#94280: Pharmacologic and Medical Advances in Obesity Management

NHES 1960–1962 included adults 18 to 79 years of age. NHANES 1971–1974 and 1976–1980 excluded individuals age older than 74 years. Therefore,Table 2 is limited to adults 20 to 74 years of age for consistency in long-term trends. Prevalence rates are age-adjusted to the U.S. Census 2000 estimates. As the table demonstrates, the 1980s and 1990s mark the onset of the obesity epidemic.

Following slow increases during the 1960s and 1970s, obesity rates increased sharply through the early 2000s, modestly from 2005 to 2011, then continued climbing through 2017–2018. Male obesity surpassed female rates for the first time in 2017–2018.

Female severe obesity increased 36.4% from 1960–1962 to 1976–1980, in contrast to slowly increasing obesity and male severe obesity rates, and have exceeded male rates throughout 1960 to 2018 by a wide margin. Including ages 20 years and older lowers the 2017–2018 prevalence for obesity (42.4%) and severe obesity (9.2%), which increased approximately 39% and 96%, respectively, from 1999–2000 [1].

During 2017–2018, non-Hispanic Black Americans (49.9%) had the highest age-adjusted obesity prevalence, followed by Hispanic Americans (45.6%), non-Hispanic White Americans (41.4%), and non-Hispanic Asian Americans (16.1%), who also have lower BMI thresholds for adiposopathic (adipocyte and adipose tissue dysfunction) complications [1,29].

The association between obesity and income or educational level is complex and differs by sex and race/ethnicity. Overall, men and women with college degrees had lower obesity prevalence compared with those with less education [43].

The same obesity and education pattern occurred among non-Hispanic White, non-Hispanic Black, and Hispanic women, and non-Hispanic White men, but the differences were not all significant. Among non-Hispanic Black men, obesity prevalence increased with educational attainment. No differences in obesity prevalence by education level were noted among non-Hispanic Asian women and men or Hispanic men [43].

Among men, obesity prevalence was lower in the lowest and highest income groups compared with the middle-income group. This pattern occurred among non-Hispanic White and Hispanic men. Obesity prevalence was higher in the highest income group than in the lowest income group among non-Hispanic Black men [43].

Severe obesity patterns illustrate demographic differences, by sex (women 11.5%, men 6.9%), age (40 to 59 years 11.5%, 20 to 39 years 9.1%, and ≥60 years 5.8%), and race/ethnicity (non-Hispanic Black 13.8%, non-Hispanic White 9.3%, Hispanic 7.9%, and non-Hispanic Asian 2.0%) [1].

By 2030, it is projected that 48.9% of adults will be obese, 24.2% will have severe obesity, with severe obesity projected to become the most common BMI category among women (27.6%), non-Hispanic Black adults (31.7%), and low-income adults (31.7%) [2].

Obesity prevalence studies using higher BMI cut-offs suggest a population shift toward the upper end of the BMI distribution. For example, BMI ≥35 was greater than men than women in 1959 (1%/5%), 1988–1991 (5%/9%), and 2007–2008 (11%/19%) [40].

Defining abdominal obesity as waist circumference in men (≥102 cm) and women (≥88 cm), increasing prevalence rates were found [40]:

Obesity and physical inactivity among the military-aged U.S. civilian population (17 to 42 years of age) are considered potential national security threats because of their impact on military recruitment. Fitness eligibility for military service is defined as BMI 19.0–27.5, and adequate physical activity as ≥300 minutes per week of moderate-intensity aerobic physical activity [44].

Among military-aged participants in the 2015–2020 NHANES, only 34.3% were BMI- and activity-eligible. The prevalence of eligible and active status was higher among men, persons who were younger and non-Hispanic White, college graduates, and those with higher family income than among their counterparts [44].

The BMI-ineligibility in this study exceeds those in previous studies. This upward trend in military ineligibility mirrors the increase in population prevalence of obesity. This study also draws attention to the military preparedness repercussions of the inequitable distribution of unhealthy weight and inadequate physical activity [44].

Although adult obesity is the focus of this course, long-term population trends in pediatric obesity (age 2 to 19 years) provide an informative companion to adult trends. InTable 3, note that pediatric obesity increased >300% from 1976–1980 to 2003, but only 11.4% from 2003 to 2017–2018. Compared with adult obesity, pediatric obesity shows a smaller relative increase over the past 20 years, and pediatric severe obesity has consistently greater prevalence in boys.

Changes in macronutrient proportion of average daily calories and BMI have been examined in the context of dietary recommendations [36]. U.S. adults have largely followed dietary guidelines. From 1965 to 1999, total calories from fat decreased (46% to 32%) while carbohydrates concurrently increased (39% to 52%) [36]. From 1965 to 2011, the increased caloric share from carbohydrate explained 85% of increased BMI in men and 91% in women. Increases in total caloric intake since 1971 were unlikely to explain the increase in BMI [36]. In other words, increased carbohydrate proportionality, not total calories, drove rising BMI.

As discussed, the onset of rising obesity occurred during the 1980s and 1990s as the DHH became an ideology propagated by federal government dietary recommendations, public health policies, and popular health media, which these authors suggest may have initiated the obesity epidemic [36,54,63]. While observational data cannot establish causality, these and other findings suggest the origin of the obesity epidemic may be partially iatrogenic.

From 1999 to 2016, data showed increases in total fat (1.2%) as proportion of diet, including saturated (0.36%), monounsaturated (0.19%), and polyunsaturated (0.65%) fatty acids; decreases in total (-2.02%) and low-quality (mostly sugar) (-3.25%) carbohydrates; increases in high-quality (1.23%) carbohydrates; and increased intake of whole grains, poultry, and nuts [37].

Opposing trends during 1999–2016 partly reversed those of 1971–2000, when emphasis on low-fat diets was associated with decreased fat intake and increased refined grains and added sugar intake. During the 2000s, the benefits of healthy fats and plant sources of protein and harms of excess sugar became popularized, independent of dietary guidelines. Regardless of influence, dietary macronutrient intake during 1999–2016 shows clear evidence of improvement [37].

Changes in physical activity, macronutrient intake, and BMI during 1971 to 2008 were examined using NHANES dietary (1971–2008) and physical activity (1988–2006) data of participants with BMI 18.5–50.0. Physical activity was defined as the weekly frequency of leisure time activities of moderate or greater metabolic intensity [39].

Between 1971 and 2008, BMI increased 10% in men and 11% in women, most of which occurred after 1988 [39]. Total calories per day increased by approximately 10% in men and 14% in women from 1971 to 1999, peaked in 2003, and declined to 1999 levels for both sexes by 2008. Relative caloric intake (i.e., total calories converted to cal/kg of body weight) in 2008 was similar to 1971 but increased modestly between 1988 and 1994 in both sexes. Percent of daily calories (men and women) increased for carbohydrate (13% and 10%) but decreased for fat (9% and 8%) and protein (5% and 7%) [39].

Between 1988 and 2006, physical activity per week increased 47% in men and 120% in women [39]. Adjusted for physical activity and carbohydrate and fat intake, for an equivalent amount of energy intake or physical activity, BMI was up to 2.3 higher in 2006 than in 1988. Thus, BMI increased between 1988 and 2006, even after holding energy intake, macronutrient intake, and physical activity constant.

Decreased physical activity and increased caloric consumption do not fully explain this increase in BMI. The authors conclude that other unrecognized factors may be significantly modifying how energy intake and expenditure influence body weight over time [39].

Over the past 40 years, as obesity prevalence increased about threefold, the prevalence of weight loss attempts by adults increased from 34% in 1999–2000 to 42% in 2015–2016. During 2013–2016, past-12-month attempts to lose weight were made by 49% of adults overall and by 67% of those with obesity. Since the late 1980s, the prevalence of dieting to lose weight has been ≥40% among women and ≥25% among men [64,65].

Repeated weight loss efforts may also contribute to weight gain, which experts have suggested has created a ''weight-loss futility cycle'' that characterizes the rising prevalence of both obesity and weight loss attempts since 1980. The increasing prevalence of obesity and weight loss attempts has also been paralleled by an increase in body weight stigma, which in turn is associated with many adverse health outcomes, including higher risk of all-cause mortality, and disproportionately affects individuals with obesity [65].

The dominant additive model assumes a dose-dependent, additive effect of physical activity on total energy expenditure; with each increment of physical activity, total calories burned correspondingly increases [75]. This calories in/calories out paradigm of obesity led to energy restriction diets and exercise as the standard obesity intervention to reverse positive energy balance for weight loss [76,77].

Energy compensation, or metabolic adaptation, is a normal physiobehavioral response to a change in activity or diet such that the impact of the change is blunted [12]. DLW data suggest the relationship between physical activity and total energy expenditure is more complex than additive models allow [75].

An earlier DLW study involved Hadza people, traditional hunter-gatherers who live off of wild plants and animals in Tanzania expending hundreds of calories a day on activity. Hadza men ate and burned about 2,600 calories per day and Hadza women consumed and burned about 1,900 calories per day. Even after controlling for effects of body size, fat percentage, age, and sex, the Hadza burned about the same daily calories as city dwellers in the United States [78].

DLW evidence led to the constrained model, where total energy expenditure increases with low physical activity but plateaus at higher activity levels as the body adapts to maintain total energy expenditure within a narrow range. By accounting for energy compensation, the constrained model provides a unifying framework for seemingly contradictory results from studies of physical activity and total energy expenditure [12,75].

The compensation may take several weeks or months. Exercise will raise energy expenditure in the short-term, and lifestyle change may also affect total energy expenditure until compensation occurs, after which physical activity will have little measurable effect on total energy expenditure [12].

Increasing activity levels may bring diminishing returns due to compensatory responses in nonactivity energy expenditure [66]. In 1,754 adults with DLW measured seven years apart, only 72% of the extra calories burned during activity translated into extra calories expended that day, because the body offset the calories burned in activities by 28%. Among those with BMI ≥34, compensation of burned activity calories increased to 46% [72].

To explain the causality of this relationship, individuals with greater body fat are either predisposed to adiposity because they are stronger energy compensators or because they become stronger compensators as they gain adiposity. Prescribing increases in activity to increase total energy expenditure and thus control weight gain or promote fat loss assumes that costs of activity are additively related to basal costs, which this study suggests is untrue [72].

Contrary to popular belief that lean individuals "eat what they want" and exercise more, a cohort of 150 healthy underweight (BMI <18.5) adults exhibited significantly lower physical activity and food intake relative to 173 normal-BMI controls and much higher than expected resting energy expenditure, measured using DLW [79]. The healthy underweight subjects were metabolically healthier than normal-BMI controls, which suggests low body weight/fat is a more potent driver of metabolic health than higher physical activity. The results extend previous longitudinal findings into a much lower range of BMI and show that markers of metabolic health continue to improve as BMI falls below 18.5 [79].

The obesity epidemic is often blamed on declining energy expenditure due to reduced occupational physical activity combined with increased sedentary behavior and screentime. This was examined in 4,800 adults with DLW data obtained between 1987 and 2017. All results were adjusted for age and body composition [80].

Men and women both showed significant declines in total energy expenditure and significantly increased activity energy expenditure, while physical activity increased significantly in men and non-significantly in women. Basal energy expenditure decreased significantly in men and non-significantly in women. Men and women showed declines in total energy expenditure (7.7% and 5.6%) and basal energy expenditure (14.7% and 2%), respectively. In both sexes, the decline in basal energy expenditure was sufficient to explain the reduction in total energy expenditure. There was no evidence that reduced physical activity leading to lowered total energy expenditure contributed to the obesity epidemic [80]. This is counterintuitive, given the established decrease in occupational physical activity and the suggested progressive increase in sedentary behavior. The increased leisure physical activity between 1965 and 1995 (and 1988–2006) may have offset reduced occupational physical activity. Increased time on computers has largely come at the expense of time watching television; with comparable energy costs, this tradeoff would have little effect on overall activity energy expenditure [80,81].

In addition, the reduction in total energy expenditure was linked to a decline in basal energy expenditure. Declining basal energy expenditure is less easily understood, but consistent with data that body temperatures also declined over the same period as decreasing basal metabolic rate. The magnitude of change in basal metabolic rate is consistent with studies showing that basal metabolic rate increases 10% to 25% with every 1°C increase in core temperature [80]. The authors conclude that a declining basal metabolic rate may be contributing to the obesity epidemic. Identifying the cause, and if it can be reversed, is an urgent priority.

During 1985 to 2014 in most countries, the concurrent increases in BMI and the proportion of populations living in cities compared with rural areas led to a widely accepted view that urbanization, and the resultant sedentary lifestyle, is an important contributor to the global rise in obesity [82]. However, an analysis of 2,009 population studies with direct anthropometric measurements in 112 million adults from 1985 to 2017 demonstrated that 55% of the global rise in adiposity (and >80% in some low- and middle-income regions) is explained by increased adiposity in rural areas [83].

There is substantial clustering of obesity within social and geographic networks. Whether this results from causal pathways (e.g., social contagion, shared environments) or self-selection is unclear and was studied in 1,519 military families from 38 military installations around the United States who relocated to counties with obesity rates of 21% to 38% [84]. Exposure to communities with higher obesity prevalence was associated with higher BMI and overweight/obesity in parents and children. Specifically, a 1% higher county obesity rate was associated with 5% higher odds of obesity in parents and 4% higher odds of overweight/obesity in children [84].

All associations were strengthened by duration (i.e., >24 months at their current installation) and proximity (living off-base) of exposure and were unchanged after controlling for the shared built environment in the county and neighborhood of residence. There was no evidence to support self-selection or shared environment as explanations, which may suggest the presence of social contagion in obesity [84]. Although data on the previous county obesity rate was unavailable, exposure to communities with higher obesity rates may increase individuals' BMI via the presence of social contagion, possibly by common social norms associated with obesity [85].

In 2017–2018, 20.3% of U.S. adults used an obesogenic medication (compared with 13.2% in 1999–2000) [86]. Many widely used drugs cause weight gain that may lead to obesity in susceptible individuals. Weight gain is consistently associated with many older antidiabetic agents, atypical antipsychotics, antidepressants, and antiepileptic drugs [87].

A study that pooled three population-based prospective cohorts of Finnish adults to examine diet and weight gain over seven years found no associations between total carbohydrate, dietary fiber, sugar, or sucrose intake and ≥5% increase in weight or waist circumference. However, the authors state that low sugar-sweetened beverage consumption in Finland compared with the United States may partially explain the lack of association between carbohydrate intake and weight gain [88].

In the United States from 1965 to 2002, daily sugar-sweetened beverage caloric consumption increased 306% per capita and 86% among consumers of sugar-sweetened beverages only. However, from 1999 to 2010, total daily caloric intake from sugar-sweetened beverages among youth (2 to 19 years of age) and adults (≥20 years of age) decreased 31% and 21%, respectively [57].

Evidence for the mainstream view that high sugar consumption leads to obesity and related metabolic diseases is inconsistent, and high sugar intake from s ugar-sweetened beverages may differ from sugar-containing foods (i.e., solid sugars) in BMI/metabolic impact [89].

In a review of prospective evidence, most studies linking high sugar intake to adverse health outcomes examined sugar-sweetened beverages, while studies of solid sugar intake mostly reported null findings. High sugar-sweetened beverage consumption was dose dependently associated with increased risks of cardiovascular disease morbidity and mortality through weight gain; solid sugar sources (e.g., ice cream) were not [89,90].

Sugar-sweetened beverages may be more likely to induce metabolic syndrome. The faster gastric emptying time of sugar-sweetened beverages and higher absorption of its fructose component may lead to fatty accumulation in the liver. Compared with solid sugars, sugar-sweetened beverages induce less satiety and may subsequent cause overeating. The gut can convert low-concentration fructose to glucose, but transports high-concentration fructose (e.g., in sugar-sweetened beverages) to the liver [89].

