Aims: To investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D). Methods: In this double-blind, placebo-controlled, single-centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12-week crossover periods of once-weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L). Results: The mean (range) participant age was 54.2 (41-64) years, body mass index 29.4 (23.3-36.1) kg/m(2), glycated haemoglobin 60.8 (44.3-83.6) mmol/mol (7.7 [6.2-9.8]%), and diabetes duration 4.5 (0.3-13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval -7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide. Conclusions: Semaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

Introduction Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects. Methods In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg ( n = 8), 1.0 mg ( n = 8), placebo 0.5 mg ( n = 3) or 1.0 mg ( n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC 0–168h )]. Results Steady-state exposure of semaglutide was similar for both populations: AUC 0–168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration ( C max ) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC 0–168h ERR 1.11; C max ERR 1.14). Dose-dependent increases in AUC 0–168h and C max occurred in both populations. Accumulation was as expected, based on the half-life ( t 1/2 , ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified. Conclusions The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects. Funding Novo Nordisk A/S, Denmark. Trial registration ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.

Semaglutide is a human glucagon-like peptide-1 analogue in clinical development for the treatment of type 2 diabetes. The absorption, metabolism and excretion of a single 0.5mg/450μCi [16.7MBq] subcutaneous dose of [3H]-radiolabelled semaglutide was investigated in healthy human subjects and compared with data from nonclinical studies. Radioactivity in blood, plasma, urine and faeces was determined in humans, rats and monkeys; radioactivity in expired air was determined in humans and rats. Metabolites in plasma, urine and faeces were quantified following profiling and radiodetection. The blood-to-plasma ratio and pharmacokinetics of both radiolabelled semaglutide-related material and of semaglutide (in humans only) were assessed. Intact semaglutide was the primary component circulating in plasma for humans and both nonclinical species, accounting for 69-83% of the total amount of semaglutide-related material, and was metabolised prior to excretion. Recovery of excreted radioactivity was 75.1% in humans, 72.1% in rats and 58.2% in monkeys. Urine and faeces were shown to be important routes of excretion, with urine as the primary route in both humans and animals. Semaglutide was metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain, and metabolism was not confined to specific organs. Intact semaglutide in urine accounted for 3.1% of the administered dose in humans and less than 1% in rats; it was not detected in urine in monkeys. The metabolite profiles of semaglutide in humans appear to be similar to the profiles from the nonclinical species investigated.

The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D.

The effect of semaglutide, a once‐weekly human glucagon‐like peptide‐1 (GLP‐1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide‐free) and during (steady‐state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady‐state and semaglutide‐free periods was within prespecified limits (0.80–1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0–24 h) for semaglutide steady‐state/semaglutide‐free; 1.11 (1.06–1.15). AUC0–24 h was 20% higher for levonorgestrel at semaglutide steady‐state vs. semaglutide‐free (1.20 [1.15–1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (–1.1 ± 0.6%) and weight (–4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once‐weekly dosing; the semaglutide dose and dose‐escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow‐up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.

SummaryObjectives Recombinant human growth hormone (rhGH) replacement therapy in children and adults currently requires daily subcutaneous injections for several years or lifelong. The current study examined safety, tolerability, pharmacokinetic and pharmacodynamic response parameters after single and multiple doses of a long‐acting rhGH preparation (NNC126‐0083).Design Randomized, double‐blinded, placebo‐controlled, multiple‐dose, dose‐escalating (0·02, 0·04, 0·08 and 0·16 mg protein/kg), sequential dose group trial.Subjects Forty adult Japanese healthy male volunteers (aged 20–45; body mass index: 18·0–27·0 kg/m2). Five groups (n = 8) were randomized to receive multiple doses of NNC126‐0083 (n = 6) or placebo (n = 2).Methods Primary outcome was safety, and tolerability of multiple doses of NNC126‐0083 compared with placebo. Blood samples for the assessment of pharmacokinetics (PK) and pharmacodynamics response [insulin‐like growth factor I (IGF‐I) and IGF binding protein 3 (IGFBP‐3)] were taken after multiple ascending doses.Results NNC126‐0083 was well tolerated and not associated with any local injection‐site reactions or lipoatrophy. Following administration, NNC126‐0083 levels increased rapidly and remained elevated for several days, returning to baseline before each weekly injection. Steady‐state PK was achieved after the third dosing. A more than dose‐proportional exposure was observed at the highest NNC126‐0083 dose (0·16 mg protein/kg). A strong dose‐dependent pharmacodynamic response in circulating concentrations of both IGF‐I and IGFBP‐3 compared with placebo (P < 0·0001) was observed during the administration of all doses.Conclusions Multiple administration of NNC126‐0083 in healthy male volunteers indicates that NNC126‐0083 has the potential for an efficacious, well‐tolerated, once‐weekly rhGH compound in the treatment of GH deficiency.