A systematic review and meta-analysis indicated that the addition of metformin resulted in a modest weight loss of −3.3 kg over a period of 12–24 weeks . Previous research indicates that lifestyle counselling, exercise interventions, antipsychotic substitution, discontinuation and dose reduction may represent potential avenues for treatment, although their efficacy is limited 11,12,13,14,15. Consequently, antipsychotic-induced weight gain (AIWG) represents a significant clinical challenge for both patients and clinicians. However, the most effective APs carry a higher risk of weight gain 4, 5, which can result in severe general adverse health effects . Subsequently, the results were compared with those of a control group of AIWG patients taking metformin. In North America and Europe, human papillomavirus infections are responsible for a growing percentage of oral cancers among young people. Tobacco, alcohol and areca nut (betel quid) use are among the leading causes of oral cancer. Oral cancer is more common in men and in older people, more deadly in men compared to women and it varies strongly by socio-economic circumstances. Losing teeth is generally the end point of a lifelong history of oral disease, mainly advanced dental caries and severe periodontal disease, but can also be due to trauma and other causes. Acute pancreatitis and pancreatic cancer have been a concern of incretin-medications as a class.67 No clear signal linking incretin-based therapies and acute pancreatitis or pancreatic cancer has been identified, though the FDA and EMA have indicated that pancreatitis should be considered a risk with incretin medications until further data are available. Pregnancy is a contraindication for use of semaglutide, and semaglutide should be discontinued at least 2 months before a planned pregnancy due to the long half-life. Patients should seek medical treatment and discontinue the medication if they develop a serious hypersensitivity. Across both treatment periods, mean observed waist circumference decreased with both oral semaglutide (2.4 cm) and placebo (2.0 cm). Changes in body weight from baseline over time in subjects completing the trial are shown in Figure S5. Overall appetite scores remained lower at all time points with oral semaglutide compared with placebo, particularly after the fat‐rich breakfast (Figure S3). Endpoints were analysed using an analysis of variance model, with the endpoint as dependent variable and treatment (oral semaglutide or placebo), treatment period (two levels) and subject as fixed factors. Furthermore, it is not known whether baseline body mass index (BMI) affects the degree of semaglutide‐induced weight loss. Change from baseline in body weight was assessed within each trial and subgroup. Indeed, it is interesting to note that, despite the dosing conditions and potential for gastrointestinal effects with oral semaglutide, satisfaction and convenience of treatment was reported to be comparable with sitagliptin . A potential limitation of oral semaglutide is the need to dose patients in a fasted state upon waking and 30 min before consuming food, drink, or other oral medications. Seven GLP-1RA CV outcomes trials were included in this analysis after screening, and the results showed that oral semaglutide was statistically better than lixisenatide (HR 0.43; CI 0.19−0.92), albiglutide (HR 0.45; CI 0.19−0.97), dulaglutide (HR 0.46; CI 0.20−0.97), and exenatide (HR 0.47; CI 0.21−0.99) in reducing CV deaths. Review Thankfully, there are different types of diabetes medications available. But is metformin the best medication to treat Type 2 diabetes? It’s a first-choice medication to lower blood glucose (blood sugar) among people living with diabetes, and it’s very commonly prescribed. If you or a loved one are living with Type 2 diabetes, chances are you’ve heard of metformin. Data are for the full analysis set during the in-trial observation period (from randomization to the final follow-up visit). Interestingly, the observations from PIONEER 6 are also broadly consistent with those of the SUSTAIN 6 CV outcomes trial for s.c. However, the study was not sufficiently powered to demonstrate superiority . Semaglutide dose was escalated to 25 mg over the course of 12 weeks and maintained for 52 weeks.Oral semaglutide 25 mg once daily significantly reduces body weight and improves physical function in adults with overweight or obesity without diabetes.The principal strength of this study is the inclusion of patients from daily real-world clinical practice, with straightforward and simple inclusion criteria, which enhances the generalisability of the findings.Serious side effects, like pancreatitis, are rare but require immediate medical attention.Clinical trials have demonstrated clear benefits of the GLP-1RA drug class with respect to improvements in glycemic control (HbA1c), body-weight loss, and blood-pressure reduction, without the risk of hypoglycemia .Our study was retrospective and observational, based on real-world data from clinical practice.Given the robust amount of literature demonstrating injectable semaglutide’s ability to provide significant weight loss, it was our expectation that treatment with injectable semaglutide would result in more weight loss than its oral counterpart.Oral semaglutide shows promise in enhancing glucose control and reducing cardiovascular risks. Reductions in HbA1c with oral semaglutide 7 mg were similar to those seen with s.c. BL baseline, HbA1c glycated hemoglobin, ins insulin, met metformin, MRI moderate renal impairment, OAD oral antidiabetes drug, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes Exposure to ethinylestradiol and levonorgestrel was similar when administered alone or with oral semaglutide, indicating that their bioavailability is not affected by co-administration with oral semaglutide . Although the pharmacokinetics of levothyroxine were influenced by oral semaglutide, no change in clinical practice is required as close monitoring of thyroxine is already part of medical guidance . The impact of concomitant administration of this new oral formulation of semaglutide with other drug classes that are commonly administered in patients with T2D has also been evaluated (Table 1). This new study was designed to observe how the drug behaves in people with type 2 diabetes. Its peptides break down too quickly in stomach acid, ruling out oral doses of the medication. GLP-1 drugs are synthetic mimics of that hormone, triggering the same pathways in ways that can help people with diabetes regulate their blood sugar, and, more recently, assist people in losing weight. "Overall," the researchers write in their paper, "the findings indicate that orforglipron could address the unmet need for oral therapy by achieving outcomes similar to those of injectable GLP-1 receptor agonists, potentially shifting treatment paradigms." Diet and exercise alone may not always lead to significant or sustainable results, which is where semaglutide can make a difference. Losing even a small amount of weight can improve health outcomes and reduce these risks. By acting on GLP-1 receptors, semaglutide can help reduce hunger, increase feelings of fullness, and slow down digestion. This hormone plays a crucial role in regulating blood sugar levels, but it also has an effect on appetite and how the body processes food. Data were exported to RevMan v5.4, where meta-analysis was conducted using a DerSimonian and Laird random-effects model.Iacobellis and Villasnte Fricke 2020 reported that semaglutide decreased epicardial adipose tissue thickness by almost 20% after 12 weeks in subjects with type 2 diabetes and obesity, suggesting a reduction in cardiometabolic risk.At week 52, the difference between oral semaglutide 14 mg and liraglutide (ETD − 0.3) was no longer significant.Overall, 6 patients (5.7%) experienced an adverse effect (AE) related to semaglutide during the study period, 2 patients (16.7%) in the oral group and 4 patients (4.9%) in the injectable group.At 52 weeks, 19% of subjects were receiving oral semaglutide 3 mg, 30% were receiving oral semaglutide 7 mg, and 59% were receiving oral semaglutide 14 mg.Approximately half of the participants experienced a clinically significant reduction in body weight, although this reduction was mostly less than 10%.Because many patients are reluctant to initiate or intensify therapy