Increased lipogenesis and circulating triglycerides, very-low-density cholesterol, and uric acid associated with high sugar-sweetened beverage intake may induce hyperglycemia, glucose intolerance and dyslipidemia to increase risks of type 2 diabetes and cardiovascular disease. High intake of fructose-sweetened beverages may disrupt the production of appetite control hormones (decreasing leptin and insulin, increasing ghrelin), suggesting different effects on metabolic and endocrine health of liquid versus solid sugars [89].

Individuals who ingest high dietary sugar often have other unhealthy behaviors that may contribute to the pathogenesis of obesity and related disorders, complicating causal inferences. Although definitive evidence is needed, and reducing sugar remains a general recommendation, there is evidence of greater health risks with sugar-sweetened beverages that might not be comparable to those with sugar in food [89,91].

Glucose and free fatty acids are monomers, the oxidizable fuels for ATP production that cells require. Monomers are the breakdown products of macronutrients, released by digestion and distributed into oxidizable fuels or storage by energy partitioning, depending on current energy balance status [70,102,103].

Excess energy is stored as fat in adipose depots, carbohydrate (as glycogen) in liver, or protein in muscle. The energy density of adipose tissue is nearly 10-fold greater than liver (glycogen) or muscle (protein). The small storage capacity for carbohydrate can cover overnight energy needs during sleep. The larger energy stores of fat are mobilized to cover longer-term energy shortages [70,102,103].

However, as a substrate for energy metabolism, fat is last in the hierarchy that determines fuel selection; it is mostly stored before oxidation and is less likely to be oxidized than carbohydrate or protein. Body-fat mass and oxidation of dietary fat are inversely related—higher fat mass lowers the oxidation rate of dietary fat [70,102,103]. Energy expenditure is the sum of ATP generated by oxidizing monomers to drive physiological processes.

Oxidizable fuels from food can fail to meet (negative), equal (balanced), or exceed (positive) requirements to maintain ATP availability within its narrow range. These are the three states of energy balance [70,102,103]:

Unlike fuels, ATP cannot be stored. An animal can survive for days or weeks without food, but its survival time is measured in seconds if a toxin shuts down oxidative phosphorylation and ATP production. Lacking ATP storage capacity, daily ATP turnover in humans is dramatic [103].

The OMA recommends that patients with obesity have access to safe, effective, personalized, and evidence-based healthful nutritional intervention. Patients should optimally have access to nutrition therapy via a registered dietitian or via nutritional counseling from obesity medicine clinicians trained in nutritional counseling. Approaches to overcome barriers to nutritional intervention engagement include individual or group videoconferencing, personalized artificial intelligence (AI)-mediated interventions applicable to precision medicine, incorporation of cultural norms, and awareness of the impact of social determinants of health [122].

The OMA recommends patients with obesity be treated with a safe and effective personalized physical activity plan (i.e., physical activity prescription) based on the patient's underlying health and mobility. To achieve physically active objectives, the OMA recommends that patients with obesity learn the benefits of non-exercise activity thermogenesis, target dynamic goals (e.g., steps per day), and safely incorporate resistance training. The intent is to improve body composition, support weight loss maintenance, improve balance and flexibility, and reduce the risk of injury from falls or joint stress. Improving or maintaining mobility can be achieved via training to promote activities of daily living (e.g., self-dressing, -meal preparation, -bathing, -laundry). Physical activity and exercise training may occur individually or in groups, via live classes/instruction, video format, or AI educational interactions, and may be especially important in patients with sarcopenic obesity [122].

The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians offer or refer patients with a BMI of 30 or greater intensive, multicomponent behavioral interventions.

(https://jamanetwork.com/journals/jama/fullarticle/2702878 Last Accessed: November 28, 2023)

Strength of Recommendation: B (The USPSTF strongly recommends that clinicians routinely screen eligible patients. The USPSTF found good evidence that obesity screening improves important health outcomes and concludes that benefits substantially outweigh harms.)

The OMA recommends patients with obesity be treated with evidence-based behavior modification. Important aspects include personalized tracking and regular clinician encounters. Optimizing social support at home and in the community may be helpful. Patients often benefit from behavior modification provided by a knowledgeable physician, nurse practitioner, physician assistant, nurse, or dietitian, or via a psychologist/psychiatrist, health coach, or another appropriate counselor. For patients for which record keeping and accountability metrics may improve health outcomes, other potential interventions include fitness trackers, smartwatches, and use of social media. Behavior modification may also be delivered through AI chatbots [122].

Antiobesity Medications

Medical treatment with antiobesity medication and/or bariatric procedures is the fourth pillar of obesity management. Evidence-based treatment of obesity, including pharmacotherapy, represents a standard of care for patients with obesity [122].

Obesity is associated with $174 billion in excess healthcare costs annually. To mitigate such expenditures, obesity should be treated early and effectively before its complications arise. In patients without acute complications of obesity, a "treat obesity first" approach through antiobesity medications may reduce or eliminate the need (and cost) for antidiabetic medications, antihypertension medications, lipid medications, pain medications, and possibly other medications (e.g., antidepressants) or other treatments (e.g., continuous positive airway pressure devices) [122].

When appropriate for the patient, use of lower-cost antiobesity medications may improve the cost effectiveness of medication. The forthcoming generic status of some current agents and market entry of new antiobesity medications may drive competition and lower costs [122]. However, the OMA stresses the importance of a patient-centered, personalized approach to pharmacotherapy for obesity and that such an approach may depart from the recommended prescribing information [122].

Bariatric Procedures

The OMA recommends that patients with obesity should have access to evidence-based bariatric procedures, when appropriate, as an adjunct to healthful nutrition, physical activity, behavior modification, and pharmacotherapy. Currently, less than 1% of eligible patients receive bariatric surgery, despite extensive evidence of its cost-effectiveness. Importantly, bariatric surgery is associated with reductions in overall mortality, cardiovascular events, risk of cancer, cardiovascular risk factors (e.g., type 2 diabetes, hypertension, dyslipidemia), and improvements in osteoarthritis, skin disorders, and possibly depression [116,122,127,128,129,130].

Setmelanotide (Imcivree)

Setmelanotide is the first antiobesity medication approved specifically for the treatment of rare genetic conditions associated with obesity. The drug binds to melanocortin-4 receptor (MC4R) in the hypothalamus, downstream of the leptin signaling pathway [135]. Setmelanotide re-establishes the activity of the MC4R pathway, thus reducing hunger and promoting body weight loss by lowering caloric intake and increasing energy expenditure [140].

Setmelanotide is indicated for patients with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin-leptin receptor (LEPR) deficiency. The condition must be confirmed by genetic testing demonstrating pathogenic variants in POMC , PCSK1 , or LEPR genes [30]. Setmelanotide is contraindicated for patients with other causes of obesity, polygenic obesity, or benign variants of the gene mutations. Dosing is subcutaneous 2 mg daily (maximum: 3 mg daily). Adverse effects include hyperpigmentation, vomiting, and nausea [135]. Setmelanotide is not associated with adverse effects on blood pressure observed with other MC4R agonists [141].

Bremelanotide

Bremelanotide is another MC4R agonist that also binds to MC3R and is FDA-approved for treatment of low sexual desire in premenopausal women. Data from two small randomized controlled trials in premenopausal women with obesity showed reduced caloric intake and weight loss with bremelanotide, without adverse effects on blood pressure, suggesting this may be an effective treatment of obesity [141].

Metreleptin

Metreleptin is a synthetic leptin analog approved by the FDA in 2014 for patients with congenital leptin deficiency or congenital/acquired lipodystrophy and is administered subcutaneously once daily. The recommended starting daily dose in adults with body weight ≤40 kg is 0.06 mg/kg (maximum: 0.13 mg/kg daily), while adults with body weight >40 kg are started on 2.5 mg or 5 mg for men or women, respectively (maximum: 10 mg daily). No leptin analog has been approved by the FDA or European Medicines Agency (EMA) as an antiobesity medication for generalized obesity [92].

Phentermine, diethylpropion, phendimetrazine, and benzphetamine were approved for short-term use as antiobesity medications in 1959–1960, before obesity was understood as a chronic disease requiring long-term management. As a consequence, long-term (one year or longer) data on these drugs are limited [3].

All sympathomimetic amines are contraindicated in patients with hyperthyroidism, glaucoma, or in patients taking monoamine oxidase (MAO) inhibitors; all four are DEA Schedule IV controlled substances [131].

Phentermine (Adipex-P, Lomaira)

Phentermine HCl is a centrally acting sympathomimetic, with therapeutic effects mediated through increased levels of norepinephrine in the hypothalamus [123]. It was approved for short-term use in 1959 based on a 36-week trial that showed a mean placebo-subtracted weight loss of 8.2 kg [92]. Two more recent randomized controlled trials in Korea confirmed the short-term efficacy of phentermine, both showing significant weight reduction compared with placebo over 12 weeks [131].

Common adverse effects in clinical trials include dry mouth (55%) and insomnia (34%), without significant differences in systolic or diastolic blood pressure, headache, or palpitations between phentermine and placebo groups [131]. Other common side effects include dizziness, flushing, fatigue, and constipation [92]. Phentermine is not recommended for patients with cardiovascular disease, and uncontrolled hypertension is a relative contraindication. Phentermine is available in 8-mg tablets taken three times daily and in 15-mg, 30-mg, and 37.5-mg capsules taken once daily [131].

Phentermine is the most commonly prescribed antiobesity medication and is discussed further in the section on clinical use of antiobesity medications as a potential low-cost generic option to more recently approved agents.

Diethylpropion (Tenuate)

Diethylpropion and bupropion are very closely related structurally [142]. In contrast to phentermine, diethylpropion has been used infrequently in the United States. This contrasts with Mexico, Brazil, and other countries in which diethylpropion is a preferred antiobesity medication and where recent randomized controlled trials have evaluated its safety and efficacy. Outside the United States, diethylpropion is called amfepramone [143].

In one study, weight loss after 52 weeks was greater in patients randomized to diethylpropion than placebo (10.0 kg vs 3.1 kg), and more participants achieved weight loss ≥5% (71.4% vs 33.3%) [144]. Of 156 patients randomized to diethylpropion (75 mg/daily) or placebo, mean weight loss at three months (4.9 kg vs 0.7 kg) and six months (7.7 kg vs 1.1 kg) showed clinical benefit persisting beyond the short-term. Improvements in triglycerides, heart rate, and systolic and diastolic blood pressure with diethylpropion were non-significant [145].

Potential adverse effects of diethylpropion are dry mouth and somnolence (most common), constipation, anxiety, and irritability, all described as mild and nonpersistent, except dry mouth [143,144,145].

Diethylpropion is available in 25-mg short-acting and 75-mg extended-release tablets that are taken three times or once per day, respectively [136].

Other Medications

In analyses of two small 12-week randomized controlled trials, phendimetrazine (Obezine) appears to have similar weight-loss effects as other noradrenergic drugs [146].

Benzphetamine (Didrex) is the least prescribed among the four noradrenergic antiobesity medications, and there are few data from controlled trials evaluating its safety or efficacy [136].

Gelesis100 Oral Hydrogel (Plenity)

Gelesis100 superabsorbent hydrogel is ingested orally, similar to drugs, but is regulated by the FDA as a class II medical device, because it acts mechanically as a transient, space-occupying device in a swallowed capsule that absorbs water to expand and fill up the stomach to induce satiety. Gelesis100 is FDA approved for patients with BMI 25–40. Recommended dosing is three capsules (2.25 g/dose) with water before both lunch and dinner [30,123].

After 24 weeks, more patients on Gelesis100 than placebo had weight loss >5% (58.3% vs 42.3%) and >10% (27.4% vs 15.0%), but the mean weight loss difference (2.02%) did not meet the pre-determined threshold of 3%. The AGA guideline recommends the use of Gelesis100 be limited to clinical trials due to its uncertain benefit [123].

Orlistat (Xenical, Alli)

Orlistat is a pancreatic and gastric lipase inhibitor that blocks the lipase-catalysed breakdown and absorption of around 30% of dietary fats. Orlistat is the only antiobesity medication that does not exert action in the brain; its modest weight-loss effect depends mostly on diet [147].

Orlistat is available in 60-mg capsules over the counter and 120-mg capsules by prescription, both taken three times daily [131]. In the four-year XENDOS trial that randomized 3,304 subjects with obesity to orlistat (120 mg three times daily) or placebo, weight loss was significantly higher with orlistat (5.8 kg vs 3.0 kg). The study also showed a reduced progression from prediabetes to diabetes with orlistat. Adverse effects observed in ≥10% of study populations included rectal leakage, abdominal pain, abdominal stress, flatulence with discharge, fecal urgency, steatorrhea, fecal incontinence, and increased defecation [140].

Overall weight loss with orlistat is of a small magnitude (2.78%). In contrast, the adverse effects are considered very bothersome and result in high treatment discontinuation rates. Therefore, the 2022 AGA obesity guideline suggests against the use of orlistat [123].

Phentermine/Topiramate ER (Qsymia)

Topiramate is an antiepileptic drug that was approved for seizures in 1996 and migraine prevention in 2004. The weight loss observed during epilepsy treatment led to clinical trials as a treatment for obesity, but topiramate development as an antiobesity medication was discontinued due to the associated adverse effects. However, clinical observations in private practice indicated that phentermine mitigated topiramate adverse effects and increased weight-loss efficacy when used together. This led to clinical trials to approve the combination as an antiobesity medication [136].

Topiramate is thought to suppress appetite by increasing dopamine release, inhibiting glutamate receptors, and modulating neuropeptide-Y, an orexigenic hormone. Phentermine/topiramate was approved in 2012 at fixed-dose 7.5/46-mg and 15/92-mg tablets, both taken once-daily [131].

Three phase 3 randomized controlled trials assessed the efficacy of phentermine/topiramate on weight loss: EQUIP, CONQUER and SEQUEL. In EQUIP, patients with obesity (mean BMI: 42) were randomized to 3.75/23 mg, 15/92 mg, or placebo. Mean weight loss was 5.1% (low-dose), 10.9% (high-dose), and 1.5% (placebo) at 56 weeks [140].

CONQUER randomized 2,487 adults with overweight or obesity and at least two weight-related complications to placebo, 7.5/46 mg, or 15/92 mg. Mean weight loss (1.4 kg, 8.1 kg, and 10.2 kg, respectively) and patients with ≥5% (21%, 62%, and 70%, respectively) and ≥10% (7%, 37%, and 48%, respectively) weight loss at 56 weeks were significantly greater with both phentermine/topiramate dose levels [131].

SEQUEL was a 52-week extension of CONQUER involving 676 subjects [148]. At week 108, mean weight loss from baseline was 1.8%, 9.3%, and 10.5% with placebo, 7.5/46 mg, and 15/92 mg, respectively. Absolute weight loss was 2.1 kg, 9.6 kg, and 10.9 kg. Across all levels, weight loss was greater for subjects in the treatment arms than in the placebo group, with more kilograms lost among the higher dosage. After 108 weeks, 50.3% and 53.9% of patients receiving phentermine/topiramate lost at least 10% of their body weight; 9.2% and 15.3% lost 20% or greater. This compares with 11.5% and 2.2%, respectively, of participants in the placebo group. At week 108, mean waist circumference reductions were -3.6 cm for placebo, -9.8 cm for the 7.5/46-mg dose, and -10.6 cm for the 15/92-mg group. The types of adverse events in SEQUEL were similar to those in CONQUER, but the incidence was markedly lower in the second year. Drop-out due to adverse events by week 108 were 3.1%, 4.5%, and 4.4% in placebo, 7.5/46 and 15/92 treatment arms. Both systolic and diastolic blood pressure decreased from baseline by 3–5 mm Hg at 108 weeks in all three treatment arms [148].

