Effect of needle-free injection on psychological insulin resistance and insulin dosage in patients with type 2 diabetes.

Background and objective: Psychological insulin resistance (PIR), which refers to the reluctance of diabetic patients to use insulin, is a frequently encountered clinical issue. Needle-free injection (NFI) offers advantages in terms of expediting insulin absorption and mitigating adverse reactions related to injection. To evaluate the effects of subcutaneous injection of insulin aspart 30 with NFI on PIR and insulin dosage in patients with type 2 diabetes mellitus (T2DM). Methods: Sixty-four patients with T2DM participated in this randomized, prospective, open, crossover study. Insulin aspart 30 was administered subcutaneously to each subject via QS-P NFI and Novo Pen 5 (NP) successively. The effects of NFI on PIR were analyzed. Differences in insulin dosage, glycemic variability, and injection safety were compared at similar levels of glycemic control. Results: After the administration of NFI, the insulin treatment attitude scale score decreased (53.7 ± 7.3 vs. 58.9 ± 10.7, p<0.001), the insulin treatment adherence questionnaire score increased (46.3 ± 4.9 vs. 43.8 ± 7.1, p<0.001), and the insulin treatment satisfaction questionnaire score increased (66.6 ± 10.5 vs. 62.4 ± 16.5, p<0.001). At the same blood glucose level, NFI required a smaller dosage of insulin aspart 30 compared with that of NP (30.42 ± 8.70 vs. 33.66 ± 9.13 U/d, p<0.001). There were no differences in glycemic variability indices (standard deviation, mean amplitude of glycemic excursion or coefficient of variation) between the two injection methods. Compared with NP, NFI did not increase the incidence of hypoglycemia (17.2% vs. 14.1%, p=0.774), and it decreased the incidence of induration (4.7% vs. 23.4%, p=0.002) and leakage (6.3% vs. 20.3%, p=0.022) while decreasing the pain visual analog scale score (2.30 ± 1.58 vs. 3.11 ± 1.40, p<0.001). Conclusion: NFI can improve PIR in patients with T2DM and be used with a smaller dose of insulin aspart 30 while maintaining the same hypoglycemic effect. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2400083658.

Comparative assessment of immunogenicity of recombinant insulin Aspart from BioGenomics and its originator NovoRapid® in adult patients with type 2 diabetes mellitus.

OBJECTIVES: To assess and compare the immunogenicity of recombinant Insulin Aspart [manufactured by BioGenomics Limited (BGL-ASP)] with its originator NovoRapid® (manufactured by Novo Nordisk) in adult patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: BGL-IA-CTP301 study was a randomized, open label, parallel group, multicenter phase-III clinical study to compare the efficacy and safety of recombinant Insulin Aspart 100 U/mL [manufactured by BioGenomics Limited (BGL-ASP)] with its reference medicinal product (RMP); NovoRapid® [manufactured by Novo Nordisk], in adult patients with Type 2 diabetes mellitus (T2DM). The primary objective of the study was to compare the immunogenicity of BGL-ASP and RMP; NovoRapid® in patient serum samples collected from phase-III clinical study. Immunogenicity was studied as the incidence of patients positive for anti-insulin Aspart (AIA) antibodies, developed against BGL-ASP/RMP at baseline, end of 12 week and end of 24 week of the treatment period. The changes in incidence of patients positive for AIA antibodies post-baseline were also studied to assess and compare the treatment-emergent antibody response (TEAR) between the treatment groups (BGL-ASP and RMP). Statistical evaluation was done by Fisher's exact test to compare the overall incidence of patients positive for AIA antibodies and the TEAR positives observed post-baseline in both the treated groups. An in-vitro neutralizing antibody assay (Nab assay) was also performed to study the effect of AIA antibodies in neutralizing the biological activity/metabolic function of the insulin. The neutralizing potential of AIA was studied by its effect on %glucose uptake. We also evaluated the association between AIA antibody levels and its impact on biological activity by studying the correlation between them. RESULTS: Analysis of immunogenicity data suggested that the percentage of patients positive for AIA antibodies until week 24 was similar and comparable in both the treatment groups, BGL-ASP and RMP; NovoRapid®. The changes in incidence of patients positive for AIA post-baseline in terms of TEAR positives were also similar and comparable between the treatment groups. The results of the Nab assay with confirmed positive AIA samples from BGL-ASP- and RMP-treated groups did not have any negative impact on %glucose uptake by the cells in Nab assay, confirming the absence of neutralizing antibodies in both the treatment groups. The correlation studies also showed absence of association between AIA antibody levels and percentage glucose uptake in both BGL-ASP and RMP-NovoRapid® treatment groups. CONCLUSIONS: The immunogenicity assessment based on the overall incidence of patients positive for AIA, changes in incidence of patients positive for AIA post-baseline, TEAR rates and absence of neutralizing antibodies, were found to be apparently similar and comparable in both the treatment groups (BGL-ASP and RMP). We conclude from our studies that the immunogenicity of BGL-ASP is similar and comparable to RMP and the observed immunogenicity in terms of anti-insulin Aspart antibody levels had no impact on the biological activity of insulin.