by injection, oral semaglutide might be an effective treatment option, potentially leading to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care.In the PIONEER trials, the oral formulation of semaglutide has also shown efficacy and safety in patients with an eGFR as low as 30 mL/min per 1.73 m2 and has also shown improvement in the urine albumin creatinine ratio 18, 19. To TCTMD, Knop stressed that there are very good data from the diabetes trials supporting a reduction in hard cardiovascular events—MI, stroke, and CVD-death—with injectable semaglutide in the SUSTAIN-6 trial and with the oral formulation, albeit at a lower dose, in PIONEER-6. PIONEER 4 compared the addition of oral semaglutide or subcutaneous liraglutide to background metformin with or without a sodium–glucose cotransporter 2 (SGLT2) inhibitor in patients with type 2 diabetes and a baseline A1C of 7.0–9.5%. This systematic review analyzed five studies (three RCTs/two non-RCTs) evaluating weight loss outcomes in patients with obesity treated with semaglutide compared to liraglutide and efinopegdutide. Whether compared to other pharmacological options or weight loss surgeries, oral semaglutide holds its ground as a viable and effective treatment, particularly for those who prefer non-surgical methods. Skipping or shortening this wait time can reduce how much semaglutide your body absorbs. This is because most of the dose reaches your bloodstream, and it takes your body about 1 week to remove half of it. The study included adults considered obese, or considered overweight with at least one weight-related health condition. But separately, both forms appear to result in similar amounts of weight loss. HbA1c glycated hemoglobin, SBP systolic blood pressure, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes, TZD thiazolidinedione For patients achieving HbA1c or composite targets, observed proportions are given except for PIONEER 3 (where estimated proportions were reported) and p values are for the odds of achieving target The proportion of patients achieving HbA1c 3) 47–49, 53–55, which is perhaps not surprising given the progressive nature of T2D. A weight loss of at least 5% is considered clinically significant, while a 15% reduction effectively improves most obesity-related complications and conditions. The primary goal of obesity treatment is to improve health, with weight monitoring serving as a proxy indicator of treatment efficacy. Clinically, its definition is based on the body mass index (BMI), which is calculated as the ratio of body weight to the square of height. Clinically significant weight loss was achieved in 46% of all participants, with rare individuals experiencing a decrease of ≥ 15%. Safety was assessed in participants who received at least one dose of trial drug. The Wegovy pill launched early this year, offering 25 mg daily for weight loss. Data from clinical trials on FDA-approved medications should NOT be used to make assessments related to compounded medications. As research continues and awareness grows, semaglutide is likely to play an increasingly significant role in addressing obesity and its related complications. Secondary outcomes include the dose-response relationship of semaglutide, assessing different dosages and their impact on weight loss. 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. The results indicated that both subcutaneous and oral formulations of semaglutide were effective in promoting weight loss, with subcutaneous administration often yielding greater results. Search terms will include variations of “semaglutide,” “obesity,” “overweight,” and “randomized controlled trial.” The year of publication is 2017-present (Figure 1). Tan et al. found that subcutaneous semaglutide led to an 11.85% reduction in weight , while Gao et al. reported a significant reduction in body weight, body mass index (BMI), and waist circumference . Efficacy and safety of these drugs have been proven for a representative sample of patients with different comorbidities, from the various demographic, ethnic and racial groups .A combination of glucagon-like peptide-1 receptor agonist and dietary intervention could Be a promising approach for obesity treatment.The Peptide Report makes no claims about how the action or treatment presented can cure, treat or prevent any medical conditions or diseases.A sensitivity analysis is necessary if the included studies are high risk.Listen to your body and team up with pros.There was no change in appetite in this study, a finding that is inconsistent with observations for the s.c.These findings reinforce the established safety and tolerability record of semaglutide, supported by more than 37 million patient-years of use worldwide.Mean change in HbA1c from baseline to week 26 was − 0.7 to − 1.9% with increasing doses of oral semaglutide, − 1.9% with once-weekly s.c.While the injectable forms, Ozempic and Wegovy, have gotten plenty of coverage, there’s been much less hype for Rybelsus, an oral form of the exact same drug. However, none of these incidents required the patients to stop their treatment (19). With its effect size estimate plotted against the appropriate treatment period, each trial is shown as a circle. The asymmetry and publication bias of the meta-analysis are visually inspected using the funnel plot regarding (A) glycemic control and (B) weight loss. It was found that the exclusion of no single study affects the outcome of glycemic control efficacy data (Fig. 3A). Investigators were provided with guidelines for, and encouraged to follow, evidence-based recommendations for medical treatment and lifestyle counseling to optimize management of underlying CVD as part of the standard of care. The starting dose was 0.24 mg once weekly, with dose increases every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg per week) until the target dose of 2.4 mg was reached after 16 weeks. National and institutional regulatory and ethical authorities approved the protocol, and all patients provided written informed consent. The trial protocol was designed by the trial sponsor, Novo Nordisk, and the academic Steering Committee. Figure 3 demonstrates the proportion of patients with ⩾ 5% of weight loss from baseline for liragutide and/or semaglutide vs. placebo. Altogether, we identified six RTC studies with liraglutide 3 mg 9–14, four RCT studies with semaglutide 2.4 mg/week 15–18 and one study that compared efficacy of semaglutide and liraglutide in participants without diabetes. The mean weight loss difference between GLP-1 RAs and placebo as add-on to lifestyle intervention in patients with diabetes was 4% to 6.2% compared to 6.1 to 17.4% in people without diabetes. This trial included 3183 patients with uncontrolled T2DM who were either ≥50 years old with established CV disease or CKD or ≥60 years old with CV risk factors only randomized to oral semaglutide 14 mg or placebo in addition to standard of care. Despite the rates of nausea observed in the PIONEER trials, only a small increase in discontinuation of oral semaglutide as compared with the active drug arms was found.15,16,17,18,19,20,21,22 Semaglutide 2.4 mg has consistentlydemonstrated clinically significant weight loss across all phase 3 STEP(semaglutide treatment effect in people with obesity) trials, and long-termefficacy and safety have been confirmed for up to 2 years. The phase II trial included an arm in which patients received subcutaneous semaglutide 1.0 mg; however, the primary endpoint of glycemic efficacy was only statistically significant compared with placebo, not between active oral vs. injectable treatment groups (41). For the PIONEER trials shown, estimated mean changes from baseline in body weight are regardless of trial product discontinuation or rescue medication (treatment policy estimand). Furthermore, oral semaglutide plasma exposure did not differ between healthy subjects receiving 40 mg and subjects with T2DM receiving 40 mg. The healthy subjects were randomized to oral semaglutide 20 mg and 40 mg once daily with SNAC 300 mg and subjects with T2DM received oral semaglutide 40 mg once daily with SNAC 300 mg. The primary outcome studied was the number of treatment-emergent adverse effects in each group, and secondary outcomes included area under the concentration–time curve (AUC), plasma concentration, and change from baseline in fasting plasma