New Insulins,Biosimilars,and Insulin Therapy

Ann Intern Med 2023; 176: 1476–1485

Background

Inadequate dose titration and poor adherence to basal insulin can lead to suboptimal glycemic control in persons with type 2 diabetes (T2D). Once-weekly insulin icodec (icodec) is a basal insulin analogue that is in development and is aimed at reducing treatment burden.

Objective

The objective of this study is to compare the effectiveness and safety of icodec titrated with a dosing guide app (icodec with app) versus once-daily basal insulin analogues (OD analogues) dosed per standard practice.

Design for this study is a 52-week, randomized, open-label, parallel-group, phase 3a trial with real-world elements.

Setting

Setting for this study included 176 sites in seven countries.

Participants

Participants were 1,085 insulin-naive adults with T2D.

Intervention

Intervention adopted was Icodec with app or OD analogue (insulin degludec, insulin glargine U100, or insulin glargine U300).

Measurements

The primary outcome was change in glycated hemoglobin (HbA1c) level from baseline to week 52. Secondary outcomes included patient-reported outcomes (Treatment-Related Impact Measure for Diabetes [TRIM-D] compliance domain score and change in Diabetes Treatment Satisfaction Questionnaire [DTSQ] total treatment satisfaction score).

Results

The estimated mean change in HbA1c level from baseline to week 52 was greater with icodec with app than with OD analogues, with noninferiority (P < 0.001) and superiority (P = 0.009) confirmed in prespecified hierarchical testing (estimated treatment difference [ETD], −0.38 percentage points [95% CI, −0.66 to −0.09 percentage points]). At week 52, patient-reported outcomes were more favorable with icodec with app than with OD analogues (ETDs, 3.04 [CI, 1.28 to 4.81] for TRIM-D and 0.78 [CI, 0.10 to 1.47] for DTSQ). Rates of clinically significant or severe hypoglycemia were low and similar with both treatments.

Limitations

Limitations include inability to differentiate the effects of icodec and the dosing guide app.

Conclusions

Compared with OD analogues, icodec with app showed superior HbA1c reduction and improved treatment satisfaction and compliance with similarly low hypoglycemia rates.

Diabetes Care 2024; 47: 729–738

This manuscript is also discussed in Chapter 2, page 52

Objective

This post hoc analysis assessed continuous glucose monitoring (CGM)-based metrics and hypoglycemia duration with once-weekly insulin icodec versus once-daily basal insulin analogs in insulin-experienced individuals with long-standing type 2 diabetes from two 26-week phase 3a trials (ONWARDS 2 and ONWARDS 4).

Research Design and Methods

Time in range (TIR) (3.9–10.0 mmol/L), time above range (TAR) (>10.0 mmol/L), and time below range (TBR) (<3.9 mmol/L and <3.0 mmol/L) were assessed during three CGM time periods (switch [weeks 0–4], end of treatment [weeks 22–26], and follow-up [weeks 27–31]) for icodec versus comparators (ONWARDS 2, insulin degludec [basal regimen]; ONWARDS 4, insulin glargine U100 [basal-bolus regimen]) using double-blind CGM data. CGM-derived hypoglycemic episode duration (<3.9 mmol/L) was assessed.

Results

In both trials, there were no statistically significant differences in TIR, TAR, or TBR (<3.0 mmol/L) for icodec versus comparators across all time periods. In the end-of-treatment period, mean TIR was 63.1% (icodec) vs. 59.5% (degludec) in ONWARDS 2 and 66.9% (icodec) vs. 66.4% (glargine U100) in ONWARDS 4. Mean TBR <3.9 mmol/L and <3.0 mmol/L remained within recommended targets (<4% and <1%, respectively) across time periods and treatment arms. Hypoglycemic episode duration (<3.9 mmol/L) was comparable across time periods and treatment arms (median duration ≤40 min).

Conclusions

In insulin-experienced participants with long-standing type 2 diabetes, CGM-based TIR, TAR, and CGM-derived hypoglycemia duration (<3.9 mmol/L) were comparable for icodec and once-daily basal insulin analogs during all time periods. TBR remained within recommended targets.

Comments

The underlying studies have been reported in 2023’s ATTD yearbook (9, 10). However, both studies included studies phases during which CGM data were recorded. They showed no differences between treatment arms and periods. Thus, one can assume, without any general risk for deterioration of glycemic control, PwD with type 2 diabetes could possibly save six injections per week after changing to icodec.

Diabetes Obes Metab 2023; 25: 3716–3723

Aims

This study aims to characterize the pharmacokinetic and pharmacodynamic properties of once-weekly insulin icodec in type 2 diabetes (T2D).

Materials and Methods

In an open-label trial, 46 individuals with T2D (18–75 years; body mass index 18.0–38.0 kg/m²; glycated hemoglobin ≤75 mmol/mol [≤9%]; basal insulin-treated) received subcutaneous once-weekly icodec for ≥8 weeks at individualized doses, aiming at a prebreakfast plasma glucose concentration of 4.4 to 7.0 mmol/L (80–126 mg/dL) on the last three mornings of each weekly dosing interval. Frequent blood sampling to assess total serum icodec concentration (i.e., albumin-bound and unbound) occurred from first icodec dose until 35 days after last dose. Icodec trough concentrations following initiation of once-weekly dosing were predicted by pharmacokinetic modeling. During the final 3 weeks of icodec treatment, while at steady state, the icodec glucose-lowering effect was assessed in three glucose clamps (target 7.5 mmol/L [135 mg/dL]): 0 to 36, 40 to 64, and 144 to 168 h post dose, thus covering the initial, middle, and last part of the 1-week dosing interval. Glucose-lowering effect during a complete dosing interval was predicted by pharmacokinetic-pharmacodynamic modeling.

Results

Model-predicted icodec steady state was attained after 3 to 4 weeks. At steady state, model-predicted daily proportions of glucose-lowering effect on days 1 to 7 of the 1-week dosing interval were 14.1%, 16.1%, 15.8%, 15.0%, 14.0%, 13.0%, and 12.0%, respectively. Icodec duration of action was at least 1 week in all participants. Once-weekly icodec was overall safe and well tolerated in the current trial.

Conclusions

The pharmacokinetic and pharmacodynamic characteristics of icodec in individuals with T2D support its potential as a once-weekly basal insulin.

Diabetes Obes Metab 2024; 26: 1941–1949

Aims

This study aims to investigate the pharmacokinetic/pharmacodynamic properties of once-weekly insulin icodec in individuals with type 1 diabetes (T1D).

