Subcutaneous Semaglutide Research Articles

Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials

BackgroundExploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes.MethodsTrials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions.ResultsGeometric mean baseline hsCRP was similar across trials (range 2.7–3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70–0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67–1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6–61.8%) by change in HbA1c and BW.ConclusionsSemaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials.Trial registrations: ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).

P8.087: Semaglutide May Be Safe After Kidney Transplant

Background: The most common cause of end-stage renal disease (ESRD) is diabetes mellitus (DM). Kidney transplantation offers better outcomes for ESRD patients. Patients could develop post-transplant DM (PTDM). Management of DM after transplantation (whether the patient had it from before or after the transplant) is challenging. Different medications could be used to manage PTDM. Those medications have good safety and efficacy record in general population and patients with mild degrees of kidney disease. At the same time, weight gain is a major issue after kidney transplant. Methods: We conducted a retrospective single center analysis of safety and efficacy of Semaglutide after kidney transplantation. The study was approved by institutional review board. We collected data (demographics, laboratory tests and any symptoms or hospitalizations) for 28 patients for 12 months. Results: All 28 patients took subcutaneous Semaglutide at an average of 0.5 mg/week throughout the study period. Patients’ average age was 64. Thirteen were females and all from Middle Eastern decent and had kidney transplant on average of 29 months when they were included in the study. Eleven patients had DM before the transplant and the rest had PTDM. 15 patients were on metformin and 10 were on insulin while the rest were not on any other medications at the start of the study. Baseline average creatinine was 1.2 mg/dL (106.3 mmol/L) and glycated hemoglobin (HbA1c) of 8.4 g/dL at the start of the study while creatinine was 1.1 mg/dL (97.5 mmol/L) and HbA1c was 7.1 g/dL at the end. HbA1c dropped 1.2 on average within 6 weeks of starting Semaglutide and stayed around the same level for the rest of the study. Urine protein decreased significantly within 6 months and was maintained throughout the study. One patient developed unstable angina during the study and another one was hospitalized with acute pancreatitis. A third patient developed bacterial pneumonia. Ten patients had nausea and vomiting after starting Semaglutide but that resolved 2 weeks later with lowering the dose. No allergic reactions or hypoglycemia episodes were reported. The average weight dropped 3.1 kg throughout the study and body mass index changed from 28.9 to 27.3. Only one patient stopped the medication during the study (the one who had acute pancreatitis). Conclusion: In this retrospective analysis, Semaglutide seems to be safe and efficacious after kidney transplantation. It can be considered to manage DM after transplantation.

Cardiovascular effects of incretins: focus on glucagon-like peptide-1 receptor agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from European Association for the Study of Diabetes/American Diabetes Association, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or multiple cardiovascular risk factors. European Society of Cardiology suggests starting with a sodium-glucose cotransprter-2 inhibitor or a GLP-1 RA in drug naïve patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (CVD) or high CV Risk. However, the results from cardiovascular outcome trials (CVOT) are very heterogeneous suggesting that some GLP-1RAs are more suitable to prevent CVD than others. The CVOTs provide a basis upon which individual treatment decisions for patients with T2D and CVD can be made.

Hemoglobin A1c Reduction With the GLP-1 Receptor Agonist Semaglutide Is Independent of Baseline eGFR: post hoc Analysis of the SUSTAIN and PIONEER Programs

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective treatments for reducing hemoglobin A1c (HbA1c) in people with type 2 diabetes (T2D), including those with reduced kidney function. This post hoc analysis assessed the HbA1c-lowering efficacy of semaglutide, a GLP-1RA, in participants with a range of kidney functions in the SUSTAIN 4-6 and 10 (subcutaneous semaglutide) and PIONEER 5 and 6 (oral semaglutide) clinical trials. Trial-level changes from baseline to end of treatment (EOT) in HbA1c and body weight (BW) were assessed in participants with estimated glomerular filtration rate (eGFR) >15 ml/min per 1.73 m2 by subgroups categorized according to baseline eGFR. Adverse events were also evaluated. The analysis included 8859 participants. The mean comparator-adjusted reduction in HbA1c from baseline to EOT with semaglutide ranged from 0.6% to 1.6% points across trials, with similar reductions across the eGFR subgroups (interaction P-value≥ 0.33 for difference between eGFR subgroups within each trial). Greater weight loss from baseline to EOT with semaglutide versus comparator was observed across almost all baseline eGFR subgroups, with nominally greater weight loss with lower versus higher eGFR in SUSTAIN 6 and 10 and PIONEER 5 and 6 (interaction P< 0.05). No new safety concerns with semaglutide were identified. The HbA1c-lowering effect of semaglutide in participants with T2D was comparable irrespective of eGFR, which ranged upwards from eGFR >15 ml/min per 1.73 m2.

