives (T-shirts, magnets, weight graphs. newsletters |
One of the biggest challenges is to maintain this weight loss over the medium- and long-term periods [77]. It is important to make these changes durable enough to allow a significant improvement in their comorbidities, quality of life [85, 86], and body composition [87].
One of the few clinical trials focused on the treatment of morbid obesity was the Louisiana Obese Subjects Study (LOSS Study) [23] (Table 4). The main objective of the study was to test whether, with brief training, primary care physicians could effectively implement weight loss for individuals with a BMI of 40–60 kg/m2. In this 2-year randomized, controlled, clinical trial, the recommendations for patients in the Intensive Medical Intervention (IMI) group included a 900 kcal liquid diet for 12 weeks or less, group behavioral counseling, structured diet, and choice of pharmacotherapy (sibutramine hydrochloride, orlistat, or diethylpropion hydrochloride) during months 3–7 and continued use of medications and maintenance strategies for months 8–24.
Table 4.
Comparison of different lifestyle interventions: (2) LOSS vs. TRAMOMTANA
Frequency of sessions/visits | Format | Weight loss goal | Physical activity goal | Special features | Weight loss drugs | Meal replacements | |
|---|---|---|---|---|---|---|---|
LOSS phase 1 (12 weeks or less) | No | No | Lose 10 % of initial weight | Exercise 150 min/week | Flexibility | Low-calorie liquid diet (900 kcal/day), 5 shakes per day | |
LOSS phase 2 (months 3–7) | 4 weekly, then every 2 weeks | Group sessions + individual monthly physician visit | Individualized treatment strategies | Sibutramine | Two daily meal replacements | ||
Monthly physician visit | Orlistat | ||||||
LOSS phase 3 (months 8–24) | Monthly | Group sessions | $100 gift card rewarded attendance at month 24 | Diethylpropion | One daily meal replacement, low-calorie liquid diet in 4- to 12-week episodes | ||
TRAMOMTANA phase 1 (months 1–3) | Weekly | Four group sessions + 1 individual visit with specialist every 3 months | Lose 10 % of initial weight | Exercise 150 min/week by month 12 | Social toolbox | Sibutramine until withdrawal (40 % patients during 1–2 months) | No |
Rockport test | |||||||
Healthy cooking show | |||||||
Small incentives (umbrellas, magnets) | |||||||
TRAMOMTANA phase 2 (months 4–24) | Two per month | Two group sessions + 1 individual visit with specialist every 3 months | Social toolbox | No | |||
Rockport test | |||||||
Workshop: eat slowly and chew |
Ryan et al. [23] obtained data indicating that severely obese patients randomized to an intensive weight loss program in primary care lost a significant amount of weight, compared to those receiving usual care (21 % of patients lost 10 % or more of the initial weight). The authors reported a weight loss of 5 % or higher in 31 % of the analyzed patients and a 10 % weight loss in 21 % of cases, with a significant improvement in many metabolic parameters. These results suggest that, with minimal training, primary care professionals could treat, successfully, a high percentage of morbidly obese patients. However, retention (retention rate in IMI group = 51 %) and weight loss maintenance were two key points to improve, according with the researchers.
In a 1-year non-randomized controlled trial, Johnson et al. [88] compared changes in the dietary patterns of morbidly obese patients undergoing either laparoscopic gastric bypass surgery or a comprehensive lifestyle intervention program. Lifestyle intervention was associated with more favorable dietary 1-year changes than gastric bypass surgery in morbidly obese patients, as measured by intake of vegetables, whole grains, dietary fiber, and saturated fat.
A Spanish randomized clinical trial, performed in Mallorca (multidisciplinary treatment of morbid obesity—TRAMOMTANA) [89, 90], was designed to examine the effects of an Intensive Lifestyle Intervention (ILI) on the therapy of morbid obesity in comparison with a conventional obesity therapy group (COT) and with a third group consisting of patients already included in the bariatric surgery waiting list (SOG). The ILI group received behavioral therapy and nutritional/physical activity counseling. These morbidly obese patients attended weekly group meetings from weeks 1 through to 12 and biweekly from weeks 13 to 52. Meetings included 10–12 subjects, lasted 90 min, and were led by a registered nurse, who mastered in nutrition. The group sessions were focused on the qualitative aspects of the dietary habits, such as the distribution of energy intake, frequency of consumption, and food choices. The research team provided information on the benefits of the Mediterranean diet and encouraged the patients to follow this diet. There were no restrictions in calorie intake. A sport medicine physician prescribed daily home-based exercise (led by a physiotherapist), with gradual progression toward a goal of 175 min of moderate-intensity physical activity per week. Patients could receive treatment with weight loss medicines, such as orlistat or antidepressants at the endocrinologist discretion. Forty percent of the patients included in this group received treatment with sibutramine for a period of 1–2 months until it was withdrawn from the market in January of 2010.
