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Ildiko Lingvay - One of the best experts on this subject based on the ideXlab platform.

  • effect of continued weekly subcutaneous Semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity the step 4 randomized clinical trial
    JAMA, 2021
    Co-Authors: Domenica Rubino, Ildiko Lingvay, Melanie J Davies, Ofri Mosenzon, Niclas Abrahamsson, Dan Hesse, Frank L Greenway, Camilla B Jensen, Julio Rosenstock
    Abstract:

    Importance The effect of continuing vs withdrawing treatment with Semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. Objective To compare continued once-weekly treatment with subcutaneous Semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous Semaglutide titrated to 2.4 mg weekly. Design, setting, and participants Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. Interventions A total of 902 participants received once-weekly subcutaneous Semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk Semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous Semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. Main outcomes and measures The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). Results Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued Semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P Conclusions and relevance Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous Semaglutide, 2.4 mg once weekly, maintaining treatment with Semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. Trial registration ClinicalTrials.gov Identifier: NCT03548987.

  • impact of patient characteristics on efficacy and safety of once weekly Semaglutide versus dulaglutide sustain 7 post hoc analyses
    BMJ Open, 2020
    Co-Authors: Richard E Pratley, Emre Yildirim, Ildiko Lingvay, Vanita R Aroda, Jorg Ludemann, Andreimircea Catarig, Adie Viljoen
    Abstract:

    OBJECTIVE In SUSTAIN 7, once-weekly Semaglutide demonstrated superior glycated haemoglobin (HbA1c) and body weight (BW) reductions versus once-weekly dulaglutide in subjects with type 2 diabetes (T2D). This post hoc analysis investigated the impact of clinically relevant subject characteristics on treatment effects of Semaglutide versus dulaglutide. DESIGN Analyses by baseline age ( 5-10, >10 years), HbA1c (≤7.5, >7.5-8.5, >8.5% (≤58, >58-69, >69 mmol/mol)) and body mass index (BMI) (<30, 30-<35, ≥35 kg/m2). SETTING 194 sites; 16 countries. PARTICIPANTS Subjects with T2D (n=1199) exposed to treatment. INTERVENTIONS Semaglutide 0.5 mg versus dulaglutide 0.75 mg (low-dose comparison); Semaglutide 1.0 mg versus dulaglutide 1.5 mg (high-dose comparison), all subcutaneously once weekly. PRIMARY AND SECONDARY OUTCOME MEASURES Change in HbA1c (primary endpoint) and BW (confirmatory secondary endpoint) from baseline to week 40; proportion of subjects achieving HbA1c targets (<7%, ≤6.5% (<53, ≤48 mmol/mol)) and weight-loss responses (≥5%, ≥10%) at week 40; and safety. RESULTS HbA1c and BW reductions (estimated treatment difference ranges: -0.22 to -0.70%-point; -1.76 to -3.84 kg) and proportion of subjects achieving HbA1c targets and weight-loss responses were statistically significantly greater for the majority of comparisons of Semaglutide versus dulaglutide within each subgroup category and, excepting glycaemic control within the low-dose comparison in HbA1c subgroups, this was irrespective of subgroup or dose comparison. Gastrointestinal adverse events, the most common with both treatments, were reported by more women than men and, with Semaglutide, decreased with increasing BMI. CONCLUSIONS Consistently greater improvements in HbA1c and BW with Semaglutide versus dulaglutide, regardless of age, sex, diabetes duration, glycaemic control and BMI, support the efficacy of Semaglutide across the continuum of care in a heterogeneous population with T2D. TRIAL REGISTRATION NUMBER NCT02648204.

  • Effects of Semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials.
    Cardiovascular diabetology, 2020
    Co-Authors: Mansoor Husain, Anders Gaarsdal Holst, Stephen C. Bain, Thomas Mark, Søren Rasmussen, Ildiko Lingvay
    Abstract:

    Semaglutide is a glucagon-like peptide-1 (GLP-1) analog treatment for type 2 diabetes (T2D) available in subcutaneous (s.c.) and oral formulations. Two cardiovascular (CV) outcomes trials showed that in subjects with T2D at high risk of CV events there were fewer major adverse CV events (MACE; defined as CV death, non-fatal stroke, non-fatal myocardial infarction) with Semaglutide than with placebo (hazard ratio [95% CI]: 0.74 [0.58;0.95] for once-weekly s.c. Semaglutide and 0.79 [0.57;1.11] for once-daily oral Semaglutide). However, there is little evidence for an effect of Semaglutide on MACE in subjects not at high risk of CV events. This post hoc analysis examined CV effects of Semaglutide in subjects across a continuum of baseline CV risk. Data from the s.c. (SUSTAIN) and oral (PIONEER) Semaglutide phase 3a clinical trial programs were combined according to randomized treatment (Semaglutide or comparators) and analyzed to assess time to first MACE and its individual components. A CV risk model was developed with independent data from the LEADER trial (liraglutide vs placebo), considering baseline variables common to all datasets. Semaglutide data were analyzed to assess effects of treatment as a function of CV risk predicted using the CV risk prediction model. The CV risk prediction model performed satisfactorily when applied to the Semaglutide data set (area under the curve: 0.77). There was a reduced relative and absolute risk of MACE for Semaglutide vs comparators across the entire continuum of CV risk. While the relative risk reduction tended to be largest with low CV risk score, the largest absolute risk reduction was for intermediate to high CV risk score. Similar results were seen for relative risk reduction of the individual MACE components and also when only placebo comparator data were included. Semaglutide reduced the risk of MACE vs comparators across the continuum of baseline CV risk in a broad T2D population. Trial registrations ClinicalTrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208, NCT02128932, NCT02305381, NCT01720446, NCT02207374, NCT02254291, NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02692716, NCT02849080, NCT03021187, NCT03018028, NCT03015220.

  • Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk
    Diabetes obesity & metabolism, 2020
    Co-Authors: Mansoor Husain, Ildiko Lingvay, Stephen C. Bain, Ole K. Jeppesen, Rasmus Sørrig, Marianne Bach Treppendahl, Tina Vilsbøll
    Abstract:

    Aim To investigate the effects of Semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous Semaglutide) and PIONEER (oral Semaglutide) trials across subgroups of varying CV risk. Methods Post hoc analyses of individual patient-level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. Results In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of Semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were 0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of Semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). Conclusions In SUSTAIN and PIONEER combined, glucagon-like peptide-1 analogue Semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of Semaglutide on MACE was observed in subjects with prior HF.

  • oral Semaglutide versus empagliflozin in patients with type 2 diabetes uncontrolled on metformin the pioneer 2 trial
    Diabetes Care, 2019
    Co-Authors: Helena W. Rodbard, Julio Rosenstock, Ildiko Lingvay, Marianne Bach Treppendahl, Luis Henrique Santos Canani, Chaicharn Deerochanawong, Janusz Gumprecht, Soren Lindberg, Anette Luther Sondergaard, Eduard Montanya
    Abstract:

    OBJECTIVE Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral Semaglutide and the sodium–glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS Patients were randomized to once-daily open-label treatment with oral Semaglutide 14 mg (n = 412) or empagliflozin 25 mg (n = 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS Four-hundred (97.1%) patients in the oral Semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral Semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy –1.3 vs. –0.9% [–14 vs. –9 mmol/mol], estimated treatment difference [ETD] –0.4% [95% CI –0.6, –0.3%] [–5 mmol/mol (–6, –3 mmol/mol)]; P CONCLUSIONS Oral Semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral Semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.

Tine A Baekdal - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Oral Semaglutide on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women and Furosemide and Rosuvastatin in Healthy Subjects.
    Clinical pharmacokinetics, 2021
    Co-Authors: Andreas B Jordy, Astrid Breitschaft, Thomas W. Anderson, Erik Christiansen, Muna Albayaty, Azadeh Houshmand-Øregaard, Easwaran Manigandan, Tine A Baekdal
    Abstract:

    The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises Semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral Semaglutide may alter the pharmacokinetics of co-administered drugs via effects of Semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral Semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin. Healthy, postmenopausal women (n = 25) received once-daily combined ethinylestradiol and levonorgestrel (Trial 1) and healthy male and female subjects (n = 41) received single doses of furosemide and rosuvastatin (Trial 2), either alone, with SNAC alone or with oral Semaglutide. Lack of drug-drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration-time curve (AUC) or maximum concentration (Cmax), with/without oral Semaglutide, were within a pre-specified interval (0.80-1.25). The AUC values of ethinylestradiol and levonorgestrel were not affected by oral Semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01-1.10] and 1.06 [0.97-1.17], respectively); Cmax was not affected. The no-effect criterion was not met for furosemide or rosuvastatin for the AUC (1.28 [1.16-1.42] and 1.41 [1.24-1.60], respectively) or Cmax. SNAC alone did not affect the AUC or Cmax of ethinylestradiol, levonorgestrel or rosuvastatin; the Cmax of furosemide was slightly decreased. Adverse events were similar to those previously observed for GLP-1RAs (both trials). Co-administration with oral Semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance. NCT02845219 and NCT03010475.

  • Effect of Oral Semaglutide on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women and Furosemide and Rosuvastatin in Healthy Subjects
    Clinical Pharmacokinetics, 2021
    Co-Authors: Andreas B Jordy, Astrid Breitschaft, Thomas W. Anderson, Erik Christiansen, Muna Albayaty, Azadeh Houshmand-Øregaard, Easwaran Manigandan, Tine A Baekdal
    Abstract:

    Background The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises Semaglutide co-formulated with the absorption enhancer, sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral Semaglutide may alter the pharmacokinetics of co-administered drugs via effects of Semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral Semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin. Methods Healthy, postmenopausal women ( n  = 25) received once-daily combined ethinylestradiol and levonorgestrel (Trial 1) and healthy male and female subjects ( n  = 41) received single doses of furosemide and rosuvastatin (Trial 2), either alone, with SNAC alone or with oral Semaglutide. Lack of drug–drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration–time curve (AUC) or maximum concentration ( C _max), with/without oral Semaglutide, were within a pre-specified interval (0.80–1.25). Results The AUC values of ethinylestradiol and levonorgestrel were not affected by oral Semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01–1.10] and 1.06 [0.97–1.17], respectively); C _max was not affected. The no-effect criterion was not met for furosemide or rosuvastatin for the AUC (1.28 [1.16–1.42] and 1.41 [1.24–1.60], respectively) or C _max. SNAC alone did not affect the AUC or C _max of ethinylestradiol, levonorgestrel or rosuvastatin; the C _max of furosemide was slightly decreased. Adverse events were similar to those previously observed for GLP-1RAs (both trials). Conclusion Co-administration with oral Semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance. Clinical Trial Registration Numbers NCT02845219 and NCT03010475.

