Semaglutide Group Research Articles

Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial

Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk. This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score<-1.0at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516. Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5kg/m2 (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8μg/L [95% CI-5.6 to 13.3]; p=0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3μg/L versus placebo 62.3μg/L [95% CI-10.8 to 15.0]; p=0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4ng/L [95% CI 25.5-307.3]; p=0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide groupafter 52 weeks ((ETD lumbar spine-0.018g/cm3 [95% CI-0.031 to-0.005]; p=0.007); ETD total hip-0.020g/cm2 ([95% CI-0.032 to-0.008]; p=0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p=0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD-6.8kg [95% CI-8.8 to-4.7]; p<0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported. In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss. Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.

Improvement of β-Cell Function After Switching From DPP-4 Inhibitors to Oral Semaglutide: SWITCH-SEMA2 Post Hoc Analysis.

Whether continuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) or switching to oral semaglutide is more beneficial for β-cell function is unclear. To assess the efficacy of switching from DPP-4is to oral semaglutide for β-cell function compared with DPP-4i continuation. Post hoc analysis of SWITCH-SEMA 2, a multicenter prospective randomized controlled trial on the switch to oral semaglutide vs DPP-4i continuation without dose adjustment for 24 weeks in subjects with type 2 diabetes treated with DPP-4is, was conducted. Changes in markers for glucose metabolism, including homeostatic model assessment (HOMA2) scores and disposition index (DI), were compared between the groups. A total of 146 subjects (semaglutide group, 69; DPP-4i group, 77) were analyzed. In the semaglutide group, glycemic control, liver enzyme deviations, and lipid profiles improved after 24 weeks. Regarding indices for β-cell function, changes in HOMA2-β as well as DI, reflecting the ability of β-cells to compensate for insulin resistance, were significantly higher in the semaglutide group compared with the DPP-4i group (mean change, +10.4 vs +0.6 in HOMA2-β [P = .001] and +0.09 vs 0.0 in DI [P < .001]). Improvement in DI in the semaglutide group was correlated significantly to changes in body mass index (BMI), HbA1c, and fatty liver index reflecting liver steatosis. Multiple linear regression analysis revealed that dose of semaglutide (≥ 7 mg/day), reduction in fatty liver index, and metformin nonuse were independently associated with improvement of DI. Switching to oral semaglutide ameliorated β-cell function compared with DPP-4is, presumably via tissue-to-tissue crosstalk between liver and β-cells.

Efficacy and safety of semaglutide in patients with heart failure with preserved ejection fraction and obesity.

Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, has shown promise in weight management and cardiovascular outcomes in other populations. This study aimed to evaluate the efficacy of semaglutide in heart failure with preserved ejection fraction(HFpEF) patients with obesity. A retrospective study analyzed 318 patients with HFpEF, of which 104 received semaglutide and 214 received placebo. Primary endpoints included evaluating changes in exercise capacity and weight management. Semaglutide treatment led to significant improvements in the primary endpoints. Patients in the semaglutide group demonstrated substantial enhancements in exercise capacity, as measured by the 6-min walk distance, compared to the placebo group (mean difference 15.1 meters, 95% CI 5.8 to 24.4, p = 0.002). Additionally, semaglutide resulted in substantial weight loss compared to placebo (mean difference -2.9%, 95% CI -4.1--1.7, p = 0.001). Several secondary endpoints, including reductions in C-reactive protein levels and improvements in other clinical parameters, further supported the efficacy of semaglutide. Adverse events were generally well-tolerated, with no unexpected safety concerns. Semaglutide demonstrated significant clinical benefits in HFpEF patients with obesity, as evidenced by improved symptoms, physical function, and weight reduction.

Semaglutide attenuates pathological electrophysiological remodeling in diabetic cardiomyopathy via restoring Cx43 expression.

