11 RCTs 44, 48, 49, 51, 55,56,57,58,59, 61, 62 were included in the meta-analysis, comprising 5 CR, 9 EX and 2 CREX independent intervention groups, and involving a total of 895 participants (Fig. 3). However, due to a limited number of studies for some protocols, separate analyses were only feasible for examining the effects of MICT on total ghrelin in both RCTs and non-RCTs, as well as on acylated ghrelin in RCTs, and for CR interventions across all hormones in non-RCTs. However, one study was excluded from the meta-analysis due to its exceptionally large effect sizes, which were between ten and twenty times higher than those observed in the other studies and significantly skewed the results according to the sensitivity analyses. Meta-regression analysis was performed to investigate the relationship between changes in appetite hormone concentrations in response to the extent of weight loss (%). The discrepancies in findings may be attributed to differences in study design, the populations studied, and potentially the formulations of GLP-1 receptor agonists examined. This would indicate that there is no substantial risk of thyroid cancer linked to semaglutide use when evaluating the large sample sizes . In a systematic review encompassing 10 randomized controlled trials (RCT), isolated instances of papillary and MTC were reported, each accounting for less than 1% of the study populations. PCOS is a major cause of infertility in women of reproductive age, with oral contraceptives being commonly used for treatment. However, an important limitation is the omission of real-world data, which are often different from clinical trial results, partly because of varying patient populations. Whilst there is movement to design cannabanoid-1 receptor antagonists that are less hydrophobic to reduce blood-brain barrier penetration and therefore psychiatric side effects , we are not aware of any ongoing clinical trials yet. Therefore, cannabinoid receptor antagonists represent a further therapeutic option in the treatment of obesity. A, b Changes in longitudinal fasting blood glucose by weight-change categories in 1-year and 5-year follow-up cohorts In the 1-year follow-up cohort, those who lost ≥ 15% of their index weight had the largest mean reduction in FBG levels (26.3 mg/dL; Fig. 4a). A, b Changes in longitudinal HbA1c values by weight-change categories in 1-year and 5-year follow-up cohorts. Obesity and sleep apnea were the most commonly diagnosed comorbidities of interest across all weight-change categories. 7a, b BMI at index date among weight-change categories in 1-year and 5-year follow-up cohorts. All of the disproportionality signals had early failure type characteristics, suggesting that the majority of patients developed gastrointestinal AEs within 1 week or 1 month of semaglutide treatment, and that the risk of gastrointestinal AEs occurrence gradually decreased over time. All disproportionality clinical priority signals of semaglutide treatment were listed in Table 3. Safety study of injectable semaglutide for type 2 diabetes suggested that the thyroid and pancreatic safety had not been substantiated (43). Excitingly, our study detected the indication of semaglutide for obesity with 133 cases. We note that as the prevalence of T2D increases with the age, our model can still be useful on a large variety of T2D patients. Our multi-level architecture enabled our model to identify the underlying patterns from various sources of data. The higher importance of acceleration in the Z dimension, compared to X and Y dimensions may be related to the greater contribution of this ActiGraphy measurement in indicating the physical activity intensity (Bai et al., 2016). Another possible explanation for this could be the higher variance of the triglyceride values compared to other three sequalae, making the prediction task essentially more challenging for all models. As discussed above, we have observed that the performance of the model without considering the static features is lower than a model utilizing static and dynamic (temporal) data together. A Real-World Study of the Effectiveness and Safety of Semaglutide for Weight Loss Absolute weight loss with liraglutide 3.0 mg (Saxenda) is reported up to 5.9 kg over 56 weeks 18, 19. Subsequently, liraglutide (Saxenda) was approved in 2014 for the treatment of obesity up to a maximum dose of 3.0 mg subcutaneously once daily in people with a BMI ≥ 30 kg/m2, or ≥ 27 kg/m2 and obesity-related co-morbidity 9, 17. Liraglutide (Victoza) was approved for use in T2D in 2009 by the EMA at doses of up to 1.8 mg once daily subcutaneous injection for people with T2D as monotherapy in those unable to take metformin or as add-on treatment to oral agents and/or insulin. Indeed, high-dose liraglutide (3.0 mg daily) is already approved to support weight loss in both Europe and the US. It is these latter actions that lead to reduced appetite and early satiety thereby contributing to weight loss in people who use GLP-1 analogues . All data collected at the planned end of treatment (week 52), irrespective of discontinuation of the trial product or initiation of rescue medication, were included in the statistical analysis. In PIONEER 8, patients whose insulin dose was increased by ≥ 20% during treatment were considered to have required rescue medication. FAS full analysis set, ins insulin, met metformin, N number of patients included in analyses, OD once daily, RCT randomised controlled trial, SGLT2i sodium-glucose cotransporter-2 inhibitor, SU sulphonylurea, TZD thiazolidinedione Consequently, patients receiving oral semaglutide will typically already be receiving treatment with other glucose-lowering agents. In total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included. Change in eGFR in 47 participants with iohexol measured GFR. S.C.G. declares funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim and Novo Nordisk (all to the FIDES Research Foundation) and payment of honoraria for lectures from AstraZeneca, Novo Nordisk, Baxter, Chiesi, ChemoCentrix, Clarion and Boehringer Ingelheim. The decision to submit the paper for publication was made jointly by all authors. The study was funded through a research grant from Novo Nordisk to the University Medical Center Groningen. An index dose of 0.25 mg of semaglutide was reported for 63% of the cohort. Most of the study cohort was female (85%), White (74%), from the Southern region of the US (67%) and had commercial health insurance coverage (87%). Descriptive statistics were reported for all study measures for the overall cohort, and for the subgroups of interest. Because BP may fluctuate day to day, if more than one BP value was available within the respective baseline and follow‐up periods, the mean value of 0±30 days and mean of 182±30 days were calculated separately, and the change was calculated as the difference in means. Also, the information in the EMR database on the date of onset of T2D and medication adherence is limited. There is a possibility of missing diagnosis data as a result of either physician choice or lack of reporting by the patient. There was an improvement in LDL levels in the 1-year follow-up cohort that persisted across the weight-change categories in the 5-year follow-up cohort. It is noteworthy that the improvements in glycemic and metabolic parameters observed in the study population are independent of antihyperglycemic medications used. A, b BMI at index date among weight-change categories in 1-year and 5-year follow-up cohorts. Evidence emerging from several studies indicates that individuals who received a weekly dose of semaglutide experienced a significantly larger reduction in HbA1c compared with those receiving a weekly dose of dulaglutide.The current study aimed to assess the long-term effects of weight loss among people with T2D in the USA using real-world data derived from an EMR database and linked health care claims data.But she learned to manage the side effects and, soon after starting the medication, began to lose weight.The first action of GLP-1 to be characterised was the stimulation of insulin and inhibition of glucagon release from the pancreatic islets .With the plate on a magnet, the primary antibody solution was removed, and the beads were resuspended in secondary antibody solution (guinea pig anti-rabbit IgG (antibodies-online, catalogue no. ABIN101961)) and incubated at room temperature.Semaglutide is particularly beneficial for patients with NAFLD and features of metabolic syndrome, given its notable effects on lowering HbA1c and promoting weight loss. All of the disproportionality signals had early failure type features, suggesting that the majority of patients developed gastrointestinal AEs within 1 week or 1 month of semaglutide treatment, and that the risk of gastrointestinal AEs occurrence gradually decreased over time. The exact effects of semaglutide on these AEs and the mechanisms of this potential association were not completely explored, requiring further clinical investigation. A real-world pharmacovigilance study of semaglutide had also demonstrated a similar pooled median time-to-onset of gastrointestinal AEs (7 days, IQR 0–48 days), which further supported the findings of our analysis (13). The data on time-to-onset for moderate AEs signals were not significantly different from a recent study, indicating the median durations of nausea, diarrhea and vomiting were 8, 3, and 2 days respectively, in the semaglutide 2.4 mg arm (26). The greatest reductions in cardiometabolic risk factors were generally observed over the first 20 weeks of semaglutide treatment in both studies and mirrored the weight‐loss trajectory.18, 20 In the current analyses, data