Estimated Treatment Ratio Research Articles

Investigating the Bioavailability and Insulin-like Growth Factor-I Release of Two Different Strengths of Somapacitan: A Randomised, Double-Blind Crossover Trial.

Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5mg/1.5mL and 10mg/1.5mL strengths in equimolar doses. Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5mg/1.5mL and two periods with 10mg/1.5mL. Eligibility criteria included age 18-45years and body mass index 18.5-24.9kg/m2. Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0kg and participation in any clinical trial of an investigational medicinal product within 45days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC0-t), maximum serum concentration (Cmax), time to Cmax and terminal half-life of somapacitan and safety were assessed. In total, 33 participants were randomised. For AUC0-t, estimated treatment ratio (ETR) (5mg/1.5mL versus 10mg/1.5mL) was 0.95 (90% confidence interval [CI] 0.89-1.01). Point estimate and 90%CIs were within the acceptance range (0.80-1.25). For Cmax, ETR was 0.77 (90%CI 0.68-0.89). Point estimate and 90%CIs were outside the acceptance range (0.80-1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration-time curves for each strength were almost identical. No new safety issues were identified. Bioequivalence criterion for somapacitan 5mg/1.5mL and 10mg/1.5mL was met for AUC0-t but not for Cmax. The two strengths had equivalent IGF-I responses. ClinicalTrials.gov, NCT03905850 (3 April 2019).

Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HFpEF Program

BackgroundThe glucagon-like peptide-1 receptor agonist, semaglutide, improved health status and reduced body weight in patients with obesity-related heart failure (HF) with preserved ejection fraction (HFpEF) in the STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and HFpEF) program. Whether benefits were due to mechanical unloading or effects on HF pathobiology is uncertain. ObjectivesThis study sought to determine if semaglutide 2.4 mg reduced N-terminal pro–B-type natriuretic peptide (NT-proBNP) in patients with obesity-related HFpEF and compare treatment responses by baseline NT-proBNP. MethodsThis was a prespecified secondary analysis of pooled data from 2 double-blind, placebo-controlled, randomized trials (STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes]) testing effects of semaglutide in patients with obesity-related HFpEF. The main outcomes were change in NT-proBNP at 52 weeks and change in the dual primary endpoints of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and body weight by baseline NT-proBNP. ResultsIn total, 1,145 patients were randomized. Semaglutide compared with placebo reduced NT-proBNP at 52 weeks (estimated treatment ratio: 0.82; 95% CI: 0.74-0.91; P = 0.0002). Improvements in health status were more pronounced in those with higher vs lower baseline NT-proBNP (estimated difference: tertile 1: 4.5 points, 95% CI: 0.8–8.2; tertile 2: 6.2 points, 95% CI: 2.4-10.0; tertile 3: 11.9 points, 95% CI: 8.1-15.7; P interaction = 0.02; baseline NT-proBNP as a continuous variable: P interaction = 0.004). Reductions in body weight were consistent across baseline NT-proBNP levels (P interaction = 0.21). ConclusionsIn patients with obesity-related HFpEF, semaglutide reduced NT-proBNP. Participants with higher baseline NT-proBNP had a similar degree of weight loss but experienced larger reductions in HF-related symptoms and physical limitations with semaglutide than those with lower NT-proBNP.

Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by magnetic resonance imaging.

SummaryBackgroundGlucagon‐like peptide‐1 receptor agonists may be a treatment option in patients with non‐alcoholic fatty liver disease (NAFLD).AimsTo investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non‐invasive magnetic resonance imaging (MRI) methods.MethodsThis randomised, double‐blind, placebo‐controlled trial enrolled subjects with liver stiffness 2.50‐4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI‐PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE.ResultsSixty‐seven subjects were randomised to once‐daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA1c were also observed with semaglutide.ConclusionsThe change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.

Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes.

AimTo assess the effects of oral semaglutide on postprandial glucose and lipid metabolism, and gastric emptying, in subjects with type 2 diabetes (T2D).Materials and MethodsIn this randomized, double‐blind, single‐centre, crossover trial, subjects with T2D received once‐daily oral semaglutide (escalated to 14 mg) followed by placebo, or vice versa, over two consecutive 12‐week periods. Glucose and lipid metabolism, and gastric emptying (paracetamol absorption) were assessed before and after two types of standardized meals (standard and/or fat‐rich) at the end of each treatment period. The primary endpoint was area under the glucose 0–5‐h curve (AUC0–5h) after the standard breakfast.ResultsFifteen subjects were enrolled (mean age 58.2 years, HbA1c 6.9%, body weight 93.9 kg, diabetes duration 3.1 years; 13 [86.7%] males). Fasting concentrations of glucose were significantly lower, and C‐peptide significantly greater, with oral semaglutide versus placebo. Postprandial glucose (AUC0–5h) was significantly lower with oral semaglutide versus placebo (estimated treatment ratio, 0.71; 95% CI, 0.63, 0.81; p < .0001); glucose incremental AUC (iAUC0–5h/5h) and glucagon AUC0–5h were also significantly reduced, with similar results after the fat‐rich breakfast. Fasting concentrations of triglycerides, very low‐density lipoprotein (VLDL) and apolipoprotein B48 (ApoB48) were significantly lower with oral semaglutide versus placebo. AUC0–8h for triglycerides, VLDL and ApoB48, and triglycerides iAUC0–8h/8h, were significantly reduced after oral semaglutide versus placebo. During the first postprandial hour, gastric emptying was delayed (a 31% decrease in paracetamol AUC0–1h) with oral semaglutide versus placebo. One serious adverse event (acute myocardial infarction) occurred during oral semaglutide treatment.ConclusionOral semaglutide significantly improved fasting and postprandial glucose and lipid metabolism, and delayed gastric emptying.

Anti-interleukin-21 antibody and liraglutide for the preservation of β-cell function in adults with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled, phase 2 trial

Type 1 diabetes is characterised by progressive loss of functional β-cell mass, necessitating insulin treatment. We aimed to investigate the hypothesis that combining anti-interleukin (IL)-21 antibody (for low-grade and transient immunomodulation) with liraglutide (to improve β-cell function) could enable β-cell survival with a reduced risk of complications compared with traditional immunomodulation. This randomised, parallel-group, placebo-controlled, double-dummy, double-blind, phase 2 trial was done at 94 sites (university hospitals and medical centres) in 17 countries. Eligible participants were adults aged 18-45 years with recently diagnosed type 1 diabetes and residual β-cell function. Individuals with unstable type 1 diabetes (defined by an episode of severe diabetic ketoacidosis within 2 weeks of enrolment) or active or latent chronic infections were excluded. Participants were randomly assigned (1:1:1:1), with stratification by baseline stimulated peak C-peptide concentration (mixed-meal tolerance test [MMTT]), to the combination of anti-IL-21 and liraglutide, anti-IL-21 alone, liraglutide alone, or placebo, all as an adjunct to insulin. Investigators, participants, and funder personnel were masked throughout the treatment period. The primary outcome was the change in MMTT-stimulated C-peptide concentration at week 54 (end of treatment) relative to baseline, measured via the area under the concentration-time curve (AUC) over a 4 h period for the full analysis set (intention-to-treat population consisting of all participants who were randomly assigned). After treatment cessation, participants were followed up for an additional 26-week off-treatment observation period. This trial is registered with ClinicalTrials.gov, NCT02443155. Between Nov 10, 2015, and Feb 27, 2019, 553 adults were assessed for eligibility, of whom 308 were randomly assigned to receive either anti-IL-21 plus liraglutide, anti-IL-21, liraglutide, or placebo (77 assigned to each group). Compared with placebo (ratio to baseline 0·61, 39% decrease), the decrease in MMTT-stimulated C-peptide concentration from baseline to week 54 was significantly smaller with combination treatment (0·90, 10% decrease; estimated treatment ratio 1·48, 95% CI 1·16-1·89; p=0·0017), but not with anti-IL-21 alone (1·23, 0·97-1·57; p=0·093) or liraglutide alone (1·12, 0·87-1·42; p=0·38). Despite greater insulin use in the placebo group, the decrease in HbA1c (a key secondary outcome) at week 54 was greater with all active treatments (-0·50 percentage points) than with placebo (-0·10 percentage points), although the differences versus placebo were not significant. The effects diminished upon treatment cessation. Changes in immune cell subsets across groups were transient and mild (<10% change over time). The most frequently reported adverse events included gastrointestinal disorders, in keeping with the known side-effect profile of liraglutide. The rate of hypoglycaemic events did not differ significantly between active treatment groups and placebo, with an exception of a lower rate in the liraglutide group than in the placebo group during the treatment period. No events of diabetic ketoacidosis were observed. One participant died while on liraglutide (considered unlikely to be related to trial treatment) in connection with three reported adverse events (hypoglycaemic coma, pneumonia, and brain oedema). The combination of anti-IL-21 and liraglutide could preserve β-cell function in recently diagnosed type 1 diabetes. The efficacy of this combination appears to be similar to that seen in trials of other disease-modifying interventions in type 1 diabetes, but with a seemingly better safety profile. Efficacy and safety should be further evaluated in a phase 3 trial programme. Novo Nordisk.

A randomized trial comparing the efficacy and safety of treating patients with type 2 diabetes and highly elevated HbA1c levels with basal-bolus insulin or a glucagon-like peptide-1 receptor agonist plus basal insulin: The SIMPLE study.

To compare the efficacy and safety of a glucagon-like peptide-1 receptor agonist (GLP1RA) plus basal insulin versus basal-bolus insulin treatment in patients with very uncontrolled type 2 diabetes. The SIMPLE study was a 6-month pragmatic, randomized, open-label trial testing the effectiveness of two approaches to treat patients with type 2 diabetes and HbA1c ≥10%. We randomized patients to detemir plus liraglutide or detemir plus aspart (before each meal). The primary endpoint was change in HbA1c; changes in body weight, insulin dose, hypoglycaemia and diabetes-related quality-of-life were secondary outcomes. We randomized 120 participants aged 47.4 ± 9.5 years, Hispanic 40%, African American 42%, diabetes duration 10 [25th-75th percentile (6 to 15)] years, body mass index 37.2 ± 10.3 kg/m2 . HbA1c decreased more with GLP1RA plus basal insulin [12.2% (95% CI 11.8% to 12.6%) to 8.1% (95% CI 7.4% to 8.7%)] compared with basal-bolus insulin [11.8% (95% CI 11.5% to 12.2%) to 8.8% (95% CI 88.1% to 9.55%)]; estimated treatment difference (ETD) of -1.1% (95% CI -2.0% to -0.1%) (non-inferiority margin 0.4% and P = .0001, superiority P = .026). Compared with basal-bolus insulin, treatment with GLP1RA plus basal insulin led to a body weight ETD of -3.7 kg (95% CI -5.8 to -1.5; P = .001), fewer patients experiencing hypoglycaemia [66.1% vs 35.2% (P = .002)], and greater improvements in general/current health perception, treatment satisfaction, and fear of hypoglycaemia, while taking a lower total daily dose of insulin [estimated treatment ratio 0.68 (95% CI 0.55 to 0.84)]. In patients with HbA1c ≥10% treatment with GLP1RA plus basal insulin, compared with basal-bolus insulin, resulted in better glycaemic control and body weight, lower insulin dosage and hypoglycaemia, and improved quality of life. This treatment strategy is an effective and safe alternative to a basal-bolus insulin regimen.