Unexpected evolution of a monster case of insulin-induced skin lipohypertrophy.

In this journal, in 2020, we published the case of a 74-year-old female outpatient with type-2 diabetes mellitus who self-injected insulin four times a day according to the basal-bolus regimen, with an high glycemic variability and an high rate of severe hypoglycemic episodes. Three years before, we had found two extraordinarily large skin lipohypertrophies, with large underlying fluid collections with high insulin concentration. A long educational and intensive training completely repaired the skin lesions with the disappearance of the subcutaneous insulin reservoirs. Glycemic variability has been reduced dramatically, severe hypoglycemia has almost completely disappeared and the daily dose of insulin has been reduced by 38%. However, this extraordinary, albeit unexpected, result was achieved in five years.

Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

Optimization of pig models for translation of subcutaneous pharmacokinetics of therapeutic proteins: Liraglutide, insulin aspart and insulin detemir.

Prediction of human pharmacokinetics (PK) from data obtained in animal studies is essential in drug development. Here, we present a thorough examination of how to achieve good pharmacokinetic data from the pig model for translational purposes by using single-species allometric scaling for selected therapeutic proteins: liraglutide, insulin aspart and insulin detemir. The predictions were based on non-compartmental analysis of intravenous and subcutaneous PK data obtained from two injection regions (neck, thigh) in two pig breeds, domestic pig and Göttingen Minipig, that were compared with PK parameters reported in humans. The effects of pig breed, injection site and injection depth (insulin aspart only) on the PK of these proteins were also assessed. Results show that the prediction error for human PK was within two-fold for most PK parameters in both pig breeds. Furthermore, pig breed significantly influenced the plasma half-life and mean absorption time (MAT), both being longer in Göttingen Minipigs compared to domestic pigs (P <0.01). In both breeds, thigh vs neck dosing was associated with a higher dose-normalized maximum plasma concentration and area under the curve as well as shorter MAT and plasma half-life (P <0.01). Finally, more superficial injections resulted in faster absorption, higher Cmax/dose and bioavailability of insulin aspart (P <0.05, 3.0 vs 5.0 mm injection depth). In conclusion, pig breed and injection region affected the PK of liraglutide, insulin aspart and insulin detemir and reliable predictions of human PK were demonstrated when applying single-species allometric scaling with the pig as a pre-clinical animal model.

Pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and Japan-approved NovoRapid in healthy Japanese subjects.

This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-Cmax), area under the plasma insulin concentration-time curve to the last quantifiable concentration (INS-AUClast), area under the GIR-time curve during the clamp (GIR-AUC0-10 h), and maximum GIR (GIRmax). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval [CI] 0.94-1.05) for INS-Cmax and 1.02 (90% CI 1.00-1.04) for INS-AUClast. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93-1.06) for GIR-AUC0-10 h and 1.01 (95% CI 0.95-1.08) for GIRmax. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80-1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.

Glycaemic efficacy and safety of mealtime faster-acting insulin aspart administered by injection as compared to insulin aspart in people with diabetes mellitus: A meta-analysis of randomized controlled trials.