Materials and methods

In this randomized, open-label, two-period crossover trial, 66 individuals with T1D (age 18–64 years; glycated hemoglobin ≤75 mmol/mol [≤ 9%]) were to receive once-weekly icodec (8 weeks) and once-daily insulin glargine U100 (2 weeks) at individualized fixed equimolar total weekly doses established during up to 10 weeks' run-in with glargine U100 titrated to prebreakfast plasma glucose (PG) of 4.4–7.2 mmol/L (80–130 mg/dL). Insulin aspart was used as bolus insulin. Blood sampling for icodec pharmacokinetics was performed from the first icodec dose until 35 days after the last dose. The glucose infusion rate at steady state was assessed in glucose clamps (target 6.7 mmol/L [120 mg/dL]) at 16–52 h and 138–168 h after the last icodec dose and 0–24 h after the last glargine U100 dose. Icodec pharmacodynamics during 1 week were predicted by pharmacokinetic-pharmacodynamic modeling. Hypoglycemia was recorded during the treatment periods based on self-measured PG.

Results

Icodec reached pharmacokinetic steady state on average within 2–3 weeks. At steady state, model-predicted daily proportions of glucose infusion rate during the 1-week dosing interval were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6%, and 8.4%, respectively. Rates and duration of Level 2 hypoglycemic episodes (PG <3.0 mmol/L [54 mg/dL]) were 32.8 versus 23.9 episodes per participant-year of exposure and 33 ± 25 versus 30 ± 18 min (mean ± SD) for icodec versus glargine U100.

Conclusions

The pharmacokinetic/pharmacodynamic properties of icodec suggest its potential to provide basal coverage in a basal-bolus insulin regimen in people with T1D.

Lancet 2023; 402 (10413): 1636–1647

Background

ONWARDS 6 compared the efficacy and safety of once-weekly subcutaneous insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with type 1 diabetes.

Methods

This 52-week (26-week main phase plus a 26-week safety extension), randomized, open-label, treat-to-target, phase 3a trial was done at 99 sites across 12 countries. Adults with type 1 diabetes (glycated hemoglobin [HbA_1c] <10.0% [86 mmol/mol]) were randomly assigned (1:1) to once-weekly icodec or once-daily degludec, both in combination with insulin aspart (two or more daily injections). The primary endpoint was change in HbA_1c from baseline to week 26, tested for noninferiority (0.3 percentage point margin) in all randomly assigned participants.

Findings

Between April 30 and Oct 15, 2021, of 655 participants screened, 582 participants were randomly assigned to icodec (n = 290) or degludec (n = 292). At week 26, from baseline values of 7.59% (icodec) and 7.63% (degludec), estimated mean changes in HbA_1c were −0.47 percentage points and −0.51 percentage points, respectively (estimated treatment difference 0.05 percentage points [95% CI −0.13 to 0.23]), confirming noninferiority of icodec to degludec (P = 0.0065). Overall rate of combined clinically significant or severe hypoglycemia (baseline to week 26) was statistically significantly higher with icodec than degludec (19.9 vs 10.4 events per patient-year of exposure; estimated rate ratio 1.9 [95% CI 1.5 to 2.3]; P < 0.0001). The rate was also statistically significantly higher with icodec than degludec when evaluated over 57 weeks (52 weeks plus a 5-week follow-up period). A total of 39 serious adverse events were reported in 24 (8%) participants receiving icodec, and 25 serious adverse events were reported in 20 (7%) participants receiving degludec. One participant in the icodec group died; this was judged unlikely to be due to the trial product.

Interpretation

In adults with type 1 diabetes, once-weekly icodec showed noninferiority to once-daily degludec in HbA_1c reduction at week 26, with statistically significantly higher rates of combined clinically significant or severe hypoglycemia. For icodec, time below 3.0 mmol/L (<54 mg/dL) was at the threshold of the internationally recommended target (<1%) during weeks 22–26 and below target during weeks 48–52.

Comments

Although clinical data from large-scale phase-III trials were already presented, pharmacokinetic and pharmacodynamic data of icodec are available now for PwD with type 1 diabetes and type 2 diabetes. In PwD with type 1 diabetes, the highest proportion of exposure AUC was observed at day 2 after injections with a higher decrease to the end of the week while the whole distribution was more balanced in PwD with type 2 diabetes.

In the one-year real-life study ONWARDS 6, the hypoglycemia rate was higher in the icodec group than in degludec, with the majority of severe events in one person. These interdaily differences combined with a higher weekly bolus dose and lower weekly bolus insulin dose in Icodec group might contribute to a higher low event rate. Nevertheless, the general event rate was lower than in other studies, in CGM evaluation consensus targets for time-below-range were met and no safety concerns appeared.

Interestingly, in the weekly group some concerns where possible, that long-experienced PwD living with type 1 diabetes were not able to vary their daily injected basal insulin.

Diabetologia 2023; 66: 1413–1430

Aims/Hypothesis

This study compared the frequency of hypoglycemia, time to hypoglycemia and recovery from hypoglycemia after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100. Furthermore, the symptomatic and counterregulatory responses to hypoglycemia were compared between icodec and glargine U100 treatment.

Methods

In a randomized, single-center (Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria), open-label, two-period crossover trial, individuals with type 2 diabetes (age 18–72 years, BMI 18.5–37.9 kg/m², HbA_1c ≤75 mmol/mol [≤9.0%]) treated with basal insulin with or without oral glucose-lowering drugs received once-weekly icodec (for 6 weeks) and once-daily glargine U100 (for 11 days). Total weekly doses were equimolar based on individual titration of daily glargine U100 during the run-in period (target fasting plasma glucose [PG]: 4.4–7.2 mmol/L). Randomization was carried out by assigning a randomization number to each participant in ascending order, which encoded to one of two treatment sequences via a randomization list prepared prior to the start of the trial. At steady state, double and triple doses of icodec and glargine U100 were administered followed by hypoglycemia induction: first, euglycemia was maintained at 5.5 mmol/L by variable i.v. infusion of glucose; glucose infusion was then terminated, allowing PG to decrease to no less than 2.5 mmol/L (target PG_nadir). The PG_nadir was maintained for 15 min. Euglycemia was restored by constant i.v. glucose (5.5 mg kg⁻¹ min⁻¹). Hypoglycemic symptoms score (HSS), counterregulatory hormones, vital signs, and cognitive function were assessed at predefined PG levels towards the PG_nadir.