As with phentermine monotherapy, phentermine/topiramate ER is not recommended for patients with cardiovascular disease and is contraindicated in patients with hyperthyroidism or glaucoma or in those taking MAO inhibitors [131]. Topiramate is associated with cognitive and neuropsychiatric side effects. A meta-analysis found that, compared with placebo, adverse effects associated with phentermine/topiramate included dysgeusia or altered sense of taste, paresthesia, dry mouth, disturbance in attention, irritability, hypoesthesia, constipation, and dizziness [149]. Abrupt withdrawal of topiramate increases the risk of seizures, and downward titration should be gradual over four to five days [150].

During the two-year SEQUEL trial, the incidence of reported anxiety-related adverse events increased with dose in placebo (3.1%), 7.5/46-mg (6.5%), and 15/92-mg (9.5%) arms. Most were mild in severity, but three subjects in the 15/92-mg group experienced a severe anxiety-related adverse events and one discontinued treatment [148].

Topiramate is teratogenic, posing a risk for orofacial clefts in infants exposed in utero. Women of childbearing age prescribed any topiramate formulation should be counseled to use effective contraception [124].

Naltrexone/Bupropion ER (Contrave)

Bupropion is a norepinephrine and dopamine reuptake inhibitor with FDA-approval for depression and smoking cessation and is the antidepressant least likely to induce weight gain [131]. Bupropion stimulates hypothalamic POMC neurons, releasingα-MSH (which bind MC4R), decreasing food intake, and increasing energy expenditure. Whenα-MSH is released, POMC neurons also releaseβ-endorphin, a μ-opioid receptor (MOR) ligand, which inhibits further release ofα-MSH by activating a negative feedback loop. Naltrexone, an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorder, blocks theβ-endorphin-mediated negative feedback; the subsequent increase in POMC activity may underlie the weight loss effects of naltrexone/bupropion (Contrave) [115].

Each naltrexone/bupropion tablet contains naltrexone 8 mg plus bupropion 90 mg. The target maintenance dose of 4 tablets daily (naltrexone 32 mg/bupropion 360 mg) daily is shortened with the prolonged-release formulation (NB32). The initial dose is 1 tablet daily, increased stepwise to the target of 2 tablets twice daily. Typical weight loss seen in practice is around 5% to 6% with NB32s [131].

The Contrave Obesity Trials (COR) program evaluated NB32 versus placebo over 56 weeks in patients with obesity or overweight and weight-related complication(s) (COR-I, COR-II, and COR-BMOD) and in patients with obesity and type 2 diabetes (COR-DM). Mean weight loss with NB32 compared with placebo in COR-I (6.1% vs 1.3%), COR-II (6.4% vs 1.2%), COR-BMOD (9.3% vs 5.1%), and COR-DM (5.0% vs 1.8%) showed an average 4.35% weight loss advantage over placebo [139].

Common adverse effects of NB32 include nausea (30%), headache (14%), and constipation (15%), without significant differences in depression or suicidality events, insomnia, dizziness, or dry mouth between treatment and placebo groups [131]. NB32 has been shown effective in reducing HbA1c and is safe among subjects with type 2 diabetes taking oral antidiabetic agents [151]. NB32 can increase blood pressure and pulse despite weight loss [139]. While the cardiovascular safety of NB32 was investigated in the LIGHT trial, it was terminated prematurely after the study sponsor publicly released confidential favorable interim results after only 25% of expected vascular events had accrued, making it difficult to interpret the cardiovascular safety of this combination drug [131,139].

Contraindications include pregnancy, uncontrolled hypertension, seizure disorder, eating disorder, severe hepatic dysfunction, and concurrent administration of MAO inhibitors [131]. Naltrexone/bupropion is contraindicated in any patient prescribed opioids for pain control and in any patient receiving medication therapy for alcohol or opioid use disorder.

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs)

Endogenous GLP-1 has a very short half-life due to rapid enzymatic degradation by dipeptidyl peptidase-4 (DPP-4). Synthetic analogs modify the GLP-1 structure to resist DPP-4 by amino acid substitutions in the protein structure or by attachment to large proteins such as albumin or immunoglobulin [147]. Liraglutide shares a 97% amino acid sequence similarity with human GLP-1, while semaglutide has a 94% similarity. Compared with liraglutide, the substantially longer half-life and greater weight loss efficacy of semaglutide may involve differences in the attached fatty acids [139].

Liraglutide and semaglutide are used subcutaneously once-daily and once-weekly, respectively. Liraglutide was approved for type 2 diabetes in 2010 at a dosage of 1.8 mg daily. Subsequently, liraglutide became the first GLP-1 RA approved as antiobesity medication in 2014, and in 2020, its approval was expanded to include adolescents (12 years of age or older) at a dosage of 3.0 mg/day [147]. Liraglutide acts centrally on the arcuate nucleus in the hypothalamus to suppress appetite and potentiate satiety [151].

The SCALE Obesity and Prediabetes and SCALE Diabetes were both 56-week randomized controlled trials examining the effect of daily liraglutide 3.0 mg vs placebo on normoglycemia, prediabetes, and diabetes. Both trials demonstrated significantly greater weight loss with liraglutide. In SCALE Obesity and Prediabetes, weight loss was 8.0% with liraglutide vs 2.6% with placebo; in SCALE Diabetes, weight loss was 6.0% with liraglutide vs 2.0% with placebo. In the former trial, more participants in the liraglutide group achieved weight loss of ≥5% (63.2 vs 27.1%), ≥10% (33.1 vs 10.6%), and ≥15% (14.4 vs 3.5%) [131].

Gastrointestinal adverse effects are common, including nausea (40%), diarrhea (20%), constipation (20%), and vomiting (16%), and were the most common reason for liraglutide drop-out (6.4% vs 0.7% in the placebo group). Potentially serious adverse effects include gallbladder disease (2.5%) and pancreatitis (0.4%) [131]. A 2023 analysis of data including more than 5,000 patients receiving pharmacotherapy for obesity compared the incidence of adverse events associated with GLP-1 RAs with bupropion-naltrexone. Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of pancreatitis (hazard ratio: 9.09), bowel obstruction (hazard ratio: 4.22), and gastroparesis (hazard ratio: 3.67) but not biliary disease [152].

Liraglutide is initiated at 0.6 mg daily for one week, with weekly increases in dose (by increments of 0.6 mg) to the recommended 3.0 mg dose [131]. Semaglutide was initially approved for the treatment of type 2 diabetes at a dosage of 1.0 mg weekly in 2017 and at 2.0 mg weekly in 2022. It was subsequently approved at a dosage of 2.4 mg per week for chronic management of obesity in 2021 [147].

Semaglutide directly accesses the hypothalamus, brainstem, and septal nucleus and also induces activation in secondary brain areas without direct GLP-1R interaction, thus having direct and indirect effects on neutral pathways involved in homeostatic (appetite, hunger, satiety) and hedonic (food preference, cravings, control of eating) aspects of food intake and reward-related eating behaviors. Conversely, only a very small percentage of weight loss is explained by delayed gastric emptying and gastrointestinal side effects [151].

The STEP clinical trials program evaluated semaglutide 2.4 mg in patients with obesity or overweight/weight-related complication(s); patients with type 2 diabetes were excluded [30]. At 68 weeks, semaglutide led to greater mean weight loss (14.9%) compared with placebo (2.4%); further, more patients in the semaglutide group experienced weight loss of ≥10% (69.1%), ≥15% (50.5%), and ≥20% (32.0%) than those in the placebo group (12.0%, 4.9%, and 1.7%, respectively).

In an extension of this study, patients in both the treatment and control arms were engaged in intensive behavioral therapy. The therapy consisted of a reduced-calorie diet (1,000–1,200 calories/day for the first seven weeks, followed by 1,200–1,800 calories/day for the remaining study period), 200 minutes exercise per week, and 30 individual therapy sessions with a registered dietitian. The mean weight loss was 16.0% with semaglutide/intense behavioral therapy, compared with 5.7% with placebo and intense behavioral therapy. The authors concluded that intense behavioral therapy plus eight-week low-calorie diet ultimately may not confer significant weight-loss advantages beyond those achieved with semaglutide and less-intensive lifestyle interventions (i.e., 18 behavioral counseling sessions over 68 weeks) [30].

Another extension of the study, referred to as STEP 4, focused on weight-loss maintenance. All patients were initiated on semaglutide and, at week 20, were randomized to either semaglutide continuation or placebo for the remaining 48 weeks (i.e., weeks 20–68). The semaglutide continuation group further lost 8% of weight, for a total 17% weight loss. The placebo group gained 7% of weight during the same period, for a total 5% weight loss.

STEP 5 also examined the durability of weight reduction over two years. At week 104, mean weight loss from baseline was 15.2% with semaglutide compared with 2.6% with placebo (treatment difference: 12.6%).

Finally, STEP 8 was a head-to-head comparison of semaglutide 2.4 mg per week and liraglutide 3.0 mg per day over 68 weeks. Mean weight loss was 6.4% with liraglutide and 15.8% with semaglutide, a 9.4% advantage over liraglutide. While gastrointestinal adverse events were similarly common with semaglutide (84.1%) and liraglutide (82.7%), the drop-out rate due to adverse events was significantly higher with liraglutide than semaglutide (12.6% vs 3.5%) [140].

As of 2023, oral semaglutide is the only oral GLP-1 RA approved for the treatment of type 2 diabetes, at a dosage of 14 mg per day (Rybelsus). Higher doses are being investigated for weight effects in obesity without type 2 diabetes in the OASIS trials [147]. The phase 3 OASIS 1 trial assessed oral, once-daily semaglutide 50 mg in 667 adults with obesity without type 2 diabetes. After 68 weeks, participants on semaglutide had greater mean weight loss (15.1% vs 2.4%), weight loss ≥10% (69% vs 12%), ≥15% (54% vs 6%), and ≥20% (34% vs 3%) compared with placebo. Adverse effects (mostly mild-to-moderate gastrointestinal symptoms) occurred in 80% on semaglutide and 46% on placebo. These outcomes mirror those of semaglutide 2.4 mg subcutaneous [153]. Phase 3 trials have completed, and submission for FDA approval is expected in 2024. Of note, there are currently no registered clinical trials comparing oral with subcutaneous semaglutide for obesity [92].

The liraglutide, semaglutide, and tirzepatide labels carry a boxed warning regarding the risk of thyroid C-cell tumors. All three antiobesity medications are known to cause dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in rodents [20,137]. It is unknown whether semaglutide for obesity causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. However, semaglutide for obesity is contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2) [20,137]. All patients should be counseled regarding the potential risk of MTC and symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

In addition, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists [20,137]. These agents have not been studied in patients with a history of pancreatitis; if used as an antidiabetic agent, clinicians should consider an alternate option in such patients.

Data are lacking on use in pregnant women. However, reproduction studies in animals have shown teratogenic effects. There is no published research linking semaglutide to decreased oral contraceptive efficacy. However, any medication associated with delayed gastric emptying could theoretically impact the absorption of oral contraceptive agents.

A meta-analysis of treatment with GLP-1 RAs found liraglutide or dulaglutide associated with increased risk for gallbladder or biliary diseases; subcutaneous semaglutide and exenatide associated with non-significant increased risk; and higher-dose subcutaneous semaglutide associated with increased gallbladder or biliary diseases. Oral semaglutide, lixisenatide, and albiglutide are not associated with these increased risks [154].

GLP-1 RAs may be associated with increased risk of gallbladder or biliary diseases because GLP-1 inhibits gallbladder motility and delays gallbladder emptying by suppressing cholecystokinin secretion. The risk of gallbladder or biliary diseases was higher in trials for weight loss than diabetes control, which may relate to the greater weight loss, GLP-1 RA dose, or treatment duration [154]. When assessing potential risk to patients, prescribers should consider the denominator for essential context, when possible. The overall absolute risk increase, an additional 27 cases per 10,000 persons treated per year, was small and should be weighed against the demonstrated benefits of obesity treatment with GLP-1 RAs [154].

Tirzepatide

Tirzepatide was approved for type 2 diabetes treatment by the FDA (as Mounjaro) and the European Medicines Agency in 2022 [147]. In 2023, the FDA approved the agent for chronic weight management [155].

Tirzepatide acts as a dual incretin agonist of GLP-1R and glucose-dependent insulinotropic polypeptide (GIP) receptor and is dubbed the "twincretin" [135]. Tirzepatide has five-fold greater potency at GIPR than GLP-1R [132].

GIP was the first incretin hormone identified, but its therapeutic potential was disregarded because chronic hyperglycemia in type 2 diabetes down-regulates GIPR expression inβ-cells, blunting response to GIP. Normalizing blood glucose can restore GIPR sensitivity to GIP [139,147]. With a GIP/GLP-1 receptor agonist, GLP-1 quells the potential glucagon-stimulatory effects of GIP and (re)sensitizesβ-cells to GIP's incretin effects, while potentially enhancing GIP's beneficial effects on weight regulation mechanisms [147].

GIPR agonism may have effects on adipocytes that include increasing lipoprotein lipase, promoting lipogenesis, enhancing fatty acid and glucose uptake, and inhibiting lipolysis mediated by glucagon and adrenergic receptors [139]. However, the relative contributions of GLP-1R vs GIPR agonist effects to weight loss have yet to be clearly defined [156].

SURPASS-1 compared tirzepatide (5 mg, 10 mg, or 15 mg) to placebo for 40 weeks, finding significant mean reductions in hemoglobin A1C (-1.87%, -1.89%, -2.07%) and body weight (- 7.9%, -9.3%, -11.0%) for all tirzepatide doses versus placebo [131]. SURPASS-2 compared tirzepatide (5 mg, 10 mg, or 15 mg) with semaglutide 1.0 mg weekly, finding more effective and dose-dependent reductions in body weight, blood pressure, and hemoglobin A1C with tirzepatide [131]. (Note that semaglutide 1.0 mg is a subtherapeutic dose for weight-loss efficacy.)

SURMOUNT-2 randomized 1,514 adults to tirzepatide or placebo. At week 72, mean weight loss with tirzepatide 10 mg or 15 mg or placebo was 12.8%, 14.7%, and 3.2%, respectively. This translated to mean differences vs placebo of 9.6% and 11.6% for 10 mg and 15 mg. More participants had weight loss ≥5% with tirzepatide (79% to 83%) than placebo (32%). The most frequent adverse effects with tirzepatide were gastrointestinal-related, including nausea, diarrhea, and vomiting, mostly mild to moderate in severity, and few led to drop-out (<5%). Serious adverse events were reported by 7% of participants overall [157].

In the phase 3 SURMOUNT-1 trial, 2,539 patients with obesity without type 2 diabetes were randomized to weekly tirzepatide (5 mg, 10 mg, or 15 mg) or placebo [133]. Mean weight loss at week 72 was unprecedented (Table 7) [131]. Notably, 50% and 57% of participants in the 10- and 15-mg groups had weight loss ≥20% [131]. For the first time ever, weight loss with a medication approached levels that had only been possible with bariatric surgery.

Drop-out from adverse effects was 4.3%, 7.1%, and 6.2% with 5 mg, 10 mg, and 15 mg tirzepatide, respectively, and 2.6% with placebo. The incidence of adverse effects was similar in 10- and 15-mg groups, while the proportion of ≥10%, ≥15%, and ≥20% weight-loss was higher with 15 mg. This suggests the 15-mg dose may confer additional benefits in some patients without added safety concerns [133].

Participants treated with tirzepatide had a percent reduction in fat mass approximately three times greater than the reduction in lean mass, resulting in an overall improvement in body composition. The ratio of fat-mass loss to lean-mass loss is similar to lifestyle and surgical treatments for obesity [133].

Nearly all participants (>95%) with prediabetes initiated on tirzepatide converted to normoglycemia by 72 weeks (compared with 62% with placebo plus lifestyle changes). These improvements may translate to reduced risk of cardiovascular disease, chronic kidney disease, NAFLD, and type 2 diabetes, among other outcomes. Studies of this are still in progress [133].