Semaglutide is a relatively new anti-hyperglycemic agent that was shown to carry cardioprotective potentials. However, the exact effects of semaglutide on diabetic cardiomyopathy (DCM) and their underlining mechanism remain unclear. This study aimed to evaluate the effects of semaglutide on myocardium injury and cardiac function in DCM mice and its potential mechanisms, with emphasis on its effects on Cx43 and electrophysiological remodeling. C57BL/6 mice were randomly divided into four groups: control group, semaglutide group, diabetes group, and diabetes + semaglutide treatment group. Type 1 diabetes were induced by intraperitoneal injection of streptozotocin. Mice in the semaglutide intervention group were injected subcutaneously with semaglutide (0.15 mg/kg) every week for 8 weeks. The blood glucose, cardiac function, oxidative stress markers, apoptosis, expression of Sirt1, AMPK, Cx43, and electrocardiogram of mice in each group were evaluated. Treatment with semaglutide alleviated glucose metabolism disorders and improved cardiac dysfunction in diabetic mice. In addition, semaglutide ameliorated the increase in oxidative stress and apoptosis in diabetic heart. Sirt1/AMPK pathway was activated after semaglutide treatment. Furthermore, diabetic mice showed reduced expression of Cx43 in the myocardium, accompanied by changes in electrocardiogram, including significantly prolonged RR, QRS, QT and QTc interval. Semaglutide treatment restored Cx43 expression and reversed the above-mentioned ECG abnormalities. Our research results showed that semaglutide protected against oxidative stress and apoptosis in diabetic heart, thereby improving cardiac function and electrophysiological remodelling in DCM mice, which may attribute to activation of Sirt1/AMPK pathway and restore of Cx43 expression.

Effectiveness and Safety of Semaglutide for Weight Loss in Patients With Inflammatory Bowel Disease and Obesity.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has shown sustained and clinically significant weight loss in the general population. There are limited data on outcomes of its use in patients with inflammatory bowel disease (IBD). A retrospective cohort study was conducted between June 4, 2021, and December 11, 2023, using TriNetX, a U.S. multi-institutional database in patients with obesity who had IBD compared with patients without IBD. The primary aim was to assess the mean total body weight (TBW) change between 6 and 15 months from initiation of semaglutide compared with baseline between the 2 cohorts. One-to-one (1:1) propensity score matching was performed for demographics, comorbid conditions, smoking status, and mean body mass index. A 2-sample t test was performed to assess mean TBW change from baseline, with a P value <.05 considered to be statistically significant. We also compared the risk of IBD-specific outcomes with and without semaglutide use in patients with IBD. Out of 47 424 patients with IBD and obesity, 150 (0.3%) patients were prescribed semaglutide (mean age 47.4 ± 12.2 years; mean TBW 237 ± 54.8 pounds; mean body mass index 36.9 ± 6.5kg/m2; 66% Crohn's disease). There was no difference in mean TBW change after initiation of semaglutide in the IBD and non-IBD cohorts (-16±13.4 pounds vs -18±12.7 pounds; P = .24). There was no difference in mean TBW change between 6 and 12 months (-16±13 pounds vs -15±11.2 pounds; P = .24) and 12 and 15 months (-20±13.2 pounds vs -21±15.3 pounds; P = .49) between the 2 cohorts. There was no difference in the risk of oral or intravenous steroid use and any-cause hospitalization in the semaglutide group compared with the group without semaglutide use in patients with IBD. Semaglutide use is effective in patients with IBD and obesity similar to patients without IBD, with >5% mean weight loss. There was no increased risk of IBD-specific adverse events with semaglutide use.

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials

In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. Novo Nordisk.

Efficacy of Semaglutide in Overweight and Obese Patients with Type 1 Diabetes.

