This is why many healthcare providers discuss long-term treatment plans or transition strategies when starting these medications. Here are some typical results these weight loss medications deliver. Many patients report stronger effects on appetite and weight loss. 5. GLP-1 Agonists and Lifestyle Intervention Keep in mind that GLP-1 is quickly broken down in the body (within minutes). The researchers compared exercise alone, exercise plus liraglutide, or liraglutide alone in people without diabetes. Let’s take a look at how to increase the effectiveness of GLP-1 RA drugs, natural alternatives to GLP-1 drugs, and dietary changes that impact GLP-1. With the matched group on semaglutide, 28 reported gastroparesis.refref Out of over 17,000 patients on Tirzepatide, 10 reported gastroparesis. 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. 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. As expected, there was weight regain, but there still was an overall 5.6% net loss of weight by the end of 120 weeks . Obesity has emerged as a global epidemic, with the World Health Organization estimating that over one billion people worldwide are currently classified as overweight or obese.Some studies found that LDL-C levels significantly reduced following treatment with liraglutide 1.2 mg/day or 1.8 mg/day (-0.28 and -0.23 mmol/L), exenatide once weekly (-0.13 and -0.17 mmol/L), and exenatide twice daily (-0.25 mmol/L and -6% change from baseline) .A study showed that people eating olive oil had a higher GLP-1 response than butter.Therefore, the percentage change in body weight from baseline was calculated usingThe particular effect of GLP-1 agonists on weight loss has also made it a popular drug among patients without diabetes.Among this cohort, those who transitioned to generic AOMs (such as metformin, topiramate, phentermine, and bupropion) after the MWLB pharmacy coverage ended at 12 months were able to maintain their weight loss up to 24 months.Specifically, danuglipron stabilizes a previously inactive conformation of the GLP-1 receptor which involves amino acid tryptophan at position 33 of the peptide chain.Consenting adults donated blood samples for DNA extraction, underwent anthropometric, blood pressure and resting heart rate measurement, and provided extensive information on demographic characteristics, genealogy, education, occupation and lifestyle, as well as health status and medical history70. Others are troubled by the harm caused by social media platforms and celebrities heralding medications such as Ozempic® as quick, cosmetic fixes without acknowledging the side effects and the fact that discontinuation results in weight gain. Finally, we did not assess GLP1-RA dosing effects, because dose adjustments vary over time, higher doses do not consistently correlate with greater weight loss and inconsistent reporting across studies could introduce biases. Overall, our results showed that the considered genetic influence on weight loss in response to GLP1-RA treatment and BS may be too small to impact clinical decision-making or patient outcomes. Muscle Mass and Glucagon-Like Peptide-1 Receptor Agonists: Adaptive or Maladaptive Response to Weight Loss? For more details, you can read the full study. For people considering GLP-1 therapy for weight management, these findings highlight the importance of understanding the long-term commitment needed to maintain results. Discontinuation was defined as going 60 days without the medication while reinitiation was recorded when a patient refilled a GLP-1 prescription after stopping. Patients were tracked for two years to monitor discontinuation rates and an additional two years to assess how many restarted treatment. Researchers examined data from adults with a BMI of 27 or higher who started GLP-1 therapy between 2018 and 2023. Dots represent the estimated percentage change in body weight, error bars represent the 95% CI for the estimate. B, Multiancestry meta-analysis effect sizes for the association between percentage change in body weight and genotype at each locus. Dots represent the estimated percentage change in body weight per 1 s.d. A, Ancestry-specific and multiancestry meta-analysis effect sizes for the association between percentage change in body weight and PGS for BMI and T2D. Compared with individuals of European ancestry, all other ancestry groups had a lower change in body weight. 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. Furthermore, patients with type 2 diabetes are inherently at higher risk of pancreatitis . 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 . 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). 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 . Anti-obesity medications such as Contrave (bupropion/naltrexone) or Qsymia (phentermine/topiramate) also appear to be effective for maintaining weight loss . 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. The safety of weight reduction medications has long been a concern, with numerous drugs being withdrawn from the market owing to safety issues 28,29. However, in the covariate analysis of this study, no significant effects of baseline weight, baseline BMI, or proportion of males on the weight-reducing impact of GLP-1RA drugs were found. Previous studies have shown that the efficacy of weight reduction medications is influenced by baseline weight, with individuals having higher baseline BMI experiencing larger reductions in weight . However, the weight regain is relatively mild and by 104 weeks there is still overall weight loss. This drug leads to a weight loss nadir at around 36 weeks with a weight regain that happens at around 52 weeks . 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 . Although medication adherence is related to individual behavior, various healthcare, and system-specific factors can also dramatically affect such behavior. While the price of oral GLP-1s for weight loss have not yet been released, as these formulations are still awaiting FDA approval, they are still expected to be relatively expensive without insurance coverage (McKeown, 2022). Similarly, if providers are unavailable to address patients’ concerns or questions, it may exacerbate feelings of uncertainty and reduce motivation to continue treatment. Additionally, a lack of support or follow-up from providers can leave patients feeling isolated in managing their condition, which may further decrease adherence to treatment (Dietz, 2023; Kvarnström et al., 2021). Using a DNA-based bioreceptor (called an aptamer), the sensor was designed to detect phenylalanine, and a key biomarker released during muscle breakdown or after eating protein. A new study, presented as a late-breaking poster, demonstrates proof of concept for a continuous protein sensor as a tool to prevent muscle loss during GLP-1 therapy. The researchers are conducting studies of bimagrumab in combination with tirzepatide to evaluate its impact on both efficacy and safety. Secondary endpoints included changes in waist circumference, total body fat mass, visceral adipose tissue, and lean mass. 2. GLP1 Receptor Analogs Approved for Weight Loss 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. 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. 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. 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. 