Results

Hypoglycemia induction was initiated in 43 and 42 participants after double dose of icodec and glargine U100, respectively, and in 38 and 40 participants after triple doses, respectively. Clinically significant hypoglycemia, defined as PG_nadir <3.0 mmol/L, occurred in comparable proportions of individuals treated with icodec vs glargine U100 after double (17 [39.5%] vs 15 [35.7%]; P = 0.63) and triple (20 [52.6%] vs 28 [70.0%]; P = 0.14) doses. No statistically significant treatment differences were observed in the time to decline from PG values of 5.5 mmol/L to 3.0 mmol/L (2.9–4.5 h after double dose and 2.2–2.4 h after triple dose of the insulin products). The proportion of participants with PG_nadir ≤2.5 mmol/L was comparable between treatments after double dose (2 [4.7%] for icodec vs 3 [7.1%] for glargine U100; P = 0.63) but higher for glargine U100 after triple dose (1 [2.6%] vs 10 [25.0%]; P = 0.03). Recovery from hypoglycemia by constant i.v. glucose infusion took <30 min for all treatments. Analyses of the physiological response to hypoglycemia only included data from participants with PG_nadir <3.0 mmol/L and/or the presence of hypoglycemic symptoms; in total 20 (46.5%) and 19 (45.2%) individuals were included after a double dose of icodec and glargine U100, respectively, and 20 (52.6%) and 29 (72.5%) individuals were included after a triple dose of icodec and glargine U100, respectively. All counterregulatory hormones (glucagon, adrenaline [epinephrine], noradrenaline [norepinephrine], cortisol, and growth hormone) increased during hypoglycemia induction with both insulin products at both doses. Following triple doses, the hormone response was greater with icodec vs glargine U100 for adrenaline at PG_3.0 mmol/L (treatment ratio 2.54 [95% CI 1.69, 3.82]; P < 0.001), and cortisol at PG_3.0 mmol/L (treatment ratio 1.64 [95% CI 1.13, 2.38]; P = 0.01) and PG_nadir (treatment ratio 1.80 [95% CI 1.09, 2.97]; P = 0.02). There were no statistically significant treatment differences in the HSS, vital signs, and cognitive function.

Conclusions/Interpretation

Double or triple doses of once-weekly icodec lead to a similar risk of hypoglycemia compared with double or triple doses of once-daily glargine U100. During hypoglycemia, comparable symptomatic and moderately greater endocrine responses are elicited by icodec vs glargine U100.

Comments

The authors show a hypoglycemia induction in PwD with type 2 diabetes patients with similar effects in both insulins by doubled or tripled doses. The higher endocrine response in tripled Icodec remains unclear but might be an explanation for less low events. The authors hypothesize that the stress of receiving the new insulin in an open-labeled trial might be a trigger for that, but the vital sign data from the supplement showed no general differences and adequate reaction to the nadir event. Nevertheless, the comparable recovery after glucose infusion combined with the concept of skipping the next regular dose shows promise for upcoming emergencies after fail-dosing. To follow that concept, a recognition of failure, e.g., by smart/connected pens, is necessary.

Diabetes Ther 2024; 15: 1785–1797

Introduction

Insulin efsitora alfa (efsitora) is a basal insulin with a flat pharmacokinetic profile and long half-life, enabling weekly dosing. These attributes may provide stable glucose levels. This exploratory phase 1 study aimed to assess the hypoglycemic risk during experimental conditions that mimic situations encountered in daily life.

Methods

This was a single-site, open-label, two-period, fixed-sequence study in participants with type 2 diabetes (T2D) previously treated with basal insulin. The incidence, duration, and nadir glucose of hypoglycemia were assessed after treatment with efsitora versus insulin glargine (glargine) during three provocation conditions: 24-h prolonged fasting, prolonged fasting with exercise, and double dosing of study insulin.

Results

The 54 enrolled adults (BMI 21.8–39.7 kg/m², HbA1c 6.5–9.4%) achieved stable fasting glucose before undergoing provocation. Most hypoglycemic events were level 1 (≥54 to <70 mg/dL) and resolved spontaneously or after oral glucose. The incidences of level 1 hypoglycemia for efsitora and glargine were not significantly different: for prolonged fasting, the incidences were 44.7 vs. 42.6% and the difference in proportion was 2.1% (95% CI: −17.2, 21.4); for prolonged fasting with exercise, the corresponding values were 65.9 vs. 50.0% and 15.9% (−3.0, 34.8); for double dosing, the corresponding values were 68.1 vs. 61.7% and 6.4% (−12.8, 25.6). Level 2 hypoglycemia (<54 mg/dL) was infrequent during both treatments and all provocations. No severe hypoglycemia was observed. Mean nadir glucose (range 62.8–66.3 mg/dL) and hypoglycemia duration (range 76.6–115.2 min) were also similar for the two treatments, depending on the provocation.

Conclusions

Overall, weekly efsitora did not increase the incidence, duration, or severity of hypoglycemia compared to daily glargine during provocation periods in patients with T2D.

Comments

With efsitora, also a hypoglycemia induction study was performed. While also using the double-dose approach, two other, life-mimicking scenarios with exercise a prolonged fasting were used. While during the prolonged fasting, hypoglycemia episodes were the same in both groups, the number was higher in the efsitora group when exercise was added. The same was observed for the double-dose phase. One has to admit that general glycemia was lower in the efsitora group and level-1-hypoglycemic events were only treated when symptomatic. This procedure might have led to more level 2 events, but is a near-living approach. Data from the large-scale efsitora studies will be looked at carefully concerning this topic.

Diabetes Obes Metab 2023; 25: 2279–2289

Aims

This study aims to determine whether the use of long-acting insulin analogues is associated with an increased risk of incident diabetic retinopathy (DR) among patients with type 2 diabetes.

Methods

Using data from the Clinical Practice Research Datalink Aurum, this retrospective, population-based cohort study included patients with type 2 diabetes who initiated a long-acting insulin analogue (glargine, detemir, degludec) or Neutral Protamine Hagedorn (NPH) insulin. The primary outcome was incident DR. We used Cox proportional hazards models with inverse probability of treatment weighting to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DR with insulin analogues versus NPH insulin.

Results

There were 66,280 new users of long-acting insulin analogues and 66,173 new users of NPH insulin. The incidence rate of DR was 101.7 per 1,000 person-years (95% CI, 98.7–104.8) for insulin analogues and 93.2 (95% CI, 90.0–96.5) per 1,000 person-years for NPH insulin. Compared with the current use of NPH insulin, insulin analogues were not associated with the risk of incident DR (HR 1.04, 95% CI, 0.99–1.09). The adjusted HRs were 0.84 (95% CI, 0.66–1.07) for proliferative DR and 1.02 (95% CI, 0.97–1.08) for nonproliferative DR.