The safety profile of tirzepatide was consistent with previous findings in the SURPASS trials in patients with type 2 diabetes and similar to other incretin-based therapies for the treatment of obesity. Cholecystitis was observed more frequently with tirzepatide, but the low incidence (≤0.6%) made causal conclusions difficult. Gallbladder-related events have been reported to increase in persons with considerable weight reduction and are also observed with other obesity therapies, such as bariatric surgery and treatment with GLP-1 receptor agonists [133].

Meta-analyses have variously examined the effectiveness and safety of tirzepatide compared with semaglutide in obesity. Head-to-head comparative trials have not been conducted, so indirect comparisons were used. One analysis found greater weight loss with tirzepatide 10 mg and 15 mg than semaglutide 2.4 mg [158]. Another found no significant difference from semaglutide in gastrointestinal adverse effects [159]. Together, these trials show promise for tirzepatide as an effective and safe medication for both weight reduction and glycemic control in patients with obesity with or without type 2 diabetes. Typical adverse effects are similar to GLP-1 agonists and include nausea, vomiting, and diarrhea. No clinically significant hypoglycemia was reported in any trial [131].

GLP-1 RAs provide substantial benefits in glycemic control and weight loss while improving health-related quality of life among individuals with type 2 diabetes. GLP-1 RAs have also been shown to significantly decrease the risk of cardiovascular and all-cause mortality in type 2 diabetes, producing a significant reduction in the risk for non-fatal myocardial infarction and non-fatal stroke. However, their impact on heart failure-related outcomes is nil [160].

Compared with semaglutide in subjects with type 2 diabetes, tirzepatide produced significantly more improvements in total insulin secretion and insulin sensitivity, reflecting a significant improvement in pancreaticβ-cell function. Similar effects were also documented in another trial comparing tirzepatide with the GLP-1 RA dulaglutide, suggesting that dual receptor agonism might be responsible for improving insulin sensitivity, especially since the observed effect was only partially attributable to weight loss [160].

The question that inevitably arises is whether tirzepatide is more efficacious and equally safe compared with GLP-1 RAs. When tirzepatide was compared with GLP-1 RAs, it was not associated with a significant increase in the odds of nausea, vomiting, or diarrhea, except for tirzepatide 10 mg, which correlated with 51% greater odds for diarrhea compared with GLP-1 RA treatment. Tirzepatide use in subjects with type 2 diabetes did not significantly impact the incidence of any serious adverse effects compared with placebo, basal insulin, or GLP-1 RAs [160].

The cardiovascular safety of tirzepatide in type 2 diabetes was demonstrated in a meta-analysis of seven trials and 7,215 subjects randomized to tirzepatide, placebo, or an active comparator. Tirzepatide was associated with a non-significant decrease in the risk for major adverse cardiovascular events (e.g., cardiovascular death, myocardial infarction, stroke, hospitalized unstable angina) and all-cause death [161].

Current evidence suggests that tirzepatide might be more efficacious than GLP-1 RAs in terms of improvements in glycemia, body weight,β-cell function, and insulin sensitivity. Tirzepatide seems at least equally safe as GLP-1 RAs by not increasing the odds for serious adverse events [160].

Results of the ongoing cardiovascular outcome trial (SURPASS-CVOT) are awaited to answer whether tirzepatide exerts cardioprotective effects similar to that observed with GLP-1 RAs. In this trial, tirzepatide is compared with dulaglutide on major cardiovascular events in patients with type 2 diabetes and increased cardiovascular risk. Because dulaglutide has a confirmed cardioprotective effect, this head-to-head study will be particularly informative [160]. The study is expected to conclude in late 2024.

Tirzepatide is known to reduce the efficacy of oral contraceptive medications due to delayed gastric emptying. This delay is largest after the first dose, so patients should switch from oral to nonoral contraceptives for the first four weeks when tirzepatide is initiated [162]. Patients should be counseled regarding the risk of unintended pregnancy and the necessity of other contraceptive methods.

Amylin, a pancreatic hormone released with insulin in response to nutrient intake, acts on:

Pramlintide, the first amylin analog, was approved in 2005 as an adjunct to insulin for type 1 and type 2 diabetes and promotes weight loss in patients with diabetes by substituting three amino acids of human amylin with proline [139,147]. Cagrilintide is an emerging agent that overcomes pramlintide's short half-life and frequent administration as a long-acting amylin analog. Cagrilintide is being developed in combination with semaglutide (CagriSema) to achieve sustained weight loss in persons with obesity. Both cagrilintide and CagriSema have shown promising weight loss and safety in clinical trials that supports their further development [163].

Among 706 individuals with obesity after 26 weeks, mean weight loss with cagrilintide 4.5 mg (10.6%) and 2.4 mg (9.7%) was greater than with liraglutide 3.0 mg (8.4%) and placebo (2.8%). Side effects of cagrilintide include nausea, diarrhea, constipation, fatigue, and injection-site reactions [147].

CagriSema combines cagrilintide with semaglutide to produce an additive effect on appetite reduction and weight loss [163]. In a trial of adults with obesity, mean weight loss at 20 weeks was 17.1% with CagriSema, compared with 9.8% with semaglutide 2.4 mg [147]. Among 92 adults with type 2 diabetes and BMI ≥27 randomized to once-weekly CagriSema, semaglutide, or cagrilintide (all escalated to 2.4 mg), mean weight loss at week 32 with CagriSema (15.6%) was significantly greater than semaglutide (5.1%) or cagrilintide (8.1%). Mild or moderate gastrointestinal adverse effects were common and comparable. No moderate or greater hypoglycemia was reported [164].

A triple agonist may provide even more effective glycemic control and weight loss compared to single or dual receptor agonists. Retatrutide is a triple agonist at GCGR, GIPR, and GLP-1R [139]. A phase 2 dose-response study evaluated retatrutide in 338 adults with obesity [165]. At 48 weeks retatrutide 1 mg, 4 mg, 8 mg, and 12 mg led to 8.7%, 17.1%, 22.8%, and 24.2% mean weight loss, compared with a 2.1% reduction with placebo. Among those who received 8 mg or 12 mg retatrutide, 91% and 93% experienced weight loss ≥10% and 75% and 83% experienced weight loss ≥15% (compared with 9% and 2% among those receiving placebo).

Dose-related mild-to-moderate nausea, diarrhea, vomiting, and constipation were the most common retatrutide adverse effects, partially mitigated with a lower starting dose (2 mg vs 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter [165,166].

Survodutide is a dual GLP-1 and glucagon receptor (GCGR) agonist developed for obesity and NASH treatment. As glucagon release from pancreatic a-cells increases blood glucose, antagonism was initially pursued as a type 2 diabetes treatment. More recent studies have localized GCGR to adipose tissue, brain, and liver and have shown that GCGR activation increased energy expenditure via thermogenesis [139,147]. An agent combining selectively increased energy expenditure with appetite suppression is a reasonable strategy for effective weight loss or weight maintenance [139]. Hepatocytes express GCGR, but not GLP-1R, and drugs like survodutide that target GCGR may have greater benefit in improving liver fibrosis or NASH than GLP-1RAs [139].

In Phase 1 studies of survodutide, maximum placebo-corrected weight loss was 13.8% after 16 weeks, including 12.37% in Japanese men with no unexpected tolerability concerns [167,168]. Common survodutide adverse effects included nausea, dyspepsia, vomiting, diarrhea, abdominal pain, and headache [167].

Co-agonism is not the only possible strategy for a unimolecular antiobesity medication. AMG-133 is a GCGR antagonist and GLP-1R agonist [25]. In one study, individuals with obesity averaged 14.3% weight loss after 12 weeks on higher-dose AMG-133. AMG-133 was associated with adverse gastrointestinal effects, but its once-monthly subcutaneous use may be advantageous to weekly tirzepatide [141]. If replicated, the rapidity and extent of this weight loss provokes questions regarding the drug's mode of action and the role of GIP and GLP-1 in physiologic weight regulation [25]. As of 2023, peer-reviewed publication of the full trial results is awaited [141].

Bimagrumab is a human monoclonal antibody that binds to the activin type II receptor (ActRII). Antibody blockade of ActRII signaling stimulates skeletal muscle growth, and previous studies suggest that ActRII inhibition with bimagrumab also promotes excess adipose tissue loss and improves insulin resistance [169]. A single intravenous dose of bimagrumab increased lean mass, reduced total body fat mass (by 7.9%), and ameliorated insulin sensitivity in insulin-resistant individuals during the 10-week study [92].

A phase 2 trial randomized adults with obesity and type 2 diabetes to IV bimagrumab (10 mg/kg up to 1,200 mg) or placebo every 4 weeks for 48 weeks. Body composition changes used dual x-ray absorptiometry (DEXA) and magnetic resonance imaging. At week 48, mean changes with bimagrumab vs placebo were noted in fat mass (-20.5% vs -0.5%), lean mass (3.6% vs -0.8%), waist circumference (-9.0 cm vs 0.5 cm), and body weight (-6.5% vs - 0.8%) [169]. Muscle spasms and mild diarrhea were the most common adverse effects with bimagrumab. Further studies on the efficacy and safety of bimagrumab are ongoing [92].

Orforglipron, an oral once-daily nonpeptide GLP-1 RA, was evaluated in 272 adults randomized to orforglipron (12 mg, 24 mg, 36 mg, or 45 mg) or placebo for 36 weeks [170]. Mean weight loss with orforglipron was 9.4% to 14.7%, compared with 2.3% with placebo. In those taking orforglipron, weight loss ≥10% was noted in 46% to 75%, compared with 9% of patients taking placebo. Orforglipron led to improvement in all prespecified weight-related and cardiometabolic endpoints [170].

The most common orforglipron adverse effects were mild-to-moderate gastrointestinal events, primarily during dose escalation, and led to discontinuation of orforglipron in 10% to 17% of participants across dose cohorts. The safety profile was consistent with GLP-1RAs [170]. This trial mirrored the safety and weight reduction findings of a smaller oral orforglipron trial in patients with type 2 diabetes [171].

Danuglipron is another oral GLP-1 RA under development for type 2 diabetes and obesity and is taken twice-daily with food [147]. A phase 2b trial randomized 411 adults with type 2 diabetes to placebo or danuglipron. At week 16, mean weight loss difference vs placebo was –2.04 kg and –4.17 kg with danuglipron 80 mg and 120 mg, respectively. The most common adverse effects were nausea, diarrhea, and vomiting. Only 77% of patients completed the trial [172]. In a 12-week, dose-escalation study of adults with type 2 diabetes, discontinuation from danuglipron due to adverse effects ranged from 27.3% to 72.7% [173]. In December 2023, Pfizer halted its trial of twice-daily danuglipron in response to high drop-out rates related to unacceptable side effects; the once-daily trial continued [309].

Ecnoglutide is a novel, long-acting GLP-1 analog being explored for patients with diabetes and obesity. In laboratory tests, ecnoglutide was effective at stimulating the production of cAMP, a key signaling molecule involved in glucose control and body weight regulation. In a phase 1 clinical trial, ecnoglutide was found safe and well-tolerated, with pharmacokinetic properties that support once-weekly subcutaneous injections [174].

In a phase 2 trial of 206 participants with obesity and diabetes, weekly ecnoglutide 1.2 mg, 1.8 mg, or 2.4 mg led to weight loss of 11.5%, 11.2%, and 14.7%, respectively, vs 8.8% with daily liraglutide 3.0 mg [175]. A phase 3 dose comparison trial was initiated in early 2023 [176].

Mazdutide is a novel once-weekly GLP-1 and glucagon receptor dual agonist. As an oxyntomodulin analogue, mazdutide may also increase energy expenditure and improve hepatic fat metabolism through the activation of glucagon receptor. In a phase 2 trial in China, mazdutide 9 mg led to a mean weight loss of 15.4%, a weight change vs placebo of -14.7 kg, and weight loss ≥20% in 21.7% of participants (vs 0% with placebo) after 24 weeks [177].

APHD-012 is a novel approach to address metabolic disease through the delivery of dextrose to the lower small intestines via an oral bead formulation. In the 1960s, researchers found that glucose delivered directly distal to the jejunum better stimulated insulin release and secretion of GLP-1 and GIP compared with glucose delivered higher up the tract. This agent builds on such research [178].

As of 2023, a Phase 2 trial involving 150 adult obese participants with or without endocrine/metabolic conditions is underway [179].

ARD-101 is a potential bitter taste receptor (TAS2R) agonist that stimulates the release of the body's natural CCK, but primarily targets vagal nerve afferents located near the gut; this in turn induces positive effects on hunger, metabolism, and inflammation through gut-brain signaling. Three phase 2 trials were initiated in 2022 to assess efficacy and safety in adults with general obesity, adults with refractory post-bariatric weight gain, and those with Prader-Willi Syndrome, a rare genetic disorder characterized by persistent hyperphagia [180].

In the general obesity trial, patients treated with ARD-101 experienced a 2.51-fold greater reduction in hunger rating vs placebo [181]. Nausea or diarrhea common among available GLP-1 drugs were not noted in the ARD-101 group.

HU6 has demonstrated inhibition of phosphodiesterase 9A in mice linked to reduced body (and myocardial) fat and stimulated mitochondrial activity, without altered activity levels or food intake [182]. In this trial, positive weight loss effects were exclusively observed in male and ovariectomized female mice, suggesting a strong sexual dimorphism in treatment response. A phase 2 trial initiated in 2023 enrolled 250 participants with type 2 diabetes at risk for NASH and will compare three doses of HU6 on weight loss and hepatic function effects [183].

The endocannabinoid system is involved in the regulation of body weight and metabolism throughout the body. In the CNS, endocannabinoids bind to CB1 receptors in the hypothalamus (which control appetite), gastrointestinal tract, pancreas, and adipose tissue [184]. Elevated endocannabinoid levels can lead to increased hunger and food intake.

However, a meta-analysis of data from the National Epidemiologic Survey on Alcohol and Related Conditions and the National Comorbidity Survey-Replication found a decreased prevalence of obesity among current users of cannabis (≥3 days per week) of 14.3% and 17.2%, respectively [185]. Given this decreased likelihood of obesity in current cannabis users, research has begun to explore how the endocannabinoid system can be manipulated to promote weight loss and improve metabolic health.

Nabilone is an oral synthetic Δ9 –THC analog and partial CB1 agonist approved for the treatment of cancer and HIV cachexia for increasing appetite and body weight. A randomized controlled trial of cannabis-naive adults with obesity is underway to examine safety and feasibility, weight-loss effectiveness, changes in gut microbiome, and metabolic markers [186]. The results are expected in 2024–2025.

NNC9204-1177 is a glucagon/GLP-1 receptor co-agonist that underwent three phase 1 trials. After 12 weeks, mean weight loss was 12.6% at the higher dose level. However, dose-dependent increases in heart rate (5–22 beats per minute) and decrease in reticulocyte count, increased markers of inflammation, hepatic disturbances, and impaired glucose tolerance halted further clinical development [187].

When starting GLP-1 agonists, several strategies can promote success and decrease risk of discontinuation. Strategies to minimize adverse effects include slow dose escalation, counseling on expected adverse effects and their duration, and using a multidisciplinary team approach (including the primary care provider, pharmacists, nurses, and medical assistants) to provide regular follow-up and guidance as patients initiate the medication. It is particularly important to discuss gastrointestinal adverse effects, as patients who are not expecting these adverse effects may prematurely discontinue the medication [131].

Routine follow-up can come in many forms, including virtual visits, phone calls, pharmacist check-ins, or even portal messages at routine intervals. This type of follow-up can increase communication with the patient, normalizing expected adverse effects and allowing tighter dose titration, while also reducing the number of clinical visits a patient has to make, thereby reducing primary care provider burden and overall healthcare costs. Other strategies include a dose escalation period, with one-week dose pause when adverse effects are encountered, which may minimize nausea/vomiting. Gastrointestinal adverse effects may also be reduced by avoiding high-fat foods and focusing on small meals [131].