AIMS: To summarize all relevant randomized controlled trials (RCTs) and provide precise effect estimates of glycaemic efficacy/safety of faster-acting insulin aspart administered by injection as compared to insulin aspart in people with diabetes mellitus. METHODS: PubMed/Cochrane Library were systematically searched till October 10, 2020, to identify RCTs with duration ≥16 weeks, evaluating efficacy/safety of mealtime injections of faster aspart compared to insulin aspart in people with type 1 diabetes mellitus and type 2 diabetes mellitus. Studies using faster aspart as continuous subcutaneous insulin infusion were excluded. Continuous and dichotomous outcome variables (expressed as estimated treatment difference and rate ratio in RCTs, respectively) were pooled using generic inverse variance method with fixed/random-effects model. For each outcome variable, subgroup analysis between type 1 diabetes mellitus and type 2 diabetes mellitus was performed. RESULTS: We included five RCTs; three of type 1 diabetes mellitus (n = 1963) and two of type 2 diabetes mellitus (n = 1780). All had low risk of bias. Faster aspart was associated with small but significant improvement in HbA1c than insulin aspart (MD: -0.06%, 95% CI: -0.10, -0.02, p = 0.005, I2  = 19%). HbA1c reduction was statistically significant only in type 1 diabetes mellitus on subgroup analysis (MD: -0.08%, 95% CI: -0.14, -0.02, p = 0.005, I2  = 47%). Besides, faster aspart was associated with reduced postprandial plasma glucose (PPG) increment at 1 h/2 h after meal test and increased 1,5-anhydroglucitol compared to insulin aspart. Early postprandial hypoglycaemic episodes were higher with faster aspart; however, overall and nocturnal hypoglycaemic episodes were not different from insulin aspart. CONCLUSIONS: Faster aspart is associated with reduced HbA1c , PPG increment and comparable overall hypoglycaemic episodes with regard to insulin aspart.

Fast-Acting Insulin Aspart Use with the MiniMedTM 670G System.

Background: This study assessed the efficacy and safety of ultrarapid insulin Fiasp® in the hybrid closed-loop MiniMed™ 670G system. Methods: This was a pilot randomized double-blinded crossover study among established MiniMed™ 670G users comparing percentage time in range (TIR) and hypoglycemia for Novolog® and Fiasp. After 2 weeks optimization with their home insulin, participants were randomized to receive Novolog or Fiasp for 2 weeks, followed by the other insulin for the next 2 weeks. Data from the second week of blinded insulin use were analyzed to allow 1 week for 670G adaptation. During the second week, individuals were asked to eat the same breakfast for 3 days to assess differences in meal pharmacodynamics. Results: Nineteen adults were recruited with mean age of 40 ± 18 years, diabetes duration of 27 ± 12 years, and median hemoglobin A1c of 7.1% (6.9, 7.5), using 0.72 (0.4, 1.2) units/(kg·day). For Novolog and Fiasp, respectively, the %TIR (70-180 mg/dL) was 75.3 ± 9.5 and 78.4 ± 9.3; %time <70 mg/dL was 3.1 ± 2.1 and 2.3 ± 2.0; %time >180 mg/dL was 21.6 ± 9.0 and 19.3 ± 8.9; mean glucose was 147 ± 12 and 146 ± 12 mg/dL; coefficient of variation was 28.6% ± 4.5% and 26.8% ± 4.4%; %time in auto mode 86.4 ± 9.2 and 84.4 ± 9.2. All comparisons were nonsignificant for insulin type. Total daily dose (Novolog 48.8 ± 28.4 vs. Fiasp 52.4 ± 31.7 units; P = 0.01) and daily basal (Novolog 17.6 [15.5, 33.8] vs. Fiasp 19.1 [15.3, 38.5] units; P = 0.07) correlated with TIR and %time >180 mg/dL. For insulin delivery in auto mode there was no statistical difference in total daily dose or daily basal between arms. Paired analysis for matched breakfast meals revealed no significant differences in time to maximum glucose, peak glucose, or glucose excursion. Conclusions: In this pilot study, the use of either Novolog or Fiasp in a commercially available MiniMed 670G system operating in auto mode resulted in clinically similar glycemic outcomes, with a slight increase in daily insulin requirements using Fiasp.

Extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin adjustments in individuals with type 1 diabetes.

