Similarly, the subcutaneously once weekly formulation of the GLP-1 receptor agonist semaglutide showed equally promising results for weight maintenance . The benefit of the GLP-1 agonists may be from the reduction of adiposity, or non-adiposity related. The opposing pathway is the agouti-related peptide (AgRP) neurons which stimulate hunger and increase food intake, often referred to as the orexigenic pathway . This is referred to as the melanocortin system and is composed of two differing populations of neurons involved in satiety and food intake. Despite its somewhat attenuated impact on energy expenditure, there is evidence that exercise still helps to achieve weight loss maintenance. In simple terms, exercise is related to energy expenditure, and therefore increasing exercise increases energy expenditure and therefore weight loss. However, as detailed in this review, calorie reduction generally leads to short-term weight loss, with poor success rates for long-term weight loss maintenance. The conceptual framework for weight regain and weight loss maintenance is based on the theory that the human body acts to defend a particular body mass, via the hypothetical “settling point” of weight 226,227,228. In this setting, prevention of weight regain may be better-termed weight loss maintenance. Despite the overall efficacy of the incretin-based treatments for weight loss, there is a lack of long-term controlled studies beyond about 4 years available 221,222. The question of whether the ratio between fat mass and lean body mass is disrupted or maintained during weight loss with GLP-1 agonists is still unresolved 183,184. Avoiding Weight Regain The cardiometabolic consequences of obesity such as insulin resistance, glucose intolerance, type 2 diabetes, arterial hypertension, atherosclerosis, and dyslipidemia are all stressors on the heart and vascular system 18,19. Obesity has harmful effects on various body systems, most notably on the cardiovascular and endocrine systems, but also on the kidneys, liver, lungs, joints, and immune system . We focused primarily on clinical trials conducted in humans and also included in vitro and animal studies for mechanistic and molecular insights. Four found energy intake to be significantly reduced, whereas the remaining studies failed to find an effect – again potentially due to limited statistical power and also low GLP-1 infusion rates. By 2000, seven studies had been published on the acute effect of peripheral GLP-1 administration on ad libitum energy intake. The pivotal findings of the study in which we infused GLP-1 in human subjects showed that it enhanced satiety reduced hunger during a fixed breakfast meal and reduced spontaneous energy intake by 12% during an ad libitum lunch meal . The effects on weight, cardiovascular health, and other parameters of decreasing the dose or pausing and resuming the use of GLP-1 agonist is an area where evidence-based studies are needed. Other studies have found little to no impact of physical activity on maintaining weight loss . For instance, those with high levels of physical activity are more successful at weight loss maintenance 257,258,259. Specifically, a decrease in processed and ultraprocessed food consumption would be beneficial for weight loss maintenance. Mads Krogsgaard Thomsen, at the time R&D executive in the Diabetes Care Division of Novo Nordisk, undertook the initiative to synthesize long-acting GLP-1 analogues (Fig. 1), and the first GLP-1 analogue brought into clinical development was liraglutide, a once-daily injection.Patients should be aware of these potential unwanted effects and, to minimize loss of muscle mass, encouraged to participate in resistance exercises and increase protein intake .For Contrave, a weight loss plateau seems to occur for all the COR studies around 32 to 36 weeks with overall weight loss around 8 to 9%.Two trials have supported an increase in the risk of all types of thyroid carcinoma 200,201.GLP-1 receptor agonist drug development began in earnest in 2005 with the approval of exenatide, a synthetic form of a natural peptide hormone isolated from the saliva of the venomous lizard Gila monster .GLP-1 agonists are being explored as an adjunctive therapy to combine with bariatric surgery to avoid the weight regain that can occur post-surgery 81,82.An example would include the usage of liraglutide that helped one achieve a particular amount of weight, but continued usage of the drug led to weight regain, would switching to Contrave help to achieve weight loss maintenance?In an 8-week study using low-dose liraglutide (0.6 mg/day) in patients with type 2 diabetes no weight or fat loss was produced, but both fasting and postprandial glucose were substantially reduced, but neither fasting nor postprandial insulin (or C-peptide) response was increased .(This alone is a topic worthy of much more research, with weight gain in women over the age of 50 years – which greatly increases their cardiometabolic health risks – traditionally viewed by medical scientists as just an inevitable part of the aging process.) Certainly, teaching patients to be mindful of their eating and to consume adequate protein can contribute to weight loss maintenance success and overall health . GLP-1 agonists demonstrate efficacy for weight loss maintenance, but only while the patient is continuing to use the medication. Amylin analogs such as cagrilintide are being explored for obesity treatment in concert with GLP-1 drugs . 5.4. Mental Health At 1 year after cessation, an estimated 40.2% of the on-treatment weight loss remained. We searched MEDLINE, Embase, Cochrane Library, Scopus and Web of Science from inception to December 26, 2024 for randomised controlled trials and observational studies reporting weight outcomes after cessation of GLP-1RAs in adults with overweight or obesity. However, discontinuation is common, and clinical trials have demonstrated significant weight regain following cessation. GLP-1 Receptor Agonists and Weight Regain The emergence of GLP-1 receptor agonists has re-invigorated interest in anti-obesity medications and more effective weight management. At 3 years of follow-up, tirzepatide use led to a sustained mean loss of weight of 20% with less likelihood of deterioration to diabetes in persons with obesity and prediabetes when compared to placebo . Persistence of the weight loss plateau (or presumed weight loss maintenance) occurred up until 104 weeks . The weight loss plateau occurred after about 20 weeks and continued until the drug was stopped at 56 weeks. To date, liraglutide, and the more effective once-weekly semaglutide, have been approved in the US and Europe for the treatment of obesity, with unprecedented weight loss of up to 15–20%. Six infusion studies provided us with 147 participants, and we found that GLP-1 reduced energy intake dose-dependently in both lean and overweight participants (a mean of 13%, P 3) . Additionally, we review the evidence of four recent clinical trials, two systematic reviews, and two meta-analyses describing the efficacy of GLP-1 agonists in decreasing weight, lowering HbA1c, and improving obesity comorbidities. This review investigates the various pharmacologic