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. Likewise, the PIONEER trials established that between oral semaglutide and placebo, there was a 53% decrease in cardiovascular mortality. Various CVOT trials, such as the SELECT, SUSTAIN, and SOUL trials, have demonstrated varying effects on heart diseases over the years 13,39,46. Following the promising results of the REWIND trial, FDA approved Trulicity (Dulaglutide) in those with T2DM who either have cardiovascular disease or are at increased risk of the disease to be used preventively for reduction in MACE . The maximum weight reduction effect ranged from 4.25 kg (Liraglutide) to 22.6 kg (Retatrutide). Fifty-five studies involving 16,269 participants and 12 GLP-1RAs were included. Subgroup analyses were performed to explore efficacy differences in receptor specificity. GLP-1RA therapy was initially developed to treat type 2 diabetes. Weight loss of 5-15% can improve many obesity-related complications. Blocking the degradation of GLP-1 by inhibiting DPP-4 is how certain types of diabetes medicine work. To understand how GLP-1 works, we first need to look at how the body produces this hormone. GLP-1 receptors (GLP1R), which are found in pancreatic beta cells as well as other cell types, receive the GLP-1 signal, triggering the release of insulin. When food reaches your intestine, it triggers the release of hormones that signal to other parts of your body. Prescribing a GLP-1 agonist may be appropriate for these patients. “There may be some direct benefits of the medication in the absence of significant weight loss, which is also why you should be talking to your doctor at length about why you’re using this medication.” Cost can often be a prohibitive factor for these medications – a month’s supply of GLP-1 medications can often cost about $1,000 – but the analysis included only people who had insurance plans that covered weight-loss medication prescriptions. Findings from the Blue Cross Blue Shield data emphasize the important role that providers can play in helping patients stick with their treatment with GLP-1s. Physicians and patients have to just look at all the data and make a decision about treatment together,” she said. “These are long-term medications to treat a chronic disease,” said Dr. Disha Narang, an endocrinologist and director of obesity medicine at Endeavor Health in Chicago, who was not involved in the new research. But are GLP-1 side effects bothering you too much? Of course, if you experience any severe side effects, contact your doctor right away. Your body is incredibly adaptive, and it’s learning a new way of functioning. Most side effects are mild and tend to improve within the first few weeks. Wegovy (Semaglutide) got FDA approval specifically for weight management. Between your particular metabolism, medical history, stress levels, and dozens of other factors, your body will respond in its own way and time. Learn more about keeping genetic data safe and private. Genetic Lifehacks membership features work without transfering your data or storing it on our server. An agonist is a type of drug or other agent that binds to a receptor on a cell and triggers a physiological response.The results indicated that at 52 weeks, the weight reduction effects of mono-agonists, dual-agonists, and triple-agonists were 7.03 kg, 11.07 kg, and 24.15 kg, respectively.But now that they have been in use for several years and have been subject to more clinical trials, does that claim hold up?The central importance of the CNS in body weight regulation is substantiated by research conducted by Sisley et al. .This low perceived risk could contribute to poor adherence to prescribed medications, and the lifestyle modifications necessary to support weight loss on these medications, heightening the risk of long-term health consequences.Related comorbidities include cardiovascular diseases, dyslipidemia, hypertension, type 2 diabetes, several forms of cancer, and many more 3–5.That’s why Calibrate’s approach focuses on pairing medication with sustainable lifestyle changes in food, sleep, exercise, and emotional health.These findings led to the hypothesis that an analog of GLP-1 could deter weight accumulation by regulating gut microbiota. Recent statistics indicate that overweight/obesity continues to increase globally, with the overweight population reaching 2 billion, or 30 % of the world's population . Obesity is a major global epidemic, defined by the World Health Organization (WHO) as “an excessive accumulation of body fat that may impair health” 1,2. This systematic review of public databases included placebo-controlled randomized clinical trials of GLP-1RAs. The most common side effects (nausea, vomiting, and diarrhea) are usually mild and occur in the first few weeks of treatment, reducing over time. So far, there have yet to be any direct studies in humans to show whether GLP-1-based treatments are effective for OA, pointing to a gap in current research. While some patients might afford to pay the total price out of pocket, others might have to prioritize buying the medicines covered by insurance for other health conditions. Obesity is a chronic disease that exacerbates the risk of severe health conditions (as mentioned above) and is the leading cause of all-cause mortality. While many have popularized both Wegovy® and Ozempic®, fewer have discussed Rybelsus® and other GLP-1 agonists. Many have voiced concerns about the availability and continuity of care interruptions inevitable for individuals with diabetes as Ozempic® continues to see growing demand. Alongside Ozempic®, the Food and Drug Administration (FDA) approved Wegovy® in June 2021, which is a higher dose formulation of semaglutide compared to Ozempic®. Indeed, the prescription weight-loss drug market grew 72% more than initially forecasted in 2023, ballooning to a 2.3 billion dollar industry . Most adults stop GLP1 therapy within a 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. 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 . 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. This review explores the mechanisms underlying GLP-1 RA-induced weight loss, focusing on central and peripheral pathways. & Lavie, C.J. Balancing weight and muscle loss in GLP1 receptor agonist therapy. While current evidence is promising, especially from recent high-quality trials, further research is needed to refine patient selection, optimize treatment duration, and ensure accessibility in diverse clinical settings. Once again, a reminder system that reduces forgetfulness and allows for customization to ensure patients adhere to these requirements is likely to assist those who end up on oral GLP-1s. Ensuring administrational ease of one’s medication is also crucial for promoting adherence (Dietz, 2023; Kvarnström et al., 2021). Patients can choose a dosing schedule that aligns with their daily point and offers positive reinforcement — such as adherence streaks — to help reinforce medication routines as habitual behaviors. By integrating medication into her daily routine, Katie’s behavior has an increased likelihood of becoming a habitual part of her daily routine. How might these results change the direction of research or the focus of clinical practice? Similarly, a study found a significant reduction in LDL-C following treatment with liraglutide 1.8 mg/day (-0.44 mmol/L) and exenatide 10 µg twice a day (-0.40 mmol/L) . Some studies found that LDL-C levels significantly reduced following treatment with liraglutide 1.2 mg/day or 1.8 mg/day (-0.28 and -0.23 mmol/L), exenatide once weekly (-0.13 and -0.17 mmol/L), and exenatide twice daily (-0.25 mmol/L and -6% change from baseline) . This evidence is backed up by a study conducted by