from STEP 4 indicated that the potential benefits of semaglutide treatment on cardiometabolic risk factors were not maintained after treatment discontinuation. Among 882 participants in the semaglutide group and 472 participants in the placebo group who were aged 40‐79 years, 813 (92.2%) and 411 (87.1%), respectively, had ASCVD scores at baseline and week 68 and so were included in the analysis. Comparison of the estimated treatment differences between semaglutide and placebo in blood pressure changes for participants with controlled versus uncontrolled hypertension at baseline. Comparison of the estimated treatment differences between semaglutide and placebo in blood pressure changes for participants with baseline blood pressure above versus below the median (effect adjusted for placebo). Decrements in SBP, non‐HDL cholesterol, LDL cholesterol and FPG were generally greater with semaglutide than placebo even when compared within equivalent categories of weight loss (Figure 1 and Figure S3). Figure 4. Adipose tissue networks of obese women after a 8-week low calorie diet. If you have diabetes and already take a different medication, talk to your physician about acceptable (and safe) combinations of diabetes medication. They know your personal and family medical history and can guide you in the best treatment for your condition. But you may be able to reduce the side effects by beginning on a lower dose and then slowly increasing the amount you take. Gastrointestinal issues are the most common complaint among people just starting semaglutide. “The fundamentals of obesity management will always be changes to diet and exercise,” Dr. Surampudi says. Discontinuation of semaglutide treatment resulted in failure to maintain therapeutic benefits on cardiometabolic risk factors. These analyses of data from the STEP 1 and 4 trials report the effects of once‐weekly s.c. Proportion of participants at intermediate‐high ASCVD risk at baseline and week 68 in STEP 1. Difference between values at weeks 0 and 20 for the individual participants in the total randomized population. Participant numbers are provided for data at week 0 where the number analysed differed from the number in the full analysis set. Two triple agonists are currently in early stages of clinical trials with no yet published clinical trial data .Ozempic (semaglutide) is a GLP-1 receptor agonist that is commonly prescribed for the management of Type 2 diabetes.The DPP was a randomized controlled trial that compared weight loss with metformin, intensive lifestyle treatments, or placebo and evaluated the preventative effects of the drug on metabolic parameters in individuals at high risk for T2DM 22,23.To assess the comparative effectiveness of semaglutide, studies comparing it to a placebo, other pharmacological weight loss treatments, behavioral interventions, or surgical interventions will be included.Studies on FA composition of AT during weight control trials are scarce 9, 10.New dietary information has only added to the current confusion due to several controversial dietary regimens, and there is no clear guidance on the optimal diet for weight loss.The validation analysis reported that all root-mean-square deviation values for external validations were 3.7% or less and for internal validations (against published studies used to develop the model) were 1.1% or less.Weight change was calculated as difference between weight at baseline and weight at examinations;Accordingly, a limitation of our study is the lack of blood glucose and serum insulin measurements. Significantly enriched pathways in up/down regulated DEPs between Sema and HFD groups identified through KEGG pathway enrichment analysis. Distribution of proteins and signaling pathways between Sema and HFD groups, based on GO and KEGG analysis. The remaining DEPs were mainly located in cytoplasmic (22.73% in Sema/HFD, 25.96% in total), extracellular (16.29% in Sema/HFD, 11.47% in total), plasma membrane (15.15% in Sema/HFD, 11.47% in total) and mitochondrial (9.22% in Sema/HFD, 10.5% in total; Figures 5A, B). DEPs were mainly located in nuclear (34.72% in Sema/HFD, 38.19% in total). List of the DEPs reversed by semaglutide between HFD/NCD and Sema/HFD. The Atkins diet has gained popularity as a non-energy-restricting, low-carbohydrate, high-protein, and high-fat diet.45 In addition, diets high in protein with normal amounts of carbohydrates have been used to improve metabolic parameters.46 Diets with higher protein intake can provide significant benefits to prevent weight regain.47 A satiating effect is most significant with high-protein diets, and this effect helps decrease energy intake and maintain successful weight loss.Read on for eight possible reasons why you’re not losing weight on Ozempic and how to optimize the medication’s results, according to doctors.Although completed, the results of the STEP 5 clinical trial have not yet been published.55 This trial is similar to STEP 1, as it aims to test the durability of weight loss with 2.4 mg semaglutide versus placebo, but over a period of 2 years in 304 participants.Prediction interval is used to evaluate how heterogeneous the data are regarding (A) glycemic control and (B) weight loss.By contrast, prediction intervals indicate the range within which future study results are likely to fall, making them directly interpretable in real-world contexts.Since then, additional studies have shown similar results.Descriptive statistics were reported for all study measures for the overall cohort, and for the subgroups of interest. With 3 mg, 1.8 mg, and placebo, respectively, an average decrease of 6.4 kg, 5 kg, and 2.2 kg was seen at week 56 . In a 26-week, double-blind research, liraglutide was also assessed as an add-on therapy with insulin glargine with or without metformin . With 1.2 mg, 1.8 mg, and 100 mg of liraglutide and sitagliptin, respectively, weight reductions of 2.86 kg, 3.38 kg, and 0.96 kg were reported . Studies, where semaglutide is used primarily for glycemic control in diabetes without a specific focus on weight loss, will be excluded. To capture the effects of semaglutide across diverse ethnic backgrounds, the review will include studies with participants from various ethnic groups. Additionally, studies must include both male and female participants to provide a comprehensive understanding of semaglutide's effects across the sexes. Sustainability of weight loss - evidence suggested that weight loss achieved with semaglutide was sustainable over time, with many studies reporting continued weight maintenance during follow-up periods. Deng et al. further supported these findings, noting that semaglutide therapy resulted in a clinically relevant weight loss of 48.2% to 88.7% . STEP 4 can be considered as a multicentre, phase IIIa ‘withdrawal’ trial designed to study weight changes after switching from semaglutide to placebo.54 A total of 902 participants (79% women; 84% White, 13% Black/Afro-American, 2% Asian, 1% other; 7.8% Hispanic/Latino ethnicity; mean age 46.0 years) with obesity or overweight (mean BMI 38.4 kg/m2), at least one weight-related comorbidity and without T2D were recruited from 73 sites in 10 countries. With data from phase II and III clinical trials showing that newer drugs (i.e. the glucagon-like peptide-1 and gastric inhibitory polypeptide dual receptor agonist tirzepatide and the amylin agonist cagrilintide, either alone or combined) produce a greater sustained weight loss than semaglutide, an upstream ‘weight-centric’ strategy has emerged as a new standard for the treatment of type 2 diabetes. The SURPASS clinical trials demonstrated the efficacy and safety of tirzepatide in people with T2D and showed that patients experienced reductions in A1c and body weight when treated with tirzepatide.19-22 In the SURPASS-2 clinical trial comparing tirzepatide 5 mg, 10 mg, and 15 mg with injectable semaglutide among patients with T2D on background therapy of metformin, all 3 doses of tirzepatide were shown to reduce A1c by 2.01%, 2.24%, and 2.30%, respectively, compared with a 1.86% decrease experienced by patients treated with semaglutide 1.0 mg.20 Extended Data Fig. 8 Epigenetic memory persists after weight loss. DBP changes were more pronounced in patients with class 1 or class 2 obesity with mean (±SD) changes from baseline to follow‐up of −2.6 (±8.3) and −2.6 (±8.8), respectively, compared with patients with overweight −0.9 (±7.9) and patients with class 3 obesity −0.8 (±8.0). Proportion of patients reaching body weight reduction thresholds at 6‐month follow‐up (change from baseline). The AEMR database comprises approximately 75 million US patient records that are sourced from an ‘opt‐in’ provider research network and includes key demographic and clinical variables such as age, sex, race/ethnicity, height, body weight, BMI, risk factors, laboratory tests, diagnoses, prescription drugs prescribed or administered, procedures performed, and patient care encounters (i.e., health care visits, appointments, correspondence). Consensus‐based guidelines for the management of obesity recommend targeting sustained body weight reduction of at least 5% body weight.1, 2 Reductions of this magnitude have been linked to delaying the onset of, or reducing the likelihood of developing, a variety of conditions, including hypertension, hyperlipidemia, type 2 diabetes (T2D), and osteoarthritis.3, 4 However, it is difficult to successfully manage long‐term obesity with lifestyle changes alone.5, 6, 7 The study found that a 6‐month use of semaglutide 2.4 mg resulted in a 10% decrease in weight and a reduction of 10.5 kg in adult participants with overweight/obesity. In the present study, the disproportionality analysis