  • Relationship Between Oral Semaglutide Tablet Erosion and Pharmacokinetics: A Pharmacoscintigraphic Study.
    Clinical pharmacology in drug development, 2021
    Co-Authors: Tine A Baekdal, Morten Donsmark, Flemming L. Søndergaard, Marie-louise Hartoft-nielsen, Alyson Connor
    Abstract:

    Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral Semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single-center (Quotient Sciences, UK), open-label, 2-period crossover trial, 26 healthy men received single doses of 10 mg oral Semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96-2.37; P = .072). Area under the Semaglutide concentration-time curve from 0 to 24 hours (AUC0-24h,Semaglutide ) and maximum Semaglutide concentration (Cmax,Semaglutide ) were ∼70% higher with 50 versus 240 mL water (P = .056 and P = .048, respectively). Median time to maximum Semaglutide concentration (tmax,Semaglutide ) was 1.5 hours independent of water volume with dosing. Higher AUC0-24h,Semaglutide and Cmax,Semaglutide and longer tmax,Semaglutide were significantly correlated with longer time to CTE and later gastric emptying of tablet and water (all P < .05). The safety profile was as expected for the GLP-1 receptor agonist drug class. In conclusion, the oral Semaglutide tablet erodes in the stomach irrespective of water volume with dosing. Slower tablet erosion in the stomach results in higher Semaglutide plasma exposure.

  • effects of oral Semaglutide on energy intake food preference appetite control of eating and body weight in subjects with type 2 diabetes
    Diabetes Obesity and Metabolism, 2021
    Co-Authors: Catherine Gibbons, John E. Blundell, Kirsten Dahl, Soren Tetens Hoff, Robert Bauer, Tine A Baekdal
    Abstract:

    Aim To evaluate the effect of oral Semaglutide on energy intake and appetite in subjects with type 2 diabetes (T2D). Materials and methods In this randomized, double-blind, placebo-controlled, two-period cross-over trial, 15 subjects with T2D received 12 weeks of treatment with once-daily oral Semaglutide (4-week dose escalation from 3 to 7 to 14 mg) followed by placebo, or vice versa. Energy intake was measured during an ad libitum lunch, evening meal and snack box after a standard breakfast. Appetite ratings were measured using a visual analogue scale after standard and fat-rich breakfasts. Other assessments included eating and craving control (using the Control of Eating Questionnaire), and changes in body weight and composition. Results Following a standard breakfast, total daily ad libitum energy intake was significantly lower (38.9%) with oral Semaglutide versus placebo in 13 evaluable subjects (estimated treatment difference, -5096.0 kJ; 95% CI -7000.0, -3192.1; P = .0001). After a fat-rich breakfast, there were significant differences in favour of oral Semaglutide versus placebo for measures of satiety, hunger and for overall appetite score, with no significant differences following a standard breakfast. Fewer food cravings and better eating control were seen with oral Semaglutide versus placebo. Overall, mean body weight decreased by 2.7 kg with oral Semaglutide and 0.1 kg with placebo, mostly attributable to body fat mass loss. Conclusion After 12 weeks of treatment, ad libitum energy intake was lower with oral Semaglutide versus placebo, resulting in reduced body fat mass, and was associated with increased satiety and fullness after a fat-rich breakfast, and improved eating control. Trial registration number NCT02773381.

  • Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects
    Clinical Pharmacokinetics, 2019
    Co-Authors: Tine A Baekdal, Mette Thomsen, Cilie W. Hansen, Jeanett Borregaard, Thomas W. Anderson
    Abstract:

    Background Oral Semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog Semaglutide with the absorption enhancer sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by Semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral Semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. Methods In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral Semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral Semaglutide, as in trial 1. Results There were no apparent effects of oral Semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration ( C _max) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral Semaglutide coadministration versus metformin alone, whereas the C _max was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. Conclusions Oral Semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral Semaglutide was not considered clinically relevant.

Thomas W. Anderson - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Oral Semaglutide on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women and Furosemide and Rosuvastatin in Healthy Subjects
    Clinical Pharmacokinetics, 2021
    Co-Authors: Andreas B Jordy, Astrid Breitschaft, Thomas W. Anderson, Erik Christiansen, Muna Albayaty, Azadeh Houshmand-Øregaard, Easwaran Manigandan, Tine A Baekdal
    Abstract:

    Background The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises Semaglutide co-formulated with the absorption enhancer, sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral Semaglutide may alter the pharmacokinetics of co-administered drugs via effects of Semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral Semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin. Methods Healthy, postmenopausal women ( n  = 25) received once-daily combined ethinylestradiol and levonorgestrel (Trial 1) and healthy male and female subjects ( n  = 41) received single doses of furosemide and rosuvastatin (Trial 2), either alone, with SNAC alone or with oral Semaglutide. Lack of drug–drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration–time curve (AUC) or maximum concentration ( C _max), with/without oral Semaglutide, were within a pre-specified interval (0.80–1.25). Results The AUC values of ethinylestradiol and levonorgestrel were not affected by oral Semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01–1.10] and 1.06 [0.97–1.17], respectively); C _max was not affected. The no-effect criterion was not met for furosemide or rosuvastatin for the AUC (1.28 [1.16–1.42] and 1.41 [1.24–1.60], respectively) or C _max. SNAC alone did not affect the AUC or C _max of ethinylestradiol, levonorgestrel or rosuvastatin; the C _max of furosemide was slightly decreased. Adverse events were similar to those previously observed for GLP-1RAs (both trials). Conclusion Co-administration with oral Semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance. Clinical Trial Registration Numbers NCT02845219 and NCT03010475.