Real-life effects of adding weekly subcutaneous semaglutide to insulin for the treatment of type 2 diabetes mellitus

ObjectivesThis work aims to determine the real-life anthropometric and analytical benefits of adding subcutaneous semaglutide to previous insulin treatment in patients with type 2 diabetes. MethodsThis is a descriptive, retrospective, open-label study describing the clinical and anthropometric characteristics of 117 patients diagnosed with type 2 diabetes followed-up on in the Endocrinology and Nutrition outpatient clinic of the Hospital Universitario Central de Asturias for 53 weeks after starting treatment with subcutaneous semaglutide (October–December 2019). All patients were on previous insulin treatment with or without oral antidiabetics. ResultsOf the 117 initial patients, 17 did not complete the study due to adverse effects (nausea, vomiting), the physician’s decision, or loss to follow-up. Twelve months (week 53) after starting semaglutide, there was a decrease in HbA1c of 0.74% (95% CI 0.59–1.14, p < 0.05) as well as 3.61 kg of weight loss (95% CI 2.30–4.92, p < 0.05) and a decline in total insulin of 15.88 IU (95% CI 10.98–20.74, p < 0.05) from baseline figures. In patients without prior GLP-1 receptor analogs (GLP-1ra), the effect in terms of a reduction in HbA1c, weight, and the total insulin dose was statistically significant. However, in patients pre-treated with GLP-1ra only had improvements in terms of weight loss. No serious adverse events were observed. ConclusionsThe addition of subcutaneous semaglutide to prior insulin treatment with or without oral antidiabetics safely led to a decrease in HbA1c, weight, and the insulin dose. This effect is greater in GLP-1ra naive patients.

EE178 CEA of Once-Weekly Subcutaneous Semaglutide Versus Dulaglutide in Patients with Type 2 Diabetes with Inadequate Glycemic Control in China

The objective of the current study was to assess the long-term cost-effectiveness of once-weekly (OW) subcutaneous (s.c.) semaglutide 0.5mg and 1.0mg versus dulaglutide 1.5mg for the treatment of type 2 diabetes, based on the head-to-head SUSTAIN 7 trial, to inform healthcare decision making in China.

EE464 The Cost-Effectiveness of Subcutaneous Semaglutide 2.4MG Injection in the Management of Obesity in Canada Using the Core Obesity Model

The objective of this study was to assess the cost-effectiveness of semaglutide 2.4mg versus diet and exercise (D&E) in Canada using the Core Obesity Model (COM) and clinical outcomes from the STEP 1 and 2 studies, both of which demonstrated significantly greater weight loss with subcutaneous semaglutide 2.4mg injection versus D&E alone.

EE79 A Cost of Control Analysis of Once-Weekly Subcutaneous Semaglutide Versus Dulaglutide for Bringing Patients to Treatment Targets in China

In the SUSTAIN 7 randomized controlled trial, once-weekly subcutaneous semaglutide (OW) subcutaneous (s.c.) 0.5mg was associated with greater reduction in glycated hemoglobin (HbA1c) and body weight in people with type 2 diabetes mellitus (T2DM) comparing dulaglutide 1.5mg. The present study estimated the annual cost per patient achieving HbA1c treatment targets and weight loss responses with OW s.c. semaglutide and dulaglutide in the Chinese healthcare system setting over a one-year period.