Introduction: More than two-thirds of patients with type 1 diabetes (T1D) are overweight (OW) and/or obese (OB) in the USA and Western Europe, resulting in insulin resistance as in type 2 diabetes. None of the currently available glucagon like polypeptide 1 (GLP-1) analogs are approved for patients with T1D. A higher dose of semaglutide has been approved by the Food and Drug Administration (FDA) for subjects with body mass index (BMI) >27 kg/m2. We evaluated the real-world use of semaglutide in patients with T1D. Methods: This was a retrospective chart review study of 50 OW or OB patients with T1D who were initiated on semaglutide and followed for 1 year. The control group comprised of 50 computer-matched patients (for sex, race, weight, BMI, and diabetes duration) during a similar time period and were not on any weight loss medications. Results: Most patients (92%) were non-Hispanic white in both arms. Mean ± standard deviation (SD) age and duration of diabetes were 42 ± 11 and 27 ± 12 years, respectively. The continuous glucose monitors (CGM), insulin pump use, baseline BMI and body weight were also similar in the two groups. Baseline glycosylated hemoglobin (HbA1c) was insignificantly lower in the semaglutide group (7.6% vs. 8.2%, respectively; P = non-significant [NS]). Total daily insulin dose (TDD) and insulin dose per kg body weight were higher in the semaglutide group at baseline with no difference in basal or prandial insulin dose. There were significantly greater declines in mean (±SD), BMI (7.9% ± 2.6%), body weight (15.9 lbs ± 5.4 lbs), HbA1c, CGM glucose SD and coefficient of variation (CV), and increase in CGM time in range (TIR) in the semaglutide group compared to the control group with no difference in insulin dose changes, time above range (TAR), or time below range (TBR). Conclusions: We conclude that use of semaglutide in patients who are OW and/or OB with T1D was effective in lowering body weight and BMI, and improving glycemic metrics in this pilot real-world study. We strongly recommend performing prospective, large-randomized clinical trials with newer GLP-1 analogs like semaglutide and tirzepatide (twin-cretin) for subjects with T1D associated with OW and/or OB.

Effect of Semaglutide on High-Fat-Diet-Induced Liver Cancer in Obese Mice.

This study aims to investigate the impact of semaglutide on the expression of liver cancer proteins in obese mice induced by a high-fat diet. Sixteen obese mice were randomly divided into two groups: the high-fat diet group and the semaglutide group, each consisting of eight mice. Additionally, eight normal male mice were included as the control group. Serum samples were collected, and a differential expression analysis of total proteins in adipose tissue was performed using quantitative tandem mass spectrometry (TMT) in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Significant differential proteins were identified and subjected to a bioinformatics analysis. The findings revealed that these differential proteins, namely, integrin αV (ITGAV), laminin γ1 (LAMC1), fatty acid-binding protein 5 (FABP5), and lipoprotein lipase (LPL), regulate the occurrence and development of liver cancer by participating in the extracellular matrix (ECM) signaling pathway and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Notably, semaglutide can decelerate the progression of liver cancer by inducing the expression of ITGAV, LAMC1, FABP5, and LPL in the adipose tissue of obese mice.

Semaglutide: The First Anti-Obesity Agent Shown to Decrease Cardiovascular Events

The anti-obesity agent, semaglutide (2.4 mg/week) was evaluated in a large (n=17,604) multinational randomized trial called SELECT to examine its effects on cardiovascular (CV) outcomes in overweight/obese patients with preexisting CV disease and no diabetes. The primary outcome of SELECT trial was a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke. Over a mean duration of follow-up of 39.8 months, a primary CV outcome occurred in 6.5% in the semaglutide group and 8.0% in the placebo group; hazard ratio (HR) 0.80 (95% CI, 0.72 to 0.90; P&lt;0.001). Mean change in body weight over 104 weeks was -9.4% and -0.9% with semaglutide and placebo, respectively; estimated treatment difference (ETT) -8.5% (95% CI, -8.5 to -8.3). There was significant amelioration in blood pressure and plasma levels of lipids, glycated hemoglobin (HbA1c), and C- reactive protein (CRP). The incidences of diabetes and prediabetes were reduced by 73% and 67%, respectively with semaglutide. 16.6% of patients discontinued semaglutide due to adverse effects, mainly gastrointestinal (GI) compared with 8.2% who discontinued placebo (P&lt;0.001). In conclusion, semaglutide is the first anti-obesity agent shown to decrease CV events in overweight/obese subjects with CV disease without diabetes. Further studies are needed to examine the impact of semaglutide on CV events in obese subjects without underlying CV disease.