Conclusions

Compared with NPH insulin, long-acting insulin analogues were not associated with the risk of incident DR among patients with type 2 diabetes. This finding provides important reassurance regarding the safety of long-acting insulin analogues with respect to incident DR.

Comments

In the development of diabetic retinopathy, there is an upregulation of IGF1-receptors, treatment is e.g. intraocular anti-IGF1 agents. The hypothesis of this study was based on the older data of higher mitogenic potential due to IGF1-affinity by insulin glargine (11, 12). Although it is well known that in-vitro data does not play an in-vivo carcinogenetic role and a 5-year trial showed no increased risk for retinopathy or malignancy with glargine (13, 14), this large-scale registry data shows clearly once more the nonincreasing risk of retinopathy with long-acting analogs for long-time periods.

Diabet Med 2023; 40: e15123

Background

In youth with type 1 diabetes (T1D), high hemoglobin A1c (HbA1c) levels are associated with an increased risk for diabetic ketoacidosis (DKA).

Aims

This study examined whether daily school-supervised basal insulin injections were feasible and if they reduced the risk of morning ketosis in children and adolescents with high HbA1c levels. We hypothesized that supervised glargine and degludec would reduce the risk of ketosis and that the prolonged action of degludec would protect from ketosis after consecutive days of unsupervised injections.

Materials and Methods

After a 2–4-week run-in, youth (10–18 years, HbA1c ≥ 8.5%) managing T1D with injections were randomized to school-supervised administration of degludec or glargine for 4 months. School nurses observed daily blood β-hydroxybutyrate (BHB) and glucose checks. During COVID closures, the research team supervised procedures remotely.

Results

Data from 28 youth (age 14.3 ± 2.3 years, HbA1c 11.4 ± 1.9%, 64% F) were analyzed. School-supervised injections of both basal insulins for 1–4 days progressively lowered the percent of participants with elevated BHB. The percent of participants with elevated BHB (≥0.6 mmol/L) after 2 days of unsupervised basal insulin doses at home was greater in the glargine than degludec group but had a high P-value (17.2% vs. 9.0%, P = 0.3). HbA1c was unchanged in both groups.

Discussions

In youth with T1D at high risk for DKA, daily supervised long-acting insulin administration decreased the probability of elevated ketone levels on subsequent school days, regardless of basal insulin type. A larger sample size may have demonstrated that the longer action profile of degludec would offer additional protection from ketosis during days of not attending school.

Conclusions

Engaging school-based caregivers in management of youth with T1D on injected insulin may decrease clinically significant ketosis and minimize acute complications of diabetes.

Comments

This study recruited a population of PwD with HbA1c well above glycemic target (>8.5%). The title is misleading, as there are “ultra”-long-acting analogs mentioned. These kids had fewer ketonemic events while having supervised basal injections. Fewer ketones mean less risk for acute events. In children with such a high HbA1c, nonadherence to treatment is not the kids' fault, there are usually family issues that contribute. These kids benefit from external care. This is especially interesting for countries, where health care at school is not established. The same mean glycemic levels in both groups confirms once more, the “basic” knowledge, that basal insulin brings safety, and treatment targets are reached by bolus management.

Expert Opin Biol Ther 2024; 24: 543–561

Introduction

We evaluated a potential move from one rapid-acting insulin analog to another, or their biosimilars, to aid better and faster decisions for diabetes management.

Methods

A systematic literature review was performed according to PRISMA reporting guidelines. The MEDLINE/EMBASE/COCHRANE databases were searched for randomized control trials (RCTs) comparing aspart/lispro in type-1 (T1D) and type-2 (T2D) diabetes. The methodological quality of the included studies was assessed using the Cochrane Collaboration's risk of bias assessment criteria.

Results

Of the 753 records retrieved, the six selected efficacy/safety RCTs and the additional three hand-searched pharmacokinetics/pharmacodynamics RCTs showed some heterogeneity in the presentation of the continuous variables; however, collectively, the outcomes demonstrated that lispro and aspart had comparable efficacy and safety in adult patients with T1D and T2D. Both treatments yielded a similar decrease in glycated hemoglobin (HbA1c) and had similar dosing and weight changes, with similar treatment-emergent adverse events (TEAE) and serious adverse event (SAE) reporting, similar hypoglycemic episodes in both T1D and T2D populations, and no clinically significant differences for hyperglycemia, occlusions, or other infusion site/set complications.

Conclusions

Aspart and lispro demonstrate comparative safety and efficacy in patients with T1D/T2D. Since both are deemed equally suitable for controlling prandial glycemic excursions and both have similar safety attributes, they may be used interchangeably in clinical practice.

Diabetes Ther 2023; 14: 1563–1575

Introduction

This study utilized continuous glucose monitoring data to analyze the effects of switching to treatment with fast-acting insulin aspart (faster aspart) in adults with type 1 diabetes (T1D) in clinical practice.

Methods

A noninterventional database review was conducted in Sweden among adults with T1D using multiple daily injection (MDI) regimens who had switched to treatment with faster aspart as part of basal-bolus treatment. Glycemic data were retrospectively collected during the 26 weeks before switching (baseline) and up to 32 weeks after switching (follow-up) to assess changes in time in glycemic range (TIR; 70–180 mg/dL), mean sensor glucose, glycated hemoglobin (HbA1c) levels, coefficient of variation, time in hyperglycemia (level 1, >180 to ≤250 mg/dL; level 2, >250 mg/dL), and time in hypoglycemia (level 1, ≥54 to <70 mg/dL; level 2, <54 mg/dL).

Results

Overall, 178 participants were included in the study cohort. The analysis population included 82 individuals (mean age 48.5 years) with adequate glucose sensor data. From baseline to follow-up, statistically significant improvements were reported for TIR (mean increase 3.3%-points [approximately 48 min/day]; P = 0.006) with clinically relevant improvement (≥5%) in 43% of participants. Statistically significant improvements from baseline were observed for mean sensor glucose levels, HbA1c levels, and time in hyperglycemia (levels 1 and 2), with no statistically significant changes in time spent in hypoglycemia.

Conclusions

Switching to faster aspart was associated with improvements in glycemic control without increasing hypoglycemia in adults with T1D using MDI in this real-world setting.

Diabetes Obes Metab 2024; 26: 215–223

Aims

This study aims to compare the time to hyperglycemia recovery after ultra rapid lispro (URLi; Lyumjev®) versus Humalog in a randomized, double-blind crossover study.