was used to analyze the safety data of semaglutide to quantitative gastrointestinal positive signals based on FAERS database, which was a global, public and accessable pharmacovigilance database (14, 15). A systematic review and network meta-analysis published in 2014 revealed that, all GLP-1RAs dose regimens distinctly increased the incidence of gastrointestinal AEs compared with placebo or conventional treatment (7). Recently, in June 2021, the FDA approved semaglutide again for long-term weight management in obesity or overweight adults, which was the second GLP-1RA to be approved for weight loss after liraglutide. These weight loss outcomes are comparable with a three-month percentage weight loss of 6%-6.5% and six-month of 10.6%-12% reported in STEP 1 and STEP 4 trials 7,8, suggesting that semaglutide achieves a similar effect in routine clinical practice with that observed in RCTs. This study reported semaglutide-related percentage weight loss of 6.6% (7.4 kg) and 13.3% (14.9 kg) in three and six months, in line with the mean 6.3% and 11.8% in three and six months, respectively, observed in a similar real-world cohort study in the United States . In almost two-thirds of the participants, substantial weight loss was produced despite being treated with 1 mg weekly, lower than the maintenance-licensed semaglutide dose of 2.4 mg weekly. Regarding the effectiveness of semaglutide therapy following bariatric surgery, one individual who had undergone sleeve gastrectomy in 2008 was included, with three-month and six-month weight loss of 5.5 kg (4.9%) and 8 kg (7.1%), respectively, with mild gastrointestinal side effects. In addition, this study could not assess the impact of maintenance semaglutide dose on patient response since the decision for the titration of semaglutide dose greater than 1 mg was influenced by the magnitude of three-month weight loss, introducing a selection bias. A novel finding of this study was the overrepresentation of patients with active psychiatric disorders among non-responders. Therefore, an efficacy-effectiveness gap does not exist with respect to semaglutide in weight management, supporting the generalizability of RCT findings . In all three cases, the period of semaglutide administration coincided with significant mental health deterioration, while none of the three patients were treated with antipsychotic medications. Overall, participants with numerically greater weight loss in follow-up tended to have a higher index weight in both follow-up cohorts. In the 1-year follow-up cohort, participants with the greatest weight loss, i.e., ≥ 15%, had a 23% (25.9 kg) reduction in weight from the index weight date (Fig. 1a). The percentage of participants who experienced ≥ 15% weight loss in the 1-year follow-up cohort increased from 0.6% to 4.2% as the index BMI increased. Index BMI data for the remaining participants were unknown or 2 and are not included in this analysis. In addition, the weight-change categories in the 5-year follow-up cohort (Fig. 6a, b) revealed a similar plateauing effect beyond ≥ 10% weight loss for LDL (9.9–11.9 mg/dL) and total cholesterol (11.6–15.0 mg/dL). At LCD, energy intake, fat, protein and carbohydrate intake data issued from commercial meal replacement information. Energy intake (A), fat (B), protein (C), and carbohydrate intake (D) were investigated by a nutritionist using a weighed food record at screening, four weeks (week 4) after the end of low calorie diet (LCD) and at the end of weight maintenance diet (WMD). This emphasizes the predominant role of waist circumference, compared to blood pressure, in metabolic syndrome compared to blood pressure. On the other hand, fasting insulin and glucose are part of another module which displays an immune signature (Adhesion and Diapedesis), emphasizing the link between adipose tissue inflammatory status and insulin resistance . Growth hormone shares protein anabolic properties with insulin. This is also sometimes seen after significant weight loss from other causes, such as stomach surgery, says Miras. In 2021, Wegovy was approved for weight loss in several countries, including the US and Canada. These so-called GLP-1 analogues have several effects, including slowing stomach emptying, acting on the brain to reduce appetite and boosting the release of insulin, which helps to regulate blood sugar levels. Wegovy can bring about significant weight loss but may need to be taken long term Wegovy can bring about significant weight loss but may need to be taken long termTobias Arhelger/Shutterstock In this study, in addition to the dynamic wearable data, there are other types of information (lab test results and physical indices) that are considered static. In addition to diabetes, our approach could be useful for other serious and chronic physical illness, where dynamic (e.g., from multiple sensors) and static (e.g., demographic) data are used for creating predictive models. Lastly, our participants were relatively homogeneous in terms of their body fatness and health status. Second, other hormones or peptides such as ghrelin and cholecystokinin that might influence weigh change were not examined.4 More research is needed to investigate whether these hormones or peptides would influence the associations between thyroid hormones and weight loss. Poor sleep can induce weight gain for a variety of reasons, one being that it disturbs the body's normal hormonal balance, says Dr. Rao. For example, PCOS can make your body resistant to insulin, causing the pancreas to produce more of the hormone. What works for your friend may not work for you, so it’s critical to work with a doctor that can customize your dosage depending on your medical history, goal weight, and side effects, says Dr. Saunders. Some can see rapid weight loss, while others may not see results for a few weeks, she explains. SNP-based demultiplexing of human snRNA-seq datasets Results from observational and retrospective studies must be interpreted with caution and can only establish associations and not cause‐and‐effect relationships, which is an inherent limitation to the administrative nature of data or retrospective study design. The study, while focusing on participants naive to GLP1‐RA, did not investigate the effects of other anti‐hyperglycemic medications, warranting additional research to evaluate the effect of concomitant anti‐hyperglycemic medication use on HbA1c levels. However, this study aimed to extend the real‐world evidence base for semaglutide 2.4 mg by assessing its effectiveness in managing obesity across multiple health systems and practice settings, with no specific focus on racial or ethnic differences. Reducing portions sizes and avoiding fatty foods may also help.42,51–54,59–61,66 These GI side effects, along with slow gastric emptying, cannot, however, be considered responsible for the drug's effect on weight loss.66 Like the other GLP-1 RAs, semaglutide has a black box warning for medullary thyroid carcinoma (although thyroid cancers have not been reported in human trials) and should not be used in patients with a personal or family history of medullary carcinoma or multiple endocrine neoplasia syndrome. Preliminary reports indicate that, in addition to lifestyle intervention, weekly injection of 2.4 mg semaglutide led to weight loss from baseline to week 104 of 15.2% in the active group versus 2.6% in the placebo group (p60 From baseline to week 68, the proportion of participants with prediabetes, defined using the ADA criteria, dropped from 48% to 7% in the semaglutide group and from 53% to 26% in the placebo group. T2D was an exclusion criterion, but 40–45% of the cohort had prediabetes (defined in accordance with American Diabetes Association (ADA) criteria).56 A subpopulation of 140 participants had their body composition assessed by dual-energy X-ray (DXA) absorptiometry to test whether any weight loss was primarily caused by a reduction in fat mass. In a study reviewing the FDA Adverse Event Reporting System, primary treatment for acute gallbladder injury was a cholecystectomy, performed in 30 out of 36 cases.Next, escalate the dosage gradually to minimize side effects, adjusting the pace based on each individual’s tolerance.Data for some parameters have been reproduced with permission from the Massachusetts Medical Society (STEP 1) and the American Medical Association (STEP 4); see Tables S1 and S2 for presentation of these data in their original format.Initially, the patient tolerated the medication well, and her blood glucose levels improved, with an HbA1c reduction to 8.5 percent after four weeks of treatment.No further intensification steps were modeled as these would be the same in both treatment arms and have little effect on cost-effectiveness.The results showed that nearly two‐thirds of patients with prediabetes or diabetes at baseline who were treated with semaglutide 2.4 mg had normoglycemia at 6‐month.It should be noted that improvements in BP and lipid levels with semaglutide were maintained despite a parallel relative reduction in antihypertensive and lipid‐lowering medication use.Few studies have examined the effects of GLP‐1RAs on cardiometabolic risk factors or CV outcomes in people with overweight/obesity without T2D. Results of time-to-onset and WSP analysis for the strong, moderate and weak clinical priorities signals were shown in Table 4. Of note, 17 new and unexpected AEs which showed statistically significant RORs and were not presented in the drug label were also detected in our data analysis. The report frequency of gastrointestinal disorders related to semaglutide was significantly higher than that of non-semaglutide in the overall database with the ROR of 4.21. Gender