CO94 Changes in Demographic and Clinical Characteristics of Patients with Type 2 Diabetes (T2DM) Initiating Subcutaneous Semaglutide

Characteristics of patients prescribed new medications often evolve over time after market launch. To explore this, our analysis described baseline demographic and clinical characteristics as well as antidiabetic medication use in T2DM patients initiating subcutaneous semaglutide over time from its introduction in the US in a commercially-insured/Medicare Advantage population.

Oral versus subcutaneous semaglutide for prevention of major adverse cardiovascular events: cost per outcome analysis of SUSTAIN-6 and PIONEER-6

ABSTRACT Background Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP1a), reduces the risk of major adverse cardiovascular events (MACE) in patients with Type 2 diabetes mellitus (T2DM). An oral version of semaglutide is now available, and patients may prefer it over the subcutaneous form. Our objective was to compare the value for money of the two modalities by assessing the cost needed to treat (CNT) to prevent MACE. Methods The CNT to prevent MACE was figured by multiplying the one-year number needed to treat (NNT) with either oral or subcutaneous semaglutide by the annual cost of therapy. Efficacy estimates and the resulting NNT figures were extracted from the published results of the SUSTAIN-6 and the PIONEER-6 trials for the injectable and oral versions of semaglutide, respectively. Drug costs were estimated as 75% of the United States national average drug acquisition cost listing in June 2021. We performed a scenario analysis to mitigate the primary differences between the populations in the two trials. Sensitivity analysis was performed to evaluate the effect of price changes of the interventions. Results The CNT to prevent one MACE with subcutaneous semaglutide in SUSTAIN-6 was $966,693 ($594,888-$5,035,302) compared to $948,689 ($463,465-∞) with oral semaglutide in PIONEER-6. The scenario analysis demonstrated a 17% lower CNT for oral semaglutide. The difference between CNTs was sensitive to price fluctuations of the two interventions. Conclusions Oral and subcutaneous semaglutide prescribed to prevent MACE in patients with T2DM provide similar value for money. The choice between both therapies should be guided mainly by patient preferences.

Efficacy of subcutaneous semaglutide compared to placebo for weight loss in obese, non-diabetic adults: a systematic review & meta-analysis.

Research on semaglutide's effect on weight loss has been largely focused on Type 2 Diabetics. No meta-analyses of semaglutide's efficacy in non-diabetic individuals have been conducted to date. Expanding the knowledge of semaglutide's outcome in non-diabetics may provide impactful changes at the clinical level. This systematic review and meta-analysis quantified the efficacy of subcutaneous semaglutide in treating obesity in non-diabetic adult patients compared to placebo. Academic Search Premier, Cumulative Index to Nursing and Allied Health Literature (CINAHL) complete, MEDLINE with Full Text, Cochrane Central Register of Controlled Trials, medrxiv.org, and clinicaltrials.gov were systematically investigated using a predetermined search strategy from inception to August 21, 2021. Covidence.org was used to screen, select, and extract data by two independent reviewers. Individual study bias was assessed using the Cochrane Risk of Bias 2 tool. Data were exported to RevMan v5.4, where meta-analysis was conducted using a DerSimonian and Laird random-effects model. The initial search identified 332 relevant articles and ultimately retained four randomized controlled trials encompassing 2,882 participants with a BMI ≥ 27kg/m2. Patients treated with semaglutide experienced a clinically significant reduction in mean body weight - 11.62kg (95% CI: -13.03 to -10.21; P < 0.00001). This systematic review and meta-analysis validates the clinical efficacy of semaglutide for the treatment of obesity in the adult, non-diabetic population.

Efectos en vida real de la adición de semaglutida subcutánea semanal al tratamiento con insulina en diabetes mellitus tipo 2