glucose, C-peptide, insulin, glucagon, and HbA1c. This determined that 300 mg of SNAC proved the most appropriate amount of SNAC to enhance absorption of the oral semaglutide formulation . Plasma concentrations of oral semaglutide indicated that its absorption occurred early on, and once in the systemic circulation, it had a slow elimination rate. Therefore, 105 patients were included in the final analysis, 12 patients in the oral 7-mg group, 11 patients in the oral 14-mg group, 34 patients in the injectable 0.5-mg group, and 48 patients in the injectable 1-mg group. The most common reasons for exclusion were no available follow-up HbA1C or weight data at 26 weeks (89%) or missing or inconsistent refill history (38%). The Wilcoxon signed-rank test was used to evaluate changes in HbA1C concentration and weight from baseline to various time points. Given the retrospective nature of the study, there was a finite number of patients that could be included, and therefore, we did not perform a power calculation prior to the study start date. Discontinuation due to AEs was more common with oral semaglutide. Adverse events (AEs) occurred more frequently with oral semaglutide than with injectable semaglutide (16.7% vs 4.9%). In practice, many may think that oral and injectable semaglutide formulations are interchangeable, although there is currently limited real-world data to determine whether this is accurate. The risk of requiring coronary revascularization was 24% lower among semaglutide users, with non-fatal heart attacks being 24% less likely. Similarly, death from any cause was reduced by 20%, with the oral route being superior to the subcutaneous. Semaglutide’s anti-inflammatory effects contribute to its cardiovascular benefits, including improved coronary blood flow and reduced hepatic steatosis, helping to prevent fatty liver disease. Patients prescribed semaglutide should be advised about potential side effects that may occur and provided guidance on how to mitigate these side effects. Like other GLP-1RA medications, semaglutide has a boxed warning of a risk of thyroid c-cell tumors and is contraindicated in people with a personal or family history of MTC or in patients with MEN 2. However, some patients may be “non-responsive” to semaglutide, which using CMS guidelines is considered a Based on the availability of baseline and at least one follow-up measurement, 320, 260, 155, 200, 155, and 297 patients were included in the analyses of HbA1c, body weight, TC, LDL, HDL, and BP, respectively. Most patients (94%) initiated oral semaglutide at a dose of 3 mg/day. In the present study, researchers retrospectively assessed clinical outcomes in patients with T2D treated with oral semaglutide. The addition of oral semaglutide is an important step forward by offering an oral hypoglycemic therapy that reduces glucose levels effectively while avoiding hypoglycemia and having positive effects on weight and cardiovascular risk. Indeed, a meta-analysis of 4 major trials including more than 30,000 participants found no increased risk of either acute pancreatitis or pancreatic cancer in those taking GLP-1RA compared to placebo.59 Glucagon-like peptide-1 receptor agonist in the treatment of adult, obesity-related, symptomatic asthma (GATA-3) (GATA-3). A research study investigating semaglutide in people with early Alzheimer's disease (EVOKE Plus). A research study investigating semaglutide in people with early Alzheimer's disease (EVOKE). Effect of semaglutide treatment or placebo on mean percentage change in body weight… (b) Observed proportions of participants and odds ratio for achieving weight loss of at least 5% from baseline at week 104 in the full analysis set during the on-treatment observation period, based on the trial product estimand. Observed mean body weight (kg) over time for participants in the full analysis set during the in-trial observation period (from randomization to last contact with trial site, regardless of treatment discontinuation or rescue intervention). When interpreted together with the findings of the STEP 4 withdrawal trial and STEP 1 off-treatment extension study, which both showed weight regain after semaglutide discontinuation (after 20 weeks’ treatment in STEP 4 and 68 weeks’ treatment in STEP 1)23,24, these results support the benefit of continued semaglutide treatment for sustained weight loss. The mean weight loss of ~15% achieved with semaglutide 2.4 mg at week 104 in STEP 5 exceeds weight loss reported at similar time points in trials with other pharmacotherapies for weight management in adults with overweight or obesity10,11,12,13,14. To maximize the benefits of semaglutide for weight loss, the dosage should be gradually increased over several weeks. This initial dose allows your body to gradually adjust to the medication and minimizes the risk of potential side effects. The recommended starting dosage of semaglutide for non-diabetic weight loss is typically 0.25 mg once a week. Research and clinical trials have shown that specific dosage ranges can yield optimal results in terms of weight reduction. From promoting effective weight loss to improving satiety and insulin sensitivity, semaglutide has the potential to transform lives and enhance overall health. In PIONEER-9, oral semaglutide induced nausea in up to 10% of patients, whereas none of the liraglutide patients had nausea (liraglutide was low-dose however) (23). In PIONEER 6, unadjudicated DRP occurred in 5.8% of oral semaglutide-treated patients and in 4.8% of the placebo-treated patients (19). In PIONEER 6, AKI occurred in 2.0% of patients treated with oral semaglutide and 2.3% of placebo-treated patients (19). Semaglutide, while effective in weight management, comes with possible side effects. Semaglutide is a powerful tool for weight loss when used properly. Improper use, such as skipping doses or increasing the dose too quickly, can lead to side effects or reduced efficacy. The gradual dosing schedule ensures that your body can adapt to the medication, reducing the risk of side effects while maintaining its effectiveness. 3. Adverse events However, future studies should follow patients longitudinally to see how these effects persist long term. Time to AC onset varied, occurring within 90 days in nearly half the cases, and was shorter for patients on starting doses compared to those on maximum doses. The median age was 55 years, and over half of the patients were female, with recent weight loss reported in nine cases. If an increased dose is not tolerated, you and your provider may consider delaying dose escalation by 4 weeks. Wegovy® is slowly increased over months at 4-week intervals (from 0.25 to 0.5, 1, 1.7, then 2.4 mg) until the recommended maintenance dose of 2.4 mg once weekly is reached. Semaglutide is the active ingredient in several brand-name medications (Ozempic®, Wegovy®, Rybelsus®), which come in different forms and dose strengths. Getting the dosage right is crucial for achieving optimal results with semaglutide. This finding is not surprising considering the baseline characteristics of the enrolled patients, which initially had pathological but highly variable average values of visceral adipose tissue, with minimum values as low as 0.6 liters, within normal range. Studies focusing on GLP1-RA effects on body composition have been concordant in demonstrating the effectiveness of this drug class in reducing fat mass while preserving lean mass (26–28, 47). In our sample, median values were normal at baseline, indicating that the study population was at low risk for liver fibrosis. The significant change in FLI and not HSI in our study population, which had no signs of NASH (normal liver enzyme levels) at baseline, would reflect the predominant effect of the drug more on waist circumference, which enters the calculation of FLI alone and is more related to visceral fat, than on liver enzymes. Yes, semaglutide has been shown to be effective for weight loss in non-diabetic individuals. Seek medical advice and partner with a healthcare professional to navigate your semaglutide weight loss journey with expert guidance and support. Regular check-ups and consultations allow for adjustments to the treatment plan as needed, ensuring the best outcomes for safe and effective weight loss. Before embarking on a semaglutide weight loss journey, it is crucial to consult a healthcare professional. 