The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: A prespecified, secondary analysis from a randomized, clinical trial

AimsTo evaluate the effect of treatment with semaglutide and empagliflozin on the cortico-medullary sodium gradient (MCR; medulla/cortex ratio), urine sodium/creatinine ratio (UNACR), and estimated plasma volume (ePV) and to compare the MCR between persons with and without type 2 diabetes. MethodsUsing the 23Na magnetic resonance imaging (23Na-MRI) technique, we investigated the effects of 32 weeks of treatment with semaglutide, empagliflozin or their combination on MCR in 65 participants with type 2 diabetes and high risk of cardiovascular disease. The participants were recruited from a randomized, controlled interventional trial and further characterized by UNACR and ePV. In addition, in a cross-sectional design, we compared MCR by 23Na-MRI in 12 persons with type 2 diabetes and 17 matched controls. Data from the interventional trial were analyzed using a single, multivariate linear mixed model strategy for repeated measurements. Data from the cross-sectional study were analyzed by fitting a linear regression model adjusted for age and sex. ResultsCompared to placebo, semaglutide, but not empagliflozin, significantly decreased the MCR (−9 %, 95%CI (−18, −0.06)%, p = 0.035 and −0.05 %, 95%CI(−0.15, 0.05)%, p = 0.319, respectively). The UNACR decreased in the semaglutide group(−35 %, 95 % CI(−52, −14) %, p = 0.003) but not in the empagliflozin group (7 %, 95 % CI(−21, 44)%, p = 0.657), whereas the ePV decreased in the combination group. The MCR was not different between persons with and without type 2 diabetes. Conclusion23Na magnetic resonance imaging can identify drug induced changes in the MCR in persons with type 2 diabetes, and 32 weeks of semaglutide decreases the MCR in such persons. There is no difference in the MCR between persons with and without type 2 diabetes. Trial number and registryEUDRACT 2019-000781-38, clinicaltrialsregister.eu.

Safety and Efficacy of Semaglutide Use in Diabetes during Ramadan Fasting: A Real-world Experience from Bangladesh

Aims: The study has been conducted to observe the efficacy and safety of once-weekly subcutaneous semaglutide during Ramadan fasting among patients with type 2 diabetes mellitus (T2DM) from Bangladesh who intended to fast during Ramadan 2022. Methods: This was an open-label, single-center, two-arm parallel-group study. In this prospective observational study, patients were enrolled in two groups depending on treated with or without semaglutide for at least 3 months prior Ramadan. Initially, total 200 patients were enrolled at the first visit (4 weeks before Ramadan); among them, 58 subjects were in the semaglutide group (Group A) and 142 in other than the semaglutide group (Group B). At the end of the second visit (within 4 weeks after Ramadan) after data editing and cleaning, a total of 130 patients (55 subjects in Group A and 75 subjects in Group B) were included in the final statistical analysis. All of them were followed up for a total of 24 weeks including 12 weeks of screening period. The primary objectives were to assess the efficacy and safety of semaglutide in terms of glycosylated hemoglobin (HbA1c) (%), weight loss (kg), hypoglycemia (number of events), and episodes of gastrointestinal (GI) upset (number of events) during Ramadan fasting. Results: Patients in the semaglutide group had better glycemic control after fasting of Ramadan compared to the control group (mean decrease in HbA1c level: 0.61% vs. 0.19%; P &lt; 0.001). In addition, more than 18% of the patients in the semaglutide group achieved good glycemic control (HbA1c &lt;7%), while the rate was 13.3% in the control group. Patients treated with semaglutide achieved a better weight loss than the nonsemaglutide group (2.97 vs. 1.38 kg; P &lt; 0.001). Although there was no significant difference in terms of hypoglycemic events in both the groups (P = 0.13), but the GI symptoms were more common in the semaglutide group than the control group (P &lt; 0.05). Among other secondary endpoints, the serum levels of total cholesterol, low-density lipoprotein, and triglyceride were significantly decreased in the semaglutide group compared to the control group (P &lt; 0.05). Conclusions: Semaglutide showed better efficacy in glycemic control, weight loss, and dyslipidemia compared to other hypoglycemic drugs in patients with T2DM during Ramadan. Although patients receiving semaglutide reported fewer hypoglycemic episodes and GI upset events, they might be subjected to other medications or prolonged fasting. Semaglutide might be considered a suitable therapy during Ramadan fasting based on judicial judgment.