data were available for 5,312 patients, and females accounted for a larger proportion than males (3,064 vs. 2,248). The mean change in body weight from baseline to week 68 (the primary outcome) was -15.8% with semaglutide versus -6.4% with liraglutide (estimated treatment difference -9.4%; 95% CI -12 to -6.8; p By the end of the randomized period (week 68), participants on semaglutide had lost an additional 7.9% of their weight from the week 20 timepoint (with a plateau reached at week 60–68), while those switched to placebo had gained 6.9% (difference 14.8%, 95% CI -16.0 to -13.5; pThe adverse event profile was similar to that seen in other studies with GLP-1 RAs. The most common adverse events again concerned the GI tract, with just over 2% of participants in each arm discontinuing treatment in the randomized period because of adverse events.54 The estimated treatment difference for 2.4 mg semaglutide versus placebo was -6.2 percentage points (95% CI -7.3 to -5.2; p15% of body weight. The mean HbA1c level decreased by 1.6% (17.5 mmol/mol) and 1.5% (15.9 mmol/mol) in the 2.4 and 1.0 mg semaglutide groups, respectively, and by 0.4% (4.1 mmol/mol) in the placebo group. Change in mean body weight from baseline to week 68 was –9.6% in the 2.4 mg semaglutide group, -7.0% in the 1.0 mg semaglutide group and -3.4% in the placebo group. Adjusted geometric mean change from baseline in the semaglutide and placebo group is shown. Change from baseline in urinary albumin concentration over the study treatment period. We conducted a randomized placebo-controlled double-blind clinical trial in adults with CKD (estimated glomerular filtration rate (eGFR) ≥25 ml min−1 1.73 m−2 and urine albumin-to-creatinine ratio (UACR) ≥30 and −1) and body mass index ≥27 kg m−2. AA had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Secondary endpoints included proportion of patients achieving ≥5%, ≥10%, ≥15%, and ≥20% weight loss, and improvements in metabolic, cardiovascular, and comorbidities after 12 months of follow-up. Each participant’s diet prescription represented a reduced caloric intake of 750 kcal/day from estimated energy needs, which were calculated from the RMR at baseline. A similar pattern of associations was also observed between baseline thyroid hormones and changes in RMR. An intestinal peptide that stimulates the release of insulin. Pharmacotherapy aiming to decrease excess body fat. Their meta-analysis and network meta-analysis, which included 13 pair-wise studies and 48 monotherapy trials, respectively . However, their sensitivity analysis revealed that the outcome was unstable, a significant reduction of BMI in the acarbose group was observed (−1.82), which could be related to the drug dose and the brief treatment period . In total, 5 of them were chosen to evaluate acarbose’s impact on BMI, which included 84 participants in the control group and 80 people in the acarbose arm . A total of 343 T2DM participants were assigned to the acarbose group and 333 were assigned to the metformin arm . As expected, we observed that semaglutide exerted a weight-loss effect by lowering the proportion of visceral fat mass and increasing the brown fat mass relative to total body mass. However, the impact of semaglutide on weight loss was found to have little relevance in the pancreatic islet caused by insulin resistance (6). Gabery et al. reported that semaglutide lowers rodent body weight via distributed neural pathways (4). These findings support the safety and clinical use of semaglutide in patients with obesity, atherosclerotic CVD, and HFrEF or HFpEF with NYHA class I-II symptoms. This benefit is contingent on baseline body weight, though, since patients with higher baseline body weights and/or BMIs experienced greater weight loss . In order to highlight the promising effects of these medications as anti-obesity treatments, this study analyzed T2DM medications that have the potential to reduce weight by examining clinical trials that were published on each agent involving weight reduction effects. Although completed, the results of the STEP 5 clinical trial have not yet been published.55 This trial is similar to STEP 1, as it aims to test the durability of weight loss with 2.4 mg semaglutide versus placebo, but over a period of 2 years in 304 participants. It is important to note that weight loss peaks at week 60, although the reduction was maintained for the whole 104 weeks . Next, we will look at the STEP program, which examined semaglutide’s safety and effectiveness as an anti-obesity drug 198,199,200. Additionally, uncontrolled T2DM patients who are taking one oral antidiabetic medication or on lifestyle treatments were included in PIONEER 9, a 52-week, randomized, phase 2/3 trial conducted in Japan . At 26 weeks, the initial findings indicated that the daily doses of 3 mg, 7 mg, and 14 mg semaglutide and 100 mg sitagliptin, respectively, resulted in average weight reductions of 1.2 kg, 2.2 kg, 3.1 kg, and 0.6 kg . Moving to the second program, the Pioneer studies, which sought to determine the effectiveness and safety of oral semaglutide . Following on from the theory that molecules acting on two or more different receptors would be expected to generate more weight loss than a single receptor agonist, new molecules have been engineered. As the effects of GLP-1 RAs are glucose dependent, hypoglycaemia is not an issue in people treated with semaglutide. However, further clinical trials and clinical practice with 2.4 mg semaglutide over the long term are needed to verify whether semaglutide can maintain its benefits over the very long term. Obesity is a chronic lifelong disease, and the sustained weight loss observed over 2 years in STEP 5 is encouraging. This has been consistently observed across the STEP clinical programme, with participants experiencing improved QoL in terms of energy gain, less pain, increased movement and feeling better in everyday life.54,60 Meta-analysis was performed using random effects model expressing continuous outcomes as mean differences (MD) or standardized MDs (SMD), and dichotomous outcomes as odds ratios (OR) with 95% confidence intervals (CI). To investigate the efficacy and safety of semaglutide in patients with NAFLD. This analysis of nearly 350 patients with a follow‐up period of 6 months was a robust real‐world assessment. Following the first screening of titles and abstracts for possibly pertinent studies, a full-text screening was conducted to determine the studies' ultimate inclusion. A thorough search across numerous databases yielded the articles, and preliminary screening eliminated duplicates and irrelevant research. The analysis estimated a regression line to describe the relationship, and a significant P-value (typically 14). Other health conditions like polycystic ovary syndrome (PCOS) and hypothyroidism can make it harder to lose weight, says Dr. Rao. If you’re not losing weight on the current dose, talk with your doc. You should also avoid alcohol, fatty foods, and processed snacks, since they take longer for your body to digest and may cause gastrointestinal symptoms like nausea, bloating, and constipation, she adds. In total, 2836 patients receiving oral semaglutide 14 mg/flexibly dosed or comparators were included in the background medication subgroup analyses, and 365 patients receiving oral semaglutide 14 mg or placebo in PIONEER 8 were included in the insulin regimen subgroup analysis. Therefore, for the insulin regimen subgroup analysis, the treatment policy estimand was used to reflect the effect of initiating treatment with oral semaglutide compared with initiating treatment with placebo, both potentially followed by either discontinuation of the trial product and/or initiation of rescue medication. For the efficacy outcomes (HbA1c and body weight), treatment differences were estimated by a mixed model for repeated measurements (MMRM) using data collected prior to premature trial product discontinuation or initiation of rescue medication from all randomised patients. Noteworthy, three individuals, all females with active major depressive disorder, increased their body weight during the period of semaglutide treatment. Six-month data were available in 25 out of 40 (62.5%) semaglutide-treated patients, with the remaining 15 individuals having not completed six-month treatment due to a variety of reasons, including severe side effects in one case, poor three-month response in four cases, and supply shortages/drug affordability in 10 cases. Based on the Cochrane risk of bias assessment tool, the general quality of the included studies was low. With its effect size estimate plotted against the appropriate treatment period, each trial is shown as a circle. Meta-regression evaluating the relationship between the treatment duration and its effect size magnitude. Multiple imputation was used, in which missing data were imputed from week 68 measurements from participants in the same treatment group. For analyses by categorical weight loss, weight‐loss category was included as a factor and an interaction term with randomized treatment. Continuous endpoints were analysed using analysis of covariance with randomized treatment as a factor and baseline value as a covariate. The proportions of participants achieving ACC/AHA BP targets were compared between treatment groups using a chi‐squared test. To assess the comparative effectiveness of semaglutide, studies comparing it to a placebo, other pharmacological weight loss treatments, behavioral interventions, or surgical interventions will be included. This will ultimately contribute to better informed clinical practices and improved treatment strategies for individuals with obesity or overweight without diabetes. The magnitude of weight loss varied across studies, 13 of 16 with some reporting an average reduction of 10%-15% of body weight over a treatment period of 68 weeks. RCTs are studying the use of semaglutide (both subcutaneous and oral formulations) for weight management in individuals with obesity or overweight without diabetes. Xie et al. supported the efficacy of semaglutide in promoting weight loss in individuals with obesity or overweight without diabetes, noting that while semaglutide 2.4 mg was the most effective for loss . LC-MS/MS analysis was performed on a Q Exactive mass spectrometer (Thermo Scientific) that was coupled to Easy nLC (Thermo Fisher Scientific) for 60/90 min. The flowchart of proteomics and bioinformatics analysis is shown in Figure 1. Triglyceride (TG), total cholesterol (TC), LDL-C, and HDL-C assay kits were purchased from Jiancheng Biology Institution PeproTech (Nanjing, China). Given a correlation coefficient could not be calculated from the eligible studies, a correlation coefficient of 0.5 was applied and a series of sensitivity analyses were undertaken. 