The COT group received the standard medical treatment available for these patients (one visit with the endocrinologist every 6 months). Patients who received ILI achieved a significant weight loss compared with COT group (Fig. 1). The weight loss effect was already obtained after 6 months of ILI intervention. These results seriously question the efficacy of the COT approach to morbid obesity. Furthermore, they underscore the use of ILI programs to effectively treat morbidly obese patients which might help to reduce the number of candidate patients for bariatric surgery, at a lower cost (evaluating medical visits, surgery, sessions, and meds).
Fig. 1.
One-year weight loss in the TRAMOMTANA study.
Non-pharmacological strategies for weight reduction have reported 10 % losses that have been difficult to maintain [91]. Changes in dietary behavior, the stimulation of physical activity, and emotional support continue to be the mainstays for the management of obesity in adults, children, and adolescents.
Sustained caloric restriction (to 1,500 kcal/day for women and 1,800 for men), regardless of dietary macronutrient composition or regimen [19], has fairly similar effects on weight loss, ranging from 3 to 5 kg over 2 years [20]. The addition of physical exercise facilitates weight loss by increasing energy expenditure and increasing basal metabolic rate through an increase in muscle mass.
Unfortunately, lifestyle interventions alone rarely result in long-term weight loss and the majority of dieters return to baseline weight within 3–5 years. This even holds true for participants in weight loss trials who are offered education and intensive support to help prevent weight regain [21, 22].
The improvements described in morbidly obese patients using behavioral therapy as an element of an intensive lifestyle intervention could benefit a huge number of people: those who will undergo bariatric surgery and those who are not interested in surgery and just need to lose 5–10 % of the bodyweight. These interventions must be provided by multidisciplinary, academic, or clinical groups and can be provided at the hospital or primary care setting, to groups of 10–15 patients with an optimal duration of 20–26 weeks and a follow-up period of monitoring and maintenance (also 20–26 weeks) [57].
Overview of Current Obesity Medications
Lifestyle measures are the cornerstone of prevention and treatment of obesity. However, there is general agreement in the scientific community that the use of anti-obesity drugs should also be considered (after careful considerations of the pros and cons), in patients who did not have an optimal response to lifestyle interventions. Weight loss medications could also be considered in some cases as “jump-start” intervention, acting as coadjutant therapy to lifestyle interventions. In many circumstances adding medications to behavioral interventions helps to accomplish the recommended 10 % weight loss and also reinforces adherence to these lifestyle/behavioral interventions.
FDA guidance for the approval of new weight loss therapies intended for long-term use recommends a 5 % placebo-corrected weight reduction that should be maintained for at least 12 months after treatment initiation. Small, sustained reductions in weight can significantly improve CVR factors, particularly glycemia and BP, in overweight and obese individuals. The target adult population for drug therapy is set at BMI > 30 (or a BMI >27 plus a comorbidity such as HTA or T2DM). This opens up a potentially huge market for the development of new weight loss drugs. Despite the great strides in the understanding of the mechanisms involved in the hypothalamic regulation of appetite and energy balance, we still have a very limited armamentarium of drugs useful for the treatment of obesity.
Given the previous history of several obesity medications that have been removed from the market due to significant side effects (HTA, depression, cardiac valvular abnormalities) and the current obesity-related health crisis, the need to identify safe and efficacious weight loss drugs is more than evident. Unfortunately, the medications currently available for obesity therapy are limited in number and efficacy (Table 5).
Table 5.
Drugs approved for treatment of obesity
Drug | Mechanism of action | Effect | Daily dosage | Average weight loss (kg) |
|---|---|---|---|---|
Phenterminea (Adipex) | Augments central NE release | Decreases appetite | 5–37.5 mg QDb | 3.6 kg (12 weeks) |
Diethylpropiona (Tenuate) | Augments central NE release | Decreases appetite | 25 mg TIDc | 10 kg (12 weeks) |
Orlistatd (Xenical) | Pancreatic and gastric | Decreases fat | 120 mg TID | 6 kg (1 year) |
Orlistatd,e (Alli)b | Lipase inhibitor | Absorption | 60 mg TID | |
Lorcaserin (Belviq) | Agonist serotonin receptor 5-HT2C | Decreases appetite | 10 mg BID | 3.6 kg (1 year) |
Phentermine and | Augments central NE and GABA release | 7.5 mg/46 mg | 8.1 kg (56 weeks) | |
Topiramate CR (Qsymia®) | 15 mg/92 mg | 10.2 kg (56 weeks) |
Sympathomimetic Amines
The oldest weight loss drugs still approved by the US FDA as weight loss adjuncts are sympathomimetic (amphetamine-like drugs) such as methamphetamine, phentermine, and diethylpropion. These medications act centrally as adrenergic stimulants, reducing appetite and increasing energy expenditure through generalized sympathetic activation.