The effect of semaglutide on blood pressure in patients with type-2 diabetes: a systematic review and meta-analysis

ObjectiveTo evaluate the blood pressure (BP) lowering ability of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), in individuals with type-2 diabetes (T2D).MethodsRandomized controlled trials (RCTs) comparing subcutaneous or oral semaglutide with placebo or other antihyperglycemic agents (AHAs) in T2D patients were identified by searching PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Library. These screened studies included the outcomes of interest: systolic and/or diastolic BP. Weighted mean differences (WMDs) and 95 % confidence intervals (CIs) were used to present the meta-analysis results. Pooled and sensitivity analyses were performed, and the risk of bias was evaluated.ResultsTwenty-nine RCTs with a total of 26985 participants were recruited in the final analysis. The WMD in change from baseline in systolic BP (SBP) of semaglutide versus placebo or other AHAs was −2.31 mmHg (95% CI: −3.11 to −1.51), while that for diastolic BP (DBP) was 0.09 mmHg (95% CI: −0.16 to 0.33). It also reduced glycated hemoglobin A1c (HbA1c) by 0.75% (95% CI: −0.92 to −0.58) and body weight loss by 2.80 kg (95% CI: −3.51 to −2.08). The reduction in SBP was similar for subcutaneous and oral administration of semaglutide, with −2.36 (95% CI: −3.38 to −1.35) and −2.50 (95% CI: −3.48 to −1.53), respectively.ConclusionsIn T2D, SBP decreased significantly in the semaglutide group compared with placebo or other active controls. According to the efficacy results from this meta-analysis, subcutaneous and oral semaglutide have similar SBP-reducing effects. Therefore, the treatment of T2D patients with subcutaneous semaglutide or oral preparations is beneficial for reducing SBP.

The Impact of Semaglutide on Liver Fat Assessed by Serial Cardiac CT scans in Patients with Type 2 Diabetes: Results from STOP Trial

IntroductionThere is increasing prevalence of hepatic steatosis. Hepatic steatosis is increasingly recognized as the independent risk factor for cardiovascular mortality. However, there are limited options for the treatment of fatty liver. In this study we evaluated the effect of semaglutide on liver fat as measured by non-contrast cardiac CT scans. MethodsSTOP is a randomized controlled trial that evaluated semaglutide treatment effect on coronary atherosclerosis progression (STOP) in type 2 diabetes. We utilized unenhanced cardiac CT scans to quantify liver fat based on CT Hounsfield attenuation method. A total of 114 subjects qualified for this study of the 140 subjects randomized, 59 in semaglutide group and 55 in the placebo group and were followed for 12 months. Multivariate regression models were used to evaluate the change in liver fat content overtime. Results114 subjects were included in the study, 61% male, mean age of 57.8±8.1 years and mean BMI of 32.0±6.7. The average of the three liver measures showed an improvement in the semaglutide group 1.4±9.0 versus worsening in the placebo group of 1.9±9.5 mean HU. The multivariable linear regression models including age, gender, BMI, hypertension, hyperlipidemia, past smoking and baseline liver attenuation, showed that the semaglutide group average liver attenuation measures improved by 4.4 HU versus placebo across the trial, p=0.002 indicating improvement in the liver fat content in treatment group. ConclusionIn type 2 diabetes patients with hepatic steatosis, treatment with semaglutide resulted in a significant improvement in fatty liver resolution compared to placebo.