18 non-RCTs 11, 63,64,65, 69, 70, 73, 74, 76, 86, 91, 93, 96, 103, 109, 153, 161, 164 were included, with 27 independent and 2 cross-over intervention groups (24 CR and 5 EX groups), involving 757 participants. Therefore, all protocols within each intervention type were included in the final analysis. Separate meta-analyses were conducted to assess the effects of specific protocols within each intervention type on appetite-related hormones. The results discussed below are based on the mean correlation coefficient values obtained from the included studies for each hormone under investigation. Sign up to our weekly newsletter Additional factors may influence appetite hormone changes after weight loss. The reasons for weight regain after weight loss are multifactorial and include compensatory physiological mechanisms aimed at resisting weight loss and promoting weight regain . Among people who are successful at losing weight through diet alone or diet combined with exercise, individuals regain, on average, 80% of the lost weight within 5 years . E. Chronic Kidney Disease (CKD) Subgroup analyses were undertaken to investigate the influence of intervention type (CR vs. EX vs. CREX) and study design (RCT vs. non-RCT) for all included studies. The searches were re-run before the final analysis to identify any further studies that met the inclusion criteria (15th of March 2024). The secondary aim was to identify potential contributors, specifically FFM loss, sex, and rate of weight loss, to hormonal responses after dietary and exercise-induced weight loss as well as to examine the difference between RCTs and non-RCTs. Often these medications should be given in combination with adjuvant lifestyle or behavioral-based interventions , which emphasizes the need for a shift in the treatment paradigm of chronic management of obesity and thus novel anti-obesity medications that can produce sustained weight loss in the long run. This could be attributed to the fact that to achieve and sustain weight loss and manage obesity in the long run, it should be treated as a chronic condition, warranting continued treatment. Further, in a study conducted by Bonora et al. to evaluate the impact of dulaglutide on weight loss in people with T2D, it was reported that those with higher baseline BMI experienced numerically greater absolute weight loss. In the current study, the highest weight loss was noted in participants in the higher index BMI categories. This underscores the fact that weight loss alone, despite being a critical component, does not bring about glycemic control, as diabetes involves a complex interplay of various physiological, therapeutic, and lifestyle factors that might have varied over the course of the study period. The original contributions presented in the study are included in the article/Supplementary Material. A previous study indicated that during fat depot expansion, CD36 deficiency negatively affects preadipocyte recruitment in mature adipocytes (43). Based on the results of the study, we found 10 proteins significantly concentrated in lipid metabolism down-regulated in Sema/HFD group, including fatty acid transport and oxidation (CD36 FABP5, ACSL, ACOX3). The paper highlights that while both forms are effective, differences in inclusion criteria, trial duration, and analysis approaches across trials mean the HbA1c reductions cannot be directly compared. Methods included a literature search of PubMed, MEDLINE, and Google Scholar, as well as identifying ongoing studies from clinicaltrials.gov. The study underlines the practical implications of Wegovy’s approval, making it a viable option for weight management. Results showed that semaglutide, whether injected or taken orally, led to a significant weight reduction. Among 27 SOCs, results of Supplementary Table S4 demonstrated that SOC of gastrointestinal disorders treated with semaglutide exhibited the strongest association owing to its highest ROR with 4.21 (4.06–4.37). The selection of parameters and criteria for evaluation were described in previous studies (21, 22). The TTO statistical analysis was conducted using the WSP test, which could determine the varying ratio of incidence of AEs. The medians, quartiles and the Weibull shape parameter (WSP) test were used to evaluate the TTO in our study (21, 22). Meal timing is also an important factor in weight management, and higher-calorie breakfasts in combination with overnight fasting may help to prevent obesity. Obesity has become one of the most important public health problems worldwide, which suggests the need for evidence-based dietary strategies for weight loss and its maintenance. Analyses were performed using the TrajGWAS package28 in Julia134, for 177,472 unrelated individuals of white–British ancestry with multiple measurements of weight included in the discovery analyses. The same protocol was followed to determine rG between BMI-intercept in our in-house study and BMI in the GIANT 2019 meta-analysis. It was possible to lose weight in a dose-dependent manner; the maximum oral semaglutide dosage (14 mg once daily) produced the greatest weight loss (4.1 kg) .Different people lose weight at a different rate but generally speaking, it may take weeks to lose 20 lbs on semaglutide.Longitudinal values for vital signs and laboratory parameters, including BMI, weight, HbA1c, proportion of participants achieving HbA1c 2), overweight (25 to 2), class 1 obesity (30 to 2), class 2 obesity (35 to 2), and class 3 obesity (≥ 40 kg/m2).Body weight was significantly reduced by sitagliptin by 1.7 kg, whereas it was significantly elevated by sulfonylurea by 0.5 kg .ZJ, AT and TS were responsible for screening potentially eligible studies.The fluctuation of blood glucose levels in HFD-fed mice was alleviated by semaglutide treatment, suggesting that semaglutide could improve the rate of glucose clearance and insulin sensitivity.HbA1c remained consistent across the weight-change categories at the index date and subsequently decreased along the categories with increasing weight loss in both 1-year and 5-year follow-up cohorts. This finding is consistent with that of Wing et al. , which showed greater odds of clinically significant improvements in lipid profiles in individuals with a weight loss of 10–15% of body weight. To date, most studies have reported only the short-term effects of weight loss in people with T2D and overweight or obesity, most of them in relation to specific antihyperglycemic treatment classes 2, 24,25,26. A modest and sustained weight loss of 5–10% of total body weight in people with T2D and overweight or obesity was shown to improve glycemic control and reduce dependency on glucose-lowering medications. A systematic literature review and meta-analysis of prospective trials studying the effects of energy-reduced diets, anti-obesity drugs, and bariatric surgery showed that weight loss in people with T2D and overweight or obesity is accompanied by a reduction in glycated hemoglobin (HbA1c) levels . For analyses by categorical weight loss, weight‐loss category was included as a factor and an interaction term with randomized treatment.This analysis highlights the importance of combining semaglutide treatment with lifestyle interventions for optimal results, recommending a target dose of 2.0 mg or more once weekly for effective weight management.Dipeptidyl peptidase 4 (DPP-4) inhibitors showed a neutral or mild weight loss effect.In addition to their ability to improve glycemic control, these therapies have also been shown to promote weight loss , leading to a paradigm shift towards better management of T2D.Oral semaglutide was effective at lowering HbA1c and body weight, regardless of background medications, and appears suitable for a broad range of patients with T2D in combination with other glucose-lowering agents.5 RCTs 46, 47, 50, 53, 54 were included in the meta-analysis, comprising 6 EX groups and 1 CR group across the studies, involving 200 participants (Fig. 7).The clinical trials typically involved participants taking semaglutide for 68 weeks or more.Encouragingly, there are several ongoing and unreported preclinical, phase I/II trials investigating drugs utilising this dual mechanism of action . Over the last three decades, there has been an exponential increase in rates of obesity, which has become a global epidemic and a major public health problem . The rate of adverse events was 26 out of 40 patients (65%), mostly mild to moderate and of short duration, leading to discontinuation in only a single case (2.5%). All authors drafted the manuscript, participated in data analyses