treatments for overweight and obesity in adults, especially glucagon-like peptide 1 (GLP-1) agonists. In our discovery studies GLP-1 enhanced satiety during a meal but lacked the insulinotropic effect in the natural setting of people consuming mixed meals (Fig. 4). Mads Krogsgaard Thomsen, at the time R&D executive in the Diabetes Care Division of Novo Nordisk, undertook the initiative to synthesize long-acting GLP-1 analogues (Fig. 1), and the first GLP-1 analogue brought into clinical development was liraglutide, a once-daily injection. We therefore conducted an individual participant data analysis, pooling raw data from the existing studies . Treating Obesity: Current Therapies In this study population, 88% were able to keep 10% of their body weight off at year 5 and 87% at year 10. To participate in the study, weight loss greater than 30 pounds had to have been maintained for more than 1 year at the time of enrollment. It is worthwhile to note in both studies all participants were prescribed a reduced calorie (500 kcal/day deficit) and increased physical activity 150 min/week) regimen, which was insufficient to help preserve the initial weight loss. Cessation of these drugs to see if weight maintenance could be achieved was largely unsuccessful (Table 3). However, even during active weight loss, metabolic adaptation seems to be set into motion, and in fact may be triggered by achieving 11% of total body weight loss 236,237. And weight gain wasn't the only issue, as the rebound also negated the positive impact GLP-1 medications had on heart and metabolic health markers, including cholesterol and blood pressure. The findings raise questions about whether this "magic cure" for obesity is actually unsustainable without a life-long commitment to the medication. Data for this study were extracted from the published literature. The study used only openly available human data that were originally located in published articles indexed in MEDLINE, Embase, Cochrane Library, Scopus, and Web of Science. In this systematic review, we aimed to characterise the trajectory of weight regain after GLP-1RA cessation. Senior, M. After GLP-1, what’s next for weight loss?. The GLP-1 agonist Wegovy has re-energized the hunt for obesity treatments. Additionally, there are those who are attempting to prevent weight regain after already achieving a weight-reduced state. It is worthwhile to point out that a weight loss plateau is often stated with the assumption that additional weight loss is desired, but difficult to achieve. Definitions of weight regain may vary, namely the duration and how much is considered significant. The general trajectory of weight loss with initiation of GLP-1 therapy has been well-studied (Table 2) 218,219,220. Despite this, animal studies have demonstrated decreases in pancreatic secretion in response to GLP-1 elevation, therefore the mechanism behind this potential interaction of GLP-1 receptor analogs and pancreatitis remains elusive . It is estimated that around 80–90% of patients will develop an adverse effect from the use of this class. In addition to nausea and vomiting, other GI-related side effects include diarrhea, constipation, dyspepsia, decreased appetite, and abdominal pain 158,159,160. The most often reported side effects are nausea and vomiting which are a result of activation of specific GLP-1 receptors in the hindbrain and these symptoms can be mitigated with gradual dose escalation 155,156,157. GLP-1 medications can cause a range of side effects related to the gastrointestinal system as well as changes in muscle mass and effects on the appearance of the face and loss of hair (Figure 2). Early case reports called into question appropriate fasting times for pre-procedural and operative fasting due to retained gastric contents and risk of aspiration in patients taking GLP-1 medications and compounds 213,214. Secondarily medically induced weight loss, particularly when totaling in excess of 5% of total body weight has demonstrated effectiveness in improving fertility . The long-term effect of GLP-1 on retinopathy in patients with type 2 diabetes may in fact be beneficial. Studies to clarify this issue would particularly be needed for patients who are afflicted with sarcopenic obesity, a condition of a mismatch between muscle and fat mass. It is thus not surprising that these same side effects of rapid weight loss are seen as a class effect. While there is optimism that continuing use of GLP-1 treatments will preserve weight loss, most other anti-obesity strategies, including surgical interventions, generally have weight recidivism . It is unclear whether those without type 2 diabetes using GLP-1 for weight loss are at the same risk 197,198. The landmark GLP-1 drug trial for semaglutide, STEP 1 (semaglutide treatment effect in people with obesity), demonstrates a significant loss of total lean body mass , which has been further corroborated by other investigators . Randomized double-blinded placebo-controlled withdrawal studies were performed in both semaglutide and tirzepatide with crossover to placebo at 20 weeks and 36 weeks, respectively 242,243. In situ hybridization studies in animal models demonstrated GLP-1 receptor presence in many other brain areas such as the thalamus, nucleus accumbens, and hindbrain. Early studies demonstrated the anorectic actions of GLP-1 on the hypothalamus 238,239. While this does seem to be true over the lower ranges of physical activity, with the upper ranges of physical activity the energy expenditure appears to plateau, consistent with a “constrained total energy expenditure model” 255,256. While most of the interventions are based on targeting hunger and energy expenditure, there is little understanding of whether physical activity or exercise plays a role . However, this treatment strategy is still in the early stages although the National Institutes for Health (NIH) recently has invested in research in the area of personalized nutrition. Qsymia has demonstrated overall efficacy for weight loss maintenance, achieving sustained weight loss of 9-10% at the 108-week mark compared to 1.8% for placebo . For Contrave, a weight loss plateau seems to occur for all the COR studies around 32 to 36 weeks with overall weight loss around 8 to 9%. However, the weight regain is relatively mild and by 104 weeks there is still overall weight loss. Finally, the microbiome has a variety of mechanisms through which it affects obesity, and pre/probiotic therapies could be a helpful addition to a weight loss regimen 58,59. These include favorable effects on heart and brain health and decreased diabetes risk 55,56. However, challenges remain in such multi-agonist receptor treatments, and the focus remains predominantly on energy intake . There are conflicting data in animal models regarding GLP-1-related drugs stimulating energy expenditure . The additional properties of inhibition of glucagon secretion and inhibition of caloric intake accelerated the development of GLP-1 receptor agonists for usage in type 2 diabetes management . Subsequently, we showed that GLP-1 induces satiety equally well in people with obesity . In 1999, Gutzwiller et al. showed a dose-dependent reduction in food