AIM: To detail the extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin dose adjustments in individuals with type 1 diabetes (T1D) using multiple daily injections of insulins aspart (IAsp) and degludec (IDeg). METHODS AND RESULTS: Sixteen individuals with T1D, completed a single-centred, randomised, four-period crossover trial consisting of 23-h inpatient phases. Participants administered either a regular (100%) or reduced (50%) dose (100%; 5.1 ± 2.4, 50%; 2.6 ± 1.2 IU, p < 0.001) of individualised IAsp 1 h before and after 45-min of evening exercise at 60 ± 6% V̇O2max. An unaltered dose of IDeg was administered in the morning. Metabolic, physiological and hormonal responses during exercise, recovery and nocturnal periods were characterised. The primary outcome was the number of trial day occurrences of hypoglycemia (venous blood glucose ≤ 3.9 mmol L -1). Inclusion of a 50% IAsp dose reduction strategy prior to evening exercise reduced the occurrence of in-exercise hypoglycemia (p = 0.023). Mimicking this reductive strategy in the post-exercise period decreased risk of nocturnal hypoglycemia (p = 0.045). Combining this strategy to reflect reductions either side of exercise resulted in higher glucose concentrations in the acute post-exercise (p = 0.034), nocturnal (p = 0.001), and overall (p < 0.001) periods. Depth of hypoglycemia (p = 0.302), as well as ketonic and counter-regulatory hormonal profiles were similar. CONCLUSIONS: These findings demonstrate the glycemic safety of peri-exercise bolus dose reduction strategies in minimising the prevalence of acute and nocturnal hypoglycemia following evening exercise in people with T1D on MDI. Use of newer background insulins with current bolus insulins demonstrates efficacy and advances current recommendations for safe performance of exercise. CLINICAL TRIALS REGISTER: DRKS00013509.

Oscillations of C-peptide in the euglycemic clamp and their effect on the pharmacodynamic assessment of insulin preparations.

C-peptide should be continuously suppressed. However, increased postdosing C-peptide is not an uncommon phenomenon in euglycemic clamp studies involving healthy participants. This study aimed to determine the extent to which the postdosing C-peptide increases from the baseline that could affect the accuracy of glucodynamics in euglycemic clamp studies involving healthy subjects. First, 10 healthy males underwent a 10-h euglycemic clamp without exogenous insulin administration to obtain a reference interval (RI) for the ratio of C-peptide after 0 min (CPt ) to baseline C-peptide (CP0 ). Then, the data from a pharmacokinetic and pharmacodynamic study of insulin aspart (IAsp) were analyzed, and 70 eligible clamps were grouped by CPt /CP0 : group A ([CPt /CP0 ]max   > upper limit of RI), group B (1<[CPt /CP0 ]max  ≤ upper limit of RI), and group C ([CPt /CP0 ]max  ≤ 1). The differences in basal and clamped blood glucose, CPt /CP0 , and the pharmacokinetics and pharmacodynamics of IAsp were compared, and the relationship between elevated CPt and the accuracy of pharmacodynamics was analyzed. The RI of CPt /CP0 was 22.7%-152.1%; 1.5 × baseline might be a ceiling for the increase in CPt under stable conditions. The maximum glucose infusion rate (GIR) in group A tended to be higher than that in group B or C (Pfor trend  = 0.033). The AUCGIR,0-10h in groups A, B, and C was 1983 ± 650,1682 ± 454, and 1479 ± 440 mg/kg (P = 0.047), respectively, under comparable IAsp exposure. No intergroup difference was detected in clamped glucose, IAsp dose, or body mass index. In conclusion, postdosing C-peptide over 1.5× baseline indicates insufficient inhibition of endogenous insulin secretion, which could compromise the pharmacodynamics of insulin preparations.

Urinary detection of rapid-acting insulin analogs in healthy humans.

Human insulin and its synthetic analogs are considered as life-saving drugs for people suffering from diabetes mellitus. Next to the therapeutic use, scientific and non-scientific literature (e.g. bodybuilding forums; antidoping intelligence and investigation reports) indicate that these prohibited substances are used as performance enhancing agents. In the present report, the development and validation of a sensitive analytical strategy is described for the urinary detection of three rapid-acting insulin analogs (Lispro, Aspart, Glulisine). The method is based on sample purification by the combination of ultrafiltration and immunoaffinity purification and subsequent analysis by nano-flow liquid chromatography coupled to high resolution mass spectrometry. Next to the results on different validation parameters (LOD: 10 pg/mL; recovery: 25-48%; matrix effect: -3-(-8) %), data on urinary elimination times, which were obtained in the frame of an administration study with the participation of healthy volunteers, are presented. The determined detection windows (~9 hours) are expected to help to evaluate current routine analytical methods and aim to aid doping authorities to set appropriate target windows for efficient testing.