1984. Effects of Semaglutide on Adipose Tissue in HIV-Associated Lipohypertrophy

Abstract Background Lipohypertrophy (central adipose tissue (AT) accumulation) is a common and significant problem in people with HIV (PWH). Pathogenesis remains elusive; yet, AT abnormalities are key drivers of cardiometabolic co-morbidities in HIV. We aimed to assess effects of semaglutide, a glucagon-like peptide-1 receptor agonist, on AT in PWH with lipohypertrophy. Methods We conducted a randomized, double-blinded, placebo-controlled trial of virologically-suppressed, non-diabetic PWH ≥ 18 years of age on stable antiretroviral therapy (ART) with body mass index (BMI) ≥ 25 kg/m2, increased waist circumference/waist-to-hip ratio, and subjective increased abdominal girth after ART initiation. Participants were randomized 1:1 to 32 weeks semaglutide (8-week titration + 24 weeks 1.0 mg weekly subcutaneous injection) or matching placebo. Computed tomography and whole-body dual-energy X-ray absorptiometry were used to measure area/density in abdominal AT [total (TAT), visceral (TAT), and subcutaneous (SAT)] and body composition [lean body mass (LBM), limb/trunk/total body fat (TBF)], resp. Semaglutide effects were estimated using generalized estimating equations or simultaneous quantile regressions on outcome variables. Results 108 participants were enrolled (N = 54 semaglutide: median age = 52 years, 70% male, 61% Black, 83% integrase inhibitor). Groups were well-matched at baseline. In unadjusted models, semaglutide group had greater reductions (P &amp;lt; 0.05) in BMI, homeostatic model of insulin resistance (HOMA-IR), trunk fat, TBF (at quantile ≥ 75th), TAT, and SAT with trends (P &amp;lt; 0.1) for limb fat and VAT (Fig 1/Table 1). Semaglutide effects remained significant for BMI, HOMA-IR, trunk fat, TAT, and VAT after adjusting for age, sex, CD4, and ART duration (Table 2); caloric intake was also significant at ≤ 50th quantile. No differences were seen in LBM, AT density, or VAT/TAT ratio. Semaglutide was well-tolerated; serious adverse events were rare. Conclusion Semaglutide significantly decreased central fat in PWH with lipohypertrophy, primarily driven by reductions in VAT. Semaglutide may offer an effective treatment to decrease visceral adiposity and reduce co-morbidity risk. Further investigation is needed to determine mechanisms by which reductions in visceral adiposity occur. Disclosures Grace A. McComsey, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support

FibroScan-aspartate aminotransferase (FAST) score for monitoring histological improvement in non-alcoholic steatohepatitis activity during semaglutide treatment: post-hoc analysis of a randomised, double-blind, placebo-controlled, phase 2b trial

Currently, assessment of candidate pharmacotherapies in patients with non-alcoholic steatohepatitis (NASH) involves invasive liver biopsy. Non-invasive scores, such as the FibroScan-aspartate aminotransferase (FAST) score, are used to identify candidates for therapy, but their ability to assess disease progression or treatment effect is unknown. We aimed to assess the association between FAST score and histological endpoints. We conducted a post-hoc analysis using data from a prior randomised, double-blind, placebo-controlled, phase 2b trial at 143 sites across 16 countries. Patients (aged 18-75 years) with biopsy-confirmed NASH, fibrosis stage 1-3, and a Non-alcoholic fatty liver disease Activity Score (NAS) ≥4 were enrolled between January 2017 and September 2018, and randomly assigned to receive once-daily subcutaneous semaglutide 0.1, 0.2, or 0.4mg or placebo for 72 weeks. A subgroup analysis of patients with FAST score and histological data in the pooled semaglutide treatment and placebo arms at baseline and week 72 was performed. The original trial is registered at ClinicalTrials.gov, NCT02970942. A total of 122 patients were included in this post-hoc analysis (93 received semaglutide and 29 received placebo). FAST score reduction was associated with achieving the primary endpoint of NASH resolution without worsening of fibrosis in the pooled semaglutide group (area under the receiver operating curve 0.69; 95%confidence interval [CI] 0.58, 0.81). Mean FAST score reduction from baseline to week 72 was greatest in patients who met the primary endpoint vs those who did not in both the semaglutide (-0.40 [95% CI -0.84, 0.04] vs-0.22 [95% CI -0.74, 0.30] points; p=0.002) and placebo groups (-0.25 [95% CI -0.72, 0.23] vs 0.00 [95% CI -0.50, 0.50] points; p=0.047). Similarly, mean reductions in FAST score at week 72 were greater in those with NAS improvement vs those without in the semaglutide and placebo groups (≥1 point,-0.36 [95% CI -0.82, 0.11] vs-0.08 [95% CI -0.53, 0.38] points [p<0.001] and-0.25 [95% CI -0.64, 0.14] vs-0.06 [95% CI -0.40, 0.53] points [p=0.001]; ≥2 points,-0.40 [95% CI -0.86, 0.06] vs-0.14 [95% CI -0.56, 0.28] points [p<0.001] and-0.29 [95% CI -0.67, 0.09] vs-0.05 [95% CI -0.40, 0.50] points; [p<0.001]). A FAST score reduction of more than 0.22 points after semaglutide treatment was associated with meeting the primary endpoint (sensitivity 78%; specificity 60%; positive likelihood ratio 1.26; negative likelihood ratio 0.25; odds ratio 4.93). The potential of the FAST score as a non-invasive monitoring tool to identify histological changes following treatment requires further evaluation and validation. Novo Nordisk A/S.

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

BackgroundSemaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.MethodsIn a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.ResultsA total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).ConclusionsIn patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.)

Abstract 16589: Predicting Cardiovascular Risk in Participants Treated With Tirzepatide in the SURPASS 1-5 Trials

Predicting atherosclerotic cardiovascular disease (ASCVD) risk considers factors that individually influence the likelihood of experiencing a major cardiovascular (CV) event. Tirzepatide (TZP) is a GIP and GLP-1 receptor agonist that improved risk factors such as lipid profile and systolic blood pressure across the Phase 3 SURPASS T2D program. We compared the effect of TZP versus the comparator on calculated ASCVD risk from baseline to endpoint in each of the 5 SURPASS (S) studies. We assessed the ASCVD risk in T2D participants without CVD history from S 1-5 studies using an American College of Cardiology/American Heart Association risk engine. The risk engine considers the factors: sex, age, race, total cholesterol, high density lipoprotein, systolic blood pressure, antihypertensive medication use, smoking and diabetes status. Risk scores and categories are summarized by treatment group. The baseline characteristics vary between studies (female sex ranges from 44.9% to 54.6%, mean age in years ranges from 53.6 to 64.3) but were similar among treatment groups within each study. The median baseline risk score across the TZP dose range were 6.5-11.5 for S-1, 9.3-10.8 for S-2, 12.4-15.4 for S-3, 22.9-26.0 for S-4, and 14.8-19.1 for S5. At the primary endpoint (40 or 52 Weeks), the ASCVD risk category for 10.9-21.4% of TZP-treated participants improved versus 2.9-12.7% for placebo/comparator (Table). Also, the risk category for 1.2-9.4% of TZP-treated participants worsened versus 6.3-14.9% for placebo/comparator. The median CV risk score was decreased in all TZP treatment groups while the median CV risk score was increased in the placebo/basal insulin groups. In SURPASS-2, the decreases in CV risk score were qualitatively greater in the TZP groups compared to the semaglutide group. TZP treatment lowers CV risk and significantly more participants shift to a lower CV risk category when compared to placebo, basal insulins, and semaglutide.

Comparison of clinical efficacy and safety of weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide in Japanese patients with type 2 diabetes: Randomized, parallel-group, multicentre, open-label trial (COMING study).

To compare the clinical usefulness of once-weekly glucagon-like peptide-1 receptor agonists dulaglutide and semaglutide at the doses approved for use in Japanese patients with type 2 diabetes. In total, 120 patients with glycated haemoglobin (HbA1c) ≥7% were randomly assigned to dulaglutide (n = 59) or semaglutide group (n = 61), and 107 participants (dulaglutide/semaglutide = 53/54) completed the 24-week trial. The primary endpoint was the difference of HbA1c level between the two groups at 24 weeks. HbA1c level at 24 weeks was significantly lower in the semaglutide group (7.9 ± 0.5%-6.7 ± 0.5%) compared with the dulaglutide group (8.1 ± 0.6%-7.4 ± 0.8%) (p < .0001). Reduction in body mass index and visceral fat area were also more significant in the semaglutide group (p < .05, respectively). The achievement rate of HbA1c <7% was higher in the semaglutide group (p < .0001). The parameters such as low-density lipoprotein cholesterol, alanine aminotransferase and γ-glutamyl transpeptidase were decreased in the semaglutide group. Surprisingly, only semaglutide group significantly improved the apolipoprotein B/A1 ratio, which is considered a useful myocardial infarction risk index. Using computed tomography, the liver to spleen ratio was significantly elevated only in the semaglutide group. In contrast, gastrointestinal symptoms were observed in 13.2% of dulaglutide and 46.3% of semaglutide group (p < .01). The Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms were also superior in the dulaglutide group. This prospective trial showed that semaglutide has more pronounced glucose- and body mass index-lowering effects and reduces liver fat percentage and visceral fat area and that dulaglutide has less gastrointestinal symptoms and superior Diabetes Treatment-Related Quality of Life scores related to pain and gastrointestinal symptoms.