Phentermine (Adipex®)
Phentermine (a central norepinephrine-releasing drug) is an approved anti-obesity agent, indicated as an adjunct to appropriate nutrition and physical exercise for short-term (up to 12 weeks) treatment of obesity. In the 1970s, phentermine hydrochloride was developed, with doses ranging from 8 to 37.5 mg [92].
Phentermine remains as the most widely prescribed weight loss drug in the USA. The phentermine hydrochloride salt easily dissociates in the GI tract, resulting in immediate release of the phentermine drug causing a significant appetite suppressant effect. Phentermine is classified by the FDA as a Schedule IV drug. It carries a risk for addiction and/or habituation, though its abuse potential is considered very low [93]. Short-term use of phentermine was associated with a mean weight loss of about 3 kg more than with placebo. No long-term (>1 year) randomized controlled trials of phentermine have been reported. Phentermine was widely used in combination with fenfluramine (“phen-fen”). Unfortunately, dexfenfluramine, a related drug, was found to cause valvular heart abnormalities and primary pulmonary hypertension and was removed from the market in 1997 [94].
Data on adverse events in weight loss trials that used sympathomimetic amines are limited but include increases in HR and BP, dry mouth, nervousness, insomnia, and constipation. Phentermine is contraindicated in patients with CAD, congestive heart failure (CHF), stroke, and uncontrolled HTA. There are no long-term data suggesting that treatment with this agent reduces CVD. Given the fact that phentermine is just approved for short-term use, this medication has very limited use in the management of obesity, as a chronic disease. However, as previously mentioned, it could be a helpful tool to use as a jump start to get patients motivated to participate in a lifestyle intervention program and start making small improvements in their daily habits, which could translate in long-term weight loss.
Diethylpropion (Tenuate®)
Diethylpropion is another amphetamine-like analogue, with fewer stimulant side effects, which has been approved by the US FDA for treatment of obesity since 1959. Diethylpropion is used as part of a short-term plan, along with a low-calorie diet, for weight reduction. Although most studies evaluating the efficacy of diethylpropion for weight loss were short term (less than 20 weeks), obese patients treated with diethylpropion lost an average of 3.0 kg of additional weight compared to placebo [95].
A report evaluated the efficacy of diethylpropion 50 mg BID or placebo for 6 months. After this period, all participants received diethylpropion in an open-label extension for an additional 6 months [96]. The study included 69 obese healthy adults who received a hypocaloric diet. After the initial 6 months, the diethylpropion group lost an average of 9.8 % of initial body weight vs. 3.2 % in the placebo group (Fig. 2). From baseline to month 12, the mean weight loss produced by diethylpropion was 10.6 %. Participants in the placebo group who were switched to diethylpropion after 6 months lost an average of 7.0 % of their initial body weight. No differences in BP, pulse rate, EKG, and psychiatric evaluation were observed. As with phentermine, common side effects of diethylpropion included insomnia, dry mouth, dizziness, headache, mild increases in BP, and palpitations. Very few studies have evaluated the long-term use of diethylpropion.
Fig. 2.
Effects of diethylpropion in body weight change.
Orlistat (Xenical®)
Orlistat is currently the only medication approved by the European Medicine Agency (EMEA) for the treatment of obesity [97]. Xenical acts by inhibiting the intestinal lipase, which translates into a reduction up to 30 % of ingested fat absorption. The recommended dosage is 1 capsule TID with meals. It has a dose-dependent effect: 120 mg decreases up to 30 % fat intake, whereas a dose of 60 mg decreases up to 25 %. In 2007, GlaxoSmithKline, under license from Roche, launched a low dose of orlistat (Alli®) which is not a necessary prescription.
The XENDOS study (XENical in the prevention of Diabetes in Obese Subjects) assessed the effect of the treatment with orlistat in 3,300 obese patients with impaired glucose tolerance [21], a 4-year, prospective, randomized, double-blind, placebo-controlled study; it demonstrated that orlistat (plus lifestyle modification) significantly reduced the incidence of T2DM and improved weight loss, when compared with placebo plus lifestyle changes. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo). The 3.0 kg weight loss achieved by the placebo plus lifestyle changes group over 4 years was comparable with that in the intensive lifestyle intervention arms of the DPS (3.5 kg) and DPP (3.5 kg). XENDOS was the first study to show that a weight loss agent such as orlistat in combination with lifestyle changes was more powerful than lifestyle changes alone helping patients to obtain long-term weight loss and improvements in their CVR factors. After 4 years’ treatment, the cumulative incidence of diabetes was 9.0 % with placebo and 6.2 % with orlistat, corresponding to a risk reduction of 37.3 %. A meta-analysis of studies with orlistat [98] showed a drop of average weight of 2,39 kg. Other benefits of orlistat include a reduction of LDL cholesterol more than expected by the drop in body weight.