intake with GLP-1 infusion in 16 healthy male subjects . We found that, after the energy-fixed breakfast, GLP-1 markedly enhanced satiety and fullness compared with placebo (Fig. 2) . We conducted the trial in 20 young, healthy, normal-weight men in a placebo-controlled, randomized, blinded, crossover design. The study was conducted in 1995–1996, and we used commercially available synthetic, human GLP-1 (7–36 amide) . And, as the researchers add, the study isn't to frame GLP-1 medications as a waste of time and money, but that users should keep in mind that they need a more holistic approach to weight loss that can help sustain the results they get while taking the drugs. Endogenous hyperinsulinemia may cause weight gain and obesity , and treatment with insulin causes substantial weight gain, and may even increase cardiovascular risk . The reports of increased residual gastric content after long-term treatment with GLP-1 analogues emphasize that the effect on gastric emptying is sustained, even though that it does normally not pose a risk for postoperative respiratory complications . A large body of evidence has demonstrated that complete remission of type 2 diabetes can be achieved by a major weight loss. A multi-agonist approach is a likely road for the future of anti-obesity drug development involving novel receptors such as glucagon and amylin possibly with even more profound weight loss 286,287. Studies suggest that GLP-1 drugs are not a direct cause of depressive symptoms in weight loss . Newer strategies for weight maintenance have focused on preserving or even increasing lean body mass to counteract the decreases in energy expenditure thereby allowing for sustained weight loss 105,263. My view is that the pronounced effect of GLP-1 analogues on gastric emptying is not only an important mediator of satiety and reduced food intake but also a likely mechanism responsible for its effect on type 2 diabetes and cardiovascular disease. Until recently, the only effective treatment for obesity was bariatric surgery, and a century of drug development for obesity can be essentially described as a failure until now. Today it is well established that excessive body fat together with lack of regular physical activity, together with a genetic predisposition, are the main causes of type 2 diabetes, contributing as well to a substantial proportion of cardiovascular diseases, cancers, and other chronic degenerative diseases. The rapid weight loss can be visualized in many areas of the body and one of these manifestations known as “Ozempic face” occurs when fat pads in the face are rapidly depleted 177,178. As the newer agents in the GLP class have become incredibly potent where users are losing an estimated 15-20% of body weight, with much of the weight loss occurring in the initial weeks of initiating the drug 175,176. Early studies on patients with type 2 diabetes treated with incretin therapy including GLP-1s and dipeptidyl peptidase-4 (DPP4) inhibitors did demonstrate an association between drug usage and the development of pancreatitis . A 3-year extension of the SCALE trial showed that persons with overweight or obese and prediabetes taking liraglutide had a reduced risk for developing type 2 diabetes with greater weight loss compared to those taking a placebo Obesity may present itself with multiple clinical phenotypes and also varied treatment responses. Obesity as defined by The Obesity Society (TOS) is a multi-factorial chronic disease that results from excess fat accumulation that presents a risk to health . Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal. A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued. Severe obesity, which is defined as a BMI over 40 kg/m2, is an alarming public health issue . A BMI (in kg/m2) in the range of 18.5–24.9 is considered normal, 25–29.9 is overweight, and ≥30 is considered obese. We limited our search to studies from January 1995 onwards, with further relevant studies identified from citations within papers. However, in the last 20 years, the gastrointestinal system has been identified as the largest endocrine organ and has demonstrated the key role of gut hormones in energy homeostasis . Admittedly, the lesser potency of these drugs in the initial weight loss phase often overshadows their potential for usage for weight loss maintenance purposes.However, discontinuation is common, and clinical trials have demonstrated significant weight regain following cessation.Ideally, the chosen initial intervention for weight loss would also be effective for weight loss maintenance.The metabolic efficacy of bariatric surgery in increasing gut production of GLP-1 to supraphysiologic levels postprandially is considered a major factor in early weight loss .Background Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as breakthrough weight loss agents.A somewhat paradoxical effect has been demonstrated with GLP-1 usage and other agents for type 2 diabetes in which rapid improvement in glycemia results in worsening of retinopathy .This is referred to as the melanocortin system and is composed of two differing populations of neurons involved in satiety and food intake.In 1994 I took up the idea with Holst that GLP-1 could also be a mediator of meal-induced satiety, and we designed a study to infuse GLP-1 into normal human volunteers. Treating obesity has evolved in recent years, with various shifts in dietary, pharmacological, and surgical strategies available for the management of obesity . In this condition, excessive adiposity may restrict the lungs and impede their inflation, and adipose tissue in the diaphragm may compromise muscle strength, leading to intermittent hypoxia and hypercapnia 36,37. Obesity also elevates the risk of developing some types of cancer including colorectal, esophageal, liver, and kidney malignancies 28,29,30,31,32. The inflammatory environment incites endothelial dysfunction further contributing to cardiovascular risk and hypertension 22,23,24. GLP-1 receptor agonist drug development began in earnest in 2005 with the approval of exenatide, a synthetic form of a natural peptide hormone isolated from the saliva of the venomous lizard Gila monster . The usage of compounding pharmacies does come with risks as the medications produced are not FDA-regulated . Such a rapid increase in usage led to multiple drug shortages beginning in 2022 which continued through late 2024 . In an analysis of one US health systems database a 700% increase in GLP-1 prescribing over the past four years was noted, primarily driven by prescriptions for obesity . While GLP-1 drugs have been around for more than a decade, 2024 saw a 700% increase in the number of Americans taking the medications for weight loss. While there's no doubt that GLP-1 drugs like semaglutide and tirzepatide have transformed how we treat obesity, it's worth noting that around half of users stop taking the medication within 12 months, having achieved their weight-loss goals. "While considerable weight loss, even if temporary, may still bring some health benefits for those with obesity, people using GLP-1 receptor agonists should be aware of the high discontinuation rate and the consequences of cessation of