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In a 13-week, randomized trial involving persons 6 to 79 years of age with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction in the glycated hemoglobin level than standard care.

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.

Insulin efsitora alfa (efsitora), a once-weekly basal insulin, has the potential to reduce the treatment burden of people with type 2 diabetes who require insulin. We aimed to assess the efficacy and safety of once-weekly efsitora compared with insulin glargine U100 in adults with type 2 diabetes treated with basal and prandial insulin. This phase 3, randomised, 26-week, parallel-design, open-label, treat-to-target, non-inferiority study was done at 78 outpatient clinics and hospitals in Argentina, Germany, India, Italy, Mexico, Spain, and the USA (including Puerto Rico). Participants with type 2 diabetes (glycated haemoglobin [HbA1c] 7·0–10·0%) treated with basal and prandial insulin and up to three non-insulin glucose-lowering agents were randomly assigned (1:1) to efsitora or glargine U100, both with prandial insulin lispro. Randomisation was stratified by country, baseline HbA1c (<8% vs ≥8%; <63·9 mmol/mol vs ≥63·9 mmol/mol), and routine use of personal continuous glucose monitoring or flash glucose monitoring at randomisation (yes vs no). The primary endpoint was HbA1c change from baseline to week 26 (non-inferiority margin 0·4%). The completed trial is registered at ClinicalTrials.gov (NCT05462756). Between Aug 11, 2022, and Feb 27, 2024, 1037 study participants were screened and 730 were randomly assigned to efsitora (n=365) or glargine U100 (n=365). 369 (51%) of 730 participants were female and 361 (49%) were male, the mean participant age was 58·9 years (SD 10·5), and the mean participant BMI was 31·85 kg/m2 (SD 5·47). Using the treatment regimen estimand, the least-squares mean baseline HbA1c was 8·18% (SE 0·04; 65·9 mmol/mol [SE 0·47]) in the efsitora group and 8·18% (0·04; 65·9 mmol/mol [0·47]) in the glargine U100 group. At week 26, the least-squares mean HbA1c was 7·17% (SD 0·05; 54·8 mmol/mol [0·51]) in the efsitora group and 7·18 (0·05; 55·0 mmol/mol [0·51]) in the glargine U100 group. The change from baseline to week 26 using the treatment regimen estimand was –1·01 percentage points for the efsitora group and –1·00 percentage points for the glargine U100 group, indicating non-inferiority of efsitora versus glargine U100. Rates of overall and nocturnal level 2 (<54 mg/dL; 3·0 mmol/L) or level 3 (severe) hypoglycaemia during the treatment period were similar for efsitora versus glargine U100 (6·6 vs 5·9 events per patient-year of exposure, estimated rate ratio [ERR] 1·11, 95% CI 0·85–1·44; p=0·44; 0·67 vs 1·00 events per patient-year of exposure, ERR 0·67, 95% CI 0·44–1·01; p=0·058), respectively. Adverse event occurrence was similar between efsitora and glargine U100. Serious adverse events were reported by 25 (7%) of 365 participants in the efsitora group and 23 (6%) of 365 participants in the glargine U100 group. Efsitora showed non-inferior HbA1c reductions and similar rates of combined clinically significant or severe hypoglycaemia versus glargine U100 in participants with type 2 diabetes treated with basal and prandial insulin. These findings show that 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.

The development of effective and safe insulin analogs remains pivotal in advancing diabetes management. This study addresses the limitations of existing insulin therapies by introducing insulin lisargine, a novel long-acting insulin analog that resolves impurity formation associated with trypsin cleavage in glargine insulin. Insulin lisargine is characterized by glycine substitution at A21 and the addition of lysine and arginine at B31 and B32, respectively. High-performance liquid chromatography (HPLC) and mass spectrometry confirmed its high purity and precise molecular weight. X-ray crystallography at 2.0 Å resolution revealed structural features closely resembling human insulin, crucial for optimizing drug formulations and understanding receptor interactions.In vivo experiments demonstrated that insulin lisargine exhibits superior glucose-lowering effects compared to glargine insulin (Lantus). At a dosage of 1.5 IU/kg, lisargine achieved glucose-lowering effects equivalent to glargine in normal rats. However, at 5 IU/kg, it significantly outperformed glargine in type 1 diabetic rats. Long-term safety assessments revealed a comparable safety profile between lisargine and glargine, with no significant toxicity observed. These findings position insulin lisargine as a promising candidate for diabetes management, offering enhanced blood glucose control, improved production efficiency, and reliable safety. The study’s findings provide a foundation for the development of more effective insulin analogs, addressing critical needs in diabetes therapy.