Hasegawa et al., which found that GLP-1 administration improves dyslipidemia by inhibiting HMG-CoA reductase in T2DM patients . These results showcase the ability of semaglutide to be a treatment option for cardiovascular benefit, notwithstanding the glycemic index. With modern research, a growing body of evidence highlights the possible use of GLP-1RAs to reduce major adverse cardiovascular events (MACE) and improve overall outcomes in diabetic or obese patients. If you are taking a GLP-1 medicine, make sure you inform your healthcare team including the anaesthetist about this prior to your surgical procedure.The potential covariates examined included age, male ratio, baseline weight, and baseline BMI.Following exenatide, several other GLP-1 receptor agonists were developed, including liraglutide (Victoza), dulaglutide (Trulicity), and semaglutide (Ozempic).Your body is starting something new, and that deserves credit.Following this, the FDA-approved Wegovy® (semaglutide) was given as a treatment for weight loss in patients with a body mass index (BMI) of 27 kg/m2 or higher .However, these medications require continuous use to maintain their benefits making high discontinuation rates a significant concern.In overweight adults aged 45+, a 4-year-long study using semaglutide for weight loss also prevented HbA1c from rising over time, which was seen in the placebo arm.Katie began taking her medication immediately upon waking up at 4 am before heading out for her daily workout, eliminating worry regarding the 30-minute fasting period required for GLP-1s from impacting her routine.Lastly, among patients transitioning from GLP‐1 RAs to generic AOMs, those who underwent bariatric surgery (gastric sleeve or Roux‐en‐Y gastric bypass) introduce additional metabolic complexities that could confound treatment effects. 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. However, the prevalence of obesity along with the need for more effective anti-obesity treatments prompted the study of the first daily GLP-1 receptor agonist, liraglutide. 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. 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. For instance, the SELECT trial demonstrated the cardiovascular benefit of the GLP-1 receptor agonist semaglutide beyond that of weight loss . But now that they have been in use for several years and have been subject to more clinical trials, does that claim hold up? This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. No funding or sponsorship was received for this study or publication of this article. Ultimately, healthcare providers must work closely with patients to manage expectations, address concerns, and tailor therapies to enhance adherence—ensuring that the full benefits of GLP-1s can be realized for those who need them most. AdhereTech’s devices are able to detect when patients are running low on their medication, and will send them a reminder notification before their medication runs out. Without reminders, patients may forget to request a new prescription of their medication or shortages in GLP-1s may prevent their access, forcing patients to become nonadherent. Since GLP-RAs were created primarily for the treatment of T2DM, their effect on blood glucose will be discussed first, followed by their effect on weight management and obesity. Specifically, the STEP-4 trials recorded a 10.6% weight loss with semaglutide 8,9. This narrative review explores the metabolic effects of GLP-1 RAs in weight management, blood glucose, cardiovascular health, lipid profiles, and blood pressure. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been developed to manage type 2 diabetes mellitus. The goodness-of-fit plots for the model indicated that the model fit the observed data well, with no evident bias (Supplementary Fig. S4). Owing to the limited number of time points available for some drugs, it was not possible to estimate the k values individually for each drug. The Emax values for 12 GLP-1RA drugs ranged from 4.25 kg to 22.6 kg, with Retatrutide exhibiting the highest Emax value and Liraglutide the lowest. The detailed demographic and clinical characteristics of the participants are provided in Supplementary Tables S3 and S4. Average baseline weight ranged from 72.2 to 121 kg, with a median weight of 95.8 kg; average baseline Body Mass Index (BMI) ranged from 24.1 to 45.1 kg/m2, with a median of 33.9 kg/m2. These medications have turned traditional weight loss approaches upside down, though the initial weeks can feel like quite the adventure.Research shows GLP‑1 drugs are effective but complex.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.Given that current research points to the fact that weight loss can be maintained (though often not as much as while taking the drugs), it's clear that the risk of regain or "rebounding" is one that is likely worth taking.The research which analysed data from over 125,000 adults in the US found that people without type 2 diabetes were more likely to discontinue treatment and less likely to restart it.“If cardiovascular health is what you think is important for deciding between these drug classes, I think our most recent study provides some strong evidence.GLP-1 side effects only one factor driving patient discontinuation rates. Related article What the results of Wegovy’s longest clinical trial yet show about weight loss, side effects and heart protection Professional organizations have set this as a guideline for when to reassess whether a treatment is providing clinically meaningful weight loss. GLP-1 medications don't change the fundamentals of healthy eating, Kessler writes, and it's important to be mindful about your food choices on the drugs. GLP-1 receptor agonists have transformed the management of type 2 diabetes and obesity, offering multifaceted benefits beyond glycemic control. When switched to placebo there was invariably weight regain, implying that the loss of inhibition of hyperphagia drove this process. Early studies demonstrated the anorectic actions of GLP-1 on the hypothalamus 238,239. 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 . 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. Similarly, the analysis of various clinical trials suggests an 8% decreased risk of nonfatal myocardial infarction in patients using semaglutide compared to placebo . At the end of 30 to 52 weeks of the clinical trial, a maximum weight loss of 4.6 kg (semaglutide 0.5 mg) and 6.5 kg (semaglutide 1.0 mg) was achieved. GLP-1 RAs have been widely researched and used as antiobesity drugs in patients with or without diabetes. The effects of exogenous GLP-1 after administration to T2DM patients show improved insulin sensitivity, decreased glucagon concentration, slowed gastric emptying, increased satiety, decreased fatty acid concentration, lowered body weight, and overall decreased hemoglobin A1c (HBA1c) levels. Will my insurance cover GLP-1 weight loss medication? For health care practitioners, in-person sessions may be more successful than remote sessions, but both have value 246,274,275. 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 . 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. Specifically, a decrease in processed and ultraprocessed food consumption would be beneficial for weight loss maintenance. The Pennington symposium highlighted potential alternative approaches for nutrition management that may be beneficial for weight loss maintenance. 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. 