A randomized study investigating the effect of omeprazole on the pharmacokinetics of oral semaglutide

ABSTRACTBackground: Since the first oral glucagon-like peptide-1 analog comprises semaglutide co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which induces a transient, localized increase in gastric pH, we have investigated whether a proton pump inhibitor affects the pharmacokinetics of oral semaglutide.Research design and methods: A single-center, randomized, open-label, parallel-group trial investigated pharmacokinetic interactions of oral semaglutide with omeprazole (40 mg once-daily) in 54 healthy subjects. Primary endpoints were area under the plasma concentration-time curve over 24 h for semaglutide (AUC0−24h,semaglutide,Day10) and maximum concentration of semaglutide (Cmax,semaglutide,Day10) at day 10.Results: Exposure of semaglutide appeared to be slightly increased, although not statistically significantly, with oral semaglutide plus omeprazole versus oral semaglutide alone (AUC0−24h,semaglutide,Day10 [estimated treatment ratio 1.13; 90%CI 0.88, 1.45] and Cmax,semaglutide,Day10 [estimated treatment ratio 1.16; 90%CI 0.90, 1.49]). Gastric pH was higher with oral semaglutide and omeprazole versus oral semaglutide alone. Adverse events were mild or moderate and, most commonly, gastrointestinal disorders.Conclusions: There was a slight non-statistically significant increase in semaglutide exposure when oral semaglutide was administered with omeprazole, but this is not considered clinically relevant and no dose adjustment is likely to be required.

No Evidence of Increase in Calcitonin Concentrations or Development of C-Cell Malignancy in Response to Liraglutide for Up to 5 Years in the LEADER Trial.

To describe the changes in serum levels of calcitonin in liraglutide- and placebo-treated patients in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results-A Long Term Evaluation (LEADER) trial over a 3.5-5-year period. Patients (n = 9,340) with type 2 diabetes and high risk for cardiovascular events were randomized 1:1 to liraglutide or placebo. We analyzed calcitonin levels, thyroid and C-cell adverse events, and neoplasms. At 36 months, patients randomized to liraglutide versus placebo showed no evidence of increase in calcitonin concentrations in male (estimated treatment ratio [ETR] 1.03 [95% CI 1.00, 1.06]; P = 0.068) and female (ETR 1.00 [95% CI 0.97, 1.02]; P = 0.671) subgroups. There were no episodes of C-cell hyperplasia or medullary thyroid carcinoma in liraglutide-treated patients. There was no evidence of a difference in calcitonin concentrations between the liraglutide and placebo groups, and no C-cell malignancies occurred in the liraglutide group.

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial

Aims/hypothesisSemaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed.MethodsIn this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18–64 years) participants with type 2 diabetes (eligibility: HbA1c of 6.5–9.0% (47.5–74.9 mmol/mol); BMI 20.0–35.0 kg/m2; and treatment with diet and exercise and/or metformin monotherapy with a dose unchanged in the 30 days prior to screening) were randomised (1:1) to once-weekly s.c. semaglutide 1.0 mg (0.25, 0.5, 1.0 mg escalated) or placebo for 12 weeks. Co-primary endpoints were changes from baseline to end of treatment in the first (AUC0–10 min) and second (AUC10–120 min) insulin secretion phases, as measured by the IVGTT. An arginine stimulation test (AST) and a 24 h meal stimulation test were also conducted. A graded glucose infusion test (GGIT) assessed insulin secretion rate (ISR) in treated participants and a group of untreated healthy participants. Safety endpoints were also assessed.ResultsIn total, 37 participants received semaglutide and 38 received placebo. Following IVGTT, for insulin, both AUC0−10min and AUC10−120min were significantly increased with semaglutide (estimated treatment ratio [95% CI] 3.02 [2.53, 3.60] and 2.10 [1.86, 2.37], respectively; p < 0.0001). The 24 h meal test showed reduced fasting, postprandial and overall (AUC0–24h) glucose and glucagon responses with semaglutide (p < 0.0001). The AST showed that maximal insulin capacity increased following semaglutide treatment. During GGIT, semaglutide significantly increased ISR to levels similar to those in healthy participants. Semaglutide was well tolerated.Conclusions/interpretationTwelve weeks of once-weekly treatment with semaglutide significantly improved beta cell function and glycaemic control in participants with type 2 diabetes.Trial registration:ClinicalTrials.gov NCT02212067Funding:The study was funded by Novo Nordisk A/S.