Interest in GLP-1 RAs has expanded beyond clinicians and patients struggling to lose excessive body-fat mass. Formulations of semaglutide approved for type 2 diabetes (Wegovy and Ozempic) have gained attention as celebrities and social media influencers have described taking thee agents to lose weight in short timeframes [190]. Many people have described in the media how taking semaglutide for obesity fundamentally changed their experience of hunger and appetite [191]. Consumer demand has led to widespread supply shortages of both products and concerns that people will associate them with "vanity," not as critical medications for patients with diabetes with or without obesity [190].

Additionally, news reports have commented on the possible misuse of semaglutide and other GLP-1 analogs. The issue is facilitated by the acquisition of medications from rogue websites. Pharmacists have reported forged prescriptions and use for weight loss in patients without diabetes. Social media influencers' semaglutide promotion for weight-loss, and the associated increase in demand, have contributed to an ongoing worldwide shortage of the drug in 2023 [192].

If all antiobesity medications could be prescribed based on individualized patient need without affordability concerns, discussion of off-label use would not be needed. Unfortunately, medication cost and insurance coverage are the primary drivers in selecting antiobesity medications for an individual patient. In a 2018 review of 136 marketplace health insurance plans, only 11% had coverage for antiobesity medications [193]. Medicare excludes drug therapy for obesity, and only 11 state Medicaid programs have full antiobesity medication coverage (California, Kansas, Minnesota, Wisconsin, Michigan, Pennsylvania, Virginia, Delaware, Rhode Island, Connecticut, and New Hampshire); a limited number of other states may offer partial coverage [131]. Even for patients with insurance, cost can be a barrier due to the lack of antiobesity medication coverage under the diagnosis of obesity [124].

In this context, off-label prescribing includes prescribing an antiobesity medication for longer than its labeled duration [194]. Phentermine as a long-term option is obviously attractive given its low cost (Table 8), and there are several considerations to weigh.

The original 90-day label has not been updated since 1959, despite phentermine approval for long-term treatment of obesity when combined with topiramate as Qsymia [124]. Its short-term indication is in conflict with what is now known about the nature of obesity necessitating long-term treatment [195]. When a patient shows good therapeutic response and tolerability with phentermine, the Endocrine Society states this presents a conundrum for clinicians because it is clear that weight regain will likely occur once the medication is stopped [120].

Phentermine has long been the most commonly prescribed antiobesity medication due in large measure to its low potential for CNS stimulation and abuse, its low price as a generic drug, and clinician familiarity [136]. A large proportion has been for off-label doses and durations to sustain a positive clinical response [195].

Authors of the Endocrine Society practice guideline acknowledged little evidence of any serious side effects with long-term phentermine monotherapy and concluded it was reasonable to prescribe it long-term for patients who:

These aspects of care should be documented in the patient's medical record, and the off-label nature of the prescribing documented at each visit [120].

Subsequent to this clinical practice guideline, an observational study of 13,972 adults with obesity, including those with hypertension (21%) and type 2 diabetes (12%), initiated on phentermine found no increase in cardiovascular risk with long-term use up to 36 months versus use 3 months of less [196].

An obesity medicine specialty clinic also examined the abuse liability of phentermine treatment in 269 patients administered validated, structured addiction medicine interviews. No evidence was found of compulsive use, cravings, unsanctioned dose escalation, or withdrawal symptoms on abrupt cessation, including at doses much higher than commonly recommended and after treatment durations of up to 21 years [197].

The AGA and the ASMBS recommend phentermine as a long-term antiobesity medication option. The OMA convened a roundtable discussion of phentermine by expert clinicians, who suggested that, while not required by the prescribing label, prescribers may obtain an electrocardiogram (ECG) before starting phentermine. In addition to finding troubling wave patterns or cardiac dysrhythmias, a baseline ECG helps bring piece-of-mind to patient and clinician. Some clinicians perform ECGs on all patients before any intensive weight loss program or antiobesity medication [198]. In addition, the experts state that phentermine can be combined with GLP-1 RAs or other antidiabetic drug classes for further weight reduction, especially in patients with a high burden of obesity. Phentermine should not be used in patients with active cardiovascular disease nor as first-line antiobesity medication with advanced age or cardiovascular disease risk factors. Patients with a history of methamphetamine use are best treated with DEA unscheduled, non-stimulant antiobesity medications or bariatric procedures [198].

It is important to pick the right drug for the right patient. A patient who tends to skip meals all day and eat large volumes late at night might not be a good match for morning phentermine, which would mainly reduce daytime hunger. If phentermine is prescribed, patients should be advised that they may have trouble sleeping for two to three nights after initiating phentermine [198].

Canagliflozin is an SGLT2 inhibitor approved for type 2 diabetes. In a randomized controlled trial of 335 subjects without type 2 diabetes (mean BMI: 37.3), the weight loss effects of once-daily canagliflozin 300 mg (Cana), phentermine 15 mg (Phen), or combined Cana/Phen were compared after 26 weeks [199]. Mean weight loss with placebo, Cana, Phen, and Cana/Phen was 1.1%, 2.6%, 4.6%, and 8.1%, respectively. Weight loss with Cana/Phen continued through week 26, with no apparent plateau. The Cana/Phen group also had greater improvements in blood pressure and heart rate. This study demonstrated the complementary renal effects with canagliflozin and CNS activity with phentermine on weight loss [199].

In commenting about the cost barrier of phentermine/topiramate ER, some have suggested prescribing phentermine and generic topiramate separately at monotherapy dosages that match Qsymia to lower the cost, noting that topiramate is not approved as an antiobesity medication but has shown benefits against weight regain following bariatric surgery [150].

Low-cost, off-label prescribing has focused on phentermine due to its extensive familiarity to obesity specialists, but diethylpropion also has low cost, comparable benefit and safety as monotherapy, and is likewise endorsed as a long-term antiobesity medication option by the AGA [123].

Before undergoing bariatric surgery, a preoperative medical evaluation is optimally conducted by an obesity specialist. A bariatric surgery specialist consultation should also be performed, as well as cardiology, pulmonary, gastroenterology, and/or other specialists, as clinically indicated [127].

Potential MBS candidates should undergo a formal mental health evaluation by a qualified licensed professional to assess environmental, familial, and behavioral factors, including trauma history, suicide risk, coping mechanisms, and underlying eating, mood, and substance use disorders. Patients should receive education regarding the potential for increased suicide risk and addiction postprocedure. After RYGB and sleeve gastrectomy, high-risk groups should stop drinking due to postoperative impaired alcohol metabolism and increased risk of alcohol use disorder [125,127].

Patients should undergo nutritional assessments by registered dietitians with expertise in MBS, who can help obtain a comprehensive weight history, identify maladaptive eating behaviors or patterns, and correct any micronutrient deficiencies prior to surgery. A registered dietitian can also provide preoperative nutrition education and prepare the patient for expected dietary changes after MBS, which include an understanding that even with bariatric surgery, lifelong adherence to healthful nutrition, physical activity, and favorable behavior modification facilitates the best chance for long-term success [127].

Other preoperative evaluations include proactive medication adjustment. While individual instructions will vary depending on the individual patient, several weeks prior to the bariatric surgery, the medical and surgical team often work together in management of medications that may increase surgical risk, such as increased bleeding risk with antiplatelet therapies (e.g., clopidogrel), anticoagulants (e.g., warfarin), and increased thrombotic risk with sex hormone pharmacotherapies (e.g., estrogens). All herbal and over-the-counter supplements should be discontinued [127].

NSAIDs should be avoided before and after MBS, because they are implicated in the development of anastomotic ulcerations, perforations, and leaks. Alternative pain medication should be identified before the surgery [125].

Tobacco use, and cigarette smoking in particular, must be avoided at all times by all patients. Patients who smoke cigarettes should stop as early as possible, preferably one year but at the very least six weeks before MBS. In addition, tobacco use must be avoided post-MBS given the increased risk of poor wound healing, anastomotic ulcer, and overall impaired health. Structured intensive smoking cessation programs are preferable to general advice and should be implemented [125].

Nutrient deficiencies are common after bariatric surgery and are carefully monitored for optimal patient health and recovery. Lower levels of vitamin D are common in patients with obesity and may worsen postoperatively without adequate supplementation. High-quality bariatric-specific multivitamin/mineral/ trace element supplements are routinely recommended after MBS, with vitamin supplements often containing higher amounts of vitamin B12, iron, vitamin C (to assist with iron absorption), vitamin D, and calcium [127]. Registered dietitians can also assist postoperative patients experiencing food intolerances, malabsorption issues, micronutrient deficiencies, or weight regain [126].

Selection should be based on individualized goals of therapy (e.g., weight-loss target, improvements in specific obesity-related complication), available local/regional expertise (e.g., obesity specialists, bariatric surgeon, institution), patient preferences, and personalized risk stratification that prioritizes safety. Laparoscopic should be preferred over open procedures [125]. The decision about MBS approach should be driven primarily by informed patient preferences, but the ultimate decision for surgical readiness will be determined by the surgeon [126,215].

Preoperative Predictors of Outcome

Because weight loss after surgery is heterogeneous and not entirely predictable, particularly in the long-term, there is considerable interest in identifying individuals more or less likely to benefit from MBS based on preoperative factors [208]. Although age, gender, anthropometrics, obesity-related complications, eating behavior, genetic background, circulating biomarkers (e.g., microRNAs, metabolites, hormones), and psychological and socioeconomic factors could potentially impact post-MBS weight loss, none have shown predictive utility [216].

A study of 2,022 patients with average three-year weight loss of 31% with RYGB and 16% with LAGB concluded that preoperative factors have limited predictive value for a patient's chance of a successful weight loss outcome following MBS [217]. However, surgical volume at the clinic (more than 100 per year), surgeon experience, surgery in a tertiary care center, female sex, age 55 years or older, and respiratory status all correlated with lower complications risk [208].

As genetic variants in the leptin-melanocortin pathway are associated with obesity, their effect on long-term bariatric outcomes was examined. The weight regain pattern in these patients after RYGB and sleeve gastrectomy highlights the need for proactive lifelong management to prevent relapse and careful expectation management [218]. Additionally, genotyping patients with significant weight regain after RYGB could help individualize weight-loss interventions to improve weight maintenance after surgery [219].

Preoperative Denials or Delays of Approval for Insurance Coverage

Insurance-mandated preoperative weight loss is discriminatory, arbitrary, scientifically unfounded, and contributes to patient attrition, or worse [126]. In a large study of patients medically cleared for a bariatric procedure and for whom insurance approval was requested, 22% were denied insurance coverage. For these patients, the mortality rate increased threefold during follow-up [220]. This practice by insurers leads to unnecessary delay of life-saving treatment and progression of life-threatening comorbid conditions [126].

Postoperative Esthetic Concerns

Bariatric surgery (and possibly antiobesity medication in hyper-responders) can lead to massive weight loss, resulting in excess skin and tissue that impairs hygiene, causes discomfort, and is disfiguring. Excess skin can lead to stigma due to appearance and pronounced physical and psychological impairments, but it can be mitigated by body-contouring surgery [221]. Body-contouring surgery is best pursued after weight loss has stabilized (typically 12 to 18 months after bariatric surgery) [125]. Smoking cessation is an absolute requirement before any type of body-contouring surgery [221].

Abdominoplasty can improve mobility, reduce skin fold complications, and improve psychosocial functioning. Patients who underwent body-contouring surgery after bariatric surgery had significantly better long-term weight loss than a matched cohort of patients [222]. A subsequent meta-analysis confirmed the added long-term benefits of body-contouring surgery for selected patients after massive weight loss and recommended a multidisciplinary team involving a bariatric surgeon, a plastic surgeon, nutritionists, and psychologists for the management of patients [223].

RYGB is the criterion-standard MBS with the longest-term safety and efficacy data [226]. In this procedure, the stomach is divided; a small gastric pouch is anastomosed (cross-connected) to a severed "roux" limb of small bowel jejunum through which food passes, bypassing the larger gastric remnant, duodenum, and proximal jejunum [227]. This approach has been found to dramatically improve type 2 diabetes and is part of the treatment algorithm for uncontrolled type 2 diabetes in patients with BMI ≥35. It is also associated with modestly greater weight loss and improvements in metabolic disease compared with sleeve gastrectomy. It also improves GERD [127,135].

However, it is associated with more malabsorptive complications than sleeve gastrectomy, though fewer than duodenal switch. The bypassed portion of stomach cannot be viewed by conventional gastroscopy; if cancer occurs after surgery, early diagnosis is almost impossible [228]. RYGB is also not recommended for patients with Crohn disease. Potential adverse effects include marginal ulcers, internal hernia, small bowel obstruction, and vitamin and mineral deficiencies.

Efficacy

A prospective study followed 486 patients after RYGB. Average total weight loss at 2 years (36%) and 15 years (28%) showed good durability. Rates of improved or resolved obesity-related complication after one year for type 2 diabetes (99%), obstructive sleep apnea (97%), hypertension (95%), and GERD (97%) remained high through ≥10 years [226].

After RYGB, 418 patients were prospectively studied (with >90% follow-up) at 12-years. Mean total weight loss was 28.0% at 6 years and 26.9% at 12 years. Approximately 70% and 40% of patients maintained ≥20% and ≥30% total weight loss. Type 2 diabetes remission at 2, 6, and 12 years was 75%, 62%, and 51%, respectively; prevention of new-onset type 2 diabetes was 98% [229]. Evidence suggests that RYGB provides stable weight loss of more than 25% beyond 12 to 15 years that corresponds with sustainable resolution of obesity-related complications.

Sleeve gastrectomy, also referred to as laparoscopic sleeve gastrectomy or LSG, consists of the majority of the stomach being vertically resected; a tube-shaped remnant, or "gastric sleeve," is left along the lesser curvature [227]. This procedure improves metabolic disease while maintaining small intestinal anatomy. Due to its effectiveness, relative simplicity, and low rates of margin bleeding (1.0%), leakage (1.1%), and postoperative stenosis (0.4%), sleeve gastrectomy has become the most popular MBS [228]. Micronutrient deficiencies not as frequent with sleeve gastrectomy as with some other bariatric surgeries. If necessary, these patients can be converted to RYGB at a later stage.

Despite the benefits, rates of GERD and dysphagia are high. In some cases, these effects may be severe, requiring conversion to RYGB and/or chronic medical therapy (e.g., with proton pump inhibitors) [127,135]. Lack of bypass makes sleeve gastrectomy suboptimal for improving obesity-related complications in superobesity; other drawbacks include weight recurrence and poor diabetes control [228]. Chronic obstructive symptoms and potential strictures are additional concerns.

Efficacy

There has been concern that the popularity of sleeve gastrectomy has outpaced its long-term evidence support, especially in superseding RYGB. A systematic reviews and meta-analyses of ≥10-year sleeve gastrectomy results found 24.4% total weight loss and good remission of type 2 diabetes (45.6%) and hypertension (41.4%). However, high de novo GERD (32.3%) and 0% diabetes remission were noted in two of the reviewed studies [230].

In a randomized trial involving 240 patients with 85% follow-up at 10 years, sleeve gastrectomy led to 43.5% excess weight loss (vs 51% with RYGB), <5% weight loss in 5% of participants (vs 3% with RYGB), and similar remission of type 2 diabetes (26% vs 33%), dyslipidemia (19% vs 35%), and obstructive sleep apnea (16% vs 31%). Superior hypertension remission was noted with RYGB (8% vs 24%). The researchers found higher esophagitis rates after sleeve gastrectomy (31% vs 7%) but similar Barrett esophagus (4% vs 4%) and reoperation (15.7% vs 18.5%) rates. Longer preoperative type 2 diabetes duration was associated with lower remission, emphasizing the importance of early surgical treatment [231].

In LAGB, an adjustable silicone band is placed around the upper stomach and connected to a port in the subcutaneous tissue, which can be used to restrict the food-holding capacity of the stomach [127,135]. LAGB is the considered safest bariatric surgical procedure, and it is reversible if necessary [203]. Today, LAGB is disfavored due to lack of durable long-term weight loss, limited metabolic benefits, and the risks of device complications and revisional surgery [127,135].