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. The popularity of GLP-1 receptor analogs may have to do with their profound effects on the CNS. Therefore, treating hyperphagia is the strategy for both weight loss and weight loss maintenance. In this setting, prevention of weight regain may be better-termed weight loss maintenance. 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. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in GLP1R. The data from Dandelion Health showed that the 10% of people with the best response to GLP-1s had results that mirrored what clinical trials found, but the 10% with the least success with the treatments had no weight change, or even an increase in weight, over time. In clinical trials, some of the stronger medications like Wegovy and Zepbound have been found to help people lose at least 10% of their starting weight. The findings are based on pharmacy and medical claims data for about 170,000 people with insurance coverage under Blue Cross Blue Shield plans who were prescribed GLP-1 medications that were approved to treat weight management between 2014 and 2023. Statistical model STEP TEENS was conducted regarding the efficacy and safety of semaglutide in adolescents . In oral pills, salcaprozate sodium (SNAC) is added to semaglutide to increase absorption since it prevents PH breakdown . The hormone binds to the GLP-1R receptor, and by doing so, it increases the sensitivity of the beta cells in the pancreas to glucose. Semaglutide which is given subcutaneously was first approved by the FDA in 2017 for the use of type 2 diabetes management under the brand name of Ozempic® . Therefore, combining this medication with exercise and/or diet may have beneficial results which have been investigated extensively in existing literature. Stay connected with healthcare providers who understand these medications. How do you cope with the side effects from GLP-1s for weight loss? Clinical studies show Wegovy users typically lose about 2% of their body weight in the first month. The lipid profile in obesity is marked by an increase in triglycerides and free fatty acids . 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 . Clinical trials show an average weight loss of about 4% of your starting body weight after just four weeks. It’s designed for people with obesity or those who carry extra weight and have related health conditions. GLP-1 medications work like the natural hormones in your body that control hunger and blood sugar. So you’re starting a GLP-1 medication for weight loss. For those considering or currently using GLP-1 medications, here are several strategies that can enhance their effectiveness while minimizing side effects. Tirzepatide, evaluated in the pooled SURPASS trials, maintained superior glycemic control and ≥5% weight loss at weeks in a population with type 2 diabetes, outperforming semaglutide and insulin comparators .For future development of GLP-1-based therapies (and other therapies) designed for weight loss, as well as for patient-centered treatment optimization, the introduction of more objective and comprehensive ways of assessing muscle health (including accurate and meaningful assessments of muscle quantity, composition, function, mobility, and strength) is important for the substantial numbers of patients who will likely be taking these medications well into the future.The study highlights the potential of older‐generation generic AOMs in maintaining weight loss and the need for future research to validate these findings across diverse patient groups.Dr. David A. Kessler has always been in the business of keeping people healthy – but by his own admission, he hasn't always applied that to himself.Want the latest stories on the science of healthy living?An analysis was conducted on the total dropout rates for the 12 types of GLP-1RA drugs.This led to approval of the first GLP1-RA for treatment of type 2 diabetes (T2D) in 2005, followed by approval for obesity treatment in 2014 after its association with reduced food intake was established5. It also noted a few adverse effects of semaglutide, which included diarrhea and other gastrointestinal disturbances . Semaglutide is available in oral and subcutaneous injection forms, and FDA-approved doses of semaglutide for chronic weight management are 1.7 mg or 2.4 mg weekly. Most recently, Wegovy® was approved for weight loss in adults in June 2021 and adolescents ≥12 years old in December 2022 . In 2019, the oral form of semaglutide, under the brand name Rybelsus®, was approved for individuals with type 2 diabetes to manage glucose control . While there are several advantages to the medication, it is not without its side effects. Katie began taking her medication immediately upon waking up at 4 am before heading out for her daily workout, eliminating worry regarding the 30-minute fasting period required for GLP-1s from impacting her routine. Meanwhile, if an individual feels confident in their ability to take their medication as prescribed, such as eliminating forgetfulness by using a reminder system, adherence is likely to increase. For instance, AdhereTech’s smart devices use positive reinforcement by celebrating adherence “streaks” and providing access to a seven-day care team, creating a reliable and motivational support structure for patients. Similarly, fears of the potential impacts of obesity may also translate into increased motivation to remain adherent (Dietz, 2023; Kvarnström et al., 2021). Patient demographics, weight‐related medical complications, percentage weight reduction from the initial visit, percentage BMI reduction, and AOM utilization data were collected. Initial anthropometrics were defined by the measured weight and height entered into the electronic health record at the first visit with the MWLB provider. At the time of the study, three large employers and/or institutions were participating in the MWLB, and therefore patients were located within the inner city or regionally. Given the recent FDA approval of novel GLP‐1 RAs and the consequent scarcity of long‐term efficacy data, we initiated a prospective real‐world cohort study among our program participants. In response to pressing health challenges, our institution implemented a comprehensive weight management program initiated on January 1, 2022, as detailed by Srivastava et al. . For instance, liraglutide has been shown to reduce oxidative stress in macrophages through GLP-1 receptor signaling . When GLP-1 receptors are activated, they influence the balance between two macrophage pathways, promoting the M2 anti-inflammatory type 84,86. However, the absolute risk for the abovementioned complications was less than 1% per year of use. The effects were consistent in BioMe and UCLA-ATLAS for admixed American ancestry, and in AoU and MGBB for African ancestry. Ancestry can provide more useful information about population health than racial and ethnic categories because it is not directly influenced by geographic, cultural and sociopolitical forces60. These results were not attributable to high heterogeneity across studies or across major continental ancestry groups. Moreover, because the biological underpinning of weight change is partially distinct from weight at baseline, we also consider the few replicated genetic signals for BMI variability and BMI trajectories. Instead, we tested hypotheses based on the largest genome-wide association studies of BMI and T2D and examined biologically plausible mutations in candidate genes. As weight loss progresses, protein helps preserve your hard-earned muscle, keeping your