Combination therapy with liraglutide and insulin in Japanese patients with type 2 diabetes: A 36-week, randomized, double-blind, parallel-group trial.

Aims/IntroductionTo assess efficacy and safety of liraglutide in combination with insulin compared with insulin monotherapy in Japanese patients with type 2 diabetes.Materials and methodsThis was a 36‐week, multicenter, double‐blind, parallel‐group trial, where patients on stable insulin therapy (basal/premixed/basal–bolus) were randomized 1:1 to additional liraglutide 0.9 mg/day (n = 127) or placebo (n = 130). The insulin dose was fixed for 16 weeks, and titrated based on self‐measured plasma glucose thereafter. The primary end‐point was change in glycosylated hemoglobin after 16 weeks.ResultsSuperiority of liraglutide plus insulin versus insulin monotherapy was confirmed based on estimated mean difference in glycosylated hemoglobin after 16 weeks of −1.30% (−14 mmol/mol; 95% confidence interval −1.47 to −1.13 [−16, −12]; P < 0.0001). Statistical significance was maintained to week 36. More patients on liraglutide achieved a glycosylated hemoglobin target of <7.0% (<53 mmol/mol) at week 16 (estimated odds ratio 50.57; 95% confidence interval 16.59 to 154.16; P < 0.0001). Improvements in seven‐point self‐measured plasma glucose and fasting plasma glucose were significantly greater with liraglutide than the placebo at week 16. Insulin dose after 36 weeks was lower with liraglutide than the placebo (estimated treatment ratio: 0.82 [95% confidence interval 0.76–0.90; P < 0.0001]). Occurrence of adverse events was similar in the two groups (85.8 and 81.5%, respectively); most were mild in severity. There were no significant differences in the number of hypoglycemic episodes during the 36 weeks.ConclusionsAdding liraglutide to insulin results in superior glycemic control compared with insulin alone in Japanese patients with type 2 diabetes, and is generally well tolerated.

Efficacy and Safety of Liraglutide Versus Placebo as Add-on to Glucose-Lowering Therapy in Patients With Type 2 Diabetes and Moderate Renal Impairment (LIRA-RENAL): A Randomized Clinical Trial.

Renal impairment in type 2 diabetes limits available glucose-lowering treatment options. This trial was conducted to establish the efficacy and safety of liraglutide as an add-on to existing glucose-lowering medications in patients with inadequately controlled type 2 diabetes and moderate renal impairment. In this 26-week, double-blind trial, 279 patients with HbA1c 7-10%, BMI 20-45 kg/m(2), and moderate renal impairment (estimated glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m(2); MDRD) were randomized (1:1) to once-daily liraglutide 1.8 mg (n = 140) or placebo (n = 139). The estimated treatment difference in HbA1c from baseline to week 26 was -0.66% (-7.25 mmol/mol) (95% CI -0.90 to -0.43 [-9.82 to -4.69]), P < 0.0001). Fasting plasma glucose decreased more with liraglutide (-1.22 mmol/L [-22.0 mg/dL]) than with placebo (-0.57 mmol/L [-10.3 mg/dL], P = 0.036). There was a greater reduction in body weight with liraglutide (-2.41 kg) than with placebo (-1.09 kg, P = 0.0052). No changes in renal function were observed (eGFR relative ratio to baseline: -1% liraglutide, +1% placebo; estimated treatment ratio [ETR] 0.98, P = 0.36). The most common adverse events were gastrointestinal (GI) adverse effects (liraglutide, 35.7%; placebo, 17.5%). No difference in hypoglycemic episodes was observed between treatment groups (event rate/100 patient-years of exposure: liraglutide, 30.47; placebo, 40.08; P = 0.54). The estimated ratio to baseline for lipase was 1.33 for liraglutide and 0.97 for placebo (ETR 1.37, P < 0.0001). Liraglutide did not affect renal function and demonstrated better glycemic control, with no increase in hypoglycemia risk but with higher withdrawals due to GI adverse events than placebo in patients with type 2 diabetes and moderate renal impairment.