Medical Weight Management: A Multidisciplinary Approach

Abstract

A wide and interacting range of individual, environmental and socioeconomic factors contribute to obesity. As a consequence, weight management strategies almost always comprise a mixture of several parallel approaches, each with its challenges and unique goals. Broadly, weight management strategies comprise of two main strands. The non-pharmacotherapy approach includes various lifestyle modifications in terms of dietary therapy, exercise, and behavioral modifications, including the prevention of possible relapses. Pharmacotherapy, on the other hand, involves several anti-obesity medications, employed as single or combination therapy. Generally, the goals of weight management should be realistic and individualized to patient’s experiences, abilities, and risks in order to maximize the likelihood of success. This chapter tackles these weight management strategies in turn, explaining each, as well as highlighting their distinctive features and challenges, effectiveness and safety, requisites, and where appropriate, indications and contraindications.

1. Introduction

Obesity has significantly increased over the last years. Obesity is defined as excessive fat accumulation that adversely affects health, caused by consuming excess energy in relation to energy expenditure. Its etiology is complex and includes genetic, physiologic, environmental, lifestyle, psychological, social, economic, and political factors that interact to cause obesity (Table 1) [1, 2, 3, 4, 5, 6, 7]. Obesity is diagnosed using body mass index (BMI, kg/m²), weight in kilogram divided by the height in meters squared. Obesity is defined as BMI ≥ 30 kg/m² while having a BMI 25.0–29.9 kg/m² is considered as overweight.

Factors
Individual
Genetic predisposition	Monogenic single gene mutation: deficiency of melanocortin-4 receptor (MC4R), leptin, or proopiomelanocortin (POMC). Polygenic obesity: contribution of many genes. Syndromic obesity: Prader-Willi syndrome
Epigenetic modifications	DNA methylation: metabolic status of mother can influence DNA methylation of leptin at birth causing obesity. Adiponectin epigenetic status related to obesity
Prenatal	Maternal obesity, high weight gain during gestation, gestational diabetes
Neonatal	Prematurity
Post-natal	Formula versus breast feeding, infant overfeeding
Family history	Parental obesity: 3 fold increase risk in offspring if 1 parent is obese and 10 fold increase if 2 parents.
Excessive energy intake	High calorie diet rich in processed fat and carbohydrates
Physical inactivity	Sedentary lifestyle: prolonged screen time, sitting at home or work
Sleep deprivation associated with obesity	Due to imbalance of hormones, impaired glucose tolerance, increased nocturnal cortisol
Psychological	Depression, anxiety, stress
Drug-induced	Steroids, insulin, antidepressants (amitriptyline), antipsychotics (clozapine, quetiapine)
Gut microbiomes	Alteration causes changes in host weight and metabolism leading to obesity
Environmental
Obesogenic environment	Easily accessible fast food/ high calorie diets, affordability of food
Built environment	Few sidewalks/green spaces, low access to recreational resources
Transport/technology	Utilization of cars for transport, less manual jobs
Socioeconomic
Demographic	Age, ethnicity (black, Hispanic), menopause
Socioeconomic	Low income and educational level

Table 1.

Factors contributing to obesity.

Obesity increases the probability of many ailments, with increased morbidity/mortality and decreased quality of life. It is implicated in many health problems and complications e.g., hypertension, type 2 diabetes (T2DM), hyperlipidemia, cardiovascular conditions, obstructive sleep apnea, metabolic syndrome, chronic kidney disease (CKD), nonalcoholic fatty liver disease (NAFLD), osteoarthritis, depression and some cancers [8]. These are mainly a consequence of the increased body fat, which result in endocrine and metabolic disturbances as well as increased mechanical pressure on various organs [9].

Obesity is a chronic disease given its multifaceted etiology and complex pathophysiologies. It has characteristic signs and symptoms consistent with anatomical changes across various organs (cardiovascular, endocrine, immunological functions) and results in complications. Hence, it needs treatment for life; and because it is a heterogeneous condition, individual assessment, risk stratification, and management are necessary [9].

At the societal level, existing weight loss (WL) therapies are not likely to reduce the obesity epidemic, however, at the individual level, they can be useful in reducing the morbidity and mortality associated with obesity [10]. Current treatment guidelines for overweight and obesity recommend diet, exercise, and behavior modification for individuals whose BMI is ≥30 and those with BMI > 27 in addition to two weight-related comorbidities [11].

2. Goals of treatment

Management targets should be realistic and individualized according to the person’s experience, ability, and risks [9]. This is specially important as the long-term treatment success is subject to the person agreement to change the daily lifestyle and to follow the suggested recommendations. Although improvements in cardiovascular (CV) risk factors are observed with as little as 2–3% WL, the existing guidelines propose ≥5–10% (clinically significant WL) during a range of 6 months such WL leads to greater improvement in CV risk [12]. Therefore, the aim is long-term weight reduction is to achieve WL target of >5% of baseline weight for BMI 25–35 kg/m², WL target of >10% of baseline weight for BMI > 35 kg/m²; improvement in obesity-associated risk factors; eduction in obesity-related comorbidities; lowering early mortality risk; prevention of work disability and early retirement; as well as improving the quality of life improved quality of life [9].

3. Weight loss strategies

3.1 Lifestyle modification

Lifestyle modification program requires holistic approach and the plan of care should involve multidisciplinary team of interventionists including physician, dietitian, psychologist, exercise physiologist, health care professionals. In this program, patients should be followed every week (30–90 minutes) for 16–26 weeks to ensure compliance, then every other week for 6–12 months for weight maintenance [9]. Treatment plan includes counseling individuals regarding proper balanced nutrition, appropriate physical activity, and long-term weight control strategies.

Lifestyle modification programs can be implemented in many venues e.g., specialized obesity clinics, primary care, commercial, private dietetics practice or academic medical centers [13, 14, 15, 16]. Typically, these programs induce modest WL that results in significant improvement in obesity-associated health conditions (sleep apnea, T2D, hypertension, hyperlipidemia) as well as positive psycho-social effects (mood, quality of life, body image) [17, 18]. Several studies have demonstrated the efficacy of life style modification in promoting WL and improving obesity-associated comorbidities. We outline two examples of lifestyle modification interventions that validate that WL and long-term health advances that can be accomplished via lifestyle modification.

The Diabetes Prevention Program (DPP) randomized more than 3200 participants with overweight/obesity and impaired glucose tolerance to placebo, metformin, or intensive lifestyle intervention, aiming for 7% WL [19]. Dietitians counseled the lifestyle intervention group for 16 individual sessions in the initial 24 weeks, followed by ≥1 interaction every other month for the rest of the study [19]. The participants were advised to reduce their caloric intake and to follow low fat diet, and to perform 150 minutes of physical activity per week [19]. After an average of 2.8 years, the mean weight loss in the lifestyle intervention group was 5.6 kg vs. 0.1 and 2.1 kg in the placebo and metformin groups, respectively [19]. This 5.6 kg WL was equivalent to 58% relative decrease in the likelihood of developing T2DM [19]. Ten years after the start of the study, the lifestyle intervention group had regained most of the weight they lost, although their T2DM incidence stayed 34% below that of the placebo group [19].

The Look AHEAD Study (Action for Health in Diabetes) enrolled >5100 overweight/obese persons with T2DM [20, 21]. Participants were randomized to diabetes support and education group (3 group-education meetings per year for the first 4 years) or an intensive lifestyle intervention group (weekly group treatment sessions, monthly individual visit, meal replacement with liquid supplement and 1200–1800 kcal/day dietary plan individualized by weight) [20]. After 1 year, the lifestyle intervention group lost 8.6% of their weight vs. 0.6% for the diabetes support and education group; at the fourth year, average WL was 4.7% vs. 1.1%, respectively [20]. The WL was maintained at 8 years (4.7%) for the lifestyle intervention group vs. 2.1% for the diabetes support and education participants [22]. In addition, the lifestyle intervention participants exhibited significantly lower HbA1C (glycated hemoglobin) and showed improvements in CV risk factors including reduced systolic, diastolic pressure and triglycerides [22, 23]. Moreover, the lifestyle intervention group consumed less diabetes, hypertension, and lipid-lowering medications and had remissions or decreased in the severity of obstructive sleep apnea as well as improved depression symptoms [22, 23].

3.2 Dietary therapy

Several dietary approaches are utilized to achieve WL among overweight and obese adults (Table 2). Individuals with obesity should receive personalized nutritional plans in line with their therapeutic goals and risk in order to achieve sustainable and healthy weight. The choice of a diet should address their preferences to facilitate compliance with the dietary plans. Dietary therapy involves individual or group nutritional counseling. Group sessions are usually more effective. Weight management recommendations include healthy eating that emphasize reducing intake of energy dense food, portion control, and improving diet quality leading to energy deficit that results on WL on the long term without impairing health [24]. For instance, energy deficit of 500–600 kcal/day permits about 0.5 kg/week WL over 12 weeks, up to a maximum of 24 weeks [25]. To achieve WL, various nutrition strategies are employed, and because all the diets assessed below have near equivalent short and long-term safety, the selection can be driven by the required control of comorbidities such as T2DM and hypertension (HTN).

Weight loss strategies	Summary
Lifestyle modification
Dietary therapy
Low carbohydrate diet	Restrict carbohydrates to 20–120 g per day
Low fat diet	10–30% total calorie intake from fat
High protein diet	25% of total calorie from protein
Mediterranean diet	35–40% fat, rich in omega-3, whole grains, fruits, vegetables, legumes, nuts, fish
Low calorie diet	Energy deficit of 500–800 kcal/day
Ketogenic diet	Reduced carbohydrates (<50 g/day), rich in protein
Very low-calorie ketogenic Diet	Energy intake < 800 calories, protein 1.2–1.5 g/kg of ideal body weight, fat 15–30 g/day, carbohydrates < 30 g/day
Meal replacements	Liquid formula or bars
Exercise
Aerobic	Important during weight loss phase
Resistance	Increase muscle mass, for weight maintenance
Behavioral modifications
Behavioral skills
Self-monitoring	Weight, food record, exercise minutes
Goal-setting	Weight, calorie intake, exercise
Stimulus control	Keep tempting foods out of sight
Behavioral substitution	Relaxation techniques
Cognitive skills
Problem-solving	Tactics to deal with weight-related health behaviors (social eating)
Cognitive restructuring	Identify/modify maladaptive thoughts contributing to overeating/physical inactivity
Relapse prevention	Learn to get back on track, maintain long term motivation, stress management
Pharmacotherapy	Single/combination anti-obesity medications

Table 2.

Summary of weight loss strategies.

3.2.1 Low carbohydrate diet (LCD)

LCD provides 20–120 g carbohydrates/day [26] and is used as treatment for obesity, T2DM and other obesity-related conditions, with good short and medium-term WL as well as cardiometabolic control [27, 28]. Reported WL with LCD was 11% at 1 year and 7% at 2 years [29]. At the first 6 months, LCD reduces diastolic blood pressure (DBP), triglyceride (TG), very-low-density lipoprotein cholesterol (VLDL), along with improvement in high density lipoprotein cholesterol and to a lesser extend in the low density lipoprotein cholesterol (LDL) [27, 29].

3.2.2 Low fat diet

Comprises 10–30% of total calorie intake from fat [11]. At 2 years, mean weight and BMI changes were −3.3 ± 4.1 kg and −1.0 ± 1.4 kg/m² respectively [27]. Low fat diet also results in significant improvement in the CV risk including reduction in waist circumference (−2.8 ± 4.3 cm), systolic blood pressure (SBP), total cholesterol (TC), LDL, fasting glucose and insulin levels [27, 30, 31].

3.2.3 Low-carbohydrate versus low-fat diets

Several studies compared low-carbohydrate to low-fat diets. A study found that, at 6 months, participants assigned to LCD lost significantly more weight than those on a low-calorie and low-fat regimen [32, 33]. However, the WL was not different at 12 months (−5.1 vs. −3.1 kg) [32, 33]. In another study, participants were assigned to LCD or low fat diet in combination with lifestyle modification and both groups lost 11% and 7% of their TW at 1 and 2 years respectively with no significant difference between the two group [29]. Hence, successful WL can be accomplished with LCD or low-fat diet in conjunction with behavioral therapy. Furthermore, lifestyle modification that enables adherence to the proposed calorie goals is more critical for WL than the macronutrient constituents per se [29, 34, 35].

3.2.4 High protein diet

In this diet, 25%, 30% and 45% of the total calories are from protein, fat, and carbohydrate respectively, whilst providing foods that achieve energy deficit [11]. Expected WL is −3.5 kg at 6 months and may achieve 15% TWL% at 1 year [36, 37]. High protein diet could result in significant reduction in BP, fasting glucose and insulin level as well as significant improvement in lipid profile including LDL, TC, TG and HDL [36, 37].

3.2.5 Mediterranean diet

It has moderate amount of fat (35–40%) and is rich in Omega-3, where the primary fat source is extra virgin olive oil. Mediterranean diet has more whole grains, fruits, vegetables, legumes, nuts, fish and seafood, with limited poultry, dairy, red meat and usually prescribed with energy restriction to achieve WL [11, 27]. Reported WL at 2 years is −3.4 kg (−5.1 to −3.0). In addition, it decreases waist circumference, improves SBP, HDL and glucose levels [27].

3.2.6 Low calorie diet

Low calorie diet is based on balanced nutrition where 45 – 55% of intake is from carbohydrates, 15–25% is from proteins, and 25–30% is from fat [38]. It must be tailored to individual energy requirements, sex, age, and physical activity [38]. The diet’s composition should be modified to minimize comorbidities e.g., T2DM, HTN, hyperlipidemia [38]. This diet is should be designed to result in energy deficit of 500–800 kcal/d. Therefore, women can be prescribed 1200–1500 kcal/d and men 1500–1800 kcal/d. Low calorie diet with relatively high protein contents facilitates WL and prevents weight regain due to the greater satiety and energy expenditure through diet-induced thermogenesis and preservation of lean muscle mass. Studies reported weight loss of 11 kg at 26 weeks [39]. In addition, significant improvement in CV risk factors was observed with this diet such as BP, waist circumference, glucose, insulin level and lipid profile (TC, TG) [40, 41, 42].

3.2.7 Ketogenic diet

This diet has been utilized since 1920s as treatment for epilepsy and has been shown in some case to reduce or eliminate the need for epilepsy medications for epilepsy drugs. It became a common method for obesity treatment since the 1960s. This diet has therapeutic potential in many obesity-associated conditions, e.g., T2DM, polycystic ovary syndrome, acne, and cancer [43]. Ketogenic diets comprise reduced carbohydrates (<50 g/day) with an increase in protein and fat [43].

3.2.8 Very low-calorie ketogenic diet (VLCKD)

This provides energy intake of <800 calories/day, protein 1.2–1.5 g/kg of ideal body weight, carbohydrates of <30 g/day and 15–30 g of fat/day [26, 44, 45]. The low carbohydrate stimulates lipolysis of stored fat and synthesis of ketone bodies utilized as fuel by extrahepatic tissues. Ketosis associated with VLCKD is always moderate (ketonemia never >3 mmol/L) and is different than diabetic ketoacidosis [45]. WL (0.5–2.0 kg/week) is achieved as a result of the proteins’ satiety effect on appetite hormones, appetite-suppressant actions of ketone bodies and also due to the decrease in diminished lipogenesis along with increase in lipolysis [46].

VLCKD is delivered through a mix of meal replacements that include protein (milk, peas, whey, soy) and natural food to improve patient compliance. Daily vitamins and minerals are also provided [45]. VLCKD is advised for BMI ≥30 kg/m² for a maximum of 12 weeks. This diet should be under medical supervision as there is increased risk of side effects such as dehydration, nausea, diarrhea, constipation, hyperuricemia, gallstones, and vitamin/microelement deficiencies [45]. Studies have shown that at 4 weeks, VLCKD resulted in significant WL (6–37% TWL%), improvement in BMI (−5.3 kg/m²), SBP, DBP, insulin resistance (HOMA-IR) and lipids (TG, TC, HDL) [47, 48, 49]. Similar findings were also reported among obese diabetic patients, where VLCKD achieved significant WL at 3 months (8.5%) and 12 months (11.5%) and improvement in blood glucose [50]. Moreover, 26.6% of the patients who completed the study were able to stop all antidiabetic medications, while 73.3% took metformin only [50].

3.2.9 Meal replacements

Meal placements is produced in different forms such as drink, bars or soup to substitute solid food. They have controlled calories and nutrient contents and are commonly used in energy restricted diet to facilitate WL. It also contains the necessary vitamins and minerals. Many studies reported the effectiveness of utilizing meal replacements as dietary intervention for weight management [51, 52, 53]. Participants who replaced two meals and two snacks per day with liquid shakes and meal bars lost 7.1 kg in 3 months compared to 1.3 kg for individuals on conventional foods with the same calories (1200–1500 kcal/d) [54]. Moreover, those who substitute 1 meal and 1 snack a day during follow-up maintained a WL of 10.4 kg at 27 months [54]. Similarly, the use of meal replacement in patients with T2DM resulted in significant WL at 12 months compared to conventional diet (−4.4 vs. −2.4 kg, P = 0.07), with significant glycemic (HbA1c) improvement and reduced medications [52].

3.3 Exercise

Exercise improves body composition and CV health independent of WL [55, 56]. In the absence of significant WL, aerobic exercise improves blood pressure (BP), lipids, and visceral fat [57, 58, 59, 60, 61]. The reduced visceral fat improves glucose tolerance and insulin sensitivity in nondiabetic individuals as well as glycemic control in diabetic patients [62, 63]. Exercise also leads to positive changes in quality of life, vitality and mental health [56]. Therefore, individuals with obesity should be encouraged to exercise to improve their CV health, rather than lose weight only [34, 64].

Guidelines for care of patients with obesity include recommendations for “aerobic training of ≥150 min/week of moderate intensity, with better outcomes with increasing amounts and intensity of exercise” [12]. However, PA alone induces limited WL [65], unless it is accompanied by energy restriction. For instance, losing 0.45 kg/week, requires high PA is (e.g., walking 35 miles/week), but is feasible to be accomplished by decreasing food intake by 500 kcal/day. Hence, effective WL requires exercise >150 min/week with 1200–1800 kcal/week energy consumption [65]. Exercise combined with decrease caloric intake produces greater WL than exercise or caloric restriction alone. Hence, PA should be paired with adjusted caloric intake to achieve optimal WL and body composition. Physical activity should be prescribed according to patient’s ability, preference. It is also important to ascertain that there are no contraindications to physical activity particularly in individuals with BMI of 35 kg/m² or higher.

3.3.1 Aerobic exercise

Aerobic exercise is essential for weight management. It facilitates weight loss and improves body composition by inducing fat and visceral fat loss [66]. One study found that supervised exercise with 400 or 600 kcal/session five days/week for 10 months resulted in 3.9 ± 4.9 and 5.2 ± 5.6 kg among overweight or obese individuals respectively compared with weight gain (0.5 ± 3.5 kg) for controls [67]. Aerobic exercise intensity also influences WL. Among sedentary college students with obesity, 12 weeks of high and moderate intensity training led to significant reduction in body weight, BMI, waist circumference, and body fat percentage than light intensity training [68]. Likewise, the time of the session is essential for body weight outcomes, where early-exercise (50% of sessions between 7 and 11.59 am) led to significantly more weight loss compared to late-exercise (>50% of sessions between 3 and 7 pm) [69]. In contrast, there is no significant difference in terms of weight loss between continuous and intermittent exercise. For example a study compared the effect of 18 months of continuous (3 times/wk, 30 min/session) versus intermittent (5 times/wk, 15 min/session) aerobic exercise in overweight and obese individuals and found small reductions in weight (2.0%) in the continuous training group with no significant change in intermittent groups [70].

3.3.2 Resistance exercise

This type of exercise may not result in WL if performed alone because it does not generate enough negative energy balance to achieve clinically significant weight loss when compared with aerobic exercises [71]. Aerobic exercises have superior total energy expenditure when compared to resistance exercises [72]. Combinations of aerobic and resistance exercise provide greater benefits for WL, fat loss and cardio-respiratory fitness than aerobic or resistance exercise alone [73]. Resistance training might support negative energy balance by augmenting the lean mass, resting metabolic rate, and the oxidation of fat and may assist with weight maintenance [65, 72].

3.4 Behavioral modifications

The cornerstone treatment of obesity is a lifestyle modification program that consist of diet, exercise, and behavior therapy. Psychotherapists use group or individual behavior therapy to provide principles, techniques and skills to alter the eating and exercise patterns and to facilitate achievement of energy intake and expenditure goals [10]. When overweight/obesity is accompanied with serious symptoms (e.g., depression, eating disorders, and lack of motivation), then psychiatrists should be involved in the care patients [74]. Various strategies should be adapted to the individual situation and the patient’s needs [75]. Typical behavioral WL programs include 60–90 min weekly sittings for 6 months followed by maintenance gatherings every other week through another 12 months to prevent weight regain [34].

3.4.1 Behavioral skills

3.4.1.1 Self-monitoring

Teaching participants to self-monitor their eating, PA and progress is a behavioral therapy technique known as self-monitoring. It is a key strategy in behavioral therapy of obesity. Self-Monitoring increases self-awareness of personal behaviors as it slows down the decision-making processes, allowing individuals to make healthier choices [76]. Although self-monitoring of food and energy is considered the most important skill in behavior therapy, however it can be difficult to implement. For example, reporting the lack of ability to lose weight underestimated their food consumption by 50% [77]. Hence, patients require education on using measurement tools, nutrition labels, and calorie guides. They should also be encouraged to make note of the time, amount, preparation, and calorie of foods and beverages and bring their records to group meetings for feedback.

PA is also important to be monitored in behavior therapy. Participants are instructed to record the type and amount of their PA. Pedometers provide immediate feedback, encouraging participants to gradually increase their energy expenditure and the number of steps reach the target of 10,000 steps per day [78]. Self-monitoring should be daily for the first 6 months and then intermittently during maintenance. Participants are instructed to record their intake and PA daily and bring their books to individual or group meetings. Research demonstrated strong associations between adherence to self monitoring of dietary consumption, self-weighing, and PA and WL where greater frequency and more days of self-monitoring corresponded to greater monthly WL [79, 80].

3.4.1.2 Goal-setting

Setting personal targets is an important behavioral element in weight management. To modify behavior, participants need to set specific quantifiable achievable PA and dietary goals (e.g., consume ≤1200 kcal) [76]. Setting weight management goals is better when tied to health benefits such as better blood pressure control or improved lipid profile to increase motivation and adherence [76]. Similarly, short-term goals are more effective than longer-term goals. More importantly, goals need to be realistic, yet challenging. Deciding on reasonable, achievable goals supports long-term success. Therefore, is better to set easier goals initially and increase them gradually as the participant progresses to facilitate adherence and increase the sense of accomplishment [81, 82]. Patients frequently assume they need to lose much weight to be successful. Helping patients choose an achievable WL goal (e.g., 5% WL) strengthens adherence. Studies have shown that participants who set targets were 10.3 times more likely to accomplish WL ≥10% at 1 year was compared to those who did not [81]. Goal setting related to diet or PA was found to be more predictive of adherence to dietary and physical activity strategies than goal setting related to weight loss [82].

3.4.1.3 Stimulus control

Stimulus control strategies focus on changing an individual's environment to reinforce healthy changes [76]. Behavioral treatment teaches participants to reorganize their environment in order to lessen the cues for inappropriate food consumption, and increase those for appropriate diet or physical activity [83]. For instance, if a person frequently snacks on the couch or while watching television, the act of sitting on the sofa or watching television becomes a cue to future snacking. To modify this, participants need to confine their meals to the dining room to decrease the cues associated with eating [84]. Likewise, individuals may keep tempting food out of sight or remove them from home to limit consumption. Similarly, individuals are encouraged to buy more fruits and vegetables and make them more visible by storing in obvious places. A reminder notes about healthy eating and exercise on the refrigerator or bathroom mirror could also be a useful strategy to alter the home environment and promote healthy habits.

3.4.1.4 Behavioral substitution

Many individuals eat as a reaction to emotional stimuli (e.g., anger, boredom, stress, anxiety, frustration), with has substantial impacts on weight and health. Self-monitoring assists individuals in behavior therapy to recognize non-hunger cues to snack and replace eating with different behaviors. Individuals and their relatives need to find other means to deal with negative feelings [76]. If a person eats when anxious, practicing relaxation techniques or alternative activities such as writing, knitting, housekeeping, and exercising in response to anxieties could be more useful as these activities hinder eating.

3.4.2 Cognitive skills

Cognitive approaches to behavior change are also utilized in the behavioral treatment of obesity. The two most commonly taught skills are problem-solving and cognitive restructuring.

3.4.2.1 Problem-solving

Individuals may face obstacles when attempting to make lifestyle changes [76]. In order to support participants during this process, it is important to train them in problem-solving skills. This problem solving tactics help patients explore their weight-related health behaviors. Using a multistep interactive behavioral strategy, they identify a problem that hinders their WL, contemplate outcomes associated with different choices, choose the healthiest, implement a specific plan, assess the success of the selected solution and repeat the problem-solving process if necessary [74, 76]. Group visits is useful in helping participants to engage in problem solving of a given health aspect, learn from the way other people solved similar problems and creating solutions specific to their situation [76]. A 6-month lifestyle intervention for obesity involving problem-solving skills resulted in 8.8% reduction in body weight [85]. Weight change was associated with increased problem-solving skills and higher adherence to treatment [85]. Moreover, participants with WL > 10% had greater problem-solving skills than those with <5% reduction [85].

3.4.2.2 Cognitive restructuring

Behavior therapy trains individuals to observe the thoughts that hinder their capacity to achieve behavioral targets, recognize distortions in those thoughts, and exchange dysfunctional thoughts with more rational ones. Cognitive restructuring identifies and modifies maladaptive thoughts that promote overeating and lack of exercise. Such thoughts can be dichotomous thinking (“As I am unable to exercise for 30 minutes, I might then not exercise at all”) and rationalization (“I had a stressful day, this justifies a portion of cake”). Participants are unaware of the effect of these thoughts on behavior. With cognitive restructuring participants learn how to develop a positive self statement to facilitate behavioral modifications [86].

3.4.3 Cognitive behavioral therapy

Behavior therapy include cognitive strategies to modify eating and activity behaviors [87]. It focuses on altering the cognitive and behavioral mechanisms that causes the problem behavior, and utilize cognitive and behavioral strategies to make positive changes in such behavior. Cognitive behavioral therapy resulted in significant improvement in anthropometric profile, eating behaviors, quality of life across physical, psychological, social, environmental domains, as well as reduced depression [88].

3.4.4 Relapse prevention

Assisting individuals to prepare and plan for relapse prevention includes educating them to foresee challenging situations that could result in overeating, and to utilize strategies to overcome such intervals. Individuals are motivated to plan so that one overeating mistake does not become a full-scale relapse [89]. A WL maintenance program, implemented via telephone that addressed outcome satisfaction, relapse-prevention planning, self-monitoring, and social support found that at 56 weeks, there was statistically significantly less weight regain in the intervention group (0.75 kg) than those receiving usual care [89].

As for the technology use for lifestyle modification: Behavioral treatment improves adherence to lifestyle intervention, but face-to-face delivery is time and resource intensive and travel time is costly and inconvenient. Using the telephone or internet provide cost-effective delivery of lifestyle interventions to many individuals [84, 90]. A study compared the efficacy of phone versus face-to-face clinic approach to achieve 10% WL found that WL at 12 weeks was 10.4% for phone, 13.7% for clinic visits, and both were significantly more than the control group (0.24%) [91]. Individual telephone counseling to provide extended care for obesity management in rural communities diminished the weight regain and increased the proportion of participants who maintained clinically significant WL [92]. Likewise, evidence indicates that Internet-based interventions are better when compared to no or minimal intervention but are less efficacious than in-person treatment [93] . An Internet behavioral WL program resulted in 8 kg, 5.5 kg and 6 kg WL for in person, internet, and hybrid respectively (p < 0.01), suggesting that internet is a viable alternative for delivery and dissemination of behavioral weight-control interventions [93]. Smart-phone applications are recently gaining popularity for weight management but its effectiveness has not been proven in the long term. A randomized controlled trial among overweight/obese young adults reported that at 6 months, individuals who received personal coaching enhanced by self-monitoring using a smartphone lost significantly more weight than the controls, but not at 12 or 24 months [94]. Moreover, WL loss outcomes in the group who received lifestyle intervention through interactive smartphone application only was not superior to control in WL [94].

4. Pharmacotherapy

Pharmacotherapy can counteract the increase in appetite the decrease in energy expenditure that occur as an adaptive mechanism to weight loss which, improve adherence to lifestyle modifications. Pharmacotherapy is indicated for BMI ≥30 or BMI ≥27 with obesity-associated conditions [95]. It is prescribed together with comprehensive diet, physical activity and behavioral therapy to achieve adequate WL, and should result in clinically significant WL (≥5% mean TWL%). Anti-obesity medications are prescribed according to their efficacy and safety, the type of obesity associated comorbidities. Several medications are approved for obesity management (Table 3).

	Mode of action	Dose	Side effect/s	Contraindication/s
Single drug
Phentermine ^* Schedule IV controlled substance	Sympathomimetic amine Adrenergic agonist	8 mg, 15 mg capsule, 37.5 mg tablet	Dry mouth, insomnia, agitation, constipation, tachycardia	G, severe HTN, CV disease, history of drug/alcohol abuse, pregnancy, MOI, selective serotonin reuptake inhibitor use
Orlistat	Pancreatic and gastric lipase inhibitor	60 mg OTC, 120 mg TID	Steatorrhea, oily spotting, flatulence/discharge, fecal incontinence, fat soluble vitamins deficiencies, malabsorption	P, malabsorption syndromes/GI conditions that predispose to GI upset/diarrhea
Liraglutide	GLP-1 agonist	3.0 mg daily	Nausea, vomiting, diarrhea, constipation. Rarely pancreatitis, cholecystitis	Severe renal/hepatic insufficiency, pregnancy, Personal/family history of MTC or MEN2 and major depression/psychiatric disorder
Semaglutide	GLP-1 agonist	2.4 mg weekly	Nausea, vomiting, diarrhea, constipation, headache rarely pancreatitis, cholecystitis	Severe renal/hepatic insufficiency, pregnancy, personal/family history of MTC or MEN2. Past history of P + major depression or psychiatric disorder
Combination
Phentermine- Topiramate. Schedule IV controlled substance	Sympatho-mimetic amine, anorectic, extended-release anti-epileptic drug	3.75/23 mg, 7.5/46 mg, 11.25/69 mg, 15/92 mg	Paraesthesia, dry mouth, constipation, insomnia, dizziness, altered taste sensation, cognitive effects Rare: closed angle glaucoma, depression, suicidal ideation	G, renal stones, pregnancy (when utilized for WL)
Naltrexone-Bupropion	Opioid receptor antagonist, inhibits dopamine/norepinephrine reuptake	8/90 mg daily to 16/180 mg BID Tablet	Nausea, vomiting, constipation, dizziness, insomnia, headache, dry mouth	Pregnancy, uncontrolled HTN, uncontrolled pain, recent MOI use, history of seizures/conditions that predispose to seizure e.g., anorexia/BN, abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptic drugs

Table 3.

Pharmacotherapy: anti-obesity medications.

^*

Approved for short-term use; MEN2multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma, BN bulimia nervosa, CV cardiovascular, HTN hypertension, MOI monoamine oxidase inhibitors

4.1 Single medication

4.1.1 Phentermine

Phentermine is a sympathomimetic amine approved in 1959. It increases hypothalamic catecholamine secretion and resting energy expenditure to suppresses appetite. Phentermine is the most frequently used obesity medication in the USA [96]. It is indicated for short-term (3 months), as no long-term safety research exists, but it was approved in combination with topiramate extended release (ER) for long-term therapy. However, many obesity physicians prescribe it for >3 months as off-label therapy for weight management [96]. It is available in 8, 15, 30 and 37.5 mg (single dose early in the day to prevent insomnia). Side effects are mild and due to sympathomimetic effects e.g., dry mouth, insomnia, agitation, constipation and tachycardia. Administering the lowest effective dose decreases the side effects. Phentermine is a schedule IV-controlled substance, and it is contraindicated in patients with history of cardiovascular disease, anxiety, hyperthyroidism, drug or alcohol abuse/dependence. Other contraindications include concomitant treatment with monoamine oxidase inhibitors, pregnancy and breastfeeding [97]. Expected WL with phentermine is 3.6 kg at 6 months [98]. After 6 months, phentermine 15 mg induced a WL of 4.5 kg over placebo [99]. Forty-six percent of participants on phentermine lost ≥5% of their weight, while 20.8% lost ≥10% [99].

4.1.2 Liraglutide

Liraglutide 3 mg is an FDA-approved injectable GLP-1 agonist. A gut-derived incretin hormone, it stimulates the GLP-1 receptor in the pancreatic islets, increases the delivery of insulin and lowers glucagon secretion [100]. It mediates WL through peripheral and CNS pathways, inhibits gastric emptying, promotes satiety and reduces hunger thereby decreasing food intake. The most common side effects encountered with liraglutide are nausea, vomiting, diarrhea, constipation and dyspepsia. These symptoms are usually mild and improve within days or weeks with continuation of treatment and gradual dose titration of the dose. WL with liraglutide may also increase the risk of symptomatic gallstones, and in rare cases may cause pancreatitis. Liraglutide is contraindicated in severe renal/hepatic insufficiency, pregnancy, history of pancreatitis or major psychiatric disorder [101]. In terms weight loss, liraglutide resulted in 5.4% weight loss at one year in large RCT [102]. A total 63.2% of the participants in the liraglutide group lost at least 5% of their weight compared with 27.1% in the placebo group (P<0.001)[102]. Likewise, 33.1% of liraglutide group lost more than 10% of their body weight versus 10.6% in the control group(P<0.001) [102]. Moreover, cardiometabolic risk, inflammatory markers, glycaemic parameters, blood pressure and lipids also improved [102]. For weight maintenance, the SCALE study found that among individuals who lost 5% of their initial body weight on a low-calorie diet, liraglutide added another 6.2% TWL% vs. 0.2% in the placebo group [103].

4.1.3 Semaglutide

Approved in 2019, semaglutide is a long-acting GLP-1 analogue that mimics the effects of native GLP-1, stimulating WL by decreasing the energy intake and hunger, increasing satiety, and enhancing glycemic control [104]. It is approved for treatment of T2D using ≤1.0 mg once weekly subcutaneously or as tablets at a dosage of up to 14 mg. Side effects and contraindications are similar to liraglutide (Table 3). In STEP 1 trail, semaglutide 2.4 mg resulted in significant TWL% at 68 weeks compared to placebo (−14.9% vs. − 2.4%) [105]. More participants on semaglutide than placebo achieved ≥5% TWL% (86.4% vs. 31.5%), ≥10% (69.1% vs. 12.0%), and ≥ 15% (50.5% vs. 4.9%) [105]. Moreover, semaglutide led to more improvement in cardiometabolic risk and physical functioning than placebo [105]. In the STEP 4 trial, individuals completing a 20-week run-in period with semaglutide 2.4 mg once per week, maintenance with semaglutide resulted in continuous WL over the next 48 weeks compared to switching to placebo (−7.9% vs. +6.9%) [106].

4.1.4 Orlistat

Approved in 1999, orlistat is the single anti-obesity medication that does not function via the CNS pathway. Instead, it inhibits pancreatic and gastric lipases, reducing absorption of 25–30% of ingested fat [101]. The recommended dose is 120 mg three times per day up to 1 hour after food intake. Side effects are related to fat malabsorption and include steatorrhea, oily spotting, flatulence, and fecal incontinence. The gastrointestinal symptoms can be reduced by a low-fat diet and increasing intake the dietary fiber [107]. Multivitamin supplementation is essential, as orlistat decreases absorption of fat-soluble vitamins (A, D, E, K). Orlistat resulted in a mean 2.9–3.4% weight loss at one year [107]. Long term WL (4 years) can reach 5.8 kg, where 53% of participants lost ≥5% of their weight, and 26.2% lost ≥10% of their weight [108]. Orlistat also reduces the serum glucose levels and increases insulin sensitivity. Individuals with T2DM prescribed orlistat 120 mg exhibited significantly more reduction in fasting blood glucose and HbA1c compared to placebo [109].

4.2 Combination medications

4.2.1 Phentermine-topiramate ER

This long-acting combination was approved in 2012. Phentermine is a short-term appetite suppressant; topiramate is an antiepileptic and migraine medication [107]. The mechanisms of appetite suppression is not well understood, perhaps vis modulation of gamma-aminobutyric acid receptors [110]. Because of its anorexigenic properties, it is used off-label for obesity and binge eating, alone or combined with phentermine. Phentermine/topiramate ER is available as 4 doses daily (Table 2), taken in the morning, titrated every 2 weeks and stopped if 5% WL is not accomplished within 12 weeks on maximum daily dose 15/92 mg [111]. Phentermine/topiramate ER, a schedule IV controlled substance. The FDA (Food and drug administration) requires a Risk Evaluation and Mitigation Strategy to inform physicians and women of reproductive age about potential increased likelihood of orofacial clefts in infants exposed to phentermine/topiramate ER during the first trimester of pregnancy [97]. The side effects are those of phentermine and topiramate. Topiramate has dose-dependent side effects and this include cognitive side effects such as psychomotor slowing, diminished concentration, memory impairment and language difficulties (Table 3) [111]. Many side effects of topiramate are due to the inhibition of carbonic anhydrase activity, such as metabolic acidosis, hypokalemia, renal stones, angle-closure glaucoma, myopia, and anhidrosis. Therefore, topiramate should not be given with other medications that inhibit carbonic anhydrase [111]. Rare side effects also include increased suicidal thoughts or ideations, where the drug should be stopped immediately.

Phentermine/topiramate ER resulted in significantly greater WL compared to placebo where participants in the 3.75/23, and 15/92 groups lost 5.1%, and 10.9% of their baseline weight, respectively compared with 1.6% in the placebo group [112]. Moreover, 44.9% of 3.75/23 group, and 66.7% of 15/92 group, lost ≥5% of their weight after 56 weeks of treatment compared to 17.3% of the placebo group (p<0.0001) [112]. Phentermine/topiramate ER for 52 weeks also resulted in 76% reduction in the progression to diabetes in participants receiving 15/92 mg and a 54% reduction in participants receiving 7.5/46 mg compared with placebo [113].

4.2.2 Naltrexone-bupropion sustained release (SR)

A combination approved in 2014, bupropion (dopamine and norepinephrine reuptake inhibitor) is used for depression and smoking cessation treatment while naltrexone is an opioid antagonist [97, 111]. Their combined use has synergistic effect on appetite suppression [111, 114]. Bupropion inhibits food consumption and increases energy expenditure by stimulating the neuropeptide pro-opiomelanocortin (POMC) and supplementing dopamine activation, which is lower among obese individuals [111]. Naltrexone is used for treating opioid and alcohol dependence [97]. It inhibits the appetite-enhancing influence of beta-endorphin caused by cannabinoid-1 receptor stimulation.

Starting with one tablet (8 mg ER naltrexone and 90 mg ER bupropion) daily, the dose is increased by one tablet per week to a therapeutic dosage of two tablets two times per day (32/360 mg). The medication should be discontinued if WL ≥ 5% is not achieved at 16 weeks [97]. The most common side effects are highlighted in Table 3. The medication is contraindicated with monoamine oxidase inhibitors and chronic opioids. It is also contraindicated in patients with uncontrolled HTN, and history of seizures. Bupropion increases the risk of suicidality in patients younger 24 years and therefore they need to be observed closely for mood changes [97].

Studies have shown that patients on naltrexone/bupropion 360/32 mg had a mean 6.1% WL in comparison to 1.3% for those on placebo; and 48% of naltrexone/bupropion individuals lost >5% body weight compared to 16% of placebo patients [114]. Others reported that 44.5% of patients on naltrexone/bupropion lost ≥5% of their body weight after 56 weeks vs. 18.9% on placebo [115]. Furthermore, the medication resulted in better glycemic control and improvements in triglycerides and HDL cholesterol when compared to those on placebo [115].

5. Conclusions

Obesity is a chronic condition with considerably increased morbidity and mortality. Obesity has complex genetic, physiological, behavioral, sociocultural, and environmental etiologies. Hence, a multi-pronged and comprehensive strategy is critical. Lifestyle and behavioral modifications are key in the treatment of obesity, combined with diet, exercise, and behavioral therapy to achieve adequate WL. Pharmacology should be considered for individuals not responding to lifestyle modifications or those who have difficulty maintaining the weight loss initial achieved by lifestyle modifications.

Acronyms and abbreviations

BMI

body mass index

T2DM

type 2 diabetes

CKD

chronic kidney disease

NAFLD

nonalcoholic fatty liver disease

WL

weight loss

CV

cardiovascular

vs

versus

HbA1c

glycosylated hemoglobin refers to glucose and hemoglobin joined together (the hemoglobin is ‘glycated’) and the normal range for the HbA1c level is between 4% and 5.6%

BP

blood pressure

SBP

systolic blood pressure

DBP

diastolic blood pressure

TG

triglyceride

VLDL

very-low-density lipoprotein

LDL

low-density lipoprotein

HDL

high-density lipoprotein

TW

total weight

TWL%

total WL percentage

TC

total cholesterol

HTN

hypertension refers to high blood pressure defined as systolic 140 mm Hg or higher and diastolic: 90 mm Hg or higher

VLCKD

very low-calorie ketogenic diet

HOMA-IR

homeostasis model assessment-insulin resistance

PA

physical activity

ER

extended release

SR

sustained release

POMC

pro-opiomelanocortin