metabolism strong and your energy steady. Use the appetite-suppressing effects of your medication to your advantage. These medications intentionally slow your digestion. This blog post delves into the history, market introduction, controversies, and future prospects of GLP-1 receptor agonists. For my medullary patients — the ones with the FDA warning — I'm still saying, until we have better data, I can't recommend it. There was a French study about a year ago that showed increased risk specifically in papillary thyroid cancer, which is the most common differentiated thyroid cancer. If you have medullary thyroid cancer or genetic testing that puts you at risk for thyroid cancer, or you have a family member who has medullary thyroid cancer, they say you shouldn't use these drugs. If you’re like me, you may be wondering what caused obesity to skyrocket over the past three decades – and whether GLP-1 has a role. Studies show that this type of diet actually alters the circadian rhythm of GLP-1 secretion, both in lab animals and in people with type 2 diabetes.ref Your circadian rhythm is the 24-hour rhythm of your body’s functions. The effectiveness of GLP-1 is also influenced by our body’s natural daily rhythms. Residues originate from GLP-1, GIP, and semaglutide, and some residues are distinct. Tirzepatide targets GLP-1 receptors by attaching to them and activating the release of insulin. Clinical trials SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) and PIONEER (Peptide Innovation for Early Diabetes Treatment) investigated the effect of semaglutide 1.0 mg subcutaneously as well as oral forms. The mean reduction in body weight for these drugs ranges between 7% to a remarkable 21% for Zepbound, which features the GIP component. Let’s delve into the real-world outcomes of GLP-1s for weight loss, considering both their clinical impact and the financial implications for pharmacy benefit plans. Glucagon-like peptide-1 (GLP-1) receptor agonists, or GLP-1s, are hailed by some as the magic bullet for obesity. Switching without medical advice may increase the risk of experiencing side effects or make the treatment less effective. Fifth, although T2D medications like metformin can affect weight loss, our T2D-adjusted sensitivity analyses likely accounted for first-line treatments. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Still, GLP-1 medications may have benefits far beyond weight loss – for heart and liver health, for example – which may extend even to people who don’t lose as many pounds as they might have expected, experts say. These injected medications, called GLP-1 agonists, are in high demand because they have proved to be so effective for weight loss. Related article People using popular drugs for weight loss, diabetes are more likely to be diagnosed with stomach paralysis, studies find Although subsequent studies and meta-analyses provided reassuring data, the debate continues, and these risks remain a consideration in clinical decision-making. “We argue that this alternative framework is a viable solution that provides greater flexibility for managing a limited drug supply and giving healthcare payers financial headroom to support more patients accessing effective weight management treatment,” Kim said. “We know these drugs represent a massive breakthrough in our long fight against obesity-related clinical conditions, but their high cost has been the subject of substantial debate,” said David Kim, PhD, a UChicago health economist. These drugs are extremely effective for blood glucose control and weight management, which, combined with their relatively limited side effect profile, makes them very appealing for diabetes treatment — the purpose for which they originally received FDA approval. Does insurance cover weight-loss medications such as Wegovy or Zepbound?. Lifetime health effects and cost-effectiveness of tirzepatide and semaglutide in US adults. Patient adherence to anti-obesity medications. Pseudonymized data and/or biological samples can be accessed for research and development purposes in accordance with the Estonian Human Genome Research Act. Registered researchers whose institutions have Data Use and Registration Agreements in place with All of Us that include the Controlled Tier can access genomic data. Restrictions apply to the availability of these data, which are available to MGB-affiliated researchers via a formal application. Clinical data are extracted from the EMR of the Hamad Medical Corporation. If communication between patients and providers is lacking, research has shown that the risk of nonadherence increases (Zolnierek & DiMatteo, 2010). However, risk of coronary heart disease and heart failure increases by 46% and 96% respectively, even for obese individuals with no signs of metabolic disease, abnormal blood pressure, cholesterol, or diabetes (Medical News Today Team, 2022). Another study found that for patients on weekly and monthly oral bisphosphonates, only 44% reported complying with all dosing instructions (Vytrisalova et al., 2015). One study found that orange juice lowered medication absorption rates by up to 60%, highlighting the importance of adhering to this dosing regimen (Hannemann & Ulrich, 2024). Notably, patients on bisphosphonates, used to treat osteoporosis, are required to take their medication 30 minutes before their first food, drink, or medication of the day (Hannemann & Ulrich, 2024). How obesity in the U.S. has grown and what to do about it. Type 2 diabetes and metabolic surgery fact sheet. Advances like the development of oral formulations aim to address some of these barriers, with the potential to possibly improve the patient experience and commitment to treatment. Factors such as side effects, dosing convenience, cost, and supply availability all play a role in influencing adherence. This is because GLP-1 medicines may reduce the effectiveness of oral contraceptives in those who are overweight or obese. If you are using a GLP-1 medicine and think you might be pregnant, speak to a healthcare professional straight away. In some animal studies, GLP-1 medicines were found to be harmful to the unborn foetus, although more information is needed to see whether or not this same effect would be seen in humans. This is because there is not enough safety data to know whether taking a GLP-1 medicine can cause harm to the baby. Does Using GLP-1 Drugs, Like Zepbound or Wegovy, Increase Your Risk of Thyroid Cancer? 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 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. 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. 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. 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. However, with significant weight loss, particularly a combination of healthy dietary modifications, GLP‐1 RA therapy, and an increase in physical activity, there is a reduction in fatty acid mobilization and uptake, which is a key process in reducing insulin resistance. Studies have shown that obesity directly mediates systemic inflammation, which contributes to insulin resistance and makes sustained weight loss difficult to achieve . These data indicate significant weight loss during the initial 12 months of GLP‐1 RA therapy, with continued weight loss after transitioning to AOM therapy. Notably, there was a reduction in BMI from 36.5 to 27.2 over the study period, and weight loss of 20.6% was maintained over 24 months. For instance, a study found that more than half of respondents who underwent rhinoplasty did so due to social media “before and after” advertisements . The prevailing approach for weight management is through a combination of diet, exercise, and pharmacotherapy . However, future studies should address these links as they pertain to specific diseases and illnesses in clearly defined contexts. It is possible that other factors such as socioeconomic status, access to preventative care, and epigenetics may play a larger role in disease risk. The potential disease impact of obesity has been widely debated and explored in recent research. 