Materials and Methods

Thirty-two adults with type 1 diabetes on continuous subcutaneous insulin infusion participated in two periods: each period included hyperglycemia induced by a missed mealtime bolus (day 1) and by suspension of basal insulin delivery (day 2). When hyperglycemia [plasma glucose (PG) >240 mg/dL] occurred, a correction bolus of URLi or Humalog was given and time to hyperglycemia recovery (PG = 140 mg/dL), pharmacokinetics, and oligodynamic were compared.

Results

Following a missed mealtime bolus, URLi significantly reduced maximum PG (−13 mg/dL; P = .02) and produced numerically more rapid decline in PG (23 mg/dL/h; P = .07), and faster recovery from hyperglycemia (−23 min; P = .1) versus Humalog, although differences were not significant. Following basal suspension, URLi significantly reduced maximum PG (−6 mg/dL; P = .02) and produced faster PG decline (24 mg/dL/h; P < .001) and faster recovery from hyperglycemia (−16 min; P < .01) vs. Humalog. Following a correction bolus of URLi, accelerated insulin lispro absorption was observed versus Humalog: early 50% t_max was reduced by 6 or 12 min, and AUC0-15min was increased 2.5- or 4.3-fold after correction boluses by subcutaneous infusion (day 1) or injection (day 2), respectively (all P < .001).

Conclusions

During episodes of hyperglycaemia commonly experienced in people with type 1 diabetes, URLi provided a faster recovery versus Humalog from a missed mealtime bolus or during basal insulin suspension. URLi shows significant acceleration of insulin absorption versus Humalog when boluses are administered by subcutaneous infusion or injection.

Lancet Diabetes Endocrinol 2023; 11: 811–821

Background

Faster-acting insulin aspart (faster aspart) is considered safe for use during pregnancy and breastfeeding but has not been evaluated in this population. We aimed to evaluate the effect of faster aspart versus insulin aspart on fetal growth, in women with type 1 or type 2 diabetes during pregnancy and postdelivery.

Methods

This open-label, single-center, superiority trial was conducted at Rigshospitalet, Copenhagen, Denmark. Participants aged 18 years or older with type 1 or type 2 diabetes were stratified by diabetes type and insulin treatment modality (multiple daily injections or insulin pump), randomly assigned 1:1 to faster aspart or insulin aspart, from 8 weeks and 0 days (8⁺⁰) of gestation to 13⁺⁶ weeks of gestation and followed up until 3 months postdelivery. Primary outcome was infant birthweight SD score. Secondary outcomes included HbA_1c as well as maternal and fetal outcomes in all participants during the trial.

Findings

Between Nov 11, 2019, and May 10, 2022, 109 participants were included in the faster aspart group and 107 in the insulin aspart group. Primary outcome data were available in 203 (94%) of 216 participants, and no participants discontinued treatment during the trial. Mean birthweight SD score was 1.0 (SD 1.4) in the faster aspart group versus 1.2 (1.3) in the insulin aspart group; estimated treatment difference −0.22 [−0.58 to 0.14]; P = 0.23. At 33 weeks of gestation, mean HbA_1c was 42 mmol/mol (SD 6 mmol/mol; 6.0% [SD 0.9%]) versus 43 mmol/mol (SD 7 mmol/mol; 6.1% [SD 1.2%]); estimated treatment difference −1.01 (−2.86 to 0.83), P = 0.28. No additional safety issues were observed with faster aspart compared with insulin aspart.

Interpretation

Treatment with faster aspart resulted in similar fetal growth and HbA_1c, relative to insulin aspart, in women with type 1 or type 2 diabetes. Faster aspart can be used in women with type 1 or type 2 diabetes during pregnancy and postdelivery with no additional safety issues.

Diabetes Obes Metab 2024; 26: 311–318

Aims

This study aims to investigate the efficacy and safety of ultra-rapid lispro (URLi) versus insulin lispro in predominantly Chinese patients with type 1 diabetes (T1D) in a prospective, randomized, double-blind, treat-to-target, phase 3 study.

Materials and Methods

Following a lead-in period, during which insulin glargine U-100 or insulin degludec U-100 was optimized, patients were randomly assigned (1:1) to URLi (n = 176) or insulin lispro (n = 178). The primary objective was to test the noninferiority of URLi to insulin lispro in glycemic control (noninferiority margin = 0.4% for glycated hamoglobin [HbA1c] change from baseline to week 26), with testing for the superiority of URLi to insulin lispro with regard to 1- and 2-hour postprandial glucose (PPG) excursions during a mixed-meal tolerance test and HbA1c change at week 26 as the multiplicity-adjusted objectives.

Results

From baseline to week 26, HbA1c decreased by 0.21% and 0.28% with URLi and insulin lispro, respectively, with a least squares mean treatment difference of 0.07% (95% confidence interval −0.11 to 0.24; P = 0.467). URLi demonstrated smaller 1- and 2-hour PPG excursions at week 26 with least squares mean treatment differences of −1.0 mmol/L (−17.8 mg/dL) and −1.4 mmol/L (−25.5 mg/dL), respectively (P < 0.005 for both) versus insulin lispro. The safety profiles of URLi and insulin lispro were similar.

Conclusions

In this study, URLi administered in a basal-bolus regimen demonstrated superiority to insulin lispro in controlling PPG excursions, with noninferiority of HbA1c control in predominantly Chinese patients with T1D.

Diabetes Ther 2023; 14: 1933–1945

Introduction

This study aims to assess time in range (TIR) (70–180 mg/dL) with postprandial glucose (PPG)-focused titration of ultra rapid lispro (URLi; Lyumjev®) in combination with insulin degludec in people with type 1 diabetes (T1D).

Methods

This phase 2, single-group, open-label, exploratory study was conducted in 31 participants with T1D on multiple daily injection therapy. Participants were treated with insulin degludec and Lispro for an 11-day lead-in and then URLi for a 46-day treatment period consisting of 35-day titration and 11-day endpoint maintenance period. Glucose targets for the titration period were PPG <140 mg/dL or <20% increase from premeal, fasting glucose 80–110 mg/dL, and overnight excursion ±30 mg/dL or less. Participants used the InPen™ bolus calculator and Dexcom G6 continuous glucose monitoring (CGM).

