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In a phase 3a trial involving adults with type 2 diabetes who had not previously received insulin, glycemic control was better with once-weekly insulin icodec than with once-daily insulin glargine U100.

Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This phase 3 study aimed to assess the efficacy and safety of efsitora compared with insulin degludec (degludec) in adults with type 1 diabetes. This randomised, 52-week, parallel-design, open-label, treat-to-target non-inferiority study conducted at 82 global health-care centres, randomly assigned (1:1) adults (ie, those aged ≥18 years) with type 1 diabetes glycated haemoglobin A1c (HbA1c) 7·0–10·0% (53·0–85·8 mmol/mol) to efsitora (n=343) or, degludec (n=349), both in combination with insulin lispro. The primary endpoint was the change in HbA1c from baseline to week-26 (non-inferiority margin=0·4%). The trial was registered at ClinicalTrials.gov (NCT05463744) and is completed. Between Aug 12, 2022, and May 7, 2024, of 893 participants enrolled, 692 (77%) participants were randomly assigned to once-weekly efsitora or once-daily degludec, and 623 (90%) participants completed the study. Mean HbA1c decreased from 7·88% (62·66 mmol/mol) at baseline to 7·41% (57·5 mmol/mol) at week 26 with efsitora and from 7·94% (63·3 mmol/mol) at baseline to 7·36% (56·9 mmol/mol) at week 26 with degludec. Mean HbA1c change from baseline to week 26 was –0·51% with efsitora and –0·56% with degludec (estimated treatment difference 0·052%, 95% CI –0·077 to 0·181; p=0·43), confirming a non-inferiority margin of 0·4% for efsitora compared with degludec. Rates of combined level 2 (<54 mg/dL [3·0 mmol/L]) or level 3 severe hypoglycaemia were higher with efsitora compared with degludec (14·03 vs 11·59 events per patient year of exposure; estimated rate ratio 1·21, 95% CI 1·04 to 1·41; p=0·016) during weeks 0–52, with the highest rates during weeks 0–12. Severe hypoglycaemia incidence was higher with efsitora (35 [10%] of 343) versus degludec (11 [3%] of 349) during weeks 0–52. Overall incidence of treatment-emergent adverse events was similar across treatment groups. One death not related to the study treatment occurred in the degludec group. In adults with type 1 diabetes, once-weekly efsitora showed non-inferior HbA1c reduction compared with daily insulin degludec. Higher rates of combined level 2 or level 3 hypoglycaemia and greater incidence of severe hypoglycaemia in participants treated with efsitora compared with participants treated with degludec might suggest the need for additional evaluation of efsitora dose initiation and optimisation in people with type 1 diabetes. Eli Lilly and Company.

Once-weekly insulin efsitora alfa (efsitora) is in development for the treatment of people with diabetes. The aim of the current study was to assess the efficacy and safety of once-weekly efsitora compared with daily insulin degludec (degludec) in adults with type 2 diabetes using basal insulin. This randomised, 78-week, phase 3, parallel-design, open-label, treat-to-target, non-inferiority study (QWINT-3) was conducted at 127 sites across nine countries. Adults (aged ≥18 years) with type 2 diabetes currently treated with basal insulin, up to three non-insulin glucose-lowering medications without prandial insulin, and glycated haemoglobin A1c (HbA1c) 6·5–10·0% (48–86 mmol/mol) were eligible. Participants were randomly assigned (2:1) to receive efsitora (n=655) or degludec (n=331). The primary endpoint was the change in least-squares mean HbA1c concentration from baseline to week 26, assessed in all randomly allocated participants who took at least one dose of study drug (excluding those who discontinued due to inadvertent enrolment), with a non-inferiority margin of 0·4% for efsitora versus degludec. The completed trial is registered at ClinicalTrials.gov (NCT05275400). Between March 8, 2022, and May 15, 2024, 1229 participants were enrolled and 986 (80%) were randomly allocated: 655 to the efsitora group and 331 to the degludec group, all of whom received at least one dose of study treatment. 871 (88%) of those randomly allocated completed 78 weeks of treatment. The population comprised 431 (44%) female and 555 (56%) male patients, median age was 62·0 years (IQR 54·0–68·0), baseline BMI was 29·65 kg/m2 (IQR 26·32–34·12), and HbA1c concentration was 7·7% (7·1–8·4). The least-squares mean change from baseline to week 26 in HbA1c concentration was –0·81 percentage points (SE 0·03; –8·85 mmol/mol [0·33]) in the efsitora group and –0·72 percentage points (0·04; –7·88 mmol/mol [0·46]) in the degludec group (estimated treatment difference –0·09 percentage points [95% CI –0·19 to 0·01]), indicating non-inferiority of efsitora to degludec. Combined level 2 hypoglycaemia (glucose concentration <54 mg/dL [<3·0 mmol/L]) or level 3 (severe) hypoglycaemia events from baseline to week 78 occurred at a similar rate for efsitora (0·84 events per patient-year of exposure; 754 events in 268 [41%] participants) and degludec (0·74 per patient-year of exposure; 346 events in 123 [37%] participants; estimated rate ratio 1·14 [95% CI 0·83–1·56]; p=0·43). Serious adverse events occurred in 103 (16%; 7 [1%] related to treatment) efsitora-treated and 37 (11%; 1 [<1%] related to treatment) degludec-treated participants; the most frequent (at ∼1%) were primarily cardiovascular-related in both groups. Nine deaths (seven in the efsitora group and two in the degludec group) occurred during the trial, but none were related to study treatment. Efsitora is a well tolerated and efficacious once-weekly alternative to daily basal insulin, with a reduced injection frequency, for the treatment of adults with type 2 diabetes. Eli Lilly and Company.

In vivo, after subcutaneous injection, insulin glargine (21(A)-Gly-31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly-human insulin (metabolite 1 [M1]). 21(A)-Gly-des-30(B)-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects. Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units · kg(-1) glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng · mL(-1) (33 pmol · L(-1)) per analyte. Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve between time of dosing and 30 h after dosing (AUC(0-30h)) was 1,261 (66), 2,867 (35), and 4,693 (22) pmol · h · L(-1) at doses of 0.3, 0.6, and 1.2 units · kg(-1), respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC(0-30h) of the glucose infusion rate following glargine administration (r = 0.74; P < 0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points. After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine is marginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21(A)-Gly-human insulin), which mediates the metabolic effect of injected glargine.

Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes. In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin [HbA1c] ≤10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA1c after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228. Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA1c had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference −0·01% points [95% CI −0·14 to 0·11]; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA1c of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1·07 [0·89 to 1·28]; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 [0·59 to 0·96]; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups. Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy. Novo Nordisk.

In this randomized, double-blind trial involving patients with type 2 diabetes at high risk for cardiovascular events, basal insulin degludec was noninferior to glargine with respect to major cardiovascular events.

In this randomized, double-blind, double-dummy, phase 2 trial, the efficacy and safety of once-weekly treatment with the basal insulin analogue icodec were compared with those of once-daily insulin glargine U100 in patients with type 2 diabetes who had not taken insulin. Once-weekly icodec had glucose-lowering efficacy and a safety profile similar to those of once-daily glargine.