Possible adverse events include band slippage, erosion, bowel obstruction, and dilatation of the esophagus. Band overfilling may underlie some LAGB problems. In one study, among 699 LAGB patients (pBMI: 41.4) with low (≤3 mL) or high (≥4 mL) band filling, low filling led to superior BMI (30.3 vs 35.8) and excess weight loss (49.1% vs 38.2%) at four to six years, and substantially lower rates of vomiting, epigastric pain, reflux, band slippage, migration, removal, and revision compared with high filling. Using low-volume band filling and strict follow-up, the authors suggest that abandonment of LAGB should be reconsidered [232].

Efficacy

Following LAGB, excess weight loss at 10 to 20 years is approximately 47%. However, the distribution of weight loss is heterogeneous. At seven years, 62% of patients have 15% total weight loss, and equal rates have ≥35% (19%) and <5% (19%) total weight loss [233].

Due to late complications, de novo GERD in up to 70% of patients, and comparatively mediocre long-term effectiveness, trends over the past decade indicate that LAGB is managed in patients treated years or decades earlier, rather than initiated as MBS [201,233].

BPD/DS involves sleeve gastrectomy, transection of the duodenum distal to the pylorus, and creation of an alimentary limb 200–250 cm long, thereby reducing anastomotic ulcers and dumping syndrome [228]. This approach is associated with the highest weight loss and metabolic disease resolution of all MBS techniques.

Technical complexity and risk of long-term nutritional deficiencies limits the acceptance of BPD/DS, which is reserved for super-obese (BMI ≥50) patients or those with nonresponse after sleeve gastrectomy without GERD, with nadir excess weight loss of 70% to 80% after two years [200,228,234]. Patient unwillingness or inability to follow/afford long-term nutritional recommendations, which can lead to life-threatening micronutrient deficiencies, is considered an absolute contraindication to this approach [127,135]. Other possible adverse effects include protein malnutrition, anemia, diarrhea, stomach ulceration, duodenal dissection, and internal hernias.

Efficacy

As RYGB can lead to insufficient weight loss in patients with super-obesity (BMI >50), some surgeons advocate BPD/DS in this group [132]. In a study involving 47 patients (pBMI: 54.5) randomized to BPD/DS or RYGB (81% with 15-year follow-up), 1-, 3-, and 15-year BMI was superior with BPD/DS (28, 31, 34) compared with patients who had undergone RYGB (33, 39, 41), reflecting 20.4 vs 12.4 BMI loss and 37.5% vs 23% total weight loss [132].

Unfortunately, BPD/DS also led to greater adverse events (2.7 vs 0.9 per patient), GERD (22.2% vs 0%), and severe adverse effects (0.9 vs 0.3 per patient), including malnutrition and bowel perforation. Long-term mortality did not differ. The trial was not powered for significant differences in obesity-related complication remission.

That half of patients with RYGB remained severely obese is greatly concerning, as BMI >40 reduces life expectancy by 8 to 10 years. The benefits of BPD/DS should be weighed against the increased risk of complications, which may be severe, and the need for rigorous follow-up. However, weight and comorbidity recurrences are problematic, creating health consequences and reducing life expectancy [132].

SADI-S creates a single, end-to-side anastomosis between the created gastric sleeve pouch with preserved pylorus and distal ileum, with the division at the level of the duodenum [135]. This approach was introduced in 2010 as a simplified version of BPD/DS and is characterized by strong metabolic effects. Short-term outcomes appear similar to BPD/DS in measure of excess weight loss (BPD/DS: 81%; SADI-S: 75%), improvement of obesity-related conditions, malnutrition, and complications [228]. Potential drawbacks include micronutrient deficiencies and duodenal dissection.

Efficacy

In one study, 121 patients (pBMI: 52) had BMI ≤29, excess weight loss 80%, and total weight loss 57% after 31 months. Post-30-day adverse events (3.3%) were malnutrition or chronic diarrhea [235]. A SADI-S review noted little weight regain after 24 months, resolution of type 2 diabetes (73%), dyslipidemia (77%), and hypertension (59%) [236].

In another study, three-year total weight loss was superior with SADI-S (39%) compared with RYGB (29%). Weight loss with RYGB (30%), SADI-S (35.5%), and BPD/DS (35%) was similar in obesity with type 2 diabetes. Diabetes improved comparably with SADI-S and BPD/DS and better than RYGB [234]. For unclear reasons, longer-duration data on SADI-S are lacking.

OAGB was introduced as a simplified version of RYGB, with a significantly reduced difficulty, learning curve, and operation time [228]. It consists of a single gastrojejunal anastomosis between a long gastric pouch and a jejunal omega loop [228]. It may be simpler and safer than BPD/DS, with strong metabolic effects. It may also have less micronutrient deficiencies than BPD/DS.

OAGB is suitable in patients who are elderly, with low BMI (30–35) and obesity-related complications, and high BMI (>50) as one-stage procedure. It may also be suitable for patients with large/concurrent hiatal hernia [202].

This procedure is not reversible and is not recommended for patients with GERD or esophagitis [125]. Potential adverse effects include abdominal pain, nausea, liver abscess, micronutrient deficiencies, and duodenal dissection.

Efficacy

OAGB showed substantial, durable weight loss in a trial involving 1,200 patients (pBMI: 46), with 6-, 9-, and 12-year BMI (28.5, 29.6, 29.9), excess BMI loss (83%, 78%, 76%), and excess weight loss (77%, 72%, 70%) all showing improvement. Approximately 70% of patients had data at 12 years [237]. Patients showed remission of presurgery type 2 diabetes (94%), insulin resistance (100%), hypertension (94%), hyperlipidemia (96%), GERD (92%), obstructive sleep apnea (90%), respiratory insufficiency (100%), and fatty liver (100%). In addition, improvement/remission was noted in osteoarthritis (82%/18%) and urinary incontinence (78%/22%). All affected patients experienced improvement in polycystic ovarian disease. Complications included early severe events (2.7%), late severe events (1%), and bile reflux symptoms (2%). No followed patient required conversion for weight regain [237].

ESG reduces gastric volume by 70% to 80%, creating a narrowed luminal sleeve—similar to sleeve gastrectomy, but without incisions or laparoscopy—using an endoscopic suturing device (OverStitch, Apollo Endosurgery, Austin, TX, USA) [238,239]. It is approved by the FDA for patients with BMI 30–50 [238]. It acts via gastric remodeling that increases PYY and GLP-1 by decreasing leptin and preventing rising ghrelin release, which increases fullness, decreases hunger, and promotes greater weight loss [238].

ESG is associated with fewer adverse effects than other bariatric procedures, with no obvious disadvantages [239]. The most common possible adverse effects include postprocedure nausea, vomiting, and epigastric pain. Severe adverse effects are rare (0% to 2%) [228,238].

In one study, 6-month weight loss robustly predicted 24-month weight loss, allowing early prediction of nonresponse and initiation of adjunctive therapies [238]. The MERIT trial randomized 209 participants to lifestyle modification with or without ESG. At 52 weeks, ESG showed superior excess weight loss (49% compared with 3%) and weight loss (14% compared with 0.8%) to controls. At 104 weeks, 68% of patients with ESG maintained ≥25% excess weight loss. No deaths, surgical interventions, or intensive care stays occurred [240].

In the longest prospective outcomes, weight loss at three and five years was 15% and 16%, respectively [228]. In 404 adults (pBMI: ≥40) after three years, weight loss was 20.3% and excess weight loss was 47% [62]. A meta-analysis of studies assessing efficacy of ESG found short-term and medium-term weight loss of 16.2% and 15.4%, respectively, and resolution of type 2 diabetes (55%), hypertension (63%), dyslipidemia (56%), and obstructive sleep apnea (52%) in patients with moderate obesity [241].

A study of ESG in 189 overweight patients (pBMI: 28) showed weight loss at 12, 24, and 36 months of 15%, 15.3%, and 15%, respectively. At 12 and 24 months, 76% and 86% of participants achieved normal BMI, with mean BMI reductions of 4.1 and 4.3. ESG was safe and effective in treating overweight patients, with high BMI normalization rates that could halt progression to obesity [242].

Overall, ESG looks promising as a minimally invasive bariatric procedure but needs longer-term data.

Laparoscopic gastric plication is also referred to as a primary obesity surgery endoluminal (POSE) procedure. This incision-less procedure creates full-thickness plications in the gastric fundus and body using anchors that effectively reduce gastric capacity. Whereas endoscopic suturing is somewhat reversible, laparoscopic gastric plication places polypropylene anchors with baskets cinched on either end of tissue folds and is designed for permanent gastric remodeling. To accomplish this, it uses the incisionless operating platform, a medical device. As with ESG, laparoscopic gastric plication is associated with fewer adverse events compared with other bariatric procedures. The most common complaints are abdominal pain, nausea, and vomiting [127,135,239].

In a meta-analysis of the original laparoscopic gastric plication procedure, excess weight loss was 49% and weight loss 13% at 12 to 15 months. Severe adverse events occurred in 3% of cases and included bleeding, hepatic abscess, severe pain, nausea, and vomiting [243].

Laparoscopic gastric plication outcomes after five or more years are scarce. Among 88 patients at two and six years, weight loss was 21% and 12% and excess weight loss was 60% and 32%. The six-year weight regain of 58% led to a high revision rate (23.5%) [244].

Intragastric balloon devices are filled with liquid or gas to reduce the effective volume of the stomach, thereby lowering the satiety threshold of meals, stimulating gut chemo-motor receptors, regulating ghrelin and other peptide hormone levels, reducing food intake, and delaying stomach emptying to achieve weight loss [228].

Three intragastric balloon devices are ASMBS-endorsed and FDA-approved for six-month dwell-time. The Orbera and Reshape balloons are both filled with methylene blue and saline. A leak or rupture releases the dye, which turns the urine blue to rapidly reveal the problem [135,228].

Contraindications to intragastric balloon devices use include prior abdominal or weight-reduction surgery, inflammatory bowel disease, obstructive disorders, GI ulcers, severe reflux, prior GI bleeding, severe liver disease, coagulopathy, ongoing alcohol use disorder, or intestinal varices, stricture, or stenosis [239,245].

Orbera Balloon Device

Orbera, the most widely and longest used intragastric balloon device, is an endoscopically inserted single gastric balloon filled with 400–750 mL of fluid [245]. In a meta-analysis of 1,683 patients, weight loss at 6 and 12 months was 13.2% and 11.3%, respectively. Common adverse events were pain (34%), nausea (29%), GERD (18%), gastric mucosal erosion (12%), and balloon removal due to intolerability (7.5%). Severe events included gastric ulcers (2.0%), balloon displacement (1.4%), small bowel obstruction (0.3%), perforation (0.1%), and death (0.08%). All perforations occurred in patients with prior gastric surgery; all deaths were secondary to perforation or aspiration. Thus, individualized, detailed risk assessment is necessary for patients planning to undergo intragastric balloon device placement [228]. Orbera early removal is also associated with use of selective serotonin or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) [125].

Obalon Balloon System

Obalon uses up to three deflated balloons, swallowed as capsules. Gas is then injected into the balloons under x-ray observation. Weight loss typically is about 6.6%. In a registry of 1,343 patients, weight loss was 10.0% in the indicated BMI category (BMI 30–40), 10.3% in BMI 25–30, and 9.3% in BMI >40. Adverse event (14%) and severe adverse event (0.15%) rates included seven balloon deflations, none of which resulted in obstruction [246].

Common adverse effects are mainly nausea and mild abdominal pain, and serious events are rare. However, leaking occurs more easily with gas-filled than liquid-filled balloons, and leaking balloons must be removed by gastroscopy, a disadvantage with Obalon [228,245].

ReShape Duo Balloon

With the ReShape Duo balloon device, two balloons are connected by a soft silicone rod. Each balloon is filled with 450 mL of fluid. The two-balloon design is intended to prevent premature failure, better conform to the stomach curvature, and improve patient tolerability. The ReShape device significantly reduces severe adverse effects rates compared with Orbera, but postoperative adverse event rates remain relatively high [228]. Average weight loss is approximately 6.8% [135].

AspireAssist

AspireAssist was a form of aspiration therapy via modified percutaneous endoscopic gastrostomy. In 2022, the maker of AspireAssist terminated production of this FDA-approved product [247].

In 2019, the FDA approved the TransPyloric Shuttle (TPS) to promote weight loss in patients with BMIs 30–40 for a dwell time of 12 months. TPS provides a mechanism similar to intragastric balloon devices, with easy reversibility. The device contains a space-occupying balloon and a flexible silicone catheter that connects to a smaller bulb designed to intermittently advance through the pylorus to induce gastric outlet obstruction [239].

The initial TPS feasibility study in 22 patients demonstrated 14% weight loss at six months. The pivotal TPS trial randomized 302 patients to TPS or sham device. Weight loss at 12 months was superior with TPS (9.8 vs 2.8%). The few adverse events included esophageal rupture and gastric impaction [239].

With vagal nerve blocking therapy, a pacemaker-like implantable device is surgically placed under the skin, with lead wires placed laparoscopically around the vagus nerve just above the stomach. Activation of the device causes intermittent vagal blockade to induce a sense of satiety. It is FDA approved for weight management in patients with BMI >40 or BMI >35 with weight-related complications [127,135]. Contraindications include cirrhosis, portal hypertension, hiatal hernia, and other implanted devices (e.g., pacemakers, defibrillators) [127,135].

In one study, weight loss ≥10% and ≥15% at 12 months (39% and 22%) and 24 months (34% and 21%) was similar among all 123 patients. Adverse events included nausea, reflux, and pain at regulator site. No new adverse effects were noted in the second year of the two-year trial [248]. Weight loss is superior to sham-treated controls but lower than conventional MBS. Despite good safety, the modest efficacy may limit the desirability of intermittent vagal blockade [4].

While not a bariatric procedure, liposuction is a common esthetic procedure that can remove significant amounts of subcutaneous adipose tissue without affecting visceral adipose tissue. In a small 12-week study, women with and without diabetes had 9.1–10.5 kg body fat loss and reduced waist circumference but no improvement in blood pressure, inflammatory markers, or insulin sensitivity [4]. Removal of subcutaneous adipose tissue without reducing ectopic fat depots has little influence on the risk factors related to overweight or obesity [4].

Antiobesity medications may work synergistically with MBS, and treating patients with obesity via a multimodal approach has the potential to increase and possibly enhance MBS efficacy and durability. The ASMBS supports preoperative use of antiobesity medications for reducing perioperative risk and increasing postsurgery attainment of weight-loss goals and comorbidity resolution as well as post-MBS for ameliorating weight recurrence [124].

Phentermine is one of the most commonly used antiobesity medications in MBS patients. Pairing phentermine with topiramate may be advantageous in weight-loss efficacy through combinatory mechanisms and cost considerations in post-MBS patients. GLP-1 agonists offer high efficacy, few drug interactions, and few side effects, but cost can be a deterrent [124].

In most patients, MBS results in supraphysiological levels of circulating GLP-1. However, patients with poor postsurgery weight loss demonstrate an unfavorable postoperative gut hormone profile, including lower circulating GLP-1 levels. As such, GLP-1 analogs may benefit these patients [256].

In the BARI-OPTIMISE randomized placebo-controlled trial, patients with poor weight loss (≤20%) and suboptimal nutrient-stimulated GLP-1 response one or more years following sleeve gastrectomy or RYGB received liraglutide 3.0 mg or placebo. After 26 weeks, mean total weight loss with liraglutide was 8.82%, compared with 0.54% with placebo [256].

Patients receiving liraglutide for late weight recurrence after RYGB were prospectively followed. After 24 months, patients lost >85% of weight recurrence from nadir; hypertension and dyslipidemia also improved [257].

Weight recurrence studies of GLP-1 RAs have largely used liraglutide. However, semaglutide may be superior to liraglutide for weight recurrence, regardless of MBS procedure. In one study, semaglutide was superior on with 12-month weight loss (13% vs 9%) and odds ratio for ≥15% weight loss (2.55) compared with liraglutide [258].