Results

Primary endpoint mean TIR (70–180 mg/dL) with URLi during the maintenance period was 70.2%. TIR (70–180 mg/dL) and times below/above range were not significantly different with URLi (maintenance) versus lispro (lead-in). HbA1c decreased from 7.1% at screening to 6.8% at endpoint (least squares mean [LSM] change from baseline, −0.36%; P < 0.001). Fructosamine and 1,5-anhydroglucitol improved (P < 0.001). Mean hourly glucose using CGM was reduced from 8:00 AM to 4:00 PM with URLi. Overall highest PPG excursion across meals was significantly reduced at URLi endpoint compared with lispro lead-in (mean 56.5 vs 72.4 mg/dL; P < 0.001). Insulin-to-carbohydrate ratio (U/X g) was reduced (more insulin given) at breakfast at URLi endpoint vs lead-in (LSM 9.0 vs 9.7 g; P = 0.002) and numerically decreased at other meals. Total daily insulin dose (TDD) was higher at URLi endpoint compared with lispro lead-in (mean 50.2 vs 47.0 U; P = 0.046) with similar prandial/TDD ratio (mean 52.1% vs 51.2%). There were no severe hypoglycemia events during the study.

Conclusions

URLi in a basal-bolus regimen focusing on PPG targets demonstrated improved overall glycemic control and reduced PPG excursions without increased hypoglycemia in participants with T1D.

J Diabetes Complications 2024; 38: 108648

Aims

This study aims to investigate contributions of changes in fasting plasma glucose (FPG) and postprandial glucose (PPG) to changes in hemoglobin A1c (HbA1c) and time-in-range (TIR, 70–180 mg/dL) in people with type 1 diabetes (T1D) and type 2 diabetes (T2D) treated with multiple daily injections (MDI) of insulin lispro (rapid/ultra-rapid formulations).

Methods

Multivariate regression models were used to quantify the contributions of FPG and PPG reductions to change in HbA1c and TIR using data from the PRONTO-T1D (N = 1,222) and PRONTO-T2D (N = 673) clinical trials. TIR was derived from 10-point self-monitored blood glucose (SMBG) profiles overall, as well as from continuous glucose monitoring (CGM) in the PRONTO-T1D CGM substudy (n = 269/1,222).

Results

A 1 mmol/L FPG reduction corresponded with a 0.09–0.12% (95% confidence interval [CI] 0.06–0.15%) HbA1c reduction in PRONTO-T1D and 0.17–0.26% (95% CI 0.13–0.30%) in PRONTO-T2D (both P < 0.0001). A 1 mmol/L PPG reduction corresponded with a 0.05–0.09% (95% CI 0.01–0.12%) HbA1c reduction in PRONTO-T1D (P < 0.001) and 0.10–0.15% (95% CI 0.05–0.19%) in PRONTO-T2D (P < 0.0001). Reductions in FPG and PPG were significantly associated with increased TIR whether derived from SMBG (7.87–12.95% [95% CI 6.81–14.23%]; all P < 0.0001) or CGM (3.35–4.18% [95% CI 2.11–5.39%]; all P < 0.05).

Conclusions

FPG and PPG significantly impact HbA1c and TIR. Balanced management of both FPG and PPG is important to achieve glycemic goals for people with diabetes on MDI insulin therapy.

J Diabetes Sci Technol 2024; 18: 676–685

Background

It has been shown that insulin acceleration by itself might not be sufficient to see clear improvements in glycemic metrics, and insulin therapy may need to be adjusted to fully leverage the extra safety margin provided by faster pharmacokinetic (PK) and pharmacodynamic (PD) profiles. The objective of this work is to explore how to perform such adjustments on a commercially available automated insulin delivery (AID) system.

Methods

Ultra-rapid lispro (URLi) is modeled within the UVA/Padova simulation platform using data from previously published clamp studies. The Control-IQ AID algorithm is selected as it leverages carbohydrate-to-insulin ratio (CR in g/U), correction factor (CF in mg/dL/U), and basal rate (BR in U/h) daily profiles that are fully customizable. An experiment roadmap is proposed to understand how to safely modify these profiles when switching from lispro to URLi.

Results

Simulations show that a 7% decrease in CR (approximately an 8% increase in prandial insulin) and a 7.5% increase in BR lead to cumulative improvements in glucose control with URLi. Comparing with baseline metrics using lispro, a clinically significant increase in time in the range of 70 to 180 mg/dL (overall: 70.2%–75.2%, P < 0.001; 6 am–12 am: 62.4%–68.5%, P < 0.001) and a reduction in time below 70 mg/dL (overall: 1.8%–1.2%, P < 0.001; 6 am–12 am: 1.8%–1.3%, P < 0.001) were observed.

Conclusions

Properly adjusting therapy parameters allows to fully leverage glucose control benefits provided by faster insulin analogues, opening opportunities to take another step forward into a next generation of more effective AID solutions.

Diabetes Technol Ther 2023; 25: 612–621

Objective

This study aims to evaluate the use of faster acting (FIA) and standard insulin aspart (SIA) with hybrid automated insulin delivery (AID) in active youth with type 1 diabetes.

Research Design and Methods

In this double-blind multinational randomized crossover trial, 30 children and adolescents with type 1 diabetes (16 females; aged 15.0 ± 1.7 years; baseline HbA1c 7.5% ± 0.9% [58 ± 9.8 mmol/mol]) underwent two unrestricted 4-week periods using hybrid AID with either FIA or SIA in random order. During both interventions, participants were using the hybrid AID (investigational version of MiniMed™ 780G; Medtronic). Participants were encouraged to exercise as frequently as possible, capturing physical activity with an activity monitor. The primary outcome was the percentage of sensor glucose time above range (180 mg/dL [10.0 mmol/L]) measured by continuous glucose monitoring.

Results

In an intention-to-treat analysis, mean time above range was 31% ± 15% at baseline, 19% ± 6% during FIA use, and 20% ± 6% during SIA use with no difference between treatments: mean difference = −0.9%; 95% CI: −2.4% to 0.6%; P = 0.23. Similarly, there was no difference in mean time in range (TIR) (78% and 77%) or median time below range (2.5% and 2.8%). Glycemic outcomes during exercise or postprandial periods were comparable for the two treatment arms. No severe hypoglycemia or diabetic ketoacidosis events occurred.

Conclusions

FIA was not superior to SIA with hybrid AID system use in physically active children and adolescents with type 1 diabetes. Nonetheless, both insulin formulations enabled high overall TIR and low time above and below ranges, even during and after documented exercise.

Diabetes Technol Ther 2023; 25: 856–863

Introduction

This study aims to evaluate hybrid closed-loop with ultra-rapid insulin lispro (Lyumjev) compared with hybrid closed-loop with standard insulin lispro in adults with type 1 diabetes.

Materials and Methods

In a single-center, double-blind, randomized, crossover study, 28 adults with type 1 diabetes [mean ± standard deviation (SD): age 44.5 ± 10.7 years, glycated hemoglobin (HbA1c) 7.1 ± 0.9% (54 ± 10 mmol/mol)] underwent two 8-week periods comparing hybrid closed-loop with ultra-rapid insulin lispro and hybrid closed-loop with standard insulin lispro in random order. The same CamAPS FX closed-loop algorithm was used in both periods.