medications." Regular physical activity is also recommended as a component of weight loss programs not only for energy expenditure, but for cardiometabolic health as well . Exceeding 6-12 months of use may have undesired effects by increasing LDL cholesterol and cardiovascular risk in some studies, but others have found no difference 50,51,52,53. Numerous studies have demonstrated that dietary macronutrient composition is not the most significant contributing factor for weight loss 44,45,46. Dietary advice historically has seen energy restriction as the foundation for weight loss. Keywords were then refined based on the relevance of the results, and additional terms were searched to survey related areas including “cardiometabolic risk factors”, ‘sarcopenia”, “exercise”, “body mass index (BMI)”, and “appetite”. While largely successful as an anti-diabetic drug therapy, the effects on both reducing food intake and promoting weight loss in persons with diabetes and animal models prompted further study as an anti-obesity medication 87,88. For the first time in the history of obesity medications we see weight loss efficacy of a magnitude that might raise concern about excessive loss of lean body tissue due to the initial pronounced reduction in energy intake and subsequent risk of protein deficiency. Perhaps the least successful of the FDA-approved weight loss drugs in terms of achieving weight loss maintenance is Orlistat (tetrahydrolipstatin). Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Health consequences of excess weight include cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality. (This alone is a topic worthy of much more research, with weight gain in women over the age of 50 years – which greatly increases their cardiometabolic health risks – traditionally viewed by medical scientists as just an inevitable part of the aging process.) In August 2025, researchers found that 12% of US adults have tried a GLP-1 drug to manage their weight – with a fifth being women aged 50 to 64 years, when menopausal hormonal shifts make it much harder to lose pounds by diet and exercise alone. "This evidence cautions against short term use of weight management medications, emphasizes the need for further research into cost effective strategies for long term weight control, and reinforces the importance of primary prevention." However, over the years, many studies have shown no differences in achieving weight loss from a variety of macronutrient approaches and calorie reduction is likely the more successful approach for weight loss maintenance 250,251. Not surprisingly, food composition is often an area of question by both scientific communities and the food industry to determine the right “mix” of macronutrients to facilitate weight loss and weight loss maintenance. Clinical studies have supported this with GLP-1 receptor analogs such as liraglutide and semaglutide in both weight loss and weight loss maintenance trials. Incretin-based medications and other anti-obesity medicines target hunger, therefore fostering both weight loss and weight loss maintenance. This can be attributed to the persistent effects of metabolic adaptation, the phenomena seen in weight regulation that may cause weight regain and potentially a weight loss plateau . In this review, we explore the current medical therapies for obesity, including all major categories, individual mechanisms of action, pharmacokinetics and pharmacodynamics, adverse effects, risks, and absolute contraindications. However, even surgical weight loss reaches a peak weight nadir 1 to 2 years after surgery and weight regain tends to occur after. However, the only truly long-term strategy that has been the most successful for long-term weight loss is surgical weight loss. There is an existing network of neurons within the hypothalamus that is widely studied for its role in energy homeostasis. However, in a murine model, knockout of glucagon genes originating from the bowel elicited no increase in food intake, and thus appetite suppression is attributed to GLP-1 produced within the CNS . GLP-1 secretion seems to be impaired in obese subjects, which informs at least the partial role of GLP-1 in the pathophysiology of obesity 94,95,96. Energy balance is buffered by fat stores and the adipose compartment therefore potentially producing an obesogenic state . Explore content Obesity-driven inflammatory processes are responsible for a large portion of the damage inflicted by excess weight (Figure 1). Kim et al. found a linear association between waist circumference and all-cause mortality in a study on 23,263,878 subjects over the age of 20 years . It should be noted, however, that BMI, although easy to gauge, has limitations when utilized as a diagnostic tool because it does not account for the exact muscle mass or fat mass, especially visceral adipose tissue. Energy balance is dependent on nutrient intake and subsequent nutrient oxidation rates 89,90. The initial attention in the clinical space for GLP-1 was related to the glucose-dependent insulin secretion effect, often referred to as the incretin effect . Possible complications of the gastric bypass include bowel obstruction and malabsorption, while possible complications of the sleeve gastrectomy include venous thromboembolism and gastroesophageal reflux disease 78,79. Obesity is traditionally defined as an excess of body fat, and is classically categorized in clinical practice in terms of body mass index (BMI). In order to present these drugs with a balance of their pros and cons, the longer-term studies showing cardiovascular benefits are also taken into account. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. With the GLP-1 discontinuation rate high among adults who are overweight or obese – one 2025 study of 125,474 individuals found that 46.5% of patients stopped taking the medication after a year – the researchers call for more work to support people in managing their weight long-term. This new study, however, shines a light on how GLP-1 medications can lead to people putting more importance on drug intervention than nutrition, diet and physical activity for weight management – all things crucial for long-term cardiometabolic health. These findings provided a better understanding of the physiology of GLP-1 and the pharmacology of its analogues and have revolutionized the management of obesity and several comorbidities. According to this scenario, obesity and hyperinsulinemia initiate a vicious metabolic cycle leading to deterioration of glucose tolerance and eventual development of T2DM. Whereas general obesity and central adiposity, in particular, are the primary factors responsible for the development of insulin resistance, postprandial increases in insulin secretion causes a further expansion of the adipose tissue mass, which further worsens insulin resistance. The overall reduction in insulin secretion is also shown by reduced levels of C-peptide in the same studies. Due to the reduced food intake total carbohydrate ingestion is also reduced, which will further reduce glycemia. These effects could be at least partially attributed to the slowing of gastric emptying. However, that study was done in only 6 subjects, raising