Background This study was performed to satisfy a US Food and Drug Administration post-marketing requirement to compare the dose responses for Technosphere ® Insulin (TI; MannKind Corporation, Westlake Village, CA, USA) and subcutaneous insulin lispro (LIS) across a wide range of doses. Objectives This single-center, open-label, randomized, cross-over study defined the pharmacokinetic/pharmacodynamic curves for inhaled TI vs subcutaneous LIS in persons with type 1 diabetes mellitus. Methods Each volunteer received six treatments while undergoing euglycemic clamps: three doses of TI (10, 30 and 120 U) and LIS (8, 30, and 90 U). Primary endpoint was area under the glucose infusion rate vs time curve from start of treatment administration to end of clamp. Key secondary endpoints included readouts of insulin exposure and timing of pharmacokinetic/pharmacodynamic profiles. Results Insulin exposure was more than dose proportional, increasing with dose 1.08 for LIS and dose 1.35 for TI. Time to reach 10% of the maximum glucose infusion rate was 7 to 15 min for TI vs 21 to 38 min for LIS. End of effect was dose dependent for both treatments, ranging from 2 to 6 h (TI) and 5 to 10 h (LIS). Glucose infusion rate exhibited saturation for both treatments. Technosphere Insulin produced a lesser total effect per unit insulin than LIS due to its faster absorption and correspondingly shorter duration of exposure. The difference was large enough to require significantly different doses to achieve the same total effect. Conclusions Technosphere Insulin has a considerably faster onset and shorter duration of action than LIS. Consequently, the overall effect of TI is smaller than that of LIS and unit-for-unit dose conversion is not appropriate. Clinical Trial Registration ClinicalTrials.gov, NCT02470637; 12 June, 2015

Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.

To evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL). This 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A(1c) [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning. At 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (-0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: -0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001). In patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.

Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects. This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured. Across all 3 doses, insulin lispro appeared in the serum 2–5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%–52% lower, and duration of exposure was 67–86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7–9 min faster and insulin action was ~3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%–45%, and duration of action was reduced by 47–67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro. URLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited dose-proportional increases in exposure in healthy subjects. ClinicalTrials.gov identifier: NCT03286751. •Insulin absorption was up to 7-fold faster with URLi vs Lispro for all doses.•Early glucose lowering was greater with URLi vs Lispro across all dose levels.•Late insulin exposure and action were reduced with URLi vs Lispro for all doses.•Dose proportional increases in exposure were observed for URLi.•Both URLi and Lispro showed less than dose proportional increases in insulin action.

Subcutaneous insulin resistance syndrome is a rare condition that causes difficulty in glycemic control due to severe resistance to subcutaneous insulin injections. We herein present a case of a 40‐year‐old woman with type 2 diabetes mellitus who had been diagnosed with subcutaneous insulin resistance syndrome since the age of 29 years, and had been persistently treated with continuous subcutaneous insulin infusion using a mixture of insulin lispro and heparin. The patient was switched from insulin lispro plus heparin to ultra‐rapid insulin lispro; given that it contains treprostinil and citrate, it is expected to have similar effects as heparin, and shows similar glucose‐lowering effects and insulin absorption. Our results suggest that treatment with ultra‐rapid insulin lispro is effective for subcutaneous insulin resistance syndrome. We reported a case of subcutaneous insulin resistance syndrome that achieved good glycemic control with ultra‐rapid insulin lispro, novel insulin formulation. Although it has been reported that the combination of insulin lispro and heparin is effective for subcutaneous insulin resistance syndrome, it is suggested that ultra‐rapid insulin lispro might provide good glycemic control without heparin.

ABSTRACT Purpose Determine the pharmacokinetics of insulin peglispro (BIL) in 5/6-nephrectomized rats and study the absorption in lymph duct cannulated (LDC) sheep. Methods BIL is insulin lispro modified with 20-kDa linear PEG at lysine B28 increasing the hydrodynamic size to 4-fold larger than insulin lispro. Pharmacokinetics of BIL and insulin lispro after IV administration were compared in 5/6-nephrectomized and sham rats. BIL was administered IV or SC into the interdigital space of the hind leg, and peripheral lymph and/or serum samples were collected from both LDC and non-LDC sheep to determine pharmacokinetics and absorption route of BIL. Results The clearance of BIL was similar in 5/6-nephrectomized and sham rats, while the clearance of insulin lispro was 3.3-fold slower in 5/6-nephrectomized rats than in the sham rats. In non-LDC sheep, the terminal half-life after SC was about twice as long vs IV suggesting flip-flop pharmacokinetics. In LDC sheep, bioavailability decreased to <2%; most of the dose was absorbed via the lymphatic system, with 88% ± 19% of the dose collected in the lymph after SC administration. Conclusion This work demonstrates that increasing the hydrodynamic size of insulin lispro through PEGylation can impact both absorption and clearance to prolong drug action.