Results

In an intention-to-treat analysis, the proportion of time sensor glucose was in target range (3.9–10 mmol/L [70–180 mg/dL]; primary endpoint) was greater with ultra-rapid lispro compared with standard insulin lispro (mean ± SD: 78.7 ± 9.8% vs. 76.2 ± 9.6%; mean difference 2.5 percentage points [95% confidence interval 0.8 to 4.2]; P = 0.005). Mean sensor glucose was lower with ultra-rapid lispro compared with standard insulin lispro (7.9 ± 0.8 mmol/L [142 ± 14 mg/dL] vs. 8.1 ± 0.9 mmol/L [146 ± 16 mg/dL]; P = 0.048). The proportion of time with sensor glucose <3.9 mmol/L [70 mg/dL] was similar between interventions (median [interquartile range] ultra-rapid lispro 2.3% [1.3%–2.7%] vs. standard insulin lispro 2.1% [1.4%–3.3%]; P = 0.33). No severe hypoglycemia or ketoacidosis occurred.

Conclusions

The use of ultra-rapid lispro with CamAPS FX hybrid closed-loop increases time in range and reduces mean glucose with no difference in hypoglycemia compared with standard insulin lispro in adults with type 1 diabetes.

Diabetes Technol Ther 2024; 26: 652–660

This article is also discussed in Chapter 5, page 137

Objective

This study aims to evaluate the safety and explore the efficacy of use of ultra-rapid lispro (URLi, Lyumjev) insulin in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology in children, teenagers, and adults living with type 1 diabetes (T1D).

Methods

At 14 U.S. diabetes centers, youth and adults with T1D completed a 16-day lead-in period using lispro in a t:slim X2 insulin pump with Control-IQ 1.5 technology, followed by a 13-week period in which URLi insulin was used in the pump.

Results

The trial included 179 individuals with T1D (age 6–75 years). With URLi, 1.7% (three participants) had a severe hypoglycemia event over 13 weeks attributed to override boluses or a missed meal. No diabetic ketoacidosis events occurred. Two participants stopped URLi use because of infusion-site discomfort, and one stopped after developing a rash. Mean time 70–180 mg/dL increased from 65% ± 15% with lispro to 67% ± 13% with URLi (P = 0.004). Mean insulin treatment satisfaction questionnaire score improved from 75 ± 13 at screening to 80 ± 11 after 13 weeks of URLi use (mean difference = 6; 95% confidence interval 4–8; P < 0.001), with the greatest improvement reported for confidence avoiding symptoms of high blood sugar. Mean treatment-related impact measure-diabetes score improved from 74 ± 12 to 80 ± 12 (P < 0.001), and mean TRIM-Diabetes Device (score improved from 82 ± 11 to 86 ± 12 (P < 0.001).

Conclusions

URLi use in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology was safe for adult and pediatric participants with T1D, with quality-of-life benefits of URLi use perceived by the study participants.

ACS Biomater Sci Eng 2024; 10: 3806–3812

In this work, for the first time, we demonstrate light control of a therapeutic protein's release from a depot in the subcutaneous layer of the skin. The subcutaneous layer is a standard location for therapeutic protein depots due to its large size and ease of access, but prior attempts to utilize this space failed because insufficient light can reach this deeper layer. An analysis of existing biophysical literature suggested that an increase of photoactivation wavelength from 365 to 500 nm could allow an increase of depot irradiation in the subcutaneous by >100-fold. We therefore used a green light-activated thio-coumarin-based material and demonstrated robust release of a therapeutic, insulin, in response to skin illumination with an LED light source. We further demonstrated that this release is ultrafast, as fast or faster than any commercially used insulin, while maintaining the native insulin sequence. This release of insulin was then accompanied by a robust reduction in blood glucose, demonstrating the retention of bioactivity despite the synthetic processing required to generate the material. In addition, we observed that the material exhibits slow basal release of insulin, even in the absence of light, potentially through biochemical or photochemical unmasking of insulin. Thus, these materials can act much like the healthy pancreas does: releasing insulin at a slow basal rate and then, upon skin irradiation, releasing an ultrafast bolus of native insulin to reduce postprandial blood glucose excursions.

Diabetes Obes Metab 2023; 25: 3817–3825

Background

For the successful approval and clinical prescription of insulin biosimilars, it is essential to show PK and PD bioequivalence to the respective reference products sourced from the European Union and the United States.

Methods

Three phase 1, randomized, double-blind, three-period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL-Asp, n = 36), lispro (GL-Lis, n = 38), and glargine (GL-Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU- and US-reference products in healthy male participants (GL-Asp and GL-Lis) or people with type 1 diabetes (GL-Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUCins.total) and maximum insulin concentrations (Cins.max). Primary PD endpoints were the total area under the glucose infusion rate curve (AUCGIR.total) and maximum glucose infusion rate (GIRmax).

Results

Bioequivalence to both EU- and US-reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%–125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins.

Conclusions

GL-Asp, GL-Lis, and GL-Gla are bioequivalent to their EU- and US-reference products.

Comments

These studies confirmed that no differences exist between the BioIns studied and the originator insulins, independent from which regulatory background these are coming from.

Clin Pharmacol Drug Dev 2023; 12: 1178–1184

Background

Biphasic insulin aspart 30 is a premixed formulation containing a soluble fraction of insulin aspart (30%) and a protamine-crystallized fraction (70%) that was developed to combine the rapid-acting and prolonged advantages of commercially available insulins. The aim of this bioequivalence study was to compare the pharmacokinetics (PKs) of GP-bi-asp and Novo-bi-asp and evaluate the pharmacodynamic (PD) properties as well as the safety of these drugs in the hyperinsulinemic euglycemic clamp (HEC) procedure.

Materials and Methods

This was a phase 1, randomized, double-blind, two-sequence, two-period crossover study. Thirty-four male volunteers who met the inclusion criteria underwent the HEC procedure following a single subcutaneous injection of 0.4 IU/kg of either GP-bi-asp or Novo-bi-asp in the abdomen. After the treatment, the subjects' plasma glucose levels were monitored for 24 hours and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. The PD parameters were calculated using GIR values. Insulin aspart concentrations were measured in blood plasma using validated ELISA assays to evaluate the PK parameters of the investigated drugs.

Results

The 90% confidence intervals for the geometric mean ratios of PK (Cins and AUCins-T) parameters of Gp-bi-asp and Novo-bi-asp were close to 100% and within the 80%–125% limits for establishing bioequivalence.