concerns about the lack of statistical power to detect a clinically relevant effect. Furthermore, spontaneous energy intake at the ad libitum lunch was reduced 12% by GLP-1 infusion (Fig. 2). Meanwhile, in January 1996 the first rodent study suggested that GLP-1 could be a central regulator of feeding behavior and satiety based on intracerebroventricular injection studies , but soon thereafter the results of other rodent studies using peripherally injected GLP-1 argued against an appetite effect . We found that, after the energy-fixed breakfast, GLP-1 markedly enhanced satiety and fullness compared with placebo (Fig. 2) .And, as the researchers add, the study isn't to frame GLP-1 medications as a waste of time and money, but that users should keep in mind that they need a more holistic approach to weight loss that can help sustain the results they get while taking the drugs.Dietary advice historically has seen energy restriction as the foundation for weight loss.Such a rapid increase in usage led to multiple drug shortages beginning in 2022 which continued through late 2024 .Ever since the UK Prospective Diabetes Study demonstrated modifiable retinopathy with improvements in glycemic control, clinicians and patients have aimed to improve glucose as a standard of management in type 2 diabetes .A BMI (in kg/m2) in the range of 18.5–24.9 is considered normal, 25–29.9 is overweight, and ≥30 is considered obese.However, earlier studies showed inconsistences of GIP as a cause of weight loss, although more recent studies have demonstrated increased weight loss efficacy 280,281,282,283.VAS had been mainly used to measure subjective sensations (e.g. pain) and studies of appetite lacked validated measures.“This evidence suggests that despite their success in achieving initial weight loss, these drugs alone may not be sufficient for long term weight control,” they wrote. The low carbohydrate diet involves consuming a low content of carbohydrates and a high content of fat and protein. When looking at macronutrient content, initially, dietary fat, carbohydrate, and protein content are scrutinized. For instance, high protein diet, Mediterranean-style diet, low carbohydrate diet, low-calorie diet, and low-fat diet are just several options 42,43. Although both the association of retinopathy and NAION can be seen with GLP-1 use, it is worth noting that a majority of cases occurred in patients with type 2 diabetes. Ever since the UK Prospective Diabetes Study demonstrated modifiable retinopathy with improvements in glycemic control, clinicians and patients have aimed to improve glucose as a standard of management in type 2 diabetes . Tirzepatide has demonstrated total lean mass loss as well, although additional studies are needed to determine the impact of this 134,182. And weight gain wasn't the only issue, as the rebound also negated the positive impact GLP-1 medications had on heart and metabolic health markers, including cholesterol and blood pressure.We conducted the trial in 20 young, healthy, normal-weight men in a placebo-controlled, randomized, blinded, crossover design.Qsymia has the longest-term data of the available oral anti-obesity drugs, upwards of 108 weeks .Today it is well established that excessive body fat together with lack of regular physical activity, together with a genetic predisposition, are the main causes of type 2 diabetes, contributing as well to a substantial proportion of cardiovascular diseases, cancers, and other chronic degenerative diseases.While the area of anti-obesity medication development is expanding, GLP-1 receptor agonists are already available and represent substantial progress in the growing armamentarium for use in weight loss.However, as detailed in this review, calorie reduction generally leads to short-term weight loss, with poor success rates for long-term weight loss maintenance.University of Oxford researchers assessed a range of clinical trials as well as Medline, Embase, PsycINFO, CINAHL, Cochrane and Web of Science databases, with a focus on what happened after cessation of treatment regarding adults who were overweight or obese.In addition to its effect on body weight, a variety of health benefits have been ascribed to it.The authors of this study pointed out that there appears to have been a slowing of weight regain towards the end of the study, implying a weight loss plateau below the initial pre-treatment weight.However, even during active weight loss, metabolic adaptation seems to be set into motion, and in fact may be triggered by achieving 11% of total body weight loss 236,237. A somewhat paradoxical effect has been demonstrated with GLP-1 usage and other agents for type 2 diabetes in which rapid improvement in glycemia results in worsening of retinopathy . While these cosmetic findings are an issue, the loss of lean body mass is another area of concern . It is important to note that these studies mostly included dipeptidyl peptidase-4 DPP4 and early GLP-1s, exenatide, and liraglutide. Common adverse effects of GLP-1 agonists and approaches to minimizing these consequences. The FDA and studies from a cohort of Scandinavian patients concluded no association between GLP-1 use and suicidal ideation, self -harm, or new onset of depression 208,209,210. All studies are in agreement that the greatest risk if any does occur in the initial months or year of therapy 200,201,202,203,204. All GLP-1 agents have carried an FDA black-boxed warning of increased risk of C cell thyroid carcinoma and recommended agents used in patients with a personal or family history of multiple endocrine neoplasia type 2A or 2B. Precision medicine itself is an area of medical management that tries to match personalized treatments or food content, to individual genetics, microbiome, metabolism, age, and sex. However, consumption of ultraprocessed food has been shown to induce an even greater consumption of calories, and therefore leads to weight gain. This can be attributed to the metabolic adaptations that are seen to occur in those with obesity. It is worthwhile to note these variables are all related to appetite, hunger, and caloric intake. Clinical trial outcomes will determine whether these will be useful either on their own or in conjunction with GLP-1 agonists. The effect of tirzepatide on energy expenditure appears negligible, therefore making the effect on energy intake the most impactful . Patients have also been reported to take “drug holidays” in which they pause the use of the drug intermittently for special occasions, but there is very little in the literature on this . It is a temporary and minimally invasive therapy that reduces stomach capacity and results in decreased hunger and food intake 68,69. The Mediterranean diet has a higher composition of fatty acids, unlike the conventional Western diet. It is especially suitable for individuals with type 2 diabetes and/or insulin resistance . The approval of tirzepatide, a novel long-acting dual incretin agonist of both GLP-1 and another incretin, GIP, continues to create excitement for the development of anti-obesity medications . A supportive weight management team approach considers mood changes and how they can affect quality of life 