4.4 Blood pressure, C-reactive protein, and lipid profiles changes While awaiting the CVOTs, results from several health care database studies (insurance claims, hospital registry, etc.) were published, and were somewhat conflicting. In this regard, case reports and studies using adverse event databases (such as the FDA Adverse Event Reporting System and European Eudravigilance) frequently are the first signals of potential safety risks. Whether the more rare adverse events differ between the different agents can only be answered by using observational cohort data from a very large group of patients and a longer follow-up time. With these data, the safety profiles of rare potential events (e.g. pancreatitis, thyroid cancer, kidney injury, etc.) and hypoglycemia risk are comparable for semaglutide, dulaglutide, exenatide once weekly and liraglutide. The more frequent injection site reactions with exenatide once weekly (22%) compared with semaglutide (1.2%) in SUSTAIN-3 could be a consequence of this (22). Another study by Wadden et al. considered once weekly 2.4mg semaglutide therapy and SI in post hoc analysis of STEP 1, 2, 3 and 5 clinical trials. A 49-year-old female with morbid obesity and controlled hypertension presented with 8 weeks of bilateral pedal edema, weight gain, and worsening kidney function after starting semaglutide 0.5 mg weekly for weight loss. In mice, a single subcutaneous dose showed a release half-life of approximately 36 days, leading to a 20% weight loss over one month, similar to twice daily semaglutide doses . Nørgaard et al. found that rates of dementia were lower in patients undergoing G1PR agonists compared to a placebo in both the randomized control trail patient data and nationwide cohort data . While there have been studies on the incidence of stroke in patients on semaglutide compared to a specific T2DM therapy, there is a need to understand how T2DM therapies generally compare to each other in reducing risk of stroke. This difference is also due to the different entry into the market in our country of oral semaglutide compared to the injectable formulation. Recently, in a fundamental study on obese population with pre-existing cardiovascular diseases (Select study) semaglutide determined a weight loss up to approximately the 65th week and this result on weight loss was maintained after 4 years from the beginning of the therapy with semaglutide . To provide a comparison on efficacy, patients on liraglutide 3.0 mg, at week 52, had similar weight loss as those on 0.2 mg of semaglutide . Semaglutide also demonstrated superiority in weight reduction when compared with other weight loss medications. To assess the superiority of semaglutide over placebo, comparative studies were conducted. Overall, semaglutide’s mechanisms of action contribute to weight loss by diminishing appetite, promoting satiety, slowing gastric emptying, and inhibiting the reward centers in the brain. Semaglutide, a GLP-1 receptor agonist, exerts its effects on weight loss through various mechanisms of action. While subgroup analyses could provide further insights into the impact of these factors, the limited number of studies and variability in study characteristics made such analyses impractical. As a result, some potentially relevant studies may have been excluded due to differences in study design, populations, or intervention protocols that did not align with the objectives of the current analysis. To assess the potential impact of individual studies on the meta-analysis results, a sensitivity analysis was conducted by sequentially removing one study at a time and recalculating the effect size and pooled estimate. In the present study, high heterogeneity was found among the studies included in the meta-analysis, as evidenced by prediction interval analysis, which suggested significant between-study variability. The baseline demographic and anthropometric data were normally distributed and are summarized as mean (SD) values. We also collected information on visits with dietitians and behavioral bariatric psychologists after the first day of starting semaglutide until the last day of follow-up or until the medication was discontinued. We collected patient weights in kilograms that were obtained either using a calibrated scale during office visits or reported by the patients during virtual visits and clinical communications with the physician. Owing to high insurance denials and the national shortage of semaglutide, we subsequently excluded those patients from the analysis. Several RCT investigated the role of liraglutide, alone or in combination with metformin, in women with PCOS and overweight or obesity, confirming its beneficial effect on anthropometric and metabolic features95; however, changes in menstrual cyclicity and hyperandrogenism were rarely assessed. Both the LEAN and SEMA-NASH trials showed that GLP-1RA slowed fibrosis progression and improved non-invasive markers of fibrosis but failed to demonstrate significant histological modifications93. Contrary to expectations86, CV event rate (including stroke) in SELECT was in line with that described in GLP-1RA CVOT conducted in patients with diabetes84,85. Differently from previous GLP-1RA CVOTs, being conducted in participants without diabetes, SELECT was not designed to achieve glycemic equipoise between arms. At week 104, 52.4% of patients treated with semaglutide achieved improvement in BMI category compared with 15.7% of those receiving placebo. These waterfall plots show the variation in weight-loss response that occurs with semaglutide and placebo and show that weight loss is more prominent with semaglutide than placebo. Within each obesity class (−2, 30 to −2, 35 to −2, and ≥40 kg m−2), there were fewer SAEs in the group receiving semaglutide compared with placebo. Each patient’s percentage change in body weight is plotted as a single bar.Full size imageWC change from baseline to 104 weeks has been reported previously in the primary outcome paper21. Reductions in body weight were generally greater with oral semaglutide 14 mg/flex versus comparators. Across trials and baseline HbA1c subgroups, estimated ORs consistently favoured oral semaglutide 7 and 14 mg, and flex, over comparators for the achievement of HbA1c S16), with no significant interaction across HbA1c subgroups. Because a consistent pattern of HbA1c responses with oral semaglutide 14 mg across subgroups was observed in all PIONEER trials, a pooled analysis of the placebo‐controlled trials (only performed at Week 26 as this was the latest common timepoint) was performed to investigate further. Oral semaglutide 14 mg/flex also reduced body weight more than comparators across the PIONEER trials and across BMI subgroups. Nevertheless, despite the abundant complementary benefits of GLP-RAs, their subcutaneous administration limits their usage amongst patients 14, 15. Currently, there are five GLP-1RAs, exenatide, liraglutide, dulaglutide, lixisenatide, and subcutaneous semaglutide, that are US Food and Drug Administration (FDA) approved and commercially available for the long-term management of T2DM. To reduce the occurrence and severity of these comorbidities, proper management of elevated plasma glucose levels in patients with T2DM is mandated. However, in patients with T2DM, the development of insulin resistance as well as impaired insulin secretion due to beta-cell dysfunction inhibits this homeostasis . It is worth noting that weight loss observed with semaglutide was mainly mediated by therapeutic effect, rather than the occurrence of those adverse events (Lingvay et al., 2020), indicating that semaglutide can be regarded as a weight management agent with generally acceptable safety. Ryan et al. (2020) evaluated the superiority of semaglutide on cardiovascular event reduction in people with overweight or obesity, which was implicated as an anti-inflammatory mechanism. Ji et al. (2021) revealed that semaglutide was related to a significant 26% reduction in the risk of major adverse cardiovascular events compared with placebo, with a 39% reduction in stroke. Iacobellis and Villasnte Fricke 2020 reported that semaglutide decreased epicardial adipose tissue thickness by almost 20% after 12 weeks in subjects with type 2 diabetes and obesity, suggesting a reduction in cardiometabolic risk. Additionally, semaglutide had more adverse effects than placebo, especially nausea and diarrhea, but they were transient and mild-to-moderate. B, Observed proportions of participants and OR for achieving weight loss of at least 5% from baseline at week 104 in the full analysis set during the in-trial observation period, based on the treatment policy estimand. Overall, of 304 participants, 282 (92.8%) completed the trial (attended the end-of-trial safety visit), 272 (89.5%) had a body weight assessment at the end-of-treatment visit at week 104, and 243 (79.9%) adhered to treatment (were on-treatment at the end-of-treatment visit) (Fig. 1). Second, previous studies based on semaglutide in obese patients with or without diabetes had been published, potentially affecting the innovation of our research; thus, some other aspects were discussed, such as the narrowing of patients, the specific dose of semaglutide, and the potentially beneficial effects on cardiovascular disease. Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials. First, because of the relatively limited number of studies about semaglutide treating obesity without diabetes, one of our studies was divided into seven separate trials for analyses, which might affect the homogeneity and publication bias. One role of GLP-1 is to prompt the body to produce more insulin, which reduces blood sugar (glucose). It requires lifelong treatment that’s not one size fits all.” It also highlights the value of treating obesity as a chronic metabolic disease instead of expecting people to rely solely on willpower and lifestyle changes to manage their condition. Standardizing dosages (e.g., focusing on semaglutide 2.4 mg) and delivery methods would help address confounding factors. Therefore, the study designs make it difficult to sufficiently conclude the superiority of one drug over another. Another OASIS 4 analysis showed that participants with obesity and poor physical function at baseline experienced notable improvements. GLP-1s are typically recommended as add-on therapy after metformin for patients who need better glucose control, especially when promoting weight loss. FDA approves first treatment to reduce risk of serious heart problems specifically in adults with obesity or overweight. Study results have shown average weight loss ranging from about 5% (at lower doses) to around 10% (at higher doses). It is unknown if drinking alcohol will affect Rybelsus, but alcohol may affect blood sugar levels in people with diabetes. Tell your health care provider about any medicines you are taking for diabetes. Tell your health care provider if you have diabetic retinopathy or have had vision problems related to your diabetes. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. (a-d) The proportion of participants receiving semaglutide or placebo who reported nausea (a), diarrhea (b), constipation (c), or vomiting (d) events classed as mild, moderate, or severe over the course of the treatment period. †Number of participants with prediabetes (a and b) or normoglycemia (c and d) at baseline and evaluable data at week 104. The trial product estimand addressed the average treatment effect in all randomly assigned participants, assuming that the drug or placebo was taken as intended (participants on treatment). In a phase 2 trial, daily doses ofsemaglutide (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, or 0.4 mg) were compared toliraglutide 3.0 mg daily or placebo. Two published trials directly compare semaglutide to liraglutide; another GLP-1receptor agonist indicated for weight loss. Current studies on semaglutide suggest it may help with more than diabetes and weight loss. When you begin oral semaglutide treatment, doctors often recommend slowly raising the dose. Three times as many patients preferred the oral to the injectable treatment when initially asked (77% vs 24%), but after they were given more detail on the actual dosing requirements, just over half of respondents indicated a preference for oral semaglutide (46). Research involving human participants and/or animals However, Rybelsus is currently approved only for blood sugar management, not weight loss. The most well-known oral version is Rybelsus, the only FDA-approved semaglutide tablet on the market. Ross Wollen joined Everyday Health in 2021 and now works as a senior editor, often focusing on diabetes, obesity, heart health, and metabolic health. Wegovy, the semaglutide product approved for weight loss, is available as a single-use injection pen. Because of this, the manufacturer studied the medication specifically for weight loss, but at a higher dose. People using semaglutide for Type 2 diabetes also tend to lose weight as an additional benefit. So, is using semaglutide for weight loss right for you? When used in combination with an SU or insulin, a dose reduction of these agents may be required to reduce the risk of hypoglycemia . Patients should then wait at least 30 min before consumption of food, drink, or other oral medications . Oral semaglutide should be taken on an empty stomach and swallowed whole with up to 120 mL of water. In general, there were no statistically significant treatment interactions found between treatment and subgroups . The impact of race was also examined in a subgroup analysis of the same studies. You’ll typically start with a low semaglutide dose and work your way up every 4 weeks until reaching 2.4 mg once weekly — the target maintenance dose. Other semaglutide effects, such as appetite reduction, only last as long as you’re using the medication. Certain semaglutide effects, such as slowed gastric emptying, may lessen over time. As illustrated by the gray shading, the week 104 bars present results at this time point among the subgroups of participants with baseline prediabetes (a and b) or baseline normoglycemia (c and d). (a-d) Observed mean percentage change from baseline over time for participants in the full analysis set during the in-trial observation period in waist circumference (a), systolic blood pressure (b), diastolic blood pressure (c), and HbA1c (d). †During treatment with trial product (any dose of trial medication administered within the previous 2 weeks (that is, any period of temporary treatment interruption with trial product was excluded)). W.T.G. reports a grant from Novo Nordisk; serving as site principal investigator for the current clinical trial, which was sponsored by his university during the conduct of the study; and receiving grants to serve as site principal investigator for other university-sponsored clinical trials funded by Eli Lilly & Company, Lexicon, Epitomee and Pfizer outside the submitted work. The treatment policy estimand quantified the treatment effect among all randomly assigned participants, regardless of treatment discontinuation or rescue intervention (participants in trial; intention to treat). Keep a simple symptom and weight log to share with your clinician. Start at a lower dose and increase slowly if your clinician recommends that approach. What side effects do you need to watch for and how will they be managed? How will this change your current medicines if you have diabetes? Which trial results are most relevant to someone like you? Figure 3. Percentage Weight Change at 3 and 6 Months for Patients With and Without Type 2 Diabetes. For those with diabetes, it helps the body respond better to insulin. It is used to treat both type 2 diabetes and obesity. This is especially the case when you want to lose weight or control diabetes. Compared with once-daily liraglutide, once-weekly subcutaneous semaglutide, a novel longer-acting GLP-1RA, was approved by the FDA for weight management in the United States on 4 June 2021 (Lau et al., 2015; Hall et al., 2018; Kushner et al., 2020; Singh et al., 2022). Since then, GLP-1RA has created a new field for obesity treatment (Zhang et al., 2015; Christensen et al., 2019; Ryan et al., 2021). Semaglutide exhibited a positive effect on blood pressure, C-reactive protein, and lipid profiles, expressed more adverse effects than placebo, mainly gastrointestinal reactions. Adults (≥ 18 years) with a body mass index (BMI) ≥ 30 or ≥ 27 with comorbidities (pre-diabetes, hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease) were randomized into two groups. In addition, participants in the semaglutide group with 15% or more vs. less than 15% weight loss had greater reductions in systolic BP (–10.1 mm Hg vs. –4.1 mm