and interpretation, revisions of the manuscript, and approved the final version. The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author. Our results would potentially prompt improved awareness of semaglutide-related toxicities and provide valuable references for healthcare professionals to mitigate the risk of gastrointestinal AEs by post-marketing safety assessments. Additionally, in the SUSTAIN 10 study, semaglutide’s safety and effectiveness were contrasted with liraglutide’s when administered in T2DM patients using no more than 3 oral medications . In SUSTAIN 9, a randomized, double-blinded, international trial, 302 T2DM patients on an SGLT-2 inhibitor with metformin with/without sulfonylurea were randomly assigned to receive either a placebo or 1 mg of semaglutide once per week . With semaglutide and canagliflozin, the average weight loss after 52 weeks was 5.3 kg and 4.2 kg, respectively . In total, 199 T2DM patients receiving metformin were randomly assigned to receive either 0.5 mg or 1.0 mg of semaglutide subcutaneously or 0.75 mg or 1.5 mg of dulaglutide once per week . However, when examining the extent of weight loss, more CR studies achieved 10–15% or 15–20% weight loss, whereas the EX studies tended to elicit less than 5% or between 5 and 10% weight loss. However, when controlling for the magnitude of weight loss, the variations in total ghrelin changes across different interventions were rendered non-significant. Our results showed no differences among interventions for any appetite-related hormone, except that CR led to a greater increase in total ghrelin compared with EX after removing the high-risk of bias RCT study. However, more evidence is required to confirm its effectiveness and safety.37,41,42 Similar to VLCKDs, ketogenic diet is contraindicated in pregnant women; those with T1DM, kidney failure, or cardiac arrhythmia; and in older patients with frailty. Ketogenic diet is characterized by an extreme reduction in carbohydrate intake (41 Ketogenic diets may decrease appetite and increase lipolysis, which may result in greater metabolic efficiency for fat consumption and can provide the same thermic effects as proteins.41 There are several types of carbohydrate-restricted diets, some of which limit carbohydrates to certain levels without restricting dietary protein and fat (such as the Atkins diet), whereas others allow moderate carbohydrate intake as well as moderate protein and fat intake.37 Moreover, metabolic adaptations to decrease energy expenditure can lead to a plateau with this type of diet, which individuals may misinterpret as “failure” due to “lack of willpower.” Under the “calories-in, calories-out” model, dietary management has focused on the concept of “eat less, move more,” and patients have been advised to consider and calculate their calorie balance whenever they eat. The current post-hoc exploratory subgroup analyses evaluated outcomes by background medication and insulin regimen subgroups. Semaglutide is a glucagon-like peptide-1 receptor agonist that was recently approved by the US Food and Drug Administration for chronic weight management. In particular, it has been reported that the HbA1c-lowering efficacy of GLP-1 RAs is greater in Asian-dominant groups than in non–Asian-dominant groups.66 Therefore, higher achievement rates in diabetes remission brought on by incretin hormone therapy is expected in Korea. Therefore, drugs that enhance MC4R action should modulate food intake centrally to improve weight loss. However, results in human trials are less favourable with no difference in weight between obese patients receiving ghrelin immunisation over 20 weeks, with both active and control groups losing 3.6 kg weight . Overfeeding and high total body fat stimulate release of leptin, whilst the fasting state and low-fat stores inhibit leptin secretion . Presents the observed weight loss with each of the approved SGLT-2 inhibitors in people with and without T2D To our knowledge, at the time of writing there are no trials exploring weight loss in people without T2D. Participants in both trials were aged ≥18 years with one or more self‐reported unsuccessful dietary effort to lose weight and body mass index ≥30 kg/m2 or ≥27 kg/m2 with one or more weight‐related comorbidity without diabetes. Although the exact mechanisms behind the CV effects are not fully elucidated, data suggest GLP‐1 receptor agonists (GLP‐1RAs), including semaglutide, may have direct and beneficial effects on the CV system.23, 24, 25, 26, 27 Semaglutide 2.4 mg led to mean weight losses of 15‐17% in participants without T2D and showed benefits beyond weight loss, including on patient‐reported outcomes.18, 19, 20 It has subsequently been approved for weight management.21, 22 In STEP 4, improvements in waist circumference, SBP, FPG, fasting serum insulin and lipids during the semaglutide run‐in (week 0‐20) were maintained over week 20‐68 with continued semaglutide, but deteriorated following the switch to placebo (p Reductions in SBP, non‐HDL cholesterol, low‐density lipoprotein cholesterol and FPG were generally greater with semaglutide than placebo within weight‐loss categories. In total, 680 participants in all were randomly assigned to receive 20 μg of lixisenatide in the morning, evening, or a placebo . In the GetGoal-M study, which was a 24-week, double-blinded, randomized, placebo-controlled phase 3 trial , lixisenatide was examined as an addition to metformin in individuals with uncontrolled T2DM. When compared to dulaglutide, liraglutide produced better weight loss results, with an average loss of 3.61 kg as opposed to 2.90 kg in the dulaglutide group . In total, 884 patients in total were randomly assigned to receive daily doses of 1.5 mg, 0.75 mg dulaglutide once per week, or daily doses of insulin glargine at bedtime . Moreover, AWARD-4, a phase 3 randomized, double-blind trial in which all participants were taking prandial insulin lispro, was conducted on T2DM patients. Extended Data Fig. 3 Characterization of scAT composition. Serious and non-serious cases were compared by Mann-Whitney U test or Chi-squared (χ2) test, and signals were prioritized using a rating scale. Reporting odds ratio (ROR) was employed to quantify the signals of semaglutide-related gastrointestinal adverse events (AEs) from 2018 to 2022. However, real-world data regarding its long-term gastrointestinal safety and tolerability in large sample population are incomplete. This article was submitted to Clinical Diabetes, a section of the journal Frontiers in Public Health LX, LS and HA drafted and wrote the manuscript, collected and analyzed data. Upon binding to GLP-1R, semaglutide leads to increased intracellular cyclic adenosine monophosphate (cAMP) levels, activating protein kinase A (PKA). At the molecular level, semaglutide's mechanism of action involves the GLP-1 receptor (GLP-1R), a G-protein coupled receptor . As a result, semaglutide incorporates two amino acid substitutions (Aib8, Arg34) and is modified at lysine 26 . In developing semaglutide, prioritizing the fatty acid moiety and linking chemistry was crucial for achieving high albumin affinity and GLP-1 receptor (GLP-1R) potency, enabling prolonged exposure of the GLP-1 analogue. Notably, the moderate and weak clinical priority signals tended to occur earlier than those strong AEs signals. The median onset time of strong, moderate and weak signals related to semaglutide was 23 (IQR 2–92), 6 (IQR 0–31), and 7 (IQR 0–32.25) days, respectively. A priority score between 8 and 10, 5–7 or 0–4 represents the signal with strong, moderate or weak clinical priority, respectively. The current meta-analysis therefore included both randomised controlled trials (RCTs) and non-RCTs to reduce the gap in understanding and address the differences among interventions. However, the small number of studies analysed for each hormone leaves gaps in understanding. Calorie restriction (CR) and exercise (EX) are two primary interventions for weight management via reducing energy intake and increasing energy expenditure, respectively. Weight loss induced by CR, EX, or CREX elicits an increase in total ghrelin, but varied responses in other appetite-related hormones. To assess the durability of diabetes remission and ethnic differences in incretin therapy, further studies will be required. In general, if the return to the original weight is defined as weight regain, significant weight regain is rare for patients undergoing RYGB. Weight loss in overweight and obese patients with T2D, whether achieved by lifestyle intervention, pharmacotherapy, or metabolic surgery, contributes to improved cardiovascular complications. Furthermore, in the SURPASS-2 trial comparing tirzepatide to semaglutide 1 mg, tirzepatide was non-inferior and superior to semaglutide.65 On the other hand, no clinically significant hypoglycemia (Figs. 1 and 2). The proportion of patients who achieved HbA1c levels of ≤6.5% was 86% in the tirzepatide 15 mg group.15 Patients who achieved a ≥10% reduction in the tirzepatide 15 mg group totaled 47%. Type 2 diabetes (T2D) has long been regarded as an incurable and chronic disease according to conventional management methods. “These alternative mechanisms may include positive impacts on blood sugar, blood pressure, or inflammation, as well as direct effects on the heart muscle and blood vessels, or a combination of one or more of these.” It has been suggested that by bringing people’s weight towards a healthier range, these medications may inadvertently reduce the risk of heart-related events, such as heart attacks and strokes. Ozempic can be prescribed long-term for type 2 diabetes because the condition is usually life-long. The results have led