269,270. Data from the NWCR also suggest successful weight maintainers can spend upwards of one hour per day in light physical activity . A recent multi-society joint guidance statement advocated for an individualized approach based upon each patient’s unique factors rather than a one-size approach of holding this medication for all patients undergoing procedures . Specific guidance on the usage of alternate methods of birth control is provided by drug manufacturers. Firstly, with delayed gastric emptying, nausea, vomiting, and diarrhea there is a potential for impaired absorption of oral contraceptive pills. Emerging data have established that GLP-1 agonist administration has not increased the risk of malignancy outside of the thyroid gland and may in fact reduce the risk of malignancy with potential for preventive applications 203,204. The STEP-1 trial is considered the pivotal trial that demonstrated 14.9% weight loss at 68 weeks with semaglutide 2.4 mg . Liraglutide was the first injectable daily GLP-1 receptor agonist that was approved by the FDA for weight loss in 2014. A number of clinical trials in persons with diabetes have been subsequently performed and frequently cited for the clinical efficacy of exendin-4 147,148. Since the FDA approval of liraglutide for weight loss in 2015, the use of this class of medication has exploded, particularly over the last few years with the availability of weekly GLP-1s including tirzepatide and semaglutide. An even greater weight loss is seen with this novel dual agonist, achieving upwards of a 22.5% weight loss at 72 weeks 134,135,136. Therefore, treating hyperphagia is the strategy for both weight loss and weight loss maintenance. For those with untreated obesity and seeking active weight loss, decreasing hunger and achieving caloric restriction is seemingly the primary process that needs to occur. However, if one were to choose a mechanism to prevent weight regain, targeting hunger would seem to be the better alternative due to the greater effect of metabolic adaptation on hunger, rather than the decrease in energy expenditure . GLP-1 agonists are being explored as an adjunctive therapy to combine with bariatric surgery to avoid the weight regain that can occur post-surgery 81,82. Variations of Roux-en-Y gastric bypass limb lengths have shown potentially increased weight loss and metabolic benefit, but also, possible early and late significant complications 75,76,77. It can be used as a primary treatment for obesity, as an alternative for patients who do not qualify for bariatric surgery, or as a bridge to surgery . In 1994 I took up the idea with Holst that GLP-1 could also be a mediator of meal-induced satiety, and we designed a study to infuse GLP-1 into normal human volunteers. These results provided us with the essential methodology to design the GLP-1 infusion study and provided information on the estimated number of participants needed for adequate statistical power. In an initial pilot study, we demonstrated the need for more comprehensive validation . VAS had been mainly used to measure subjective sensations (e.g. pain) and studies of appetite lacked validated measures. The putative satiety effect of a compound would be seen as an effect on satiety VAS during the breakfast meal and on the spontaneous caloric intake at the lunch meal. The lack of long-term clinical trials in weight management compels clinicians to consider potentially unforeseen long-term side effects of the GLP-1 receptor agonists. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. “This evidence suggests that despite their success in achieving initial weight loss, these drugs alone may not be sufficient for long term weight control,” they wrote. Scientists were chasing an incretin hormone, and when GLP-1 was finally discovered, we found that it had a pronounced satiety effect, slowed down gastric emptying, and actually reduced postprandial insulin response. It delays gastric emptying and acts on areas of the brain controlling appetite and signaling fullness. Amylin is a non-incretin hormone produced in the pancreas by β cells that is released upon nutrient intake. The use of GLP-1 drugs as a weight loss tool is prevalent and effective, but it is preferable to find ways to keep the weight off without a lifetime of drug treatment and this is an area that needs attention . An example would include the usage of liraglutide that helped one achieve a particular amount of weight, but continued usage of the drug led to weight regain, would switching to Contrave help to achieve weight loss maintenance? These successful subjects with weight loss maintenance reported high levels of physical activity, high levels of dietary restraint, low calorie, and fat intake, and low levels of overeating (loss of control of eating or disinhibition) . The authors of this study pointed out that there appears to have been a slowing of weight regain towards the end of the study, implying a weight loss plateau below the initial pre-treatment weight. Developing treatment paradigms for weight loss maintenance remain focused on decreasing hunger, despite the compensatory decrease in energy expenditure . We were quite excited by the findings, as this study was the first to demonstrate a physiological role of GLP-1 in appetite control and energy intake in humans. The study showed the validity of quantification of hunger, satiety, and prospective food consumption measured by VAS as well as measurement of ad libitum energy consumption and showed that the appetite recordings during the breakfast meal predicted the energy intake during the lunch meal . Gut peptide hormones such as GLP-1 could potentially also have an impact on appetite regulation by effects on gastric emptying and direct CNS effects, but we needed a robust methodology that could be used to measure acute effect of putative hormones on subjective appetite and spontaneous food intake. Their identification of the amino acid sequence of the biologically active GLP-1 hormone laid the groundwork for drugs in the management of type 2 diabetes. Moreover, the combined GLP-1 mechanisms of weight loss and delayed carbohydrate absorption may also be the key drivers of remission of type 2 diabetes and reduced cardiovascular events found by GLP-1 analogues. Obesity also elevates the risk of developing some types of cancer including colorectal, esophageal, liver, and kidney malignancies 28,29,30,31,32.The use of GLP-1 drugs as a weight loss tool is prevalent and effective, but it is preferable to find ways to keep the weight off without a lifetime of drug treatment and this is an area that needs attention .Other studies have found little to no impact of physical activity on maintaining weight loss .This can be attributed to the metabolic adaptations that are seen to occur in those with obesity.The additional properties of inhibition of glucagon secretion and inhibition of caloric intake accelerated the development of GLP-1 receptor agonists for usage in type 2 diabetes management .Endogenous hyperinsulinemia may cause weight gain and obesity , and treatment with insulin causes substantial weight gain, and may even increase cardiovascular risk .GLP-1 medications can cause a range