Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial.

BACKGROUND: Several pharmacological treatment options are available for type 2 diabetes; however, many patients do not achieve optimum glycaemic control and therefore new therapies are necessary. We assessed the efficacy and safety of semaglutide, a glucagon-like peptide-1 (GLP-1) analogue in clinical development, compared with insulin glargine in patients with type 2 diabetes who were inadequately controlled with metformin (with or without sulfonylureas). METHODS: We did a randomised, open-label, non-inferiority, parallel-group, multicentre, multinational, phase 3a trial (SUSTAIN 4) at 196 sites in 14 countries. Eligible participants were insulin-naive patients with type 2 diabetes, aged 18 years and older, who had insufficient glycaemic control with metformin either alone or in combination with a sulfonylurea. We randomly assigned participants (1:1:1) to either subcutaneous once-weekly 0·5 mg or 1·0 mg semaglutide (doses reached after following a fixed dose-escalation regimen) or once-daily insulin glargine (starting dose 10 IU per day, then titrated weekly to a pre-breakfast self-measured plasma glucose target of 4·0-5·5 mmol/L [72-99 mg/dL]) for 30 weeks. In all treatment groups, previous background metformin and sulfonylurea treatment was continued throughout the trial. We did the randomisation using an interactive voice or web response system. The primary endpoint was change in mean HbA1c from baseline to week 30 and the confirmatory secondary endpoint was the change in mean bodyweight from baseline to week 30. We assessed efficacy and safety in the modified intention-to-treat population (mITT; all randomly assigned participants who were exposed to at least one dose of study drug) and used a margin of 0·3% to establish non-inferiority in HbA1c reduction. This trial is registered with ClinicalTrials.gov, number NCT02128932. FINDINGS: Between Aug 4, 2014, and Sept 3, 2015, we randomly assigned 1089 participants to treatment; the mITT population consisted of 362 participants assigned to 0·5 mg semaglutide, 360 to 1·0 mg semaglutide, and 360 to insulin glargine. 49 (14%) participants assigned to 0·5 mg semaglutide discontinued treatment prematurely, compared with 55 (15%) assigned to 1·0 mg semaglutide, and 26 (7%) assigned to insulin glargine. Most discontinuations were due to adverse events-mostly gastrointestinal with semaglutide, and others such as skin and subcutaneous tissue disorders (eg, rash, pruritus, and urticaria) with insulin glargine. From a mean baseline HbA1c of 8·17% (SD 0·89), at week 30, 0·5 and 1·0 mg semaglutide achieved reductions of 1·21% (95% CI 1·10-1·31) and 1·64% (1·54-1·74), respectively, versus 0·83% (0·73-0·93) with insulin glargine; estimated treatment difference versus insulin glargine -0·38% (95% CI -0·52 to -0·24) with 0·5 mg semaglutide and -0·81% (-0·96 to -0·67) with 1·0 mg semaglutide (both p<0·0001). Mean bodyweight at baseline was 93·45 kg (SD 21·79); at week 30, 0·5 and 1·0 mg semaglutide achieved weight losses of 3·47 kg (95% CI 3·00-3·93) and 5·17 kg (4·71-5·66), respectively, versus a weight gain of 1·15 kg (0·70-1·61) with insulin glargine; estimated treatment difference versus insulin glargine -4·62 kg (95% CI -5·27 to -3·96) with 0·5 mg semaglutide and -6·33 kg (-6·99 to -5·67) with 1·0 mg semaglutide (both p<0·0001). Severe or blood glucose-confirmed hypoglycaemia was reported by 16 (4%) participants with 0·5 mg semaglutide and 20 (6%) with 1·0 mg semaglutide versus 38 (11%) with insulin glargine (p=0·0021 and p=0·0202 for 0·5 mg and 1·0 mg semaglutide vs insulin glargine, respectively). Severe hypoglycaemia was reported by two (<1%) participants with 0·5 mg semaglutide, five (1%) with 1·0 mg semaglutide, and five (1%) with insulin glargine. Six deaths were reported: four (1%) in the 0·5 mg semaglutide group (three cardiovascular deaths, one pancreatic carcinoma, which was assessed as being possibly related to study medication) and two (<1%) in the insulin glargine group (both cardiovascular death). The most frequently reported adverse events were nausea with semaglutide, reported in 77 (21%) patients with 0·5 mg and in 80 (22%) with 1·0 mg, and nasopharyngitis reported in 44 (12%) patients with insulin glargine. INTERPRETATION: Compared with insulin glargine, semaglutide resulted in greater reductions in HbA1c and weight, with fewer hypoglycaemic episodes, and was well tolerated, with a safety profile similar to that of other GLP-1 receptor agonists. FUNDING: Novo Nordisk A/S.

Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species.

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.

Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery-A Multicenter, Randomized, Safety Assessor-Blinded Trial.

Complex surgical procedures are increasingly performed in an outpatient setting, with emphasis on rapid recovery and case turnover. In this study, the combination of rocuronium for neuromuscular blockade (NMB) reversed by single-dose sugammadex was compared with succinylcholine followed by spontaneous recovery in outpatient surgery. This multicenter, randomized, safety assessor-blinded study enrolled adults undergoing a short elective outpatient surgical procedure requiring NMB and tracheal intubation. Patients were randomized to NMB with either rocuronium 0.6 mg/kg for tracheal intubation with incremental doses of rocuronium 0.15 mg/kg and subsequent reversal with sugammadex 4.0 mg/kg at 1-2 posttetanic counts or succinylcholine 1.0 mg/kg for intubation with spontaneous recovery. The primary efficacy end point was the time from sugammadex administration to recovery of the train-of-four ratio to 0.9; for succinylcholine, time from administration to recovery of the first twitch (T1) to 90% was assessed. From 167 patients enrolled, 150 received treatment. The all-subjects-treated population comprised 70 patients in the rocuronium-sugammadex group and 80 in the succinylcholine group. Geometric mean (95% confidence interval) time from the start of sugammadex administration to recovery of the train-of-four ratio to 0.9 was 1.8 (1.6-2.0) minutes. Geometric mean (95% confidence interval) time from succinylcholine administration to recovery of T1 to 90% was 10.8 (10.1-11.5) minutes. Health outcome variables were similar between the groups. Adverse events were reported in 87.1% and 93.8% of patients for rocuronium-sugammadex and succinylcholine, respectively. In conclusion, rocuronium for intubation followed by sugammadex for reversal of NMB offers a viable treatment option in outpatient surgery without prolonging recovery duration or jeopardizing safety.

The increases in potassium concentrations are greater with succinylcholine than with rocuronium-sugammadex in outpatient surgery: a randomized, multicentre trial.

BACKGROUND: Succinylcholine provides rapid onset of neuromuscular blockade and short duration of action, but its administration may be associated with hyperkalemia. Rocuronium is not known to increase potassium concentration, has fast onset of activity, and can be rapidly reversed by sugammadex. This study evaluated changes in plasma potassium concentrations in patients randomized either to rocuronium followed by sugammadex reversal or to succinylcholine in ambulatory surgery. METHODS: In this multicentre randomized active-controlled study, adult patients undergoing short surgical procedures in an outpatient setting received either rocuronium 0.6 mg·kg(-1) for intubation with sugammadex 4.0 mg·kg(-1) for reversal (n = 70) or succinylcholine 1.0 mg·kg(-1) with spontaneous recovery (n = 80). Blood potassium concentrations were assessed at baseline (before study drug administration) and at intervals up to 15 min after rocuronium, sugammadex, and succinylcholine. RESULTS: At the primary endpoint, five minutes post-administration, the changes in potassium concentrations from baseline were significantly smaller in patients treated with rocuronium than in those given succinylcholine [mean (SD): -0.06 (0.32) vs 0.30 (0.34) mmol·L(-1), respectively; P < 0.0001]. At baseline, potassium concentrations were similar in both groups, but they were greater at two, five, ten, and 15 min after succinylcholine than after rocuronium (P < 0.0001) for all time points. After sugammadex administration, there were no significant changes in mean potassium concentration from the pre-rocuronium baseline. No adverse effects related to hyperkalemia were observed. CONCLUSION: Succinylcholine was associated with a modest increase in potassium concentration; these changes were not seen after rocuronium or sugammadex ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00751179).