Patients treated with liraglutide or semaglutide for weight recurrence after RYGB lost 67.4% of the weight regain after six months. More patients on semaglutide had total weight loss ≥10% (47.6% vs 31%) and ≥15% (24% vs 3.5%) [254].

The optimal time to initiate antiobesity medication may be at weight plateau, rather than after weight recurrence [259]. Proactive liraglutide may significantly augment ESG efficacy. Initiated five months after ESG and assessed seven months later, liraglutide/ESG showed greater reductions in weight (25% vs 20.5%) and body fat (10.5% vs 8%) compared with ESG alone at one year postprocedure [260].

The choice of conversion depends on the type of primary operation and the indication for conversion [125]. Patients may require reoperation (to correct/adjust) or conversion following any primary MBS, but some evidence suggests that more "restrictive" procedures (e.g., LAGB, sleeve gastrectomy) lead to higher rates of reoperation or conversion.

Conversions are the third most common MBS procedure. Of 57,683 performed between 2015 and 2017, most involved gastric band (LAGB) conversion to sleeve gastrectomy (15,433), to RYGB (10,485), or removal (14,715). It is projected that sleeve gastrectomy to RYGB conversions (8,491) will likely surpass LAGB conversions with time [261].

Weight recurrence within several years of sleeve gastrectomy is described as an emerging problem. After seven years, 28% to 30% of patients had weight recurrence and 20% had revisions, mostly due to weight recurrence (13%) and GERD (3%) [262,263]. However, over 5 to 12 years after RYGB, up to 25% of patients experience <20% weight loss due to nonresponse/weight recurrence [256].

The ASMBS has made several suggestions concerning revisions/conversions, stating that in addition to improving weight loss, type 2 diabetes improvement and remission rates also increase [125]. It is important to consider behavioral factors, such as binge-eating, may be responsible for poor weight outcomes after LAGB reoperation. If necessary, conversions to RYGB or sleeve gastrectomy after LAGB can be performed in one or two stages. If conversion is required due to GERD, the preferred procedure is RYGB. Conversion of sleeve gastrectomy for additional weight loss can be RYGB or duodenal switch, which results in greater weight loss than RYGB but higher risk of long-term nutritional deficiencies [125].

For weight recurrence after sleeve gastrectomy, SADI-S led to greater total weight loss (30% vs 19%) and remission of type 2 diabetes and hypertension, fewer complications and reoperations after five years when compared with OAGB [264]. In one trial, OAGB for 1,075 patients with weight recurrence after various MBS led to two- and five-year excess weight loss of 68.5% and 71.6%, respectively. Adverse events included leak (1.5%), marginal ulcer (2.4%), anemia (2%), and mortality (0.3%) [265].

The hypothalamus, as the superordinate regulator of energy homeostasis, receives input via the bloodstream, ascending neurons from the brainstem, and descending neurons from cortical areas. It then coordinates energy balance and other homeostatic systems, integrates reciprocal orexigenic and anorexigenic responses, and governs metabolic adaptation [102,103,268].

The arcuate nucleus (ARC) of the hypothalamus is adjacent to the median eminence, a circumventricular organ outside the blood brain barrier, giving ARC neurons direct bloodstream access to detect circulating hormones and metabolites. Arcuate neurons are thus 'first-order' neurons, since circulating peripheral signals act directly on them [101,102,269].

First-order ARC neurons project to second-order neurons in the paraventricular (PVH), ventromedial, dorsomedial, and lateral hypothalamus. Second-order hypothalamic neurons project to brainstem circuits and midbrain areas [101,102,115,269]. Brainstem circuits respond rapidly to gut signals to control meal size and termination. Brainstem neurons project to hypothalamic areas and communicate to the gut via parasympathetic signals. Many antiobesity medications work by activating receptors on both hypothalamic and brainstem neurons [102,115].

The hypothalamic integrative capacity is enhanced by crosstalk with corticolimbic systems that process external sensory information, cognitive and emotional control, and reward-based decision making and mediate emotional, cognitive, and executive aspects of ingestive behavior [8].

A salience network in the frontal cortex, ventral and dorsal striatum, and amygdala, associated with motivation, desire, and craving for palatable high-energy food, is more active in obese than lean subjects. An inhibitory network in the dorsolateral prefrontal cortex is activated in subjects instructed to resist craving. This cognitive control ability is greater in patients with the highest weight loss after bariatric surgery. Connectivity between the salience and inhibitory networks (hedonic control) and the hypothalamus (homeostatic control) differs in lean versus obese subjects. The former homeostatic/ hedonic ingestive dichotomy has given way to a more unified and integrative control system [8].

The Arcuate Nucleus and the Melanocortin System

In the ARC, the melanocortin system is a critical and conserved pathway of body weight homeostasis and essential to the regulatory function of the hypothalamus in energy balance and homeostasis. The melanocortin system consists of two distinct, functionally antagonistic neuron populations [150,268,270,271,272]:

Anorexigenic melanocortin neurons (POMC), which release melanocortin peptides (α- andβ-MSH) that bind and stimulate melanocortin receptors (MC3R and MC4R) expressed on second-order neurons. Brain-derived neurotrophic factor, corticotropin-releasing hormone, and thyrotropin-releasing hormone mediate the downstream effects of MC4R activation on suppressing food intake.

Orexigenic agouti-related protein (AgRP) neurons, which antagonize melanocortin neurons and receptors by releasing AgRP, gamma-aminobutyric acid (GABA), and neuropeptide Y (NPY). AgRP antagonizes MC3/4R to prevent the anorexigenic effects ofα- andβ-MSH binding. GABA directly inhibits POMC neurons in the ARC. NPY is the most potent known short-term orexigenic stimulus.

The brainstem has a smaller number of POMC neurons. AgRP neurons solely exist in ARC and send long-distance projections throughout the hypothalamus and brainstem. AgRP neuron expression is negatively correlated with BMI [273].

POMC and AgRP neurons are tightly linked, exert opposite functions in the reciprocal regulation of downstream MC3/4R neurons, and are themselves reciprocally regulated by circulating hormones and neural inputs [274,275].

Energy Balance and Melanocortin Activity

POMC and AgRP neurons detect and respond to circulating metabolic and hormone signals of short- and long-term deficit or surplus in energy availability [8]. Circulating hormones (e.g., leptin, insulin, ghrelin, GLP-1) bind to their respective receptors (LepR, InsR, GHSR, GLP-1R) on POMC and AgRP neurons [141]. Energy surplus stimulates POMC neurons. Heightened energy demand activates AgRP neurons [3,276].

The PVH is a major output nucleus for the ARC and receives afferent inputs from POMC and AgRP neurons [102]. It has the highest number of MC4R-expressing neurons in the CNS [271].

POMC neurons are stimulated by positive energy balance, elevated leptin, and insulin. In contrast, AgRP neurons are inhibited by leptin and insulin deficit and activated by negative energy balance and ghrelin.

POMC and AgRP neuron projections both converge on MC4R neurons in the PVH, which anorexigenic melanocortin peptides activate to suppress food intake and enhance energy expenditure, and orexigenic AgRP neuropeptides inhibit to increase food intake [141,277]. Also, circulating ghrelin binds its receptor on AgRP neurons, which then release NPY [3].

Negative energy balance and prolonged caloric restriction activate AgRP neurons in part by reducing plasma levels of leptin and insulin that inhibit AgRP neurons. Inactivating this inhibitory input activates AgRP neurons and increases the drive to eat, which promotes positive energy balance and recovery of lost weight [7].

Circulating levels of leptin, insulin, and other hormones serve the hypothalamus with feedback about the availability of energy. When circulating levels of these energy signals decrease during prolonged caloric deficit, increased AgRP neuron excitation recapitulates many behaviors and physiological effects associated with starvation, such as enhanced rewarding properties of food, as well as stimulating food intake [277]. Disruption of this fine-tuned control in the arcuate circuitry leads to dysregulation of energy balance and metabolism [8,266].

Hypothalamic Regulation of Adiposity and Energy Expenditure

White adipose tissue, the dominant body fat, is comprised of fat cells (adipocytes), stores energy in the form of triglycerides, and can increase fat reserves (lipogenesis) or utilize fat as energy (lipolysis) [278]. Melanocortin signaling regulates lipid metabolism and adiposity via the sympathetic nervous system (SNS) activity; disruption promotes lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue [150,275].

The SNS innervates white adipose tissue, and sympathetic terminals are adjacent to more than 90% of adipocytes. The brain releases norepinephrine from sympathetic terminals, which activateα- andβ-adrenergic receptors on adipocytes. This sympathetic outflow is the principal initiator of lipolysis, mediated in part by MC3/4R activity on sympathetic cholinergic neurons [271,276].

A common frustration for individuals trying to lose weight is the marked compensatory reduction in energy expenditure associated with caloric restriction [277]. AgRP neurons, activated by negative energy balance, shift metabolism toward energy conservation by promoting lipid storage and adipogeneses, elevating carbohydrate fuel use, reducing lipolysis, and thus decreasing energy expenditure in adipose tissue, in part, by suppressing sympathetic outflow to white adipose tissue. NPY release increases food intake and decreases energy expenditure via NPY1R-mediated reduction in downstream sympathetic output to adipose tissue [268]. SNS neurons also produce NPY, which induces vasoconstriction and fat tissue expansion [150].

A key point is that through extensive bidirectional communication, adipose tissue importantly influences energy balance, while CNS and hypothalamus play an essential role in controlling systemic metabolism [279].

Hypothalamic POMC Neurons and Cannabinoids

Cannabis use represents a "wildcard" in appetite mediation by the melanocortin system. By activation of cannabinoid receptor 1 (CB1R), cannabis-induced eating is a hallmark of cannabis use [280].

POMC neurons also produceβ-endorphin, an opioid peptide that binds the μ-opioid receptor (MOR). CB1R activation selectively increasesβ-endorphin, but notα-MSH, release by POMC neurons. Beta-endorphin inhibits AgRP neuron activity, and acute CB1R-induced eating is blocked by naloxone, a MOR antagonist [280].

Thus, cannabis stimulates a switch fromα-MSH toβ-endorphin release by POMC neurons and subsequently increases appetite and food intake (i.e., "the munchies"). This interesting and paradoxical finding argues against an exclusively anorexigenic role of POMC neurons [266].

The gut communicates information about food ingestion to the brain via vagal afferent fibers in the NTS. Most of these signals act rapidly to promote meal termination, with less impact on energy expenditure or long-term food intake [150,281]. The NTS receives and integrates the afferent vagal information and communicates this information to other brain regions it innervates [141,282].

POMC neurons are also expressed in the NTS, where they project to and receive inputs from brain regions that both overlap and are distinct from connections of arcuate POMC neurons [269]. NTS POMC neurons respond to, among other things, gut-secreted CCK and adipocyte-derived leptin [271].

Some NTS neurons project to the parabrachial nucleus, a central node in this ascending pathway. An anorexigenic circuit implicated in satiety and meal termination arises from calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus. Activation of CGRP neurons by gastric distention, CCK, and GLP-1 decreases appetite, while inhibition increases meal size [7,266].

Arcuate nucleus signaling strongly influences CGRP neuron activity [7,266,274]. In the ARC, glutamate-releasing/oxytocin-receptor expressing (Vglut2/OxtR) neurons convey an excitatory, fast-acting satiety mechanism. Projections from these neurons converge with GABAergic AgRP projections on MC4R neurons in PVH, a critical second-order node in the regulation of feeding. In the PVH, MC4R neurons release glutamate and excite downstream CGRP neuron targets in the parabrachial nucleus. Thus, the parabrachial nucleus serves as a third-order node in feeding regulation. In addition, AgRP neurons project to the parabrachial nucleus; activation of AgRP neurons stimulate feeding and delays satiation by inhibiting CGRP [7].

Of note, the substantial complexity inherent in food intake regulation cannot be reduced to a small set of interacting neurocircuits, and much remains to be learned [7].

As will be discussed later in this course, many novel and emerging antiobesity medications act through the hypothalamic receptors of peripherally released hormones and peptides.Table 10 summarizes the effects of endogenous and pharmacological ligand-binding of these receptors.

Adipose Tissue and Pancreatic Hormones

Some peripheral signals of energy balance are released by adipocytes (leptin, adiponectin), and pancreaticαcells (GCG),βcells (insulin, amylin), and F cells (pancreatic polypeptide) [150,282].

Leptin, the canonical signal of adipose tissue mass, is produced by white adipose tissue in approximate proportion to triglyceride stores. Adequate leptin action via its receptor (LepR) on arcuate neurons indicates sufficient energy stores; reduced leptin signaling indicates an energy deficit, promoting hunger and increasing energy intake [281]. LepR activation also decreases body weight by increasing lipolysis and energy expenditure [277]. CCK potentiates leptin effects to decrease food intake and body weight [267].

Normal body-weight maintenance requires intact leptin-regulated neurocircuits. An association of obesity with leptin resistance has been suggested, but some obese individuals may simply require more leptin to fully engage relevant neurocircuits. The primary role of leptin-responsive neurocircuits may relate more to preventing loss of body fat (by decreased leptin signaling to CNS) than defending against its increase (by increased leptin levels) [7].

Adiponectin is an adipocyte-derived protein that decreases body weight and plasma lipid levels and enhances insulin suppression of hepatic glucose production. Adiponectin levels increase following weight loss interventions in obesity, and patients with obesity show an inverse correlation between plasma adiponectin and insulin resistance [115].

Insulin and leptin both circulate in proportion to fat mass. Insulin activates its receptor (IR) expressed in the melanocortin system, which mediates its central anorexigenic effects, decreasing food intake and body weight [115]. Insulin also acts centrally to decrease hepatic glucose output, in part by inhibiting hypothalamic neurons [102]. Insulin inhibits AgRP neuron firing via IR-dependent signaling. Disruption of IR in the CNS promotes obesity with increases in body fat and leptin levels, insulin resistance, elevated insulin levels, and hypertriglyceridemia [266].

Amylin is co-released with insulin from pancreaticβ-cells in response to high blood glucose levels, reduces the rate of glucose absorption and inhibits glucagon release. Amylin receptor complexes in the area postrema and brainstem NTS mediate its anorectic effects by activating a central satiety pathway. Amylin also affects hedonic eating by inhibiting reward neurocircuits [141,267]. Amylin and leptin act synergistically, in part by amylin acting directly on AgRP neurons that co-express LepR. Amylin's ability to slow post-prandial gastric emptying also contributes to satiety [141].

Glucagon (GCG)is secreted by pancreaticα-cells and binds its receptor (GCGR) in the CNS, pancreas, adipocytes, and liver. Glucagon stimulates energy expenditure, reduces food intake, and decreases body weight through multiple mechanisms, including inducing satiety and lipolysis [147,267]. Hypothalamic GCGR activity inhibits AgRP neuron activity to attenuate orexigenic effects, while central resistance to glucagon-induced hypophagia contributes to the development of obesity [141]. Glucagon's anorectic action seem to be mediated via the liver-vagus-hypothalamus axis [267].

Gut Peptide Hormones

Other signals of energy balance are released by enteroendocrine cells that line the gut, one of the largest hormone-producing organs. Enteroendocrine cells and their respective hormones include L-cells (GLP-1, OXM, PYY), I-cells (CCK), K-cells (GIP), and P/D1 cells (ghrelin). Gut hormones bind their receptors in CNS and on pancreaticβcells (GLP-1, GIP), pancreas (CCK, OXM), and adipocytes (GIP) [147,267,283].

Meal termination involves meal-induced enteroendocrine cells release of peptides (e.g., GLP-1, CCK), which promote satiety by activating vagal afferent neurons that relay GI signals to brainstem areas, including the NST [7]. Glucagon-like peptide 1 (GLP-1) increases in circulation following meals and decreases during fasting, stimulates insulin secretion and regulates energy intake, and is also produced in the NTS. GLP-1 acts on GLP-1R in the gut and brain to delay gastric emptying and decrease food intake through activation of satiety pathways and efferent pathways regulating GI function. GLP-1 also reduces glucagon secretion, inhibiting hepatic glucose production [284].