Conclusions

The safety profiles of both drugs were also comparable.

Comments

This study with healthy male subjects and a manual clamp technique provides evidence that a BioIns of such an insulin formulation is equivalent to the originator insulin; however, it appears as if differences between the two insulin formulations show up in PK and PD data in the time 6 to 12 hours after insulin administration. One wonders when and where this insulin mixture might come to the market.

Clin Pharmacol Drug Dev 2024; 13: 828–836

Background

The aim of the study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T-glu (GP40321, test drug) and reference insulin glulisine in a hyperinsulinemic-euglycemic clamp procedure.

Materials and Methods

During this study, 34 healthy male volunteers underwent the hyperinsulinemic-euglycemic clamp procedure following subcutaneous 0.3 U/kg injection of T-glu or reference insulin glulisine in a randomized, double-blind, crossover study. Plasma glucose levels were monitored every 5 minutes for 8 hours. Glucose infusion rate adjustment was based on the blood glucose measurements. Evaluation of PD was performed using the glucose infusion rate values, while PK was calculated using insulin concentrations measured via enzyme-linked immunosorbent assay.

Results

The study results showed that the 90% CI for the geometric mean ratios of primary PK and PD of T-glu and reference insulin glulisine were within 80%–125% comparability limits and that the safety profiles were comparable.

Conclusions

PK, PD, and safety similarity of T-glu and reference insulin glulisine were demonstrated.

Comments

Again, a study with healthy male subjects and a manual clamp technique provides evidence that this insulin glulisine formulation is equivalent to the originator insulin; however, the differences between the C-peptide concentrations are of interest to note, despite that the mean values were comparable between the groups. With rapid-acting insulins performance of manual clamps is more difficult in comparison to long-acting insulins, there is a good risk of not optimally adjusting the glucose infusion rate appropriately to rapidly changing glucose requirements. Concerning the insulin dose (0.3 U/kg body weight) applied, the increase in circulating insulin levels to maximal values of 15 µU/ml is surprisingly low, which at least in part might be due to the C-peptide correction applied. The induced metabolic effect (= glucose infusion rate) is as one would expect.

Diabetes Obes Metab 2024; 26: 540–547

Background

This study aims to assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR-Asp) and the insulin aspart reference product (NovoLog; NN-Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D).

Materials and Methods

This multicenter, open-label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating multiple daily injections of SAR-Asp and NN-Asp (NN-Asp for the first 4 weeks, SAR-Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN-Asp (nonswitching group). At week 16, a single dose (0.15 U/kg) of SAR-Asp in the switching group (n = 95) or NN-Asp in the nonswitching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax) of SAR-Asp versus NN-Asp after the single dose at week 16.

Results

The extent of PK exposure was similar between the two treatments (SAR-Asp in the switching group and NN-Asp in the nonswitching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8–1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8–1.25.

Conclusions

PK exposure of SAR-Asp (switching group) and reference NN-Asp (nonswitching group) were similar, supporting interchangeability between these two insulin aspart products.

J Diabetes Sci Technol 2024 Feb 29:19322968241232709. doi: 10.1177/19322968241232709. Online ahead of print

Background

SAR341402 insulin aspart (SAR-Asp) is a rapid-acting insulin analog developed as an interchangeable biosimilar to the marketed insulin aspart reference product (NovoLog; NN-Asp). GEMELLI X was a randomized controlled trial to assess outcomes with a biosimilar in line with the US Food and Drug Administration requirements for designation as an interchangeable biosimilar. This report assessed whether multiple switches between SAR-Asp and NN-Asp lead to equivalent safety and efficacy compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D) treated with multiple daily injections, using once-daily insulin glargine U100 (Lantus) as the basal insulin.

Methods

This open-label randomized (1:1), parallel-group, phase 3 trial compared four × four weeks of alternating use of individually titrated SAR-Asp and NN-Asp (NN-Asp for first four weeks, SAR-Asp in last four weeks; switching group) vs 16 weeks of continuous use of NN-Asp (nonswitching group). End points included pharmacokinetics, immunogenicity, adverse events, hypoglycemia, insulin dose, and change in efficacy parameters.

Results

Of the 210 PwD randomized, 200 (95.5%) completed the trial. PwD assigned to switching group (n = 104) and nonswitching group (n = 106) showed similar safety and tolerability, including anti-insulin aspart antibody responses, adverse events, and hypoglycemia. At week 16, there was no relevant difference between switching vs nonswitching groups in the change from baseline in glycated hemoglobin (least square [LS] mean difference = 0.05% [95% confidence interval [CI] = −0.13, 0.22]; 0.50 mmol/mol [−1.40, 2.39]), fasting plasma glucose (LS mean difference = 0.23 mmol/L [95% CI = −1.08, 1.53]; 4.12 mg/dL [−19.38, 27.62]), and changes in insulin dosages.

Conclusions

Alternating doses of SAR-Asp and NN-Asp compared with continuous use of NN-Asp showed similar safety, immunogenicity, and clinical efficacy in adults with T1D. This study supports the interchangeability between SAR-Asp and NN-Asp in T1D management.

Comments

It is no big surprise that no significant differences show up between the two insulin formulations in these two studies; however, it is good that this was confirmed.

Expert Opin Investig Drugs 2023; 32: 773–781

Background

B01411 is a biosimilar candidate manufactured by Jilin Huisheng Biopharmaceutical Co. Ltd for the reference insulin degludec (Tresiba) (IDeg). This study aimed to evaluate the PK, PD, and safety of the two IDeg products and to assess the PK/PD similarity of B01411 compared with the reference IDeg product.

Research Design and Methods

A single-center, single-dose, randomized, crossover, open-labeled, phase I, euglycemic clamp study in healthy Chinese subjects to examine the bioequivalence of B01411 (0.4 U/kg) compared with the reference IDeg product. Blood samples were collected at a predefined time for the analysis of blood glucose (BG), IDeg, and C-peptide concentrations. The glucose infusion rate (GIR) was adjusted to maintain the BG at approximately 0.28 mmol/L below baseline throughout the clamp.

Results

Thirty-two subjects (20 males and 12 females) were enrolled, 31 of whom received both treatments. The 90% confidence intervals for the ratio of the least-squares geometric means for AUCIDeg,0–24 h, AUCGIR,0–24 h, IDegmax, and GIRmax were all in the range of 0.80–1.25. Only one adverse event of puncture site bruising occurred once in a subject in the B01411 group.

Conclusion

B01411 exhibited a pharmacokinetic and pharmacodynamic similarity to the reference product. Both IDeg products were well tolerated.