Hg), diastolic BP (–4.3 mm Hg vs. –1.1 mm Hg), C-reactive protein (0.34 mg/L vs. 0.74 mg/L), non-HDL cholesterol (0.9 mg/dL vs. 0.96 mg/dL) and triglycerides (0.73 mg/dL vs. 0.87 mg/dL). ATLANTA — Oral semaglutide improved glycemic parameters and cardiovascular risk factors for adults with overweight or obesity, with greater improvements for those with weight loss of 15% or more, according to a post hoc analysis of OASIS-4. Actual weight lost is dependent on a number of factors but many Henry Meds patients lose around 5% of their initial body weight. “The OASIS 4 trial showed that once-daily oral semaglutide 25 mg worked pretty well. At baseline, nearly half of trial participants had prediabetes, while the remainder had normoglycemia. Tonum offers coaching and lifestyle services that complement oral strategies when someone wants a structured support plan around a product or medication. Successful weight management usually includes multiple elements. Pair the medicine with manageable behavioral changes such as protein forward meals adequate sleep and gentle increases in daily movement. The principal objective of the MOSA study was, therefore, to assess the feasibility of administering oral semaglutide to patients with AIWG in routine outpatient clinical practice. This corresponds to an average body weight loss of 4% for semaglutide, and 2.5% for metformin. A prospective, non-randomised cohort study was conducted with the objective of evaluating the efficacy and safety of oral semaglutide for the treatment of AIWG in routine outpatient clinical practice. XG and XH performed the literature search, extracted the data, analyzed the data, and wrote the manuscript.Further, a better understanding of the phenotypes of participants who may be well suited for specific medications and of the effects of switching medications among non-responders would enhance our understanding of best practices for patient selection and management.Oral semaglutide is a daily pill that mimics a hormone called GLP-1, which regulates appetite and blood sugar.All study data were from the literature, 3 studies were open-label, and 3 were missing data; the results were less likely to affect weight loss but may have a more significant impact on safety results.For example, in the row corresponding to HbA1c in the upper panel, all individuals receiving dapagliflozin are plotted in accordance with how much baseline HbA1c predicts the change in HbA1c, and similar for BMI, SBP etc.Participants (64.5% men) had a mean age of 64.4 years and a mean diabetes duration of 10.1 years.In addition to the glycemic benefits described, oral semaglutide has also been shown to be effective in reducing body weight in patients with T2D on a variety of different background glucose-lowering therapies (Fig. 3). While GLP-1 RAs are efficient in promoting weight loss in diabetic patients, current points of interest include understanding the effect of GLP-1 RAs in individuals with obesity, as few studies encompass direct comparisons of GLP-1 RAs for this purpose. Liraglutide 3.0 mg daily subcutaneous (SQ) injection was the first FDA-approved GLP-1 agonist approved for weight loss in patients with obesity and semaglutide 2.4 mg weekly SQ injection followed shortly after . The journey to a healthier weight is profoundly personal and often challenging, but innovations in medical treatments like oral semaglutide offer new avenues for achieving these health goals. As we conclude this comprehensive exploration of oral semaglutide, let’s revisit its potential to revolutionize individual approaches to weight loss. One of the critical takeaways is the substantial weight loss potential that oral semaglutide offers. If you miss a dose, take it soon if under 48 hours late. Oral Wegovy pills start at lower doses, building to 25 mg daily. Adjust if side effects arise, delaying hikes as needed. Non-diabetics follow the same protocols as weight-focused plans. Four studies (Rubino et al., 2021; Wadden et al., 2021; Wilding et al., 2021; Rubino et al., 2022), including 3,554 individuals, reported a change in FFA. Five studies (Wilding et al., 2021; Wadden et al., 2021; Rubino et al., 2021; Rubino et al., 2022; O'Neil et al., 2018), including 4,415 individuals, reported changes in TC, HDL, LDL, VLDL, and TG. Four studies (Wilding et al., 2021; Wadden et al., 2021; Rubino et al., 2022; O'Neil et al., 2018), including 3,612 individuals, noted a change in CRP, a marker of inflammation. Five studies (Wilding et al., 2021; Wadden et al., 2021; Rubino et al., 2021; Rubino et al., 2022; O'Neil et al., 2018), including 4,420 individuals, recorded changes of blood pressure related indicators, SBP and DBP. Six studies (Wilding et al., 2021; Wadden et al., 2021; Rubino et al., 2021; Rubino et al., 2022; O'Neil et al., 2018; Jensterle et al., 2021), including 4,444 individuals, reported a change in WC. Nevertheless, this study has several limitations, with the first one being the absence of a comparator arm due to its observational nature, not allowing us to quantify the extent to which semaglutide and lifestyle intervention contributed to weight loss. Due to its substantial and durable weight loss effect, semaglutide may herald a new era in the management of obesity, using percentage weight loss as a biomarker and applying a treat-to-target approach, in line with other chronic diseases, to prevent and treat weight-related complications . In contrast to the tortuous history of AOMs littered with numerous drug withdrawals due to adverse events, the mounting evidence for the good safety profile of semaglutide and its much greater magnitude of weight loss could change dramatically the landscape of obesity management, encompassing the widespread use of pharmacotherapy . Statins and diuretics may be used in patients with T2D for the management of dyslipidemia and hypertension, respectively. There was no change in appetite in this study, a finding that is inconsistent with observations for the s.c. Oral semaglutide significantly improved fasting and post-prandial glucose metabolism and lipid metabolism, and delayed gastric emptying during the first post-prandial hour, which is consistent with observations for s.c. This increase in SNAC was not considered clinically relevant as it has no anticipated pharmacodynamic effects . SNAC exposure did increase with decreases in hepatic function, with the greatest increase seen in patients with severe hepatic impairment (3.64 times higher than patients with normal hepatic function). Of note, the difference in HbA1c between study arms was −0.27% (95% CI −0.31 to −0.22; p Individuals were eligible if they were naïve to any hypoglycemic therapy, were taking oral agents, or were on combined therapy with oral agents and insulin. A number of other GLP-1 RA followed either as daily (liraglutide, lixisenatide) or weekly (extended-release exenatide, albiglutide, dulaglutide, and semaglutide). An unexpected change in direction occurred after the publication by Nissen and Wolski implicating rosiglitazone in adverse clinical outcome following meta-analysis.3 This precipitated a series of events culminating in the Food and Drug administration (FDA) requirement for cardiovascular safety studies for all new hypoglycemic agents. However, a difficulty with the use of these agents is the need for subcutaneous injections, which can be inconvenient to individuals living with type 2 diabetes. A future study comparing these two agents would be a beneficial addition to the literature on the efficacy of semaglutide. Gall bladder-related issues, including cholelithiasis, ranged between 0.2% and 4.9%, and cardiovascular issues, including tachycardia and arrhythmias, ranged between 1.5% and 9.8% in STEP trials 1–4. Treatment discontinuation due to GI events ranged from 4.9% to 12% and from 3% to 9.4% during the PIONEER32 35 and the SUSTAIN trials,10 23 respectively. Around 60%–93% of the population were white in SUSTAIN 1–10, STEP, and PIONEER 1–8 trials, and about 2%–10% were black or Asian. Reductions in HbA1c were greater with oral semaglutide (7 and 14 mg) versus placebo and versus active comparator in all HbA1c subgroups .In OASIS 4, common adverse reactions were similar to those previously seen in clinical trials with Wegovy® (semaglutide) injection 2.4 mg, including nausea, diarrhea, and vomiting.1This was an observational, retrospective cohort study using