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 . Severe obesity, which is defined as a BMI over 40 kg/m2, is an alarming public health issue . Obesity is traditionally defined as an excess of body fat, and is classically categorized in clinical practice in terms of body mass index (BMI). Variations in weight measurement may arise because follow‐up weights were recorded at different provider offices using different scales. Furthermore, the 24‐month follow‐up data are incomplete, which affects the reliability of the results. Some patients reported drinking socially, though there were no reports of alcoholism or marijuana use. Personalized medicine approaches, which tailor treatments based on these genetic differences, hold great promise. Full-text articles were obtained for studies meeting the initial eligibility criteria. A systematic search was performed across multiple databases, including PubMed, Cochrane CENTRAL, Embase, and ClinicalTrials.gov, for articles published between January 2018 and April 2025. This study was conducted as a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines to ensure methodological transparency and replicability . Additionally, as newer agents like tirzepatide enter clinical practice, evaluating their comparative durability becomes increasingly relevant. Pharmacological interventions have become a crucial component in the management of obesity, especially for individuals who do not respond adequately to lifestyle changes alone . Different drugs performed better in different areas, but all 15 GLP-1RAs they analyzed were very successful in lowering blood glucose and achieving weight loss. However, if you were worried about "rebounding" or regaining weight lost after stopping taking GLP1 Receptor Agonist drugs, hopefully you are a little more reassured – the current research does not show this risk to be outsized. The research which analysed data from over 125,000 adults in the US found that people without type 2 diabetes were more likely to discontinue treatment and less likely to restart it. Affordable and personalized virtual care for opioid addiction, hormone therapy, weight loss, and urgent health needs. Most people regain some weight after discontinuing GLP-1 medications. Initial studies in rats caused concerns over GLP-1 RAs causing thyroid cancer, but human studies are less clear on whether it is a concern.ref Semaglutide has also been shown to have immunomodulatory and antitumor effects in a mouse model of breast cancer. First, let me caution that this is just a mouse study, so it may not hold true in humans. GLP-1 receptors are expressed in the heart muscle cells, immune system cells in the heart, and in the lining of blood vessels.ref A number of studies have shown that GLP-1 RAs provide benefits for reducing cardiovascular disease. The second body weight (mW1) was defined as the median of body weight measurements between 26 and 52 weeks from T0 for the GLP1-RA analysis and between 180 and 1,460 days for the BS analysis. The baseline body weight measured closest to T0 and between −52 weeks and +2 weeks from T0 was defined as W0. In our primary model, for both GLP1-RA and BS we defined the outcome to be the percentage change in body weight from baseline. Even though obesity leads to an intensified probability of illness and impairment, negatively impacting life expectancy and quality, weight reduction is correlated with a moderate enhancement in cardiometabolic indicators . An overweight phenotype arises from obesity, which is a state of positive energy balance. Around the world, obesity and its related comorbidities are one of the severe medical conditions concerning public health . In some cases, metabolic/bariatric surgery may be considered an appropriate treatment for long-term weight loss. This phase 2 study reported that HbA1c% levels were reduced by 1.16% points in the 120 mg (twice a day) group and they also experienced the highest weight loss (−2.04 kg) in the cohort . When administered over 16 weeks, danuglipron significantly reduced HbA1c% levels and resulted in weight loss in all patients . In another phase 1 study conducted on patients with type 2 diabetes, researchers implemented an ascending dosage order starting from 10 mg twice a day to 120 mg twice a day . In fact, the study also found that patients who discontinued the medication had a 30–33% increased risk of cardiac disorders compared to patients who continued to take the medication 14, 15. In this case, synthetically produced GLP-1 receptor agonists can substitute for intrinsically available GLP-1 receptors in patients with diabetes. Glucagon-like peptide 1 (GLP-1) agonists belong to a class of type-2 diabetes medications that mimic the function of the GLP-1 hormone secreted by the pancreas . Regarding the impact of BMI PGS on weight loss due to BS, we observed a reduction of effect in some of the sensitivity analyses, in particular when excluding baseline weight adjustment from the model. Across all these analyses, we did not observe a significant effect of BMI or T2D PGS on weight reduction following GLP1-RA treatment, in concordance with our primary analysis. This suggests that individuals with a stronger genetic predisposition to obesity may regain weight faster post surgery. These findings underscore the importance of considering individual characteristics when designing weight loss interventions. GLP-1 RAs have been found to improve overall cardiovascular health and reduce major adverse cardiovascular events (MACE) by improving the endothelial function of the vasculature and lowering ANP (atrial natriuretic peptide) production, leading to reduced blood pressure. GLP-1 RAs have shown consistent results in managing blood glucose levels by lowering HbA1c with minimal hypoglycemic risk and increasing insulin production and synthesis. Haoyang Guo and Juan Yang wrote the manuscript; Qingshan Zheng and Lujin Li designed the research; Haoyang Guo, Jihan Huang, Ling Xu and Yinghua Lv performed the research; Haoyang Guo, Yexuan Wang, Jiyuan Ren and Yulin Feng analyzed the data. Finally, as the study included only English-language publications, there may have been a publication bias. Particularly, the safety profiles of GLP-1RA drugs that are still under development require further investigation with larger samples. As several studies have shown, lifestyle changes alone are not sufficient to sustain long‐term weight loss when severe obesity is present; often there is weight regain due to an increase in appetite and a decrease in energy expenditure and satiety. Evidently, this also requires healthcare professionals to remain in good communication with their patients ,since ignoring patients’ pressing questions or concerns may lead to a heightened risk of medication discontinuation. For instance, if a patient is informed by their provider of the long-term risks and consequences of obesity, such as cardiovascular disease or Type II diabetes, they may become more inclined to adhere to their prescribed treatment