Fat-soluble vitamin supplements should be taken 2 h before or after taking orlistat. The most common adverse effects included flatulence with discharge and fecal urgency, which occurred especially after high-fat dietary indiscretions, and were responsible for a significant rate of drug discontinuation. Serious, but very uncommon (only 12 cases), adverse effects have been reported such as liver damage, which were thought to be cases of individual hypersensitivity. Liver function should be monitored while doing Xenical therapy.
A study [99] warned of a possible link between reported cases of acute renal damage in orlistat users (incidence of 2 %). The authors hypothesized that the nonabsorbed dietary fat binds enteric calcium and reduces their ability to bind and sequestrate oxalate in the intestine that leads to excessive absorption of free oxalate with the consequent deposit in the renal parenchyma.
Xenical continues to be a useful therapy which could help obese patients to modified their dietary habits and lose weight.
Sibutramine (Meridia®, Reductil®)
Sibutramine was approved on November 1997 for weight loss and maintenance of weight loss in obese people, as well as in certain overweight people with other risks for CAD. Sibutramine induces weight loss by selectively inhibiting the neuronal reuptake of serotonin and norepinephrine within the hypothalamus. To a smaller degree, it also inhibits the reuptake of dopamine. Treatment with sibutramine resulted in an increase in satiety and a reduction in appetite [100, 101].
In a meta-analysis of randomized placebo-controlled trials of at least 1 year in duration (10 studies with 2,623 patients), sibutramine reduced body weight 4.3 kg more than placebo [102]. There was also a greater reduction in BMI in the sibutramine group and a 4 cm decrease in waist circumference with sibutramine therapy.
Sibutramine also prevented weight regain when administered after a dietary intervention. In the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) study [103], 605 obese patients were treated with sibutramine (10 mg QD) and followed a low-energy diet for 6 months. Patients achieving >5 % weight loss after 6 months (n = 467) were randomly allocated to continue sibutramine (10 mg QD uptitrated to 20 mg QD if weight regain occurred, or placebo for 18 months. The sibutramine group had less weight regain than the placebo group. In a subgroup of patients in STORM study, computed tomography showed a preferential reduction in visceral fat.
Sibutramine therapy was associated with an increase in BP and heart rate in some patients. As expected with any therapy for a chronic disease, significant weight regain was frequently observed after sibutramine therapy was discontinued. In the year 2010 both the EMA and FDA requested market withdrawal of sibutramine after reviewing data from the Sibutramine Cardiovascular Outcomes Trial (SCOUT) [104]. SCOUT was part of a post market requirement to look at cardiovascular safety of sibutramine after the European approval of the drug. It is important to emphasize that in this study patients participated for over 55 years with high CVR and that, in the vast majority of cases, they did not correspond with the type of patients for which this drug was originally approved for. After 6 years of treatment, the individuals who took sibutramine showed an increased risk of serious heart events, including nonfatal heart attack, nonfatal stroke, and death of 11.4 %, compared to 10.0 % in a placebo control group.
The results of the SCOUT were not surprising, if we take into account that most of the patients included in the SCOUT did not meet criteria for treatment with sibutramine. The odds were against sibutramine, because CVR is embedded in its mechanism of action and the study sample consisted of older obese patients, deliberately selected for high CVR, and exposed to sibutramine for 5 years (five times the maximum licensed duration of treatment) [105]. A large number of investigators and Scientific Societies felt that the SCOUT study was flawed as it only covered high-risk patients and did not consider obese patients who did not have cardiovascular complications or similar contraindications, especially considering that those were the patients who could really benefit from this medication.
Recently Approved Drugs for the Treatment of Obesity
Lorcaserin (Belviq®)
Lorcaserin is a new agonist of the 5-hydroxytryptamine (5-HT, or serotonin) receptor 5-HT2C. It binds selectively to the central 5-HT2C receptors, with poor affinity for 5-HT2A and 5-HT2B, respectively. Nonselective serotonergic agents, including fenfluramine and dexfenfluramine, were withdrawn from the market in 1997, after they were reported to be associated with valvular heart abnormalities [106]. Due to its selective agonist effect on 5-HT2C receptors, lorcaserin theoretically should not have similar cardiac adverse effects as fenfluramine.
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