The association between anti-insulin aspart antibodies and the pharmacokinetic and pharmacodynamic characteristics of fast-acting insulin aspart in children and adolescents with type 1 diabetes.

BACKGROUND: Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart (IAsp) ensuring ultrafast absorption and effect. AIM: To compare the pharmacokinetics between faster aspart and IAsp, based on free or total IAsp measurement, and investigate the association between anti-IAsp antibodies and faster aspart and IAsp pharmacological properties in children and adolescents with type 1 diabetes (T1D). METHODS: In a randomized, two-period crossover trial, 12 children, 16 adolescents, and 15 adults (6-11, 12-17, and 18-64 years) received 0.2 U/kg double-blindsingle-dose subcutaneous faster aspart or IAsp followed by a standardized liquid meal test. RESULTS: Across age groups, the pharmacokinetic profile was left-shifted including greater early exposure for faster aspart vs IAsp irrespective of free or total IAsp assay. Onset of appearance occurred 2.4 to 5.0 minutes (free) or 1.8 to 3.0 minutes (total) earlier for faster aspart vs IAsp (P < .05). Treatment ratios (faster aspart/IAsp) for 0 to 30 minutes IAsp exposure were 1.60 to 2.11 and 1.62 to 1.96, respectively (children, free: P = .062; otherwise P < .05). The ratio of free/total IAsp for overall exposure (AUCIAsp,0-t ) was negatively associated with anti-IAsp antibody level across age. Pooling with a previous similar trial showed no clear association between anti-IAsp antibodies and meal test 1- or 2-hour postprandial glucose increment independent of age and insulin treatment (R2 ≤ .070; P ≥ .17). CONCLUSIONS: In children and adolescents with T1D, faster aspart provides ultrafast pharmacokinetics irrespective of free or total IAsp assay. Elevated anti-IAsp antibodies are associated with higher total IAsp concentration, but do not impact faster aspart and IAsp glucose-lowering effect.

A survey of physician experience and treatment satisfaction using fast-acting insulin aspart in people with type 1 or type 2 diabetes.

AIMS: This survey aimed to explore real-world physician experiences and treatment satisfaction with fast-acting insulin aspart (faster aspart) in clinical practice across Europe and Canada. MATERIALS AND METHODS: An online web-based survey was used for physicians treating people with type 1 or type 2 diabetes. General practitioners and specialists, with experience using faster aspart, were interviewed. RESULTS: A total of 191 physicians participated in the survey. Most of their patients (68% of those with T1D and 63% of those with T2D) were previously treated with another mealtime insulin before switching to faster aspart. At the time of initiating faster aspart, nearly half of patients had an HbA1c level between 7.5% (59 mmol/mol) and 8.5% (69 mmol/mol). The main prescription drivers for faster aspart, versus other mealtime insulins, were faster onset of action, improved postprandial glucose (PPG) control, and dosing flexibility. Most physicians were more satisfied with faster aspart than other mealtime insulins regarding at-meal (66%) and post-meal (71%) dosing flexibility, improved PPG levels (66%), and onset of action (61%). Main reasons for not prescribing faster aspart included a good response to current treatment (76%) or patient reluctance to switch (57%). Overall, 12% of patients discontinued faster aspart, for reasons including concerns of hypoglycemia (17%), poor adherence (17%), and level of patient co-pay (17%). More than half of physicians had fewer concerns regarding postprandial hyperglycemia, and were more confident in their patients reaching their HbA1c target with faster aspart than with other mealtime insulins. LIMITATIONS: The findings of this survey are based heavily on physicians' experiences, and could therefore be subject to recall bias. CONCLUSIONS: Reported physician and patient experiences of using faster aspart have been positive, and better PPG control and increased dosing flexibility are expected to improve glycemic management.

Comparison of the effects of twice-daily exenatide and insulin on carotid intima-media thickness in type 2 diabetes mellitus patients: a 52-week randomized, open-label, controlled trial.

BACKGROUND: Exenatide, a glucagon like peptide 1 analog, has been suggested to reduce the cardiovascular disease risk factors, such as body weight, blood pressure and subclinical atherosclerosis in patients with type 2 diabetes mellitus (T2DM). This was the first randomized, open-label, controlled trial to compare the effects of exenatide versus insulin on subclinical atherosclerosis, as assessed by carotid-intima media thickness (CIