Substantial weight loss can be achieved through various treatment modalities, but long-term sustenance of lost weight is much more challenging, and weight regain is typical. The rise in obesity prevalence over the past several decades has been mirrored by industrialization of the food system involving increased production and marketing of inexpensive, highly-processed foods with supernormal appetitive properties. Long-term weight management is extremely challenging due to interactions between our biology, behavior, and the obesogenic environment.
Introduction
Weight loss can be achieved through a variety of modalities, but long-term maintenance of lost weight is much more challenging. Obesity interventions typically result in early rapid weight loss followed by a weight plateau and progressive regain. Individuals with excess weight are at a higher risk for various physical and mental health conditions. Interventions targeting weight loss can improve health, with modest weight loss of five to ten percent of body weight often considered clinically meaningful for enhancing health outcomes.
The Challenge of Sustaining Weight Loss
In a meta-analysis of 29 long-term weight loss studies, more than half of the lost weight was regained within two years, and by five years more than 80% of lost weight was regained.
Robert, a 47-year-old patient who initially weighed 270 pounds, lost 85 pounds three years ago by carefully following guidance to decrease his caloric intake to 1500 calories per day and exercise six days weekly. Today he comes in for his annual physical examination, but he had regained almost 60 pounds. “I don’t know what to do…the weight keeps coming back on. I keep trying, but there must be something wrong. I’m sure my metabolism is in the dumps. It feels like every moment of the day I can’t help but think about food - it was never like this before I lost the weight."
Factors Contributing to Weight Regain
Biological Factors
In addition to adaptations in energy expenditure with weight loss, body weight is regulated by negative feedback circuits that influence food intake. The overlapping physiological changes that occur with weight loss help explain the near-ubiquitous weight loss time course: early rapid weight loss that stalls after several months, followed by progressive weight regain. Different interventions result in varying degrees of weight loss and regain, but the overall time courses are similar.
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Appetite changes likely play a more important role than slowing metabolism in explaining the weight loss plateau since the feedback circuit controlling long-term calorie intake has greater overall strength than the feedback circuit controlling calorie expenditure. Specifically, it has been estimated that for each kilogram of lost weight, calorie expenditure decreases by about 20-30 kcal/d whereas appetite increases by about 100 kcal/d above the baseline level prior to weight loss.
Mathematical model simulations of body weight, fat mass, energy intake, energy expenditure, appetite, and effort for two hypothetical women participating in a weight loss program. The curves in blue depict the typical weight loss, plateau and regain trajectory whereas the orange curves show successful weight loss maintenance.
These mathematical model results contrast with patients’ reports of eating approximately the same diet after the weight plateau that was previously successful during the initial phases of weight loss. While self-reported diet measurements are notoriously inaccurate and imprecise, it may be possible to reconcile such data with objectively quantified increases in calorie intake. The patient’s perception of ongoing diet maintenance despite no further weight loss may arise because the physiological regulation of appetite occurs in brain regions that operate below the patient’s conscious awareness. Thus, signals to the brain that increase appetite with weight loss could introduce subconscious biases such as portion sizes creeping upwards over time.
Behavioral Factors
Behavioral strategies for initiation of weight loss are described elsewhere in this volume []. Weight-loss specific behaviors associated with long term success include: frequent self-monitoring and self-weighing, reduced calorie intake, smaller and more frequent meals/snacks throughout the day, increased physical activity, consistently eating breakfast, more frequent at-home meals compared with restaurant and fast-food meals, reducing screen time, and use of portion-controlled meals or meal substitutes.
Unlike with weight loss, during which the external reward of watching the scale decrease and clinical measures (e.g., lipid levels) improve can increase motivation, the extended period of weight maintenance has fewer of these explicit rewards. People tend to focus on what they haven’t achieved, rather than what they’ve already accomplished. To support motivation and make salient satisfaction with outcomes, call attention to patients’ progress, which often becomes overlooked. Providers can point to the magnitude of weight that has been kept off, putting it into context in terms of average expected weight loss (described below), as well as clinical improvements in risk factors, such as blood pressure and glycemic control.
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Anticipating and managing high-risk situations for “slips” and lapses helps patients minimize lapses, get back on track, and avoid giving up. Cycles of negative and maladaptive thoughts (e.g., “What’s the point…I failed again and I’ll never lose weight!”) and coping patterns (e.g., binge eating).
The use of behavior and lifestyle modification in weight management is based on a body of evidence that people become or remain overweight as the result of modifiable habits or behaviors, and that by changing those behaviors, weight can be lost and the loss can be maintained. The primary goals of behavioral strategies for weight control are to increase physical activity and to reduce caloric intake by altering eating habits. A subcategory of behavior modification, environmental management, is discussed in the next section. Typically, individuals participate in 12 to 20 weekly sessions that last from 1 to 2 hours each, with a goal of weight loss in the range of 1 to 2 lb/wk. In the past, behavioral approaches were applied as stand-alone treatments to simply modify eating habits and reduce caloric intake. However, more recently, these treatments have been used in combination with low-calorie diets, medical nutrition therapy, nutrition education, exercise programs, monitoring, pharmacological agents, and social support to promote weight loss, and as a component of maintenance programs.
Self-monitoring of dietary intake and physical activity, which enables the individual to develop a sense of accountability, is one of the cornerstones of behavioral treatment. Patients are asked to keep a daily food diary in which they record what and how much they have eaten, when and where the food was consumed, and the context in which the food was consumed (e.g., what else they were doing at the time, what they were feeling, and who else was there). Additionally, patients may be asked to keep a record of their daily physical activities. Self-monitoring of food intake is often associated with a relatively immediate reduction in food intake and consequent weight loss.
Environmental Factors
The rise in obesity prevalence over the past several decades has been mirrored by industrialization of the food system involving increased production and marketing of inexpensive, highly-processed foods with supernormal appetitive properties. Ultraprocessed foods now contribute the majority of calories consumed in America and their overconsumption has been implicated as a causative factor in weight gain. Such foods are typically more calorically dense and far less healthy than unprocessed foods such as fruits, vegetables, and fish. Food has progressively become cheaper, fewer people prepare meals at home, and more food is consumed in restaurants.
In addition, changes in the physical activity environment have made it more challenging to be active throughout the day. Occupations have become more sedentary and suburban sprawl necessitates vehicular transportation rather than walking to work or school as had been common in the past.
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A significant part of weight loss and management may involve restructuring the environment that promotes overeating and underactivity. The environment includes the home, the workplace, and the community (e.g., places of worship, eating places, stores, movie theaters). Environmental factors include the availability of foods such as fruits, vegetables, nonfat dairy products, and other foods of low energy density and high nutritional value. Environmental restructuring emphasizes frequenting dining facilities that produce appealing foods of lower energy density and providing ample time for eating a wholesome meal rather than grabbing a candy bar or bag of chips and a soda from a vending machine.
The Role of Diet Composition
Altering dietary macronutrient composition could theoretically influence overall calorie intake or expenditure resulting in a corresponding change in body weight. Alternatively, manipulation of diet composition can result in differences in the endocrine status in a way that could theoretically influence the propensity to accumulate body fat or affect subjective hunger or satiety. These possibilities do not necessarily violate the laws of thermodynamics since any change in the body’s overall energy stores (i.e. fat mass) must be accompanied by changes in calorie intake or expenditure. Therefore, it is theoretically possible that a particular diet could result in an advantageous endocrine or metabolic state that promotes weight loss.
In recent years, there has been a reemergence of low-carbohydrate, high-fat diets as popular weight loss interventions. Such diets have been claimed to reverse the metabolic and endocrine derangements resulting from following advice to consume low-fat, high-carbohydrate diets that allegedly caused the obesity epidemic. Specifically, the so-called “carbohydrate-insulin model of obesity” posits that diets high in carbohydrates are particularly fattening because they increase the secretion insulin and thereby drive fat accumulation in adipose tissue and away from oxidation by metabolically active tissues, and this altered fat partitioning results in a state of “cellular starvation” leading to adaptive increases in hunger, and suppression of energy expenditure. Therefore, the carbohydrate-insulin model implies that reversing these processes by eating a low-carbohydrate, high-fat diet should result in effortless weight loss.
Unfortunately, important aspects of the carbohydrate-insulin model have failed experimental interrogation and, for all practical purposes, “a calorie is a calorie” when it comes to body fat and energy expenditure differences between controlled isocaloric diets varying in the ratio of carbohydrate to fat. Nevertheless, low-carbohydrate, high-fat diets may lead to spontaneous reduction in calorie reduction and increased weight loss, especially over the short term. Meta-analyses of long-term weight loss have suggested that low-fat weight loss diets are slightly, if statistically, inferior to low-carbohydrate diets, but the average differences between diets is too small to be clinically significant.
In contrast to the near equivalency of dietary carbohydrate and fat, dietary protein is known to positively influence body composition during weight loss and has a small positive effect on resting metabolism. Diets with higher protein may also offer benefits for maintaining weight loss, particularly when the overall diet has a low glycemic index. This might be partially mediated by dietary protein’s greater effect on satiety compared to carbohydrate and fat along with the possibility of increased overall energy expenditure.
Individual Variability and Personalized Diets
Whereas long-term diet trails have not resulted in clear superiority of one diet over another with respect to average weight loss, within each diet group there is a high degree of individual variability and anecdotal success stories abound for a wide range of weight loss diets. Some of this variability may be due to interactions between diet type and patient genetics or baseline physiology such as insulin sensitivity. Such interactions offer the promise of personalized diets that optimize the patient’s chances for long-term weight loss success.
It is certainly possible that the patients who successfully lost weight on one diet would have been equally successful had they been assigned to an alternative diet. In other words, long-term success with a weight loss diet may have less to do with biology than factors such as the patient’s food environment, socioeconomics, medical comorbidities, and social support, as well as practical factors, such as developing cooking skills and managing job requirements.
The Importance of Ongoing Support and Interaction
Long term behavioral changes and obesity management require ongoing attention. Even the highest quality short-term interventions are unlikely to yield continued positive outcomes without persisting intervention and support. Several studies show that ongoing interaction with healthcare providers or in group settings significantly improves weight maintenance and long-term outcomes, compared with treatments that end after a short period of time. With respect to the case study at the start of this paper, the physician should not expect ongoing weight loss without ongoing support and interaction.
Pharmacological Interventions for Weight Loss
The pharmacological treatment of obesity is a fast-changing landscape, and care providers must strive continuously to stay current. Before 2012, there were few weight loss medications approved by the FDA. In the 2020s, glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) exploded in popularity and media attention. Next came a dual receptor agonist, Mounjaro, which is indicated for type 2 diabetes, and Zepbound, which is indicated for obesity.
Determining whether someone is a candidate for weight loss medications begins with BMI. For each individual case, the doctor and patient should discuss the patient’s current health issues, other medications, and family medical history. The average weight loss varies from 5% to 21%, with some people losing more and some people losing less. Most people regain weight if AOMs are discontinued. While some weight loss medications are FDA-approved only for adults, some-including semaglutide and liraglutide-are approved for children 12 and older with a BMI >/= 95th percentile.
Some weight loss medications have been on the market for many years, and new ones emerge frequently. It can be easy to overlook first-generation AOMs, but these may be appropriate for some patients, especially when cost is a factor.
Commonly Used Weight Loss Medications
- Wegovy (Semaglutide): A GLP-1 receptor agonist administered as an injection, approved for use in adults and children aged 12 years or more with obesity (BMI ≥30 for adults, BMI ≥ 95th percentile for age and sex for children) or some adults with excess weight (BMI ≥27) who also have weight-related medical problems.
- Zepbound (Tirzepatide): A dual GLP-1 and GIP receptor agonist approved to treat obesity in adults with a BMI of 30 or greater. It works by reducing appetite and is meant to be used in combination with diet and exercise to lose weight.
- Liraglutide: A daily injectable medication that acts on hormones that send signals from the gut to the brain to make the patient feel full quicker and decrease hunger signals. Some patients may lose 5-10% of body weight.
- Phentermine: The oldest and most widely used weight loss medication, now added to long-term therapy.
- Phentermine-Topiramate: Combines phentermine with topiramate to decrease appetite and cravings.
- Naltrexone-Bupropion: Combines an opioid receptor antagonist with an antidepressant to affect the pleasure-reward areas of the brain and thereby decrease cravings and appetite.
- Orlistat: A lipase inhibitor that comes in a capsule, which prevents the body from absorbing some of the fat from the food you eat.
- Setmelanotide: A melanocortin-4 receptor agonist indicated for chronic weight management in adult and pediatric patients six years and older, with obesity due to certain rare genetic disorders.
- Plenity: A medical device consisting of a capsule that releases a biodegradable, super-absorbent hydrogel into the stomach, helping to increase satiety.
The Future of Weight Loss Medications
With fervent consumer demand for weight loss medications, combined with rising obesity rates, more medications are bound for the market in the coming years. Lilly is developing at least two new options: orforglipron, an oral GLP-1 inhibitor, and retatrutide, which targets GLP-1, GIP, and glucagon. Amgen is developing MariTide, a monoclonal antibody designed to increase GLP-1 receptor activity while reducing GIP receptor activity.
Researchers continue to study hormones that play a role in appetite for other ways to target obesity with medication, including peptide tyrosine-tyrosine (PYY) and cholecystokinin (CCK).
Considerations for Weight Loss Medications
FDA-approved anti-obesity medications (AOMs) are safe, evidence-based therapies that target specific physiology to improve the disease and are most effective when used as part of a comprehensive treatment plan. A treatment plan for obesity can comprise multiple forms of treatment, including medications, diet, exercise, and/or surgery. All weight loss medications work best in the context of a healthy eating plan and exercise.
Some weight management medications are designed for short-term use and others for long-term use. Those approved by the FDA for long-term use include orlistat (Xenical, Alli), phentermine-topiramate (Qsymia), naltrexone-bupropion (Contrave), liraglutide (Saxenda), semaglutide (Wegovy, Ozempic), and tirzepatide (Zepbound, Mounjaro).
AOMs may counter the effects of metabolic adaptation and prevent weight regain. After weight reduction, the body metabolically adapts, often causing an increase in hunger hormones and a decrease in satiety hormones and resting metabolic rate, all of which can contribute to weight regain.
With prescription medications, a healthcare professional can weigh all factors affecting the patient’s lifestyle and BMI and monitor progress and side effects.
The Role of Physical Activity
Increased physical activity is an essential component of a comprehensive weight-reduction strategy for overweight adults who are otherwise healthy. One of the best predictors of success in the long-term management of overweight and obesity is the ability to develop and sustain an exercise program. For a given individual, the intensity, duration, frequency, and type of physical activity will depend on existing medical conditions, degree of previous activity, physical limitations, and individual preferences.
The benefits of physical activity are significant and occur even in the absence of weight loss. For previously sedentary individuals, a slow progression in physical activity has been recommended so that 30 minutes of exercise daily is achieved after several weeks of gradual build-up. The activity goal has been expressed as an increase in energy expenditure of 1,000 kcal/wk, although this quantity may be insufficient to prevent weight regain. For that purpose, a weekly goal of 2,000 to 3,000 kcal of added activity may be necessary.
For many individuals, changing activity levels is perceived as more unpleasant than changing dietary habits. Breaking up a 30-minute daily exercise “prescription” into 10-minute bouts has been shown to increase compliance over that of longer bouts. Individual preferences are paramount considerations in choices of activity.
When strength training or resistance exercise is combined with aerobic activity, long-term results may be better than those with aerobics alone. Because strength training tends to build muscle, loss of lean body mass may be minimized and the relative loss of body fat may be increased. An added benefit is the attenuation of the decrease in resting metabolic rate associated with weight loss, possibly as a consequence of preserving or enhancing lean body mass.
Benefits of Even Modest Weight Loss
Weight loss among individuals with excess weight can have beneficial effects on cardiovascular disease, type 2 diabetes, sleep apnea, chronic kidney disease, hypertension, and dyslipidemia. Guidelines from the UK and United States of America recommend achieving modest weight loss, ranging from five to ten percent, in order to yield clinically meaningful improvements in health outcomes.
Exploring the potential health impacts of less than five percent weight loss, could be useful in informing policy and practice.
Systematic Review of Less Than Five Percent Weight Loss
A systematic review and synthesis of evidence assessed the health benefits of losing less than five percent body weight on health outcomes or indicators such as, cardio-metabolic markers, wider physical markers, and psychosocial markers from controlled trials.
The searches resulted in 13,905 articles, of which 5778 were duplicates, leaving 8127 original articles to screen on title and abstract. After screening on title and abstract, 7158 were excluded and 969 articles were included for full-text screening, of which 11 reports were not retrieved in full-text. This led to the final inclusion of 70 studies from 68 articles.
Study Characteristics
Of the 70 included studies, the majority were randomised controlled trials (n = 47); the remaining study designs (n = 23) included before-after non-randomised intervention studies, clinical trials, cohort studies, prospective studies, and secondary analyses of trials/interventions. Most studies (n = 63) were conducted in high-income countries, including the USA (n = 34), UK (n = 3), Canada (n = 3), Japan (n = 3), and Australia (n = 2). Total study participants in the included studies ranged from 14 to 10,742. Follow-up periods ranged from six weeks to 7.4 years, with the majority of the studies (n = 54) having follow-up periods of 12 months or less.
Various intervention types were assessed but were predominantly lifestyle interventions (n = 47), with fewer studies assessing pharmacological only interventions (n = 2) or a combination of lifestyle and pharmacological (n = 21). Lifestyle interventions typically included components focussed on calorie restriction, physical activity promotion programmes, behavioural modifications, or lifestyle counselling. The most common drug utilised for pharmacological interventions were Orlistat (n = 6), Sibutramine (n = 4) and Metformin (n = 2).
The weight loss stratifications in included studies were most commonly less than five percent (n = 44), less than three percent (n = 7), or greater than two percent to less than five percent (n = 7). Studies were described based on their average baseline BMI into categories including overweight and higher (n = 42), obesity class-1 and higher (n = 9), and obesity class-2 and higher (n = 1), with 18 studies not reporting baseline BMI values.
Health Markers and Indices
A total of 201 unique health markers and indices were reported across the 70 included studies. A total of 11 health categories classified health measures, including health markers and indices. These categories were reported a total of 137 times across the 70 studies: metabolic markers (n = 42), cardiovascular markers (n = 32), anthropometric measures (n = 19), quality of life indices (n = 10), inflammatory biomarkers (n = 10), renal and hepatic markers (n = 9), psychosocial and behavioural measures (n = 8), pulmonary function (n = 3), total mortality (n = 2), ovulatory function (n = 1), and muscle strength (n = 1).
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