IQVIA Ambulatory Electronic Medical Record (AEMR) data18 linked to Longitudinal Access and Adjudication Data (LAAD)19 in the US.Antihyperglycaemic drugs are expected to have larger effects at high HbA1c levels.At 56 weeks, patients on liraglutide 3.0 mg lost on average 6.1–8.0% of BW vs. 0.2–4.0% on placebo15,16,17, with the extension of SCALE Obesity and Prediabetes suggesting a slight weight regain after the first year18.You may report side effects to the FDA at FDA-1088.The authors concluded that similar exposure−response relationships were observed for efficacy (HbA1c and body weight) and also for tolerability (nausea and vomiting) of semaglutide, regardless of the route of administration. However, weight loss may vary depending on the patient’s condition and lifestyle. Oral semaglutide, a revolutionary weight-loss medication, makes a big impact on the healthcare industry. For example, Ozempic is an injectable form of semaglutide, while Rybelsus is the first FDA-approved oral form of the medication. Changing your relationship with food and practicing mindful eating can contribute to successful weight loss. Strength training exercises can also help build lean muscle mass, boosting your metabolism and aiding in weight loss. Avoiding processed foods, sugary snacks, and excessive amounts of saturated fats can further support your weight loss goals. By making strategic changes to your daily habits, you can optimize your weight loss journey and achieve long-term success. When initiating semaglutide treatment, your healthcare provider will likely recommend regular monitoring to ensure your safety and optimize the benefits of this medication. Check if you qualify for the Novo Nordisk patient assistance program Patients assigned to tirzepatide showed a 20.9% BW loss after 36 weeks with an additional 5.5% reduction after 52 weeks, while those who switched to placebo experienced a 14% weight regain, confirming the findings from STEP 4 supporting the chronicity of obesity and the need for continuous treatment. RCT conducted in patients with T2D showed that high doses of tirzepatide represent the most efficacious incretin-based anti-diabetes drug in terms of BW reduction33, sustaining the development of the SURMOUNT program to explore its efficacy and safety in the management of obesity9. Moreover, a post-hoc analysis of the STEP 1 trial confirmed the consistency of the semaglutide 2.4 mg weight-lowering potential regardless of baseline BMI 2 and comorbidities29. In STEP 1 and STEP 3, patients on semaglutide lost 14.8–16.0% BW compared to 2.4–5.7% in the placebo group at 68 weeks26,27. Millions of people use injectable drugs like Wegovy to reach a healthier weight. Drugmakers have developed pill versions of GLP-1 medicines to treat obesity. The confidentiality of the participants was guaranteed, and no personally identifying information was utilised. Similarly, the treating clinicians were informed and required to provide consent to participate with their respective patients. The MOSA study was approved by the Mondriaan Mental Health Care Institutional Review Board (IRB no. CWO21017) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Efficacy of oral semaglutide in patients with T2D, summary of observations from key supportive secondary endpoints in the phase III clinical trials In patients at high CV risk, HbA1c levels decreased by 1.0% with oral semaglutide and by 0.3% with placebo at the end of the trial; however, no statistical comparison of the HbA1c reductions was performed . The primary and confirmatory secondary endpoints in most of the trials were change from baseline in HbA1c and body weight, respectively, at week 26, with the exception of the PIONEER 6, 7, and 10 trials (Table 2). Administration of single-dose rosuvastatin with oral semaglutide at steady state resulted in a 41% increase in AUC0–∞ and a 10% increase in Cmax for rosuvastatin compared with patients not receiving oral semaglutide. Certain medications may interact with semaglutide and affect its efficacy or increase the risk of side effects. Healthcare professionals will closely monitor individuals using semaglutide and provide guidance on managing side effects if they occur. It is important to note that not everyone will experience these side effects, and many individuals tolerate semaglutide well. Other potential side effects of semaglutide may include headache, fatigue, dizziness, and injection site reactions. For the PIONEER trials shown, HbA1c reduction at week 26 was the primary endpoint, except for PIONEER 7 where the primary endpoint was achievement of HbA1c 1c are regardless of trial product discontinuation or rescue medication (treatment policy estimand). Estimated mean changes from baseline in HbA1c included only data obtained before initiation of any rescue medication or before premature treatment discontinuation. For the SUSTAIN trials shown, HbA1c reduction at study end (weeks 30, 40, 52, or 56) was the primary endpoint. Reduction in HbA1c with semaglutide and comparators in global glycemic efficacy trials (16–20, 22–26, 31, 33). The trial product estimand evaluated the treatment effect, assuming that all patients remained on the trial product for the entire planned trial duration and did not use rescue medication. CLINICAL EVIDENCE/CLINICAL EFFICACY Liraglutide induces weight loss by reducing energy intake.(16) It has little known effect on energy expenditure.(16) Compared to placebo, liraglutide lowers ad libitum energy intake by 16%, as shown with a laboratory meal paradigm.(16) The efficacy of liraglutide 3 mg daily for weight loss was demonstrated in several large, multicenter trials. We then review data on the mechanism of action, weight-loss and cardiometabolic efficacy, and safety of semaglutide 2.4 mg/week for the treatment of obesity. A total of 307 participants were randomized, with 205 allocated to oral semaglutide and 102 to placebo. Injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide 2.4 mg have demonstrated robust efficacy in promoting weight loss but require subcutaneous administration, which can be a barrier to treatment adherence for some patients. A significant reduction in body weight should be seen as a target for treatment of type 2 diabetes . It is essential to attend these follow-up appointments and communicate any concerns or changes experienced during the course of treatment. It is important to discuss your medical history with your healthcare provider to determine if semaglutide is appropriate for you. Your healthcare provider can assess these potential interactions and make any necessary adjustments to your treatment plan. Before starting semaglutide, it is crucial to inform your healthcare bout any medications, supplements, or herbal remedies you are currently taking. These effects are generally mild and temporary, but individuals should consult their healthcare provider if they persist or worsen. Similarly, patients with type 2 diabetes were also represented in many studies51,53,54,56,57,59,62,63,65,68,69,70,71.The only apparent difference between oral semaglutide and subcutaneous semaglutide, besides slight differences in their efficacy in weight reduction, is the route of administration.Alcohol may worsen certain side effects, sabotage weight-loss progress, and offset cardiovascular benefits.Next, escalate the dosage gradually to minimize side effects, adjusting the pace based on each individual’s tolerance.While semaglutide appears to be effective for weight loss in people with diabetes, more research is needed to determine the long-term effects of the medication.The data for SUSTAIN 7 were not available at the time of this analysis, and have therefore not been included.21 Remember, the most effective weight loss plan is one that you can maintain consistently, which supports not only physical well-being but also overall life quality. While surgery may offer more significant and faster weight loss results, it also comes with higher risks and a longer recovery period. Oral semaglutide is a less invasive option compared to surgical procedures like gastric bypass or sleeve gastrectomy. But generally, with a properly managed dosage, significant weight loss can be achieved. Semaglutide in Obesity and Type 2 Diabetes Management: A Systematic Review of Clinical Outcomes Results from the SURMOUNT 1 extension will further clarify the role of tirzepatide on obesity-related