ObjectivesThis work aims to determine the real-life anthropometric and analytical benefits of adding subcutaneous semaglutide to previous insulin treatment in patients with type 2 diabetes. MethodsThis is a descriptive, retrospective, open-label study describing the clinical and anthropometric characteristics of 117 patients diagnosed with type 2 diabetes followed-up on in the Endocrinology and Nutrition outpatient clinic of the Hospital Universitario Central de Asturias for 53 weeks after starting treatment with subcutaneous semaglutide (October-December 2019). All patients were on previous insulin treatment with or without oral antidiabetics. ResultsOf the 117 initial patients, 17 did not complete the study due to adverse effects (nausea, vomiting), the physician's decision, or loss to follow-up.Twelve months (week 53) after starting semaglutide, there was a decrease in HbA1c of 0.74% (95% CI 0.59-1.14, p<0.05) as well as 3.61kg of weight loss (95% CI 2.30-4.92, p<0.05) and a decline in total insulin of 15.88 IU (95% CI 10.98-20.74, p<0.05) from baseline figures. In patients without prior GLP-1 receptor analogs (GLP-1ra), the effect in terms of a reduction in HbA1c, weight, and the total insulin dose was statistically significant. However, in patients pre-treated with GLP-1ra only had improvements in terms of weight loss. No serious adverse events were observed. ConclusionsThe addition of subcutaneous semaglutide to prior insulin treatment with or without oral antidiabetics safely led to a decrease in HbA1c, weight, and the insulin dose. This effect is greater in GLP-1ra naive patients.

Once-Weekly Semaglutide Induces an Early Improvement in Body Composition in Patients with Type 2 Diabetes: A 26-Week Prospective Real-Life Study.

Background: Body weight (BW) loss is an essential therapeutic goal in type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists are effective in reducing BW, but their effect on body composition has not yet been fully explored. The study aim was to assess the impact of Semaglutide on body composition in patients with T2D. Methods: Forty patients with T2D were treated with subcutaneous Semaglutide and evaluated at the baseline (T0) and after three (T3) and six (T6) months. Body composition was assessed by a phase-sensitive bioimpedance analyzer. Visceral adipose tissue (VAT) thickness was also measured with an ultrasonographic method (US-VAT). Anthropometric variables, muscular strength, and laboratory tests were analyzed and compared. Results: A significant decrease in VAT, the fat mass index (FMI), and BW loss was observed at all observation times. US-VAT, the skeletal mass index (SMI), the fat-free mass index (FFMI), waist circumferences, and glycated hemoglobin had lessened after three months and remained stable at T6. No variations in muscle strength, the muscle quality index, and body water were found. Discussion: In a real-life setting, Semaglutide provided significant weight loss mainly due to a reduction in the FMI and VAT, with non-clinically relevant changes in the SMI, the FFMI, and muscle strength. Most importantly, the results were obtained after three months of treatment and persisted thereafter.

89-LB: COVID-19 Outcomes in Patients Who Started GLP1-RAs during Hospitalization

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been hypothesized to exert beneficial effects on COVID-19 outcomes due to their anti-inflammatory properties. In our COVID-19 ward, patients admitted for severe interstitial bilateral pneumonia due to SARS-COV2 infection and having type 2 diabetes (T2D) or in-hospital hyperglycemia (IHH) were treated with GLP-1 RAs in addition to standard therapy according to usual care. Aim of the present study was to evaluate if GLP-1 RAs therapy was related with outcomes. A retrospective analysis was performed to assess if the GLP1-RAs were associated with a lower risk of a composite outcome (death or admission to intensive care unit) . During the COVID-19 pandemics, 135 patients were admitted (61.5% men, age 66.3±13.7 years, 49.6% with T2D and 50.4% with IHH) , of whom 23.1% initiated GLP1-RA during the hospitalization (39.1% of patients with T2D and 7.6% of patients with IHH) . Almost all patients were treated with once-weekly subcutaneous semaglutide, while dulaglutide was administered in 2 cases. Overall, 26.3% of patients not treated vs. 7.1% of patients treated with GLP1-RAs reached the composite outcome (p=0.03) . At multivariate analysis adjusted for age, gender, T2D, history of cardio/cerebrovascular disease, hypertension, pulmonary disease, and dementia, the use of GLP-1 RAs was associated with a reduced risk of composite outcome of 80% (OR 0.20; 95% confidence intervals 0.04-0.95) . Dementia resulted the only other independent correlate of the outcome. These preliminary results suggest that the addition of GLP1-RAs to standard care during hospitalization for SARS-CoV2 infection could play a role in improving clinical outcomes in patients with COVID-19 and T2D or IHH: at the best of our knowledge this is the first study showing such an effect when GLP1-RAs were started during hospitalization. Disclosure V. Provenzano: Board Member; Lilly Diabetes, Novo Nordisk, Consultant; AstraZeneca. D. Brancato: None. M. Fleres: None. F. Provenzano: None. A. R. Salvaggio: None. A. Scorsone: None.