GLP-1RA Liraglutide and Semaglutide Improves Obesity-Induced Muscle Atrophy via SIRT1 Pathway.

Obesity is related to the loss of skeletal muscle mass and function (sarcopenia). The co-existence of obesity and sarcopenia is called sarcopenic obesity (SO). Glucagon like peptide-1 receptor agonists (GLP-1RA) are widely used in the treatment of diabetes and obesity. However, the protective effects of GLP-1RA on skeletal muscle in obesity and SO are not clear. This study investigated the effects of GLP-1RA liraglutide and semaglutide on obesity-induced muscle atrophy and explored the underlying mechanisms. Thirty-six male C57BL/6J mice were randomly divided into two groups and fed a regular diet and a high-fat diet for 18 weeks, respectively. After establishing an obesity model, mice were further divided into six groups: control group, liraglutide (LIRA) group, semaglutide (SEMA) group, high-fat diet (HFD) group, HFD + LIRA group, HFD + SEMA group, and subcutaneous injection for 4 weeks. The body weight, muscle mass, muscle strength, glycolipid metabolism, muscle atrophy markers, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed. C2C12 myotube cells treated with palmitic acid (PA) were divided into four groups: control group, PA group, PA + LIRA group, PA + SEMA group. The changes in glucose uptake, myotube diameter, lipid droplet infiltration, markers of muscle atrophy, myogenic differentiation markers, GLUT4 and SIRT1 were analyzed, and the changes in related indicators were observed after the addition of SIRT1 inhibitor EX527. Liraglutide and semaglutide reduced HFD-induced body weight gain, excessive lipid accumulation and improved muscle atrophy. Liraglutide and semaglutide eliminated the increase of muscle atrophy markers in skeletal muscle and C2C12 myotubes. Liraglutide and semaglutide restored impaired glucose tolerance and insulin resistance. However, these beneficial effects were attenuated by inhibiting SIRT1 expression. Liraglutide and semaglutide protects skeletal muscle against obesity-induced muscle atrophy via the SIRT1 pathway.

Semaglutide and cancer: A systematic review and meta-analysis

BackgroundFrench national health care insurance system database has suggested 1–3 years use of glucagon like peptide-1 receptor agonists (GLP1RA) (exenatide, liraglutide and dulaglutide) may be linked with increased occurrence of thyroid cancer. Similar data on semaglutide is not-available. Hence, we undertook this systematic review to look at the safety of semaglutide focussing on different cancers. MethodsDatabases were searched for randomized controlled trials (RCTs) and real-world studies involving patients receiving semaglutide in the intervention-arm. Primary outcome was to evaluate the occurrence of pancreatic and thyroid cancers. Secondary outcomes were to the evaluate occurrence of any other malignancies or severe adverse-events. ResultsData from 37 RCTs and 19 real-world studies having 16,839 patients in placebo-control group, 16,550 patients in active-control group and 13,330 patients in real-world studies were analysed. Compared to placebo, occurrence of pancreatic cancer [OR 0.25 (95%CI: 0.03–2.24); P = 0.21], thyroid cancer [OR 2.04 (95%CI: 0.33–12.61); P = 0.44; I2 = 0%] and all neoplasms (benign, malignant and otherwise unspecified) [OR 0.95 (95%CI:0.62–1.45); P = 0.82; I2 = 0%] was similar in the semaglutide group. Compared to active controls, occurrence of pancreatic cancer [OR 0.40 (95%CI:0.09–1.87); P = 0.26; I2 = 0%], thyroid cancer [OR 1.19 (95%CI:0.15–9.66); P = 0.87; I2 = 0%] and all neoplasms (benign, malignant and otherwise unspecified) [OR 0.91 (95% CI: 0.44–1.89); P = 0.79; I2 = 0%] were similar in the semaglutide group. Real-world data analysis revealed single case each of pancreatic cancer and B-cell lymphoma. ConclusionSemaglutide use in RCTs and real-world studies was not associated with an increased risk of any types of cancer, and this conclusion is supported by a high grade of evidence.