of side effects related to the gastrointestinal system as well as changes in muscle mass and effects on the appearance of the face and loss of hair (Figure 2). The popularity of GLP-1 receptor analogs may have to do with their profound effects on the CNS. Hypometabolism, or the decrease of energy expenditure greater than what would be predicted, is known as metabolic adaptation . As with all new medications or those whose use increases due to expanded indication, ongoing monitoring and close surveillance by both patients and clinicians continue to be necessary. Though more evidence is needed such guidance is useful to patients and clinicians at the present time 216,217. This model of body fat regulation was widely adopted in the 1990s with the discovery of leptin 3,4. He suggested that adipose tissue may produce a signal that may be sensed by the brain to target a “level of body fatness”. The concept that body fat storage may be regulated was first proposed by Kennedy et al. through the concept of a “set point” . These varied treatment responses likely originate from our limited understanding of the mechanisms of weight regulation. The Satiety and Clinical Adiposity Liraglutide Evidence (SCALE) trial demonstrated one-third of patients lost 10% of their body weight in 1 year with sustained weight loss demonstrated at 2 years 149,150. Zhang et al. found that in persons with type 2 diabetes, GLP-1 drugs offered benefits whether or not the patients were also taking metformin . Benefits to the cardiovascular system extend beyond weight loss to affect other risk factors such as triglyceride level, systolic blood pressure, risk of progression to diabetes, and the inflammatory marker C-reactive protein. These cardiometabolic markers (including HbA1c, fasting glucose, cholesterol, triglycerides and blood pressure) returned to baseline even earlier than weight, at around 1.4 years after stopping treatment. They found that, on average, people regained 0.4 kg (0.88 lb) per month, with all weight loss reversed after 1.7 years. I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. Most studies were assessed to have moderate risk of bias. 1. Factors That Avert Weight Regain Patients should be aware of these potential unwanted effects and, to minimize loss of muscle mass, encouraged to participate in resistance exercises and increase protein intake . Rapid weight loss can also lead to what is known as an “Ozempic face”, where the cheeks become hollowed out, and wrinkles, as well as eye bags, become more pronounced. The SURMOUNT-1 trial demonstrated a 15 mg dosage of tirzepatide in non-diabetic obese subjects leads to 20.9% weight loss at week 72 with sustained weight loss during a 3-year extension period 134,137. The follow-up STEP-5 trial demonstrated that semaglutide could sustain weight loss over 104 weeks or nearly 2 years . Two trials have supported an increase in the risk of all types of thyroid carcinoma 200,201. The exact risk change with other histological subtypes of thyroid carcinoma is yet to be fully established. Parks and Rosebrough first expressed concerns regarding human safety with liraglutide as early rodent trials demonstrated an increased risk of medullary thyroid carcinoma . This is also why developing pharmacologic treatments is challenging without clear targets. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. "Such practises not only help prevent excess weight gain but can also lead to numerous health benefits that go beyond weight control," the scientist added. But this research provides strong evidence that short-term use – much like extreme calorie-restriction diets – delivers short-term results. In an 8-week study using low-dose liraglutide (0.6 mg/day) in patients with type 2 diabetes no weight or fat loss was produced, but both fasting and postprandial glucose were substantially reduced, but neither fasting nor postprandial insulin (or C-peptide) response was increased . It was also an early observation that a higher dose of GLP-1 is needed to produce satiety and reduced food intake than to the antidiabetic effect, so a low dose GLP-1 analog could be used to study weight loss independent effects of GLP-1. The overall mechanisms of GLP-1 agonists on weight loss are predominantly through the reduction in energy intake and not on energy expenditure. Even with information on nutrition, physical activity, anti-obesity medications, and psychological support, there is no universally effective strategy in terms of weight loss maintenance. The metabolic efficacy of bariatric surgery in increasing gut production of GLP-1 to supraphysiologic levels postprandially is considered a major factor in early weight loss . Bariatric surgery is indicated in patients with a BMI above 40 independent of coexisting comorbidities or in patients with a BMI over 35 with a history of comorbidities such as type 2 diabetes or hypertension . The intragastric balloon is an anti-obesity intervention in which a silicone balloon is endoscopically deployed and filled with saline and inflated for 6 months. For instance, the Contrave Obesity Research studies (COR-I, COR II, COR-BMOD, and COR diabetes) were performed over a 56-week period 64,65. Patients are advised to consume a low-fat diet to combat the side effects of oily stool . The Pennington symposium highlighted potential alternative approaches for nutrition management that may be beneficial for weight loss maintenance. Most effective weight loss from a dietary standpoint is seen over 3 to 6 months, with at least one-third of patients regaining lost weight within the first year and the majority of patients regaining the weight after five years 224,225. Even more recently in 2022, a symposium was convened to discuss the state of the science of weight loss maintenance, known as the Pennington Biomedical Scientific Symposium . Other studies confirm the importance of dietary restraint and physical activity in preventing weight regain 247,248. In the phase III liraglutide program (SCALE study) ~4000 participants with obesity were studied for up to three years . The trial, extended for 2 years, found that completers maintained a 7.8 kg weight loss from baseline . In close collaboration with Jens Juul Holst, we conducted a series of infusion studies on the satiety effects of other gut hormones including GLP-2 and PYY. A meta-analysis from Lin et al. showed the benefit of GLP-1 drugs in peripheral artery disease and heart failure .Hypometabolism, or the decrease of energy expenditure greater than what would be predicted, is known as metabolic adaptation .Keywords were then refined based on the relevance of the results, and additional terms were searched to survey related areas including “cardiometabolic risk factors”, ‘sarcopenia”, “exercise”, “body mass index (BMI)”, and “appetite”.Six infusion studies provided us with 147 participants, and we found that GLP-1 reduced energy intake dose-dependently in both lean and overweight participants (a mean of 13%, P 3) .When it comes to the effect of GLP-1 analogues the reduction in postprandial glucose response, and insulinemia may actually contribute to weight loss, but also be the key drivers to the anti-diabetic effect and reduction in cardiovascular disease risks.However, challenges remain in such multi-agonist receptor treatments, and the focus remains predominantly on energy intake .