  • Effect of Oral Semaglutide on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women and Furosemide and Rosuvastatin in Healthy Subjects.
    Clinical pharmacokinetics, 2021
    Co-Authors: Andreas B Jordy, Astrid Breitschaft, Thomas W. Anderson, Erik Christiansen, Muna Albayaty, Azadeh Houshmand-Øregaard, Easwaran Manigandan, Tine A Baekdal
    Abstract:

    The first oral glucagon-like peptide-1 receptor agonist (GLP-1RA) comprises Semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Oral Semaglutide may alter the pharmacokinetics of co-administered drugs via effects of Semaglutide or SNAC. Two separate one-sequence crossover trials investigated the effects of oral Semaglutide and SNAC on the pharmacokinetics of ethinylestradiol, levonorgestrel, furosemide and rosuvastatin. Healthy, postmenopausal women (n = 25) received once-daily combined ethinylestradiol and levonorgestrel (Trial 1) and healthy male and female subjects (n = 41) received single doses of furosemide and rosuvastatin (Trial 2), either alone, with SNAC alone or with oral Semaglutide. Lack of drug-drug interaction was concluded if 90% confidence intervals (CIs) for the ratio of area under the plasma concentration-time curve (AUC) or maximum concentration (Cmax), with/without oral Semaglutide, were within a pre-specified interval (0.80-1.25). The AUC values of ethinylestradiol and levonorgestrel were not affected by oral Semaglutide co-administration (estimated ratios [90% CI] 1.06 [1.01-1.10] and 1.06 [0.97-1.17], respectively); Cmax was not affected. The no-effect criterion was not met for furosemide or rosuvastatin for the AUC (1.28 [1.16-1.42] and 1.41 [1.24-1.60], respectively) or Cmax. SNAC alone did not affect the AUC or Cmax of ethinylestradiol, levonorgestrel or rosuvastatin; the Cmax of furosemide was slightly decreased. Adverse events were similar to those previously observed for GLP-1RAs (both trials). Co-administration with oral Semaglutide did not affect the pharmacokinetics of ethinylestradiol or levonorgestrel. There was a small increase in exposure of furosemide and rosuvastatin; however, these increases are not expected to be of clinical relevance. NCT02845219 and NCT03010475.

  • Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects
    Clinical Pharmacokinetics, 2019
    Co-Authors: Tine A Baekdal, Mette Thomsen, Cilie W. Hansen, Jeanett Borregaard, Thomas W. Anderson
    Abstract:

    Background Oral Semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog Semaglutide with the absorption enhancer sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by Semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral Semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. Methods In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral Semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral Semaglutide, as in trial 1. Results There were no apparent effects of oral Semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration ( C _max) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral Semaglutide coadministration versus metformin alone, whereas the C _max was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. Conclusions Oral Semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral Semaglutide was not considered clinically relevant.

  • Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects
    Clinical pharmacokinetics, 2019
    Co-Authors: Tine A Baekdal, Mette Thomsen, Cilie W. Hansen, Jeanett Borregaard, Thomas W. Anderson
    Abstract:

    Oral Semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog Semaglutide with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by Semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral Semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral Semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral Semaglutide, as in trial 1. There were no apparent effects of oral Semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral Semaglutide coadministration versus metformin alone, whereas the Cmax was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. Oral Semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral Semaglutide was not considered clinically relevant.

  • Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment.
    Journal of clinical pharmacology, 2018
    Co-Authors: Tine A Baekdal, Mette Thomsen, Cilie W. Hansen, Viera Kupčová, Thomas W. Anderson
    Abstract:

    Semaglutide is a human glucagon-like peptide-1 analog that has been co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral Semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child-Pugh criteria, and received once-daily oral Semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post-last dose. Area under the Semaglutide plasma concentration-time curve from 0-24 hours after the 10th dose (primary end point) and maximum Semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum Semaglutide concentration (median range 1.0-1.5 hours) or half-life (geometric mean range 142-156 hours). No safety concerns were identified in subjects with hepatic impairment receiving Semaglutide. Reported adverse events were in line with those observed for other glucagon-like peptide-1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral Semaglutide. The results of this trial suggest that dose adjustment of oral Semaglutide is not warranted in subjects with hepatic impairment.

Adie Viljoen - One of the best experts on this subject based on the ideXlab platform.

  • Semaglutide 2 4 mg once a week in adults with overweight or obesity and type 2 diabetes step 2 a randomised double blind double dummy placebo controlled phase 3 trial
    The Lancet, 2021
    Co-Authors: Melanie J Davies, Adie Viljoen, Julio Rosenstock, Ole K. Jeppesen, Louise Faerch, Arash Pakseresht, Sue D Pedersen, Leigh Perreault, Iichiro Shimomura, Thomas A Wadden
    Abstract:

    Summary Background This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous Semaglutide 2·4 mg versus Semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes. Methods This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7–10% (53–86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of Semaglutide 2·4 mg, or Semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for Semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , NCT03552757 and is closed to new participants. Findings From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to Semaglutide 2·4 mg (n=404), Semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was −9·6% (SE 0·4) with Semaglutide 2·4 mg vs −3·4% (0·4) with placebo. Estimated treatment difference for Semaglutide 2·4 mg versus placebo was −6·2 percentage points (95% CI −7·3 to −5·2; p Interpretation In adults with overweight or obesity, and type 2 diabetes, Semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo. Funding Novo Nordisk.

  • impact of patient characteristics on efficacy and safety of once weekly Semaglutide versus dulaglutide sustain 7 post hoc analyses
    BMJ Open, 2020
    Co-Authors: Richard E Pratley, Emre Yildirim, Ildiko Lingvay, Vanita R Aroda, Jorg Ludemann, Andreimircea Catarig, Adie Viljoen
    Abstract:

    OBJECTIVE In SUSTAIN 7, once-weekly Semaglutide demonstrated superior glycated haemoglobin (HbA1c) and body weight (BW) reductions versus once-weekly dulaglutide in subjects with type 2 diabetes (T2D). This post hoc analysis investigated the impact of clinically relevant subject characteristics on treatment effects of Semaglutide versus dulaglutide. DESIGN Analyses by baseline age ( 5-10, >10 years), HbA1c (≤7.5, >7.5-8.5, >8.5% (≤58, >58-69, >69 mmol/mol)) and body mass index (BMI) (<30, 30-<35, ≥35 kg/m2). SETTING 194 sites; 16 countries. PARTICIPANTS Subjects with T2D (n=1199) exposed to treatment. INTERVENTIONS Semaglutide 0.5 mg versus dulaglutide 0.75 mg (low-dose comparison); Semaglutide 1.0 mg versus dulaglutide 1.5 mg (high-dose comparison), all subcutaneously once weekly. PRIMARY AND SECONDARY OUTCOME MEASURES Change in HbA1c (primary endpoint) and BW (confirmatory secondary endpoint) from baseline to week 40; proportion of subjects achieving HbA1c targets (<7%, ≤6.5% (<53, ≤48 mmol/mol)) and weight-loss responses (≥5%, ≥10%) at week 40; and safety. RESULTS HbA1c and BW reductions (estimated treatment difference ranges: -0.22 to -0.70%-point; -1.76 to -3.84 kg) and proportion of subjects achieving HbA1c targets and weight-loss responses were statistically significantly greater for the majority of comparisons of Semaglutide versus dulaglutide within each subgroup category and, excepting glycaemic control within the low-dose comparison in HbA1c subgroups, this was irrespective of subgroup or dose comparison. Gastrointestinal adverse events, the most common with both treatments, were reported by more women than men and, with Semaglutide, decreased with increasing BMI. CONCLUSIONS Consistently greater improvements in HbA1c and BW with Semaglutide versus dulaglutide, regardless of age, sex, diabetes duration, glycaemic control and BMI, support the efficacy of Semaglutide across the continuum of care in a heterogeneous population with T2D. TRIAL REGISTRATION NUMBER NCT02648204.

  • 998-P: Efficacy and Safety of Semaglutide by Baseline BMI in SUSTAIN 1-5 and 7
    Diabetes, 2019
    Co-Authors: Adie Viljoen, Oluf K H Hansen, Nelun Wijayasinghe, Juan P. Frias, Theis Gondolf, Jeff Unger
    Abstract:

    Semaglutide, a once-weekly glucagon-like peptide-1 analog for type 2 diabetes, showed significant, clinically meaningful reductions in HbA 1c and body weight in the SUSTAIN clinical trial program. Higher body mass index (BMI) at baseline (BL) was associated with greater weight loss during Semaglutide therapy. This post hoc analysis evaluated change in HbA 1c by BL BMI ( 2 ) for Semaglutide vs. comparators by trial for SUSTAIN 1-5 and 7. Safety data were pooled and analyzed stratified by trial. Reductions in mean HbA 1c (%) from BL were greater in all BMI subgroups with Semaglutide vs. comparators (Figure). There were no significant interactions between treatment and BMI, indicating a consistent effect of Semaglutide vs. comparator on change in HbA 1c across BMI subgroups. In all treatment arms, adverse events (AEs) occurred in a similar proportion of subjects across BMI subgroups. Gastrointestinal AEs were higher with Semaglutide, but decreased with increasing BL BMI, vs. comparators (Semaglutide: 2 =48.8%, 25- 2 =43.0%, 30- 2 =39.4% and ≥35 kg/m 2 =39.3% vs. comparators range: 21.2-28.9%). Premature treatment discontinuation due to AEs was higher in all BMI subgroups with Semaglutide vs. comparators (5.6-15.3% vs. 2.3-8.3%). In conclusion, the efficacy of Semaglutide in lowering HbA 1c does not appear to be influenced by BL BMI. Semaglutide had an acceptable safety profile in all BMI subgroups. Disclosure A. Viljoen: Advisory Panel; Self; NAPP Pharmaceuticals Limited. Research Support; Self; Eli Lilly and Company, Sanofi-Aventis. Speaker9s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. J.P. Frias: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Gilead Sciences, Inc., Sanofi. Consultant; Self; Echosens, Genentech, Inc., Johnson & Johnson Diabetes Institute, Novo Nordisk Inc., Zafgen, Inc. Research Support; Self; AbbVie Inc., Akcea Therapeutics, Allergan, Amgen Inc., AstraZeneca, Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Cirius Therapeutics, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Enanta Pharmaceuticals, Inc., GENFIT, Intarcia Therapeutics, Inc., Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Oramed Pharmaceuticals, Pfizer Inc., Sanofi, TaiwanJ Pharmaceuticals Co., Ltd., Theracos, Inc. Speaker9s Bureau; Self; Merck & Co., Inc., Sanofi. T. Gondolf: Employee; Spouse/Partner; Chr. Hansen Holding A/S. Employee; Self; Novo Nordisk A/S. O. Hansen: Employee; Self; Novo Nordisk A/S. N. Wijayasinghe: None. J. Unger: Advisory Panel; Self; Abbott Laboratories, Novo Nordisk Inc. Speaker9s Bureau; Self; Janssen Pharmaceuticals, Inc. Funding Novo Nordisk A/S

  • perte de poids sous Semaglutide versus dulaglutide selon l imc initial dans l etude sustain 7
    Annales D Endocrinologie, 2018
    Co-Authors: B Guerci, Adie Viljoen, Matthias Bluher, Francis C C Chow, C Le W Roux, Julio Rosenstock, Nanna L Lausvig, Emre Yildirim, Ildiko Lingvay
    Abstract:

    Objectifs L’etude SUSTAIN 7, randomisee, en ouvert, a evalue l’efficacite et la tolerance du Semaglutide 0,5 mg versus dulaglutide 0,75 mg et Semaglutide 1,0 mg versus dulaglutide 1,5 mg chez des diabetiques de type 2 en ajout de la metformine. Materiel et methodes Analyse post-hoc de l’evolution du poids en fonction de l’IMC initial ( Resultats A S40, le poids moyen (initial 95,2 kg) est reduit quel que soit l’IMC initial : 3,6–5,5 kg vs 0,9–3,4 kg avec Semaglutide 0,5 mg vs dulaglutide 0,75 mg et 5,2–7,6 kg vs 2,0–3,8 kg avec Semaglutide 1,0 mg vs dulaglutide 1,5 mg. Plus de patients dans les bras Semaglutide ont presente une perte de poids ≥ 5 % et ≥ 10 %. Dans le sous-groupe ≥ 35 kg/m2, une perte de poids ≥ 10 % a ete obtenue chez 14 % des patients traites par Semaglutide 0,5 mg vs 4 % pour dulaglutide 0,75 mg, et 25 % pour Semaglutide 1,0 mg vs 6 % pour dulaglutide 1,5 mg (respectivement 39 % vs 27 % et 58 % vs 32 % pour une perte de poids ≥ 5 %). Discussion Quel que soit l’IMC initial, le traitement par Semaglutide a permis d’obtenir des diminutions plus importantes du poids. La tolerance dans cette etude a ete comme attendue par la classe sans difference significative entre les deux traitements.

  • Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes sustain 7 a randomised open label phase 3b trial
    The Lancet Diabetes & Endocrinology, 2018
    Co-Authors: Richard E Pratley, Ildiko Lingvay, Vanita R Aroda, Jorg Ludemann, Camilla Andreassen, Andrea Navarria, Adie Viljoen
    Abstract:

    Summary Background Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared Semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes. Methods This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA 1c 7·0–10·5% (53·0–91·0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either Semaglutide 0·5 mg, dulaglutide 0·75 mg, Semaglutide 1·0 mg, or dulaglutide 1·5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA 1c ; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA 1c non-inferiority (margin 0·4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204. Findings Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to Semaglutide 0·5 mg, 299 to dulaglutide 0·75 mg, 300 to Semaglutide 1·0 mg, and 299 to dulaglutide 1·5 mg. 72 (6%) patients withdrew from the trial (22 receiving Semaglutide 0·5 mg, 13 receiving dulaglutide 0·75 mg, 21 receiving Semaglutide 1·0 mg, and 16 receiving dulaglutide 1·5 mg). From overall baseline mean, mean percentage HbA 1c was reduced by 1·5 (SE 0·06) percentage points with Semaglutide 0·5 mg versus 1·1 (0·05) percentage points with dulaglutide 0·75 mg (estimated treatment difference [ETD] −0·40 percentage points [95% CI −0·55 to −0·25]; p Interpretation At low and high doses, Semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile. Funding Novo Nordisk.

Vanita R Aroda - One of the best experts on this subject based on the ideXlab platform.

  • impact of patient characteristics on efficacy and safety of once weekly Semaglutide versus dulaglutide sustain 7 post hoc analyses
    BMJ Open, 2020
    Co-Authors: Richard E Pratley, Emre Yildirim, Ildiko Lingvay, Vanita R Aroda, Jorg Ludemann, Andreimircea Catarig, Adie Viljoen
    Abstract:

    OBJECTIVE In SUSTAIN 7, once-weekly Semaglutide demonstrated superior glycated haemoglobin (HbA1c) and body weight (BW) reductions versus once-weekly dulaglutide in subjects with type 2 diabetes (T2D). This post hoc analysis investigated the impact of clinically relevant subject characteristics on treatment effects of Semaglutide versus dulaglutide. DESIGN Analyses by baseline age ( 5-10, >10 years), HbA1c (≤7.5, >7.5-8.5, >8.5% (≤58, >58-69, >69 mmol/mol)) and body mass index (BMI) (<30, 30-<35, ≥35 kg/m2). SETTING 194 sites; 16 countries. PARTICIPANTS Subjects with T2D (n=1199) exposed to treatment. INTERVENTIONS Semaglutide 0.5 mg versus dulaglutide 0.75 mg (low-dose comparison); Semaglutide 1.0 mg versus dulaglutide 1.5 mg (high-dose comparison), all subcutaneously once weekly. PRIMARY AND SECONDARY OUTCOME MEASURES Change in HbA1c (primary endpoint) and BW (confirmatory secondary endpoint) from baseline to week 40; proportion of subjects achieving HbA1c targets (<7%, ≤6.5% (<53, ≤48 mmol/mol)) and weight-loss responses (≥5%, ≥10%) at week 40; and safety. RESULTS HbA1c and BW reductions (estimated treatment difference ranges: -0.22 to -0.70%-point; -1.76 to -3.84 kg) and proportion of subjects achieving HbA1c targets and weight-loss responses were statistically significantly greater for the majority of comparisons of Semaglutide versus dulaglutide within each subgroup category and, excepting glycaemic control within the low-dose comparison in HbA1c subgroups, this was irrespective of subgroup or dose comparison. Gastrointestinal adverse events, the most common with both treatments, were reported by more women than men and, with Semaglutide, decreased with increasing BMI. CONCLUSIONS Consistently greater improvements in HbA1c and BW with Semaglutide versus dulaglutide, regardless of age, sex, diabetes duration, glycaemic control and BMI, support the efficacy of Semaglutide across the continuum of care in a heterogeneous population with T2D. TRIAL REGISTRATION NUMBER NCT02648204.

  • impact of baseline characteristics and beta cell function on the efficacy and safety of subcutaneous once weekly Semaglutide a patient level pooled analysis of the sustain 1 5 trials
    Diabetes Obesity and Metabolism, 2020
    Co-Authors: Vanita R Aroda, Julio Rosenstock, Nanna L Lausvig, Jorg Ludemann, Sten Madsbad, Matthew Capehorn, Louis Chaykin, Juan P. Frias, Stanislava Macura, Omur Tabak
    Abstract:

    AIM To evaluate the impact of relevant patient-level characteristics on the efficacy and safety of subcutaneous, once-weekly Semaglutide in subjects with type 2 diabetes. MATERIALS AND METHODS Exploratory post hoc analyses of pooled SUSTAIN 1-5 (phase 3a) randomized, controlled trials examined the change from baseline in HbA1c and body weight (BW), and the proportions of subjects achieving the composite endpoint (HbA1c 7.5%-8.0%, >8.0%-8.5%, >8.5%-9.0% and > 9.0%), background medications, diabetes duration and pancreatic beta-cell function. RESULTS Mean HbA1c (% point) reductions increased from lowest to highest HbA1c subgroups (-0.9%, -1.2%,-1.5%, -1.7% and -2.3% [effect of subgroup within treatment: P = 0.247] for Semaglutide 0.5 mg, and -1.1%, -1.4%, -1.9%, -2.1% and -2.7% [P = 0.045] for Semaglutide 1.0 mg), with mean HbA1c ranges at week 30 of 6.3%-7.3% and 6.1%-6.9%, respectively. The corresponding BW reductions generally decreased with increasing baseline HbA1c (-4.4, -3.9, -3.9, -3.3 and -2.9 kg [P = 0.004], and -6.4, -5.9, -5.2, -4.5 and -4.8 kg [P < 0.001], respectively). HbA1c and BW reductions were consistently greater for Semaglutide 1.0 mg versus 0.5 mg across background medication, diabetes duration and pancreatic beta-cell function subgroups. Adverse events with Semaglutide were consistent with the glucagon-like peptide-1 receptor agonist class, with gastrointestinal events the most common. CONCLUSIONS Semaglutide was consistently efficacious across the continuum of diabetes care in a broad spectrum of patient subgroups with a range of clinical characteristics.

  • comparative efficacy safety and cardiovascular outcomes with once weekly subcutaneous Semaglutide in the treatment of type 2 diabetes insights from the sustain 1 7 trials
    Diabetes & Metabolism, 2019
    Co-Authors: Vanita R Aroda, Bertrand Cariou, Francis C C Chow, Andrew J Ahmann, Melanie J Davies, Esteban Jodar, R Mehta, Vincent Woo, Ildiko Lingvay
    Abstract:

    Abstract In individuals with type 2 diabetes, glycaemic control and cardiovascular risk factor management reduces the likelihood of late-stage diabetic complications. Guidelines recommend treatment goals targeting HbA1c, body weight, blood pressure, and low-density lipoprotein cholesterol. Development of new treatments for type 2 diabetes requires an understanding of their mechanism and efficacy, as well as their relative effects compared to other treatment choices, plus demonstration of cardiovascular safety. Subcutaneous Semaglutide is a glucagon-like peptide-1 receptor agonist currently approved in several countries for once-weekly treatment of type 2 diabetes. Semaglutide works via the incretin pathway, stimulating insulin and inhibiting glucagon secretion from the pancreatic islets, leading to lower blood glucose levels. Semaglutide also decreases energy intake by reducing appetite and food cravings, and lowering relative preference for fatty, energy-dense foods. Semaglutide was evaluated in the SUSTAIN clinical trial programme in over 8000 patients across the spectrum of type 2 diabetes. This review details the efficacy and safety profile of Semaglutide in the SUSTAIN 1–5 and 7 trials, and its cardiovascular safety profile in the SUSTAIN 6 trial. Semaglutide consistently demonstrated superior and sustained glycemic control and weight loss vs. all comparators evaluated. In SUSTAIN 6, involving patients at high risk of cardiovascular disease, Semaglutide significantly decreased the occurrence of cardiovascular events compared with placebo/standard of care (hazard ratio 0.74, P