metabolic disorders. As for BW reduction, semaglutide 2.4 mg appeared as even more beneficial on glucose metabolism73. BW change was also a secondary outcome of the SURMOUNT OSA38 and the SYNERGY-NASH trial39. Liraglutide 3.0 mg was administered subcutaneously once daily (refs. 11,12,13,14,16,17,18,26); Semaglutide 2.4 mg (refs. 20,21,22,23,24,26,27,28), Tirzepatide 15 mg (refs. 30,31,32,33) and Retatrutide 12 mg (refs. 35) were administered subcutaneously once-weekly; Semaglutide 50 mg (refs. 36) and Orforglipron 45 mg (refs. 37.) were administered orally once daily. Moreover, the study demonstrated a dose-dependent response, indicating that higher semaglutide dosages prompted more substantial weight reduction. In a randomized controlled trial conducted by Johnson et al., non-diabetic participants were administered either semaglutide or a placebo for a duration of 68 weeks. Discover the results and key findings from clinical studies evaluating the efficacy and safety of semaglutide for weight loss in non-diabetic individuals. When it comes to achieving successful weight loss in individuals without diabetes, determining the right dosage of semaglutide is crucial. Overall, semaglutide offers several significant benefits for individuals without diabetes seeking weight loss. The relative cost-effectiveness of the two semaglutide formulations has not been directly compared. In addition, the subcutaneous version of semaglutide might be preferred for patients prescribed levothyroxine, which should itself be taken in the morning on an empty stomach, half an hour before breakfast (57). Some patients may prefer the less frequent once-weekly administration of subcutaneous semaglutide over the need to take a tablet with specific dosing instructions each morning, e.g., those with multiple concomitant medications. Many patients are reluctant to initiate injectable treatment and barriers to their use include fear of injection pain, feelings of failure related to disease progression, embarrassment/concerns about injecting in public, being nervous about injecting correctly, and adverse events (42, 43). Research shows that people who discontinue semaglutide often regain some of the weight they lost, which highlights the importance of long-term lifestyle changes. One of the challenges with semaglutide is the potential for weight regain after stopping the medication. It can be expensive, and not all insurance plans cover it for weight loss in non-diabetic individuals. These side effects often lessen as the body adjusts to the medication, but in some cases, they can persist or worsen. Further investigations are needed to fully assess the side effects and long-term safety of tirzepatide. Its long-term efficacy and safety render it a viable option for sustained weight management . These effects were usually mild-to-moderate and did not significantly affect adherence or effectiveness. We thank all the participants, investigators and trial‐site staff who were involved in conducting the SUSTAIN 1 to 5 trials. Proportion of subjects achieving ≥5% (A) and ≥10% (B) weight loss by baseline BMI. Only a small component (0.07 to 0.5 kg) of the total treatment difference in weight loss was explained by nausea or vomiting. It is important to keep in mind that while this drug is effective in aiding weight loss, the weight can return once it's stopped, unless other treatments, such as exercise, are implemented. The doses of semaglutide were accompanied by side effects, mostly involving gastrointestinal problems and nausea, though they were described as "generally non-serious, mild to moderate in severity, and transient". All of the participants, across four countries, were classed as being overweight at the start of the trial. The trial involved 205 people being given semaglutide and 102 people a placebo, alongside diet and exercise counseling for 71 weeks. When results were stratified by diabetes duration, weight loss reduction was estimated for all intervals, with greatest weight reduction in participants having lived with diabetes for less than 1 year (Fig. 3C). BL baseline, EOS end of study, HbA1C glycated hemoglobin, N total number of participants in full analysis set (FAS), n total number of participants contributing to the statistical analysis, ns non-significant, T2D type 2 diabetes. At baseline, the mean HbA1C was 8.1% (65 mmol/mol) and body weight 95.8 kg. BParticipants on oral semaglutide treatment and attended the EOS visit. In terms of serious adverse reactions, only liraglutide 3.0 mg was significantly different compared to placebo, and others were not statistically significant. Stata Software drew inverted funnel plots for weight loss, Δ HbA1c (%), total adverse events, serious adverse events, and incidence of hypoglycemic events. The results of the weight loss of the four interventions are shown in Table 4. In the loop inconsistency analysis, the results showed that the weight loss outcome indicator involved two closed loops, decreased HbA1c involved one closed loop, and the other three outcome indicators involved three closed loops, and the lower bounds of the 95%-CI for all five outcomes included 0 or P ≥ 0.05, indicating a low likelihood of inconsistency between closed loops. Study treatment was able to be completed without rescue medication for 78% of subjects taking oral semaglutide and 81% taking liraglutide compared with only 58% in the placebo group. Discontinuation from study treatment was similar between oral semaglutide and liraglutide with 11% and 9% of subjects discontinuing study treatment while only 4% receiving placebo discontinued study treatment early because of AEs. Overall, the PIONEER 1 study demonstrated superiority of oral semaglutide 3 mg, 7 mg, and 14 mg compared with placebo with regard to HbA1c and BW reduction and was considered safe and well tolerated . Adverse events leading to premature trial product discontinuation were highest with oral semaglutide 14 mg (7.4%) compared with oral semaglutide 3 mg (2.3%), 7 mg (4.0%), and placebo (2.2%), respectively, and were due to GI disorders. Overall, this study demonstrated that oral semaglutide significantly lowered HbA1c when compared with placebo and the degree of change in HbA1c with oral semaglutide 20 mg and 40 mg was not significantly different compared to subcutaneous semaglutide . In the meantime, semaglutide is contraindicated in patients with a personal or family history of MTC, as well as in patients with multiple endocrine neoplasia (MEN) type 2 in the US. In the PIONEER program, four thyroid malignancies occurred in semaglutide-treated patients, versus one in the comparator group (14–21, 23, 24). Preclinical studies with semaglutide also found no adverse signals in pancreatic tissue (76). Currently, the only clinical trial reporting an incidence of gastrointestinal AEs for both s.c. As expected, gastrointestinal AEs also occurred on treatment with GLP-1RA comparators (Table 4). AE adverse event, BG blood glucose, CV cardiovascular, GI gastrointestinal, HbA1c glycated hemoglobin, NR not reported, SGLT2i sodium-glucose co-transporter-2 inhibitor, SU sulfonylurea, T2D type 2 diabetes, TZD thiazolidinedione Efficacy and safety of oral semaglutide by subgroups of patient characteristics in the PIONEER phase 3 programme Effect of semaglutide treatment or placebo on waist circumference from baseline… Variation in weight loss response for semaglutide andplacebo. Percentage change in mean body weight from baseline through week 208 for all… However, the majority of animal studies did not find any effect of GLP-1RAs on pancreatic physiology, even with doses up to 240 the normal human dose (73–76). When combining all available CVOT data (including those from non-semaglutide GLP-1RAs) in a meta-analysis, a hazard ratio of 1.05 (95% confidence interval CI 0.78–1.40) was found for pancreatitis and 1.12 (95% CI 0.77–1.63) for pancreatic cancer (63). In the subsequent years, many pharmacovigilance and database studies followed, with conflicting results (54–60). An effect on the central nervous system has been suggested as a recent study with modified exenatide—with reduced brain penetrance—showed less vomiting in musk shrews, despite retaining effects on glucose control (46). However, whether this is also true for the combination with semaglutide, or whether lowering the dose of metformin has effect, has not been studied.