“Healthy dietary and lifestyle practices should remain the foundation for obesity treatment and management, with medications such as GLP-1 receptor agonists used as adjuncts. Reductions of glycemic index and hyperinsulinemia by GLP-1 Ideally, the chosen initial intervention for weight loss would also be effective for weight loss maintenance. What remains to be seen is if the mixing and matching of the initial weight loss strategy, whatever this may be, with another weight loss maintenance strategy will lead to successful weight maintenance. However, available studies are only seen in rodent studies, but the additive or synergistic effects of GLP-1 and GIP on hunger and satiety require further clinical research . Recent studies have now demonstrated the strongest weight loss effect with the dual agonist for GLP-1 and GIP, upwards of 22% over 1 year . However, earlier studies showed inconsistences of GIP as a cause of weight loss, although more recent studies have demonstrated increased weight loss efficacy 280,281,282,283. First, there was a greater overall weight loss of 15% and therefore the weight loss plateau was delayed to around 68 weeks. A meta-analysis from Lin et al. showed the benefit of GLP-1 drugs in peripheral artery disease and heart failure . SELECT also showed better cardiovascular outcomes in persons with obesity and without diabetes who had previously undergone coronary artery bypass graft surgery . For instance, the SELECT trial demonstrated the cardiovascular benefit of the GLP-1 receptor agonist semaglutide beyond that of weight loss . This summary of current treatments for obesity highlights both its difficulty and importance, as well as obesity’s role in exacerbating other disease processes. These mechanisms are the basis for the highly efficacious GLP-1 analogues that today offer safe and effective treatment in millions of people living with obesity. Our goal is that this review can serve as a framework to aid providers in building their knowledge and selecting the most advantageous weight loss medication for each patient. We also discuss total cost and cost-effectiveness compared to other categories, long-term adherence, barriers to use, and reasons for discontinuation of this drug category. As with the STEP trials, a comprehensive series of clinical trials were performed with tirzepatide known as the SURMOUNT trials. However, tirzepatide is a novel dual agonist drug that activates GLP-1 receptors, as well as the GIP receptor. Semaglutide was studied in a comprehensive series of clinical trials known as the Semaglutide Treatment Effect in People with Obesity (STEP). The search methodology employed in this narrative review was comprehensive and aimed to capture current relevant evidence pertaining to GLP-1 medication use for weight loss and discontinuation of these medications. In this review, we examine the health risks of obesity and the overall magnitude of the problem. The known risks of pancreatitis, gastroparesis, and lean body mass loss are variables to be considered as well. Studies with treatment with GLP-1 analogues in type 2 diabetes have found that the initial postprandial insulin is increased after treatment, and this has been misinterpreted as evidence for a GLP-1 mediated insulin stimulation . The most common side effects of GLP-1 analogues are nausea and vomiting, which have been attributed to delayed gastric emptying 14,15,16. This supports that the short-term anti-diabetic effect of GLP-1 is mainly due to slowing of gastric emptying and consequently a reduced rate of carbohydrate absorption. The mechanisms responsible for these effects are not entirely clear, but the slowing of gastric emptying may be the key driver. Presently, 19 different GLP-1 analogues are in development for the treatment of obesity by almost as many companies. While there are available therapies for hyperphagia and hunger and, in fact, appetite reduction is a key effect of GLP-1 agonists, there are no significant available therapies that can address the decrease in energy expenditure . The drivers for weight regain are hypometabolism and hyperphagia in the weight-reduced state 229,230,231. Ultimately, understanding the existing forces that occur in a weight-reduced state may help to understand what may drive weight regain 224,225. GLP-1 Usage and Adverse Effects It helped one-third of the non-diabetic study patients achieve a loss of 10% of their body weight and also helped them sustain their weight loss for upwards of 1 year . Therefore, most of the effect of weight loss via GLP-1-related pathways may be related to a decrease in energy intake, rather than the direct effects on energy expenditure . Admittedly, the lesser potency of these drugs in the initial weight loss phase often overshadows their potential for usage for weight loss maintenance purposes. The low-or very-low fat intake approach is recommended for inducing significant short-term weight loss, but its long-term efficacy is not superior to dietary interventions with higher fat content . GLP-1 exerts an important effect directly on the brain, and this effect is probably even more important for the analogues than for the endogenous GLP-1 released after ingestion of protein and fat. GLP-1 inhibits gastric emptying in human individuals as shown by the retarded absorption of ingested paracetamol . Despite all major review articles highlighting GLP-1 as an incretin hormone , meal-test studies and studies using GLP-1 analogues actually show the opposite. The reduced glucose and insulin responses are consistent with the marked reduction in gastric emptying causing delayed absorption of glucose and hence a lower glycemic index of the meal (from refs 6, 10). Much of the recommended annual weight loss diets often seen in US News and World Report reflect a variety of these dietary patterns, highlighting that diets are more than their nutrient content . In addition to its effect on body weight, a variety of health benefits have been ascribed to it. The lipid profile in obesity is marked by an increase in triglycerides and free fatty acids . Background Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have emerged as breakthrough weight loss agents. So GLP-1 therapy reduces insulin secretion and levels, which have implications for the understanding of the mechanisms behind its effect on weight loss. However, this phenomenon is rather a restoration of the first-phase insulin response due to the concomitant weight loss of typically 5–6 kg. The discovery of the gut hormone glucagon-like peptide-1 (GLP-1) and the synthesis of agonists for its corresponding receptor (GLP-1 receptor) has tremendously impacted treatment for weight reduction. In addition to this, we still don't have a lot of data relating to long-term GLP-1 use and potential health issues, with the class of drugs being relatively new and not yet enough longitudinal research. “Healthy dietary and lifestyle practices should remain the foundation for obesity treatment and management, with medications such as GLP-1 receptor agonists used as adjuncts.