GLP-1 inhibits eating mainly by activating GLP-1R on hypothalamic and brainstem NTS neurons. GLP-1R agonists also suppress hedonic eating by interacting with the mesolimbic reward system, including the ventral tegmental area and nucleus accumbens [267]. GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP-IV), leading to a circulating half-life of only two minutes for GLP-1 [150].

GIP acts in concert with GLP-1 on the pancreas after meals to regulate blood glucose by stimulating insulin and glucagon release. GIP contributes to lipid metabolism by promoting lipid storage, adipose tissue blood flow, and triglyceride uptake in adipocytes [284]. The GIP receptor (GIPR) is expressed in arcuate, dorsomedial hypothalamus, and PVH neurons; GIPR activation reduces food intake [267].

Ghrelin circulates as an orexigenic signaler, promoting hunger and meal initiation by binding its receptor (GHSR) on AgRP neurons, which stimulates NPY and AgRP release and inhibits POMC neurons by increasing GABAergic signaling. Vagal afferent neurons also have ghrelin receptors [115,267]. Compared with lean controls, individuals with obesity have lower circulating ghrelin levels and are more sensitive to its appetite-stimulating effects [115,267].

Ghrelin and leptin have a reciprocal relationship aimed at increasing or decreasing adiposity. Fasting increases ghrelin and reduces leptin, while high leptin levels suppress gastric ghrelin release and prevent ghrelin-induced NPY neuron activation [141]. Ghrelin and GLP-1 have opposite actions on eating behaviors. Ghrelin reinforces food reward by activating ventral tegmental area dopaminergic neurons; GLP-1 attenuates various palatable food-motivated efforts [267].

Ghrelin remains the only metabolic signal that potently activates orexigenic AgRP neurons. Discovery of an endogenous antagonist of ghrelin, liver-expressed antimicrobial peptide, sparked research interest in it as a possible candidate for obesity treatment [267].

CCK is secreted postprandially and binds CCK1 receptors (CCK1R) expressed in the vagal afferents, brainstem, and hypothalamus to decrease food intake. The satiety signals of CCK are transmitted to the NTS by vagal sensory neurons. CCK activates NTS POMC neurons, and brainstem MC4R signaling is required for CCK-induced appetite suppression [267]. CCK is an acutely acting signal with a very short half-life. Compensatory increases in meal frequency prevent CCK from producing long-term effects on total food intake or body weight [102].

OXM is secreted with GLP-1 and PYY in the postprandial state and exerts its anorectic action primarily via GLP-1R and secondarily via GCGR. The GLP-1R-mediated effects of OXM differ from those of GLP-1. OXM decreases body weight by lowering food intake and increasing energy expenditure and may act via different hypothalamic pathways than those of GLP-1 [267].

PYY is co-secreted with GLP-1 following a meal. Its major circulating form (PYY3-36) binds Y2R expressed on AgRP neurons, inhibiting these neurons and activating POMC neurons. Thus, PYY reduces appetite and body weight by increasing anorexigenic melanocortic activity in the arcuate [267].

Part of understanding obesity as a disease is recognizing that adipocytes and adipose tissue have vital functions beyond energy storage alone [128]. Adipose tissue is mostly comprised of adipocytes, regulates multiple body processes critical to energy and metabolic homeostasis, and is functionally classified into two types: white and brown [128,285]. White adipose tissue is an active endocrine and immune organ that includes subcutaneous adipose tissue and visceral (abdominal) adipose tissue and primarily stores energy. However, subcutaneous adipose tissue contains brown-like inducible adipocytes that perform mitochondrial and thermogenic functions and burn fat [286].

Brown adipose tissue, comprising 1% to 2% of body fat, has more mitochondria (thus its brown appearance) and is abundant in neonates but decreases in adults and decreases further in obese adults [286]. Brown adipose tissue produces heat energy, termed thermogenesis, uponβ-adrenergic stimulation [287].

Subcutaneous adipose tissue is the largest fat depot. Visceral adipose tissue is more metabolically active, vascular, and innervated than subcutaneous tissue. Ectopic fat, a third depot, is strictly pathogenic [48].

Fat depots are sexually dimorphic; on average, men have more visceral adipose tissue, and women have larger subcutaneous adipose tissue stores. Given the relative impact of fat depots on metabolic health, this sexual dimorphism may explain sex differences in metabolic disease risk until menopause, when decreased estrogen may increase low-density lipoprotein, triglycerides, visceral fat, morbidity, and mortality in women [48].

Adipocytes, which constitute the largest cell volumes in adipose tissue and are the defining fat cell type, have three important roles: lipid storage, insulin sensitivity, and secretory function. Disruption of any contributes to obesity-related metabolic disease states [288].

Some key players in adipose tissue physiology and obesity pathophysiology include glucose, glycogen, triglycerides, and insulin [289,290]. Glucose is a carbohydrate, one of three macromolecule classes (with fats and proteins); some argue alcohol is a fourth class. Glycogen is the storage form of glucose in liver and muscle. Triglyceride, the storage form of fatty acids, is made of three fatty acids linked to glycerol. The capacity to store carbohydrates (as glycogen) is limited. What cannot be stored as glycogen, or quickly used, gets stored as triglyceride. Insulin, released by pancreaticβ-cells in response to rising blood glucose, aims to store carbohydrate as glycogen or fatty acids.

Lipid Storage

During energy surplus, 60% to 80% of excess calories are stored as triglyceride by adipocytes [291]. Adipocytes can increase fat stores (lipogenesis) or release fatty acids (lipolysis) to supply other tissues with energy [278,285]. Insulin is critically involved in these processes.

For lipogenesis, adipocytes accumulate lipid through free fatty acids from circulating triglyceride and by synthesizing triglyceride from non-lipid metabolite sources, termed de novo lipogenesis [285]. For lipolysis, enzymatic cleavage of triglyceride by lipases generates glycerol and free fatty acids, which are released into circulation for use by organs as fuel (e.g., glycerol for liver gluconeogenesis) [288]. Lipolysis is controlled by sympathetic nervous system input and norepinephrine. In the fasting state, insulin levels drop, releasing norepinephrine, which promotes lipolysis [288].

Because adipose tissue is central to the regulation of systemic lipid metabolism, a balance between lipogenesis and lipolysis within adipocytes is required to maintain insulin sensitivity and energy homeostasis. Nutrient (free fatty acids and glucose) and hormonal cues regulate both processes [288].

Insulin Sensitivity

Insulin sensitivity of adipose tissue is vital to metabolic homeostasis and systemic energy balance [285]. Insulin binds to its receptor in liver, muscle, and adipose tissue to initiate several processes [48,292].

Insulin activates glucose transporter-4 (GLUT4) on cell surfaces, which transport glucose from the bloodstream into cells. On fat cells, insulin accelerates glucose delivery into adipocytes and induces breakdown of glucose into triglycerides for storage.

Insulin upregulates lipoprotein lipase on fat cell surfaces that bring free fatty acids into adipocytes to store them triglycerides. Insulin also increases triglyceride accumulation by inhibiting their breakdown and release as free fatty acids.

The primary source of glucose for all tissues and largest glucose storage site (as glycogen) is the liver. Hepatocytes are critical intermediaries in energy (lipid, carbohydrate) metabolism. Insulin decreases glucose output by the liver, the main target for pancreatic insulin and glucagon [292,293].

During caloric deficit, low insulin disinhibits lipolysis, which mobilizes lipids to meet energy demand. However, elevated insulin during caloric excess stimulates glucose uptake, inhibits lipolysis, and orchestrates de novo lipogenesis. The body goes into "storage" mode of carbohydrates and fat. These normal functions of insulin help protect against the cellular and tissue toxicity caused by high circulating glucose and free fatty acids [285,289].

Endocrine and Immune (Secretory) Function

As an endocrine/immune organ, adipose tissue releases adipokines (via adipocytes) and receives (via receptors) metabolic signals to influence and regulate adipogenesis, lipid metabolism (lipogenesis and lipolysis), appetite and energy balance, inflammatory and immune response, glucose homeostasis (insulin sensitivity), vascular homeostasis (endothelial function), blood pressure, and other processes [128,285,288].

Adipokines are hormones, cytokines, extracellular matrix proteins, and growth factors that transmit information from fat tissue to other metabolic organs. They can act locally (paracrine) and/or systemically (endocrine) [128,285]. Adipocytes express receptors for nuclear and traditional hormones, adipokines, neuropeptides, lipoproteins, prostaglandins, endocannabinoids, and others [128]. Several adipokine hormones, including leptin and adiponectin, are regulators of systemic lipid and glucose homeostasis [285,288,294].

Accordingly, adipose tissue can release pro-inflammatory hormones (leptin), cytokines (e.g., tumor necrosis factor-alpha [TNF-a], interleukin-6 [IL-6], IL-8), acute phase response proteins (e.g., C-reactive protein [CRP]), chemokines (e.g., monocyte chemoattractant protein–1 [MCP-1]), and prostaglandins. In addition, adipose tissue can release anti-inflammatory hormones (adiponectin), interleukins (IL-10), and transforming growth factor beta 1 (TGF-beta) [128; 295; 296].

An immune response appears early during adipose accumulation. With excessive fat mass, local adipose-induced inflammatory processes progress to widespread systemic inflammation that damages distant tissue and induces a host of metabolic disorders and organ tissue complications in obesity [194,297].

Local Pathogenesis

Adipose tissue contains adipocytes, vascular cells, fibroblasts, cells of the innate (e.g., monocytes, macrophages, natural killer cells) and adaptive (e.g., lymphocytes) immune systems, and other cell types essential to its normal physiology that become abnormally altered and interact in the pathophysiology of obesity-related cardiometabolic complications [285,296]. To expand triglyceride storage as obesity develops and fat mass increases further, adipocytes abnormally increase in number (hyperplasia), then in size (hypertrophy) [278,285]. Hypertrophy compromises the function of adipose tissue, degrading the extracellular matrix which promotes a switch toward fibrosis that restricts adipocyte fat storage [295,298].

Triglyceride accumulation promotes hypoxia, apoptosis, and oxidative and mitochondrial stress in adipocytes and release of pro-inflammatory factors [287,296]. As obesity advances, lipid-laden hypertrophied adipocytes undergo necrotic and/or apoptotic cell death, contributing to the recruitment of inflammatory cells and to adipose tissue dysfunction [298].

Adipose tissue macrophages are essential for maintaining adipose tissue energy homeostasis and inflammatory response [291]. The adipose tissue macrophage phenotypic correlates to BMI and adipocyte size [296]. The obesity-induced M1 phenotype is associated with inflammation and tissue destruction; M1 may comprise 50% of all adipose tissue cells (compared with 10% to 15% in lean adults) [298,299].

As adipose tissue expands, angiogenesis lags. The hypoxic state triggers an inflammatory response, which initiates monocyte recruitment and differentiation into M1 adipose tissue macrophages [299]. Circulating macrophages infiltrate adipose tissue, producing MCP-1, which recruits more inflammatory cells to adipose tissue and TNF-a and further promotes MCP-1 production by adipocytes, recruiting yet more immune cells to adipose tissue. The M2 to M1 shift aggravates a vicious cycle of chronic low-grade inflammation [128,285].

Systemic Pathogenesis

The inflammatory adipose tissue microenvironment diffuses systemically and to remote organ sites. MCP-1 recruitment and proliferation into liver, adipose, pancreatic islet, intestine, and muscle tissue induces a pro-inflammatory M1 state [299]. Cytokines (TNF-a, IL-1b, IL-6) and adipokines (leptin) activate systemic and organ-specific inflammatory signaling pathways, impairing β-cell function, suppressing insulin secretion, and promoting accumulation of ectopic fat, insulin resistance and hyperglycemia [287,297,298,300].

Adiposopathic tissue pumps free fatty acids into circulation, leading to ectopic pathogenic deposition of fatty acids into pericardial and perivascular fat depots, within/around the liver, muscle, heart, pancreas, and kidney [128]. Ectopic fat intensifies local inflammatory activity and promotes lipotoxicity [300].

Insulin resistance in adipocytes impedes fat storage, accelerates lipolysis and further increases plasma free fatty acids, promoting insulin resistance in liver and muscle, hepatic steatosis and dyslipidemia, and contributing toβ‐cell failure. Insulin resistance in muscle and fat is marked by impaired glucose transport from circulation due to M1 inhibition of GLUT4, leading to hyperglycemia [301].

Increased ectopic fat deposition, lipotoxicity from excess circulating free fatty acids, glucose toxicity, along withβ‐cell resistance to GLP-1, cause progressive failure ofβ‐cell functioning. Increased glucagon and enhanced liver sensitivity to glucagon lead to excessive hepatic glucose production. Increased renal glucose reabsorption by sodium/glucose co‐transporter 2 (SGLT2) helps maintain hyperglycemia.

Insulin resistance in obesity leads to chronic compensatory hyperinsulinemia, which in turn promotes further weight gain [302]. This is exacerbated by resistance to the anorexigenic effects of insulin, leptin, GLP-1, amylin, and PYY [303].

Insulin resistance, hyperglycemia, and hyperinsulinemia in obesity promote hypertension, dyslipidemia, endothelial dysfunction, and a prothrombotic state, leading to NAFLD and type 2 diabetes [304]. NAFLD increases the risk of liver cirrhosis and hepatocellular carcinoma and is strongly correlated with cardiovascular disease and type 2 diabetes [305].

Type 2 diabetes, the predominant consequence of insulin resistance accounting for more than 90% of all diabetes cases, can lead to disabling and life-threatening microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiovascular disease) complications [304,306].

Biomechanical Consequences of Obesity

Local biomechanical stress due to excessive fat mass and body weight (e.g., on the joints, respiratory tract, blood vessels or within the abdominal compartment) causes and/or exacerbates morbidities common in patients with obesity, such as knee osteoarthritis, back pain, restrictive lung disease, obstructive sleep apnea, gastroesophageal reflux disease (GERD), hernias, and chronic venous insufficiency. These complications are further aggravated by the adverse metabolic profile and chronic inflammatory state in obesity, amplifying the overall burden of the disease and creating a vicious cycle that can be effectively broken only by sustained weight loss [302].

"Metabolically Healthy" Obesity

The concept of metabolically healthy obesity has been described in the literature. In general, it is defined as obesity in the absence of type 2 diabetes, hypertension, and hypercholesterolemia. Some have questioned the cardiovascular disease risk of persons with metabolically healthy obesity, suggesting this as a low-risk phenotype [307]. However, a large cohort demonstrated that obesity is a risk factor for cardiovascular disease regardless of whether the individual remained metabolically healthy over long periods [308]. Furthermore, a study of 270 patients who met strict inclusion criteria for metabolically healthy obesity found that even with strict criteria to eliminate all patients with any metabolic problems, a significant proportion had unsuspected NAFLD (35.5%); some had steatohepatitis (8.2%) and liver fibrosis (4.4%) [305].

Psychiatric Disorders

The neuropathological processes that lead to psychiatric disorders share common brain pathways with those that lead to obesity, metabolic syndrome, and cardiovascular disease risk factors, each of which can influence the risk for the others. Evidence points to a critical role for two major pathways: inflammatory processes that induce alterations of brain functions, and chronic stimulation of the hypothalamic-pituitary-adrenal (HPA) axis [87].

Psychiatric disorders are often characterized by a chronic HPA axis activation and sustained cortisol elevation, both of which are linked to abdominal obesity, hepatic steatosis, insulin resistance, and cardiovascular disease. Conversely, increased adiposity leads to chronic low-grade activation of inflammatory processes, which plays a potent role in the pathophysiological brain alterations associated with psychiatric disease. Thus, adiposity-driven inflammation may contribute to the growing prevalence of mood disorders [87].