to calls to extend Wegovy’s treatment to at least four years. These genes are at top rank of the MetS signature described in AT from obese individuals . The chemokine CCL3 is up-regulated with insulin resistance in AT . Waist circumference is the most prominent clinical risk factor involved in MetS . To check similarity between all clusters with waist circumference as hub, paired comparison of the number of common nodes between clusters was performed between baseline cluster and either LCD, or WL group, or WR group cluster. To improve the significance of our findings, systematic statistical tests were performed to test the significance of the betweenness centrality of the nodes compared to their degrees. In order to ensure the accuracy of this calculation, reports with input errors (EVENT_DT earlier than START_DT), inaccurate date entries and missing specific data were excluded. Time-to-onset (TTO) was defined as the interval between the AEs onset date (EVENT_DT in DEMO file) and start date of semaglutide use (START_DT in THER file) (17, 18). According to three levels of clinical importance, a composite score between 0–4, 5–7, and 8–10 was identified as AEs with weak, moderate or strong clinical priority, respectively. The reporting odds ratio (ROR), one of the algorithms used in disproportionality analysis was based on the 2 × 2 table calculation principle (Supplementary Table S1). While specific limitations are not detailed in the summary, the study supports the overall effectiveness of semaglutide in various forms for weight reduction. The study highlights the FDA approval of Wegovy for weight loss, emphasizing its effectiveness in reducing weight. The main limitation of this study is that it focuses solely on the efficacy of semaglutide and does not compare it to other treatment options. Semaglutide led to significant reductions in body weight, waist circumference, and blood pressure, along with positive changes in glycated hemoglobin and lipid levels. Each person has a different starting weight, metabolic weight and possibly even different underlying health conditions. This is because water can help boost your metabolism, suppress your appetite, reduce cravings, improve your digestion (so your body uses all the nutrients in your food effectively), and make it easier to exercise. While drinking enough water isn't the only way to lose weight, not doing so can certainly be a barrier to your success. Of course, sometimes life gets in the way, so if for some reason you do forget to take a dose (or more) of semaglutide and are unsure what to do, be sure to contact your healthcare provider. Metformin mostly causes weight loss by lowering hunger and resulting in consuming less calories . Moreover, the only biguanide medication that has received FDA approval for the treatment of hyperglycemia in T2DM patients is metformin . Sulfonylureas, thiazolidinediones, and insulin, on the other hand, caused weight gain . The term “diabesity” captures the intimate connection between the twin epidemics of diabetes and obesity . In PIONEER 5 in patients with moderate renal impairment, and PIONEER 8 in patients receiving insulin, oral semaglutide was superior to placebo for reducing HbA1c and body weight at week 26 9, 11. In an aforementioned study, taking semaglutide once a week led to people losing about 15 per cent of their body weight, compared with 2 per cent for those taking a placebo. Fourth, the exclusion of individuals without three-month data and the significant rate of patients discontinuing semaglutide after the first three months may introduce a selection bias, potentially overestimating its impact on body weight. Another real-world study has demonstrated clinically relevant weight loss induced by low semaglutide maintenance doses, reporting a mean six-month weight loss of 9.2% in individuals receiving long-term semaglutide doses of ≤1 mg compared to 12.1% in those receiving higher doses . A global program of phase 3 clinical trials evaluating the effect of semaglutide use for weight management in people with obesity, the Semaglutide Treatment Effect in People with Obesity (STEP) trials, has reported an average placebo-subtracted weight loss percentage of 12.5%, with more than half of the participants achieving 15% or more weight loss 5,7. What are the side effects of semaglutide injections? Previous studies have established the role of weight loss in effective management of T2D 3,4,5,6. There is limited real-world evidence on long-term impact of weight loss on glycemic control and metabolic parameters in people with type 2 diabetes (T2D). Previous research indicates no significant differences in fasting acylated ghrelin, total PYY, active GLP-1, and CCK between rapid and gradual weight loss when the amount of weight loss is controlled for . The absence of significant differences between male and female-only groups in our analysis might stem from the limited number of studies that recruited exclusively male or female participants, potentially leading to underpowered results. A possible explanation is that men typically have higher baseline FFM and are therefore likely to experience more substantial FFM reductions during weight loss, as predicted by the Forbes curve 181, 182. GI adverse events (mostly mild to moderate) were reported by 64% of participants in the 2.4 mg semaglutide group, 58% in the 1.0 mg semaglutide group and 34% in the placebo group.52 Overall, 28.6% of participants in the 2.4 mg semaglutide group were able to reduce their glucose-lowering medications, versus 25.1% of participants on the 1.0 mg dose and 7.1% of those on placebo. Participants were aged ≥18 years and had a history of at least one self-reported unsuccessful dietary effort to lose body weight. Its main physiological actions include enhancing glucose-dependent insulin secretion, suppressing postprandial glucagon secretion, slowing gastric emptying and inducing satiety through hypothalamic stimulation.32 Long-acting GLP-1 receptor agonists (GLP-1 RAs) have therefore been engineered for the treatment of T2D and obesity.33–35 The term ‘metabolic’ arose from the findings that Roux-en-Y gastric bypass and sleeve gastrectomy induce deep changes in gut hormone and insulin secretion and sensitivity, independent of weight.28,29 A more anorectic hormonal profile helps patients to lose weight and counters increased appetite over the long term. Source Data Figs. 1–5 and Source Data Extended Data Figs. 1–10. In addition, non‐significant improvements in predicted ASCVD 10‐year risk were observed with semaglutide in STEP 1. The beneficial effects on these risk factors appeared to reduce the need for antihypertensive and lipid‐lowering medications in both trials. Differences between treatment groups were typically greatest in the 10% to 1 and Figure S3). CI, confidence interval; ETD, estimated treatment difference; HDL(‐C), high‐density lipoprotein (cholesterol); LDL(‐C), low‐density lipoprotein (cholesterol) Data are for the in‐trial period and the treatment policy estimand. Ertugliflozin’s impact on body weight after 26 weeks was examined in another randomized, phase 3, double-blind, multicenter trial with 621 T2DM individuals . A total of 545 subjects with T2DM participated in a recent observational, retrospective, cohort trial that assessed the effects of empagliflozin and liraglutide on weight loss outcomes . The placebo-adjusted average change in body weight with empagliflozin was −1.7 kg in cohort 1 and −1.9 kg in cohort 2 . Using 100 T2DM patients on metformin monotherapy, a recent randomized, double-blind trial examined the impact of dapagliflozin 10 mg daily on epicardial fat thickness as a primary result and body weight as a secondary outcome . C,d, UMAP visualization representing scAT pools from the LTSS study (c) and NEFA study (d) coloured by predicted cell subtypes from the Emont et al. subcutaneous AT dataset from Caucasian individuals. C,d, UMAP visualization representing omAT pools from the MTSS study (c) and LTSS study (d) coloured by predicted cell subtypes from the Emont et al. visceral AT dataset from Caucasian individuals. Mice were fasted for 6 h during dark phase before administration of 1 g of glucose per kg body weight by intraperitoneal injection. Only samples from individuals that (1) lost more than 25% BMI between T0 and T1, (2) were not diagnosed with diabetes at T0 and T1 and (3) did not take glucose-lowering medication were included in the present study (Extended Data Table 1). Categorical weight loss at 68… Percent initial weight loss at 68 weeks for STEP trials 1–4 Percent initial weight loss at… Theoretical and empirically supported mechanisms of action of semaglutide for obesity The approval of this medication provides patients with greater options for weight management. A subgroup meta-analysis of RCTs conducted by Zhang et al. explored the efficacy and safety of subcutaneous semaglutide in adults with overweight or obesity . Subgroup analyses will examine the efficacy and safety of semaglutide across different demographic or clinical subgroups, including age, sex, baseline BMI, race or ethnicity, and the presence of obesity-related comorbidities. Studies lacking a comparison group or those comparing semaglutide to treatments irrelevant to weight management will be excluded, as they do not provide the necessary comparative data. Neovascular ‘Wet’ Age-Related Macular Degeneration The review will explore predictors of response to semaglutide treatment, such as baseline characteristics (age, sex, BMI, metabolic parameters, and genetic factors), to identify factors that may influence treatment outcomes. Semaglutide represents a valuable addition to the therapeutic options available for