  • GREATER COMBINED REDUCTIONS IN HbA1C ≥1.0% AND WEIGHT ≥5.0% WITH Semaglutide VERSUS COMPARATORS IN TYPE 2 DIABETES.
    Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2019
    Co-Authors: Helena W. Rodbard, Jeppe Zacho, Yutaka Seino, Srikanth Bellary, Irene Hramiak, Robert Silver, L.h. Damgaard, Gurudutt Nayak, Vanita R Aroda
    Abstract:

    Objective: Semaglutide is a glucagon-like peptide 1 (GLP-1) analog for the once-weekly treatment of type 2 diabetes (T2D). In the global SUSTAIN clinical trial program, Semaglutide demonstrated superior glycated hemoglobin (HbA1c) and body weight reductions versus comparators. This post hoc analysis compared the proportion of patients achieving combined reductions in glycemia and body weight versus comparators. Methods: A total of 5,119 subjects with T2D in the phase 3 SUSTAIN 1 through 5 and 7 trials, from 33 countries, were included in this post hoc analysis. Subjects received subcutaneous Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg, insulin glargine, dulaglutide 0.75 or 1.5 mg). The main endpoint was a composite of ≥1.0% HbA1c reduction and ≥5.0% weight loss at end of treatment. Results: Significantly greater proportions of subjects achieved the composite endpoint with Semaglutide 0.5 (25 to 38%) and 1.0 mg (38 to 59%) versus comparators (2 to 23%). More subjects treated with Semaglutide versus comparators achieved ≥1.0% HbA1c reductions (58 to 77% and 75 to 83% for Semaglutide 0.5 and 1.0 mg versus 12 to 68%) and ≥5.0% weight loss (37 to 46%, 45 to 66% versus 4 to 30%). Proportions of subjects achieving targets were significantly higher with Semaglutide 1.0 versus 0.5 mg in four of five trials. Semaglutide was well tolerated, with a safety profile similar to other GLP-1 receptor agonists. Conclusion: Significantly more subjects achieved both ≥1.0% HbA1c reduction and ≥5.0% weight loss with once-weekly subcutaneous Semaglutide treatment versus comparators in the SUSTAIN trials. A dose-dependent effect was observed with Semaglutide. Abbreviations: AE = adverse event; CV = cardiovascular; ER = extended release; GLP-1 = glucagon-like peptide 1; GLP-1 RA = glucagon-like peptide 1 receptor agonist; HbA1c = glycated hemoglobin; OAD = oral antidiabetic drug; sc = subcutaneous; T2D = type 2 diabetes.

  • Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes sustain 7 a randomised open label phase 3b trial
    The Lancet Diabetes & Endocrinology, 2018
    Co-Authors: Richard E Pratley, Ildiko Lingvay, Vanita R Aroda, Jorg Ludemann, Camilla Andreassen, Andrea Navarria, Adie Viljoen
    Abstract:

    Summary Background Despite common mechanisms of actions, glucagon-like peptide-1 receptor agonists differ in structure, pharmacokinetic profile, and clinical effects. This head-to-head trial compared Semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes. Methods This was an open-label, parallel-group, phase 3b trial done at 194 hospitals, clinical institutions or private practices in 16 countries. Eligible patients were aged 18 years or older and had type 2 diabetes with HbA 1c 7·0–10·5% (53·0–91·0 mmol/mol) on metformin monotherapy. Patients were randomly assigned (1:1:1:1) by use of an interactive web-response system to once a week treatment with either Semaglutide 0·5 mg, dulaglutide 0·75 mg, Semaglutide 1·0 mg, or dulaglutide 1·5 mg subcutaneously. The primary endpoint was change from baseline in percentage HbA 1c ; the confirmatory secondary endpoint was change in bodyweight, both at week 40. The primary analysis population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication. The safety population included all randomly assigned patients exposed to at least one dose of trial product obtained while on treatment. The trial was powered for HbA 1c non-inferiority (margin 0·4%) and bodyweight superiority. This trial is registered with ClinicalTrials.gov, number NCT02648204. Findings Between Jan 6, 2016, and June 22, 2016, 1201 patients were randomly assigned to treatment; of these, 301 were exposed to Semaglutide 0·5 mg, 299 to dulaglutide 0·75 mg, 300 to Semaglutide 1·0 mg, and 299 to dulaglutide 1·5 mg. 72 (6%) patients withdrew from the trial (22 receiving Semaglutide 0·5 mg, 13 receiving dulaglutide 0·75 mg, 21 receiving Semaglutide 1·0 mg, and 16 receiving dulaglutide 1·5 mg). From overall baseline mean, mean percentage HbA 1c was reduced by 1·5 (SE 0·06) percentage points with Semaglutide 0·5 mg versus 1·1 (0·05) percentage points with dulaglutide 0·75 mg (estimated treatment difference [ETD] −0·40 percentage points [95% CI −0·55 to −0·25]; p Interpretation At low and high doses, Semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight, enabling a significantly greater number of patients with type 2 diabetes to achieve clinically meaningful glycaemic targets and weight loss, with a similar safety profile. Funding Novo Nordisk.