752-P: Study Design and Baseline Profile for Patients with Type 2 Diabetes in the Semaglutide Once-Weekly Randomized Pragmatic Trial (SEPRA)

SEPRA (NCT03596450) is a 2-yr, multicenter, open-label, randomized pragmatic clinical trial comparing the long-term effects of once-weekly subcutaneous semaglutide vs. standard of care (both added to ≤2 oral antidiabetic medications) in US health-insured adults with T2D and physician-determined inadequate glycemic control. SEPRA will assess glycemic control, weight loss, healthcare utilization, and patient-reported outcomes by collecting individual-level data from routine clinical practice and health insurance claims. The primary endpoint is the proportion of patients achieving HbA1c &amp;lt;7.0% at yr 1. The study design was evaluated using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS) -2 assessment; it scored 4-5 in all 9 domains, suggesting a highly pragmatic study. Of 1,278 patients enrolled, 54% were male with mean (± SD) age 57.4 ± 11.1 yrs, BMI 35.7± 8.0 kg/m2, diabetes duration 7.4 ± 6.0 yrs, HbA1c 8.48 ± 1.6%, and mean individualized HbA1c target 6.66 ± 0.5%. Of note, 86.9% of patients had HbA1c &amp;gt;7.0% and most required sizeable reductions in HbA1c to reach the clinician-assigned individualized target. SEPRA will provide real-world evidence on the long-term effectiveness of semaglutide in a population with a broad range of HbA1c levels and other clinical characteristics when used as intensification early on in usual T2D care practice settings. Disclosure V.Willey: Employee; HealthCore Inc. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. B.Harty: None. J.L.Mitchell: None. B.P.Soule: Employee; Bristol-Myers Squibb Company, Novo Nordisk. H.N.Christensen: Employee; Novo Nordisk. M.J.Cziraky: None. S.Skibsted: Employee; Novo Nordisk. Funding Funded by Novo Nordisk Inc

Glucagon-Like Peptide 1 Receptor Agonists: A Medication for Obesity Management.

The burden of obesity worldwide is high and projected to rise. Obesity increases the risk of several cardiovascular diseases and cardiometabolic risk factors; hence, utilizing effective long-term therapies for obesity is of utmost importance. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as effective therapies that achieve substantial weight loss and improve cardiometabolic risk. The purpose of this review is to discuss the role of GLP-1RAs in obesity management. Two subcutaneous GLP-1RAs, liraglutide and semaglutide, have been evaluated in several clinical trials for weight loss. Liraglutide achieves a mean weight loss of 4-7kg, and more than 50% of treated individuals achieve 5% or more weight loss. Semaglutide has a greater impact on weight loss, with a mean weight loss of 9-16kg, and more than 50% of treated individuals achieve 10-15% or more weight loss. These results led to regulatory approval of these agents for weight loss in individuals with obesity, regardless of diabetes status. In addition to weight loss, the benefits of GLP-1RAs extend to other risk factors, such as glycemic control and blood pressure. Gastrointestinal symptoms are the most frequently encountered adverse events with incidences between 5 and 30%. Finally, the cost remains one of the most critical challenges that limit GLP-1RAs use. GLP-1RAs have robust weight loss benefits and are expected to have a critical role in the management of obesity in the coming years. Upcoming studies will evaluate the durability of weight loss achieved with GLP-1RAs and the impact on cardiovascular outcomes.