individuals struggling with obesity or overweight. Secondary outcomes include the dose-response relationship of semaglutide, assessing different dosages and their impact on weight loss. Individuals were started on semaglutide in the time period between November 2021 and November 2022, with no more patients initiated on semaglutide afterward due to its supply shortages. Despite the wealth of high-quality evidence, there is a paucity of real-life data limited to one cohort study . A series of randomized controlled trials (RCTs) have consistently demonstrated the great efficacy of semaglutide for weight management 7-12. These promising results suggest that a variety of novel pharmacotherapies will become available in the next few years, revolutionizing the treatment of obesity . Besides semaglutide, numerous studies are currently exploring the potential synergistic effect of targeting multiple gut peptides. For oral semaglutide and empagliflozin, the weight loss at week 52 was 4.7 kg and 3.8 kg, respectively . It was possible to lose weight in a dose-dependent manner; the maximum oral semaglutide dosage (14 mg once daily) produced the greatest weight loss (4.1 kg) . This study showed the effectiveness of oral semaglutide on naïve T2DM patients with lifestyle interventions . At 52 weeks, semaglutide induced an average weight loss of 4.1 kg, while the aspart group experienced an average weight gain of 2.8 kg . However, recent research has identified that the inactive form, GLP-19–37, may also influence physiological processes, for instance, it may elicit a modest anti-hyperglycaemic effect independent of insulin in humans . Thus, it is possible that an increase in total ghrelin may increase appetite in humans in the absence of an increase in acylated ghrelin. Future studies could explore whether calorie restriction in RCTs also has the potential to decrease acylated ghrelin levels. The SCALE clinical studies on liraglutide were done in order to demonstrate its anti-obesity impact 138,139. Liraglutide did not statistically differ from the placebo in terms of weight loss (2.81 kg in the liraglutide group versus 1.99 kg in the placebo group) . In comparison to the placebo group, the liraglutide group saw a weight loss of 3.5 kg on average . The liraglutide and placebo groups’ average weight loss was 1.80 kg and 0.42 kg, respectively, while the glargine group’s average weight gain was 1.60 kg . Among the earlier studies in this area was the work by Mohebbi et al. (2017) that experimented several deep learning methods to identify the occurrence of T2D based on a collection of CGM datasets. Accordingly, detecting the short- and long-term complications of T2D has been the focus of many diabetes modeling studies. Also, in a comprehensive study, a rotation forest was employed as an ensemble method to combine 30 ML algorithms for diagnosing diabetes (Ozcift & Gulten, 2011). Using a Bayesian scoring algorithm, the space of events for a diabetes patient was modeled in another study (Anderson et al., 2016). Gastrointestinal problems were the most common adverse effects (6,16), with similar rates in all groups except for those receiving dulaglutide 0.75 mg, where fewer patients experienced gastrointestinal issues (15). The incidence of serious adverse effects was similar across all treatment groups. However, none of these incidents required the patients to stop their treatment (19). To assess whether this reduced value resulted in enough weight loss (5% of baseline body weight) to qualify metformin as a weight loss medication, they argued that larger and more randomized control trials are required . Metformin’s impact on weight loss was assessed in a recent meta-analysis of 21 trials including a total of 1004 participants . Liraglutide and semaglutide are two of the five Food and Drug Administration (FDA)-approved anti-obesity drugs that are FDA-approved agents for the treatment of type 2 diabetes mellitus (T2DM) patients. The phase III STEP clinical programme has shown that 2.4 mg semaglutide provides clinically meaningful and durable weight loss beyond that achieved with other currently available agents for obesity. Compared with previous clinical trials with GLP-1 RAs, no additional safety signals (e.g. retinopathy) have emerged from the STEP clinical programme.42,50–54,59–61,66 Globally, patients treated with 2.4 mg semaglutide in the STEP clinical programme have discontinued the treatment due to adverse events at a higher rate (7%) than those on placebo (3.1%), primarily due to GI adverse events (4.5% versus 0.8%).42,51–54,59–61,66 Two systematic reviews have assessed changes in circulating appetite-related hormones after dietary induced weight loss, which identified a decrease in PYY, GLP-1, and CCK, alongside an increase in ghrelin concentrations, in their total or active form 23, 24. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This initial analysis provides a valuable starting point for more in-depth investigation of the implication of myristoleic acid in weight loss. Following the similar prediction procedure presented for this dataset, we used the model to predict the blood glucose levels, as determined by the CGM measurements. CGM measurements in a two-hour window and three static variables of age, weight, and gender were used in the training process. We examined the proposed model on the publicly available OhioT1DM dataset (Marling & Bunescu, 2018). This part of the architecture receives the flattened output of the CNN network and merges it with the physical attributes data using the dense and concatenation layers. Figure 4 shows the architecture of the GRU network and the supplementary learning partition for including the static data. Therefore, differences in weight loss magnitude could be the reason driving the differences observed in previous reviews and our results for each intervention.Next, to identify sources of biological variability (factors) in our datasets on the basis of all modalities across all conditions we used multi-omics factor analysis (MOFA)50.Gastrointestinal-related side effects, including nausea, constipation, vomiting, and abdominal pain, were significantly more prevalent in patients receiving semaglutide compared to placebo.While semaglutide can be an effective tool for weight management, it is most successful when used as part of a comprehensive treatment approach that includes lifestyle modifications such as diet and exercise (D&E) .The lowest mean age (58.7 years) was observed among participants with ≥ 15% weight loss in the 1-year follow-up period.(2) Appending the more accurate UKBB assessment center measurements to the EHR data improves overall data quality.Bioinformatics analysis showed a reduction of CD36, FABP5, ACSL, ACOX3, PLIN2, ANGPTL4, LPL, MGLL, AQP7, and PDK4 involved in the lipid metabolism in the Sema group accompanied by a decrease in visceral fat accumulation, blood lipids, and improvement in glucose intolerance. However, this association was not significant in the 5-year follow-up cohort, except for DPP4 inhibitors in the ≥ 15% weight loss category (Table 2). 3a, b Percentage of participants with HbA1c HbA1c glycated hemoglobinFull size imageIn the 1-year follow-up cohort, those who lost ≥ 15% of their index weight had the largest mean reduction in FBG levels (26.3 mg/dL; Fig. 4a). Moreover, these comorbidities were most prevalent among those who experienced greater weight loss percentages. In conclusion, this meta-analysis demonstrates that weight loss triggers a consistent increase in total ghrelin and no changes in total GLP-1, while the results for other appetite-related hormones are variable. This is possibly due to changes in body composition being similar regardless of the rate of weight loss provided that total weight loss is similar . Our analysis from non-RCTs revealed that mixed-sex cohorts had greater increases in total ghrelin after weight loss than female-only cohorts, when the extent of weight loss was controlled for. Previous systematic reviews, with or without meta-analysis, have explored the effects of CR and EX separately on appetite-related hormones, suggesting a hormonal response to CR favouring appetite stimulation after weight loss 23, 24, but not EX . In patients with persistent impaired glucose tolerance after a year of metformin and lifestyle adjustments, the effects of adding linagliptin to metformin and lifestyle changes on glucose levels and pancreatic beta-cell function were investigated . With a minimal risk of hypoglycemia and weight neutrality, linagliptin (Figure 1f) is a once-daily selective DPP-4 inhibitor that has been approved for use in the treatment of T2DM 65,66. The combination of saxagliptin and dapagliflozin led to a mean weight loss of 2.1 kg, as opposed to 2.4 kg with dapagliflozin alone and 0 kg with saxagliptin monotherapy . The current study proved that vildagliptin medication has a negative caloric balance when glucose levels are below the renal threshold at baseline . Semaglutide provides weight-loss effects, and greater reduction in fat mass than that reported with liraglutide (3). (A, B) Subcellular localization analysis of DEPs in Sema/HFD group and total proteome. Enrichment analysis was applied based on Fisher’ exact test, considering the whole quantified proteins as the background dataset. The MS raw data for each sample were searched using the MASCOT engine (Matrix Science, London, UK; version 2.2) embedded into Proteome Discoverer 1.4 software for identification and quantitation analysis. Interscapular BAT (iBAT) and epididymal WAT (eWAT) were collected, weighted, and subjected to hematoxylin and eosin (H&E) staining or snap-frozen in liquid nitrogen and stored at 80°C until analysis.