to avoid such detriments. Even for those with private insurance, many insurance providers will not cover prescription medications used exclusively for weight loss purposes (Morris, 2024). The lack of symptoms directly tied to obesity or a perceived sense of urgency may result in individuals not prioritizing weight loss, highlighting a critical illness-specific barrier to prevention and treatment. This study complies with all relevant ethical regulations and was conducted in accordance with the research permits and approvals granted by the respective institutions. However, large-scale real-world data and consistent sensitivity analysis support the robustness of our results. This discretization reflects pragmatic considerations to enable comparable analyses across the different studies. Second, we could not accurately estimate treatment adherence, but overcome this limitation by considering treatments of maximum 12 months’ duration, a period for which adherence has been observed to be around 65% (ref. 53). These differences may reflect socioeconomic factors, such as disparities in treatment access. For answers, we turned to University of Colorado Cancer Center member Bryan Haugen, MD, professor of endocrinology, metabolism, and diabetes in the Department of Medicine at the CU School of Medicine. By reducing appetite and slowing down the rate at which food moves from the stomach to the intestines, GLP-1s have helped thousands of people lose significant amounts of weight over the past few years. The drugs are expensive, and experts say the recent spike in popularity has already led to shortages and increased hesitancy among insurance providers to cover these drugs. Pay attention to changes in your body beyond just weight. Most patients experience less hunger and feel full faster because of the way GLP-1s affect the body’s natural hunger mechanisms. Practice simple stress-reduction techniques like deep breathing or adequate sleep to make your weight loss experience a little easier. Your energy levels might fluctuate as your body adjusts to the medication, so listen to what it’s telling you! The general trajectory of weight loss with initiation of GLP-1 therapy has been well-studied (Table 2) 218,219,220. Common adverse effects of GLP-1 agonists and approaches to minimizing these consequences. 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 . 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). Arguably, the arrival of semaglutide more than five years later sparked the public’s attention to GLP-1 agonist therapy. They have emerged as crucial elements in weight reduction by diminishing hunger pangs, mitigating food desires, decreasing caloric consumption, enhancing feelings of fullness, and promoting better control over eating habits 14, 15. As GLP-1 is readily degraded by dipeptidyl peptidase 4 (DPP-4) in vivo, several synthetic GLP-1 analogs were designed that are resistant to degradation, mimic the naturally occurring hormone GLP-1, and exert a stimulation effect on GLP-1R that are termed GLP-1R agonists (GLP-1RA). These encompass the leptin-melanocortin trajectory, the opioid schema, the system involving glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R), and the axis of fibroblast growth factor 21 (FGF21) along with its receptor complex FGFR1c/β-klotho . Beyond these methodologies, there has been substantial advancement in the sphere of pharmacotherapy for weight reduction. However, discontinuing these lifestyle behaviors due to social, behavioral, financial, etc., make people unable to adhere to and complications after surgery results in weight gain 6, 9–11. Furthermore, underrepresented populations - including adolescents, the elderly, and individuals with psychiatric or eating disorders - require focused study. Head-to-head trials directly comparing GLP-1 RAs (e.g., semaglutide vs. tirzepatide or exenatide) are scarce and necessary to inform optimal agent selection. Reliance on post hoc analyses in certain studies also limits the strength of causal inferences. Additionally, findings from adolescent trials suggest that individual hormonal profiles, such as baseline leptin responsiveness, may influence treatment success, highlighting the potential for biologically guided personalization in the future . Behavioral adaptations such as increased cognitive restraint and reduced sedentary time were particularly notable in studies involving liraglutide combined with exercise . Moreover, a lack of trust in healthcare providers may make patients more hesitant to take these medications (Dietz, 2023; Kvarnström et al., 2021). The dose of oral semaglutide for obesity is much higher (25–50mg daily) versus the injectable semaglutide (2.4mg weekly), which doctors have suggested oral GLP-1s run the risk for more pronounced side effects (Tirrell, 2024). And as of 2025, Forbes found that 26% of Americans (roughly 1 in every 4) reported planning on using GLP-1 medications for weight loss (Valloppillil, 2025). Capitalizing on over fifteen years of GLP-1 therapeutic applications, implementing these medications in addressing diabetes and obesity is progressively expanding. In addition to these, drug therapy, such as the use of GLP-1RA in medications for weight loss, has made significant progress. Additionally, liraglutide has shown positive behavioral effects, such as enhanced cognitive restraint and reduced sedentary time, aligning with a more holistic model of obesity treatment . Despite these issues, the overall quality of evidence was considered high, reinforcing confidence in the validity and applicability of the findings for long-term obesity management using GLP-1 receptor agonists. Collectively, the studies reinforce the long-term therapeutic potential of GLP-1 RAs in obesity management and underline the importance of sustained treatment strategies. Across adult and adolescent populations, both with and without comorbidities such as type 2 diabetes or cardiovascular disease, GLP-1 RAs have led to notable reductions in body weight and improvements in metabolic parameters. 507 participants received semaglutide as a once-weekly subcutaneous injection and/or bimagrumab administered via intravenous (IV) infusion at weeks 4, 16, 28, and 40. They also reduce triglycerides and low-density lipoprotein cholesterol, mitigate adipose tissue inflammation, and minimize ectopic fat deposition, promoting overall metabolic health. These findings support the integration of GLP-1 RAs into comprehensive, individualized obesity management strategies. Their benefits extend beyond weight reduction, encompassing improved glycemic control and favorable behavioral and metabolic changes. More data and long-term studies are needed to determine the side effect profile and the long-term effects of these medications on the human body . Following this, the FDA-approved Wegovy® (semaglutide) was given as a treatment for weight loss in patients with a body mass index (BMI) of 27 kg/m2 or higher . Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), especially semaglutide (famously known as Ozempic® or Wegovy®), have become very popular in recent years for weight loss, even though their initial indication is for the management of the patient with diabetes mellitus. The clinical benefits of GLP-1 receptor agonists are well-documented. Following exenatide, several other GLP-1 receptor agonists were developed, including liraglutide (Victoza), dulaglutide (Trulicity), and semaglutide (Ozempic). In 2005, the FDA approved exenatide (Byetta), the first GLP-1 receptor agonist, marking a significant milestone in diabetes treatment. I'm doing research on the GLP-1 connection with papillary right now, because I see patients with thyroid cancer who have obesity and they're at high risk for recurrent thyroid cancer. Glucagon-like peptide-1 receptor agonist drugs (GLP-1s) such as Wegovy and Zepbound, have become game-changers in the world of weight-loss drugs. The figure on the right illustrates the model-predicted typical values of weight reduction for Liraglutide (A) and Semaglutide (B) at various age levels. The box plot on the left displays the observed weight reduction values for Liraglutide (A) and Semaglutide (B) across different age groups. Values exceeding 80 % suggest that the treatment duration has approached or reached its efficacy plateau. Novo’s Wegovy inches closer to becoming first FDA-approved GLP-1 weight-loss pill. Most insured adults still have to pay at least part of the cost of GLP-1 drugs. GLP-1 side effects only one factor driving patient discontinuation rates. At current prices, GLP‑1s aren’t cost‑effective, limiting access to patients. 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.GLP-1RAs are linked to reduced cerebrospinal fluid secretion and intracranial pressure due to their action on receptors in the choroid plexus, where they raise cyclic adenosine monophosphate (cAMP) levels and inhibit the Na+/K+ ATPase pump .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 .At least one body weight measurement between 26 and 52 weeks was necessary for each individual to be included in the analysis.Fourth, the absence of a control group in the GLP1-RA analysis may limit distinguishing intentional from unintentional weight loss.Plus, simply having people who understand the unique challenges of these weight loss treatments makes a huge difference."And that inflammatory state results in organ damage that leads to cardiometabolic disease, kidney disease, diabetes, certain forms of cancer, and potentially certain neurodegenerative changes," says Kessler. GLP-1 agonists such as semaglutide (Ozempic® and Wegovy®) have recently risen exponentially in popularity. This may be attributed to the relatively recent approval of several of these medications in adults and current ongoing trials such as STEP YOUNG for Wegovy® and SCALE KIDS for Saxenda® . Some concerns include that there has been limited research finalized on the effective, safe use of these medications in children . Obesity is largely considered a risk factor for the development of type 2 diabetes. This may contribute to the significant weight loss as a result of social media-delivered weight loss interventions compared to traditional methods such as brochures and questionnaires . All genotyped biospecimens had at least 99% call rate per array and were confirmed for sex concordance using sex in EHR and sex computed from array data.Ancestry was defined using high-dimensional PCs, specifically top 30 genetic PCs and a network-based clustering approach. More than 65,000 participants have genotype data sequenced using the Illumina Multi-Ethnic Genotyping assay or the Illumina Global Screening Array. Data that are run together can usually include the sampling date, the donor’s gender, histological and cytological examinations, diagnoses, care measures and laboratory examination results.Mass General Brigham is an integrated healthcare system located in Boston, Massachusetts for more than 1.5 million individuals per year. Diagnostic formalin-fixed paraffin-embedded tissue samples from approximately one million patients have been transferred to the biobank’s sample collection. Approximately 80,000 patients have given a blood sample based on biobank consent and used for research purposes. Konig et al. in their post hoc analysis summarized that dulaglutide caused a significant reduction of 16.7% in HBA1c and 25.4% in UACR, which, in turn, contributed to the benefits recorded for cardiovascular health 43,44. The REWIND trials, which studied a GLP-1RA named dulaglutide specifically, showed similar results, with a protective effect on heart health. A review by Helmstädter et al. in 2021 outlined these benefits, with liraglutide reducing death of heart-related disease events by 13% as per the LEADER trials and semaglutide demonstrating a 26% reduction in MACE. Numerous CVOTs have been conducted over the years, signifying significant benefits of GLP-1 RAs, with overall improved cardiovascular health and kidney function recorded . However, the sustainability of these outcomes often depends on continued treatment, reinforcing the view of obesity as a chronic disease requiring long-term pharmacological management. Additionally, while some data extend to 120 weeks, real-world evidence on treatment adherence, long-term safety, and durability beyond two years is still lacking. However, notable limitations include heterogeneity in study designs, treatment durations, comparator arms, and outcome reporting, making direct comparisons challenging. Studies captured a diverse range of populations, including adolescents and patients with comorbid conditions such as type 2 diabetes and cardiovascular disease. However, accessibility remains a barrier, especially in low- and middle-income settings, and continuous, possibly lifelong treatment may be necessary to sustain benefits, raising questions about health system sustainability and equitable implementation . Regular physical activity is also recommended as a component of weight loss programs not only for energy expenditure, but for cardiometabolic health as well . In a randomized study of overweight adults, following a low-fat or high-fat diet with average or high protein resulted in an average 7% weight loss at 6 months, irrespective of diet type . 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. The 12 GLP-1RA drugs were categorized based on receptor specificity into mono-agonists, dual-agonists, and triple-agonists. Dual agonists for GLP-1/GIP or GLP-1/GCG receptors, and triple agonists for GLP-1/GIP/GCG receptors have been developed to enhance weight reduction and metabolic outcomes . Reducing weight by 5 % or more significantly improves obesity-related health complications . This study provides a quantitative evaluation of the efficacy and safety of GLP-1RAs and offers valuable insights into the assessment of new drugs for weight reduction. Cell studies show that BPA exposure directly causes a decrease in GLP-1 and insulin release through miR-338.refref A 2025 study in mice showed that prenatal glyphosate exposure at normal levels reshapes the gut microbiome. Multiple studies have tied changes in the gut microbiome to lower GLP-1 levels, but the mechanism isn’t always clearly defined. GLP-1 is produced in the cells lining the intestines, which makes gut health important. Often, the rise in obesity is explained as being due to people eating more and food being more appealing. It is unclear whether those without type 2 diabetes using GLP-1 for weight loss are at the same risk 197,198. 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. 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 . 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 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 interesting to note that an extension study of semaglutide was performed to 120 weeks, but treatment was discontinued at 68 weeks. 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. Developing treatment paradigms for weight loss maintenance remain focused on decreasing hunger, despite the compensatory decrease in energy expenditure .