Semaglutide for the treatment of type 2 Diabetes Mellitus: A systematic review and network meta-analysis of safety and efficacy outcomes

Background and aimsTo assess the safety and efficacy of semaglutide compared with placebo and other anti-hyperglycaemic agents in type 2 diabetes (T2DM). MethodsWe searched PubMed, Scopus, Web of Science, and Cochrane library for relevant randomized controlled trials (RCTs). A network meta-analysis was conducted to compare different doses, durations, and interventions in T2DM. We presented results as mean difference (MD) or relative risk (RR) and 95% confidence interval (CI). ResultsTwenty-six included RCTs studied different doses of subcutaneous (SC) and oral semaglutide, tirzepatide, liraglutide, sitagliptin, canagliflozin, and empagliflozin compared with placebo. Tirzepatide showed the highest efficacy, however, it was comparable to semaglutide. SC semaglutide 1 mg once-weekly showed higher reduction in HbA1c (MD = −1.72, 95% CI [-2.32; −1.12]), and fasting blood glucose (MD = −1.93, 95% CI [-2.81; −1.04]) versus placebo at 30 weeks and other timepoints. Adverse events (ADs) were comparable to placebo with oral and SC semaglutide, oral sitagliptin, SC liraglutide, and oral empagliflozin at most timepoints. However, SC semaglutide 0.8 mg and tirzepatide 10 mg groups had the highest gastrointestinal adverse events. ConclusionTirzepatide, oral and SC semaglutide has a favourable efficacy in treating T2DM. The adverse events were comparable to placebo; however, gastrointestinal adverse events were highly recorded in tirzepatide, oral and SC semaglutide groups.

Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension.

AimTo explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension.Materials and MethodsSTEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight‐related co‐morbidity) without diabetes to 68 weeks of once‐weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off‐treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory.ResultsExtension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables.ConclusionsOne year after withdrawal of once‐weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two‐thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.

Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6

Background:GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.Methods:SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke.Results:A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46–1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29–0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37–0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47–1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (Pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (Pinteraction >0.05 for all).Conclusions:Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01720446 and NCT02692716.

FC 124: Real-World Use of Once-Weekly Semaglutide by Baseline Estimated Glomerular Filtration Rate—A Post-Hoc Analysis of Pooled Data From the Sure Studies (Canada, Denmark/Sweden, Switzerland and UK)

Abstract BACKGROUND AND AIMS The SURE programme of observational real-world studies is investigating once-weekly (OW) subcutaneous semaglutide in routine clinical practice across a diverse type 2 diabetes (T2D) patient population, including those with chronic kidney disease. This pooled post-hoc analysis of SURE Canada, Denmark/Sweden, Switzerland and UK evaluated OW semaglutide use and outcomes according to kidney function at semaglutide initiation. METHOD The SURE studies (all ∼30 weeks’ duration) enrolled adults (≥18 years) with T2D who received OW semaglutide and other anti-hyperglycaemic drugs prescribed at physician discretion; pooled data were analysed to determine change from baseline to end of study (EOS) in HbA1c and body weight (BW) by estimated glomerular function rate (eGFR) subgroups (&amp;lt;30, 30 to &amp;lt;45, 45 to &amp;lt;60, 60 to &amp;lt;90, and ≥90 mL/min/1.73 m2). Safety outcomes were assessed; only serious adverse drug reactions (SADRs) were systematically recorded. RESULTS Data from 913 patients with median (interquartile range) age of 61 (54–68) years and T2D duration of 11.0 (6.2–17.2) years were included. Patients with eGFR &amp;lt;45 mL/min/1.73 m2 were more likely to be older with longer T2D duration than those with eGFR ≥45 mL/min/1.73 m2. Patients with low eGFR were more likely to be receiving insulin at baseline than those in higher eGFR subgroups. At EOS, there were significant reductions in HbA1c and BW in all subgroups with eGFR ≥30 mL/min/1.73 m2 (P &amp;lt;0.0001; Figure 1). The rates of SADRs and adverse events leading to treatment discontinuation were low across all eGFR subgroups (≤0.3% and ≤1.8%, respectively). Overall, 50/72 patients who experienced more than or equal to severe or documented hypoglycaemic episode were receiving insulin at baseline. CONCLUSION OW semaglutide provided clinically relevant glycaemic control and BW improvements, and was well tolerated, in patients with varying degrees of kidney impairment at treatment initiation in a real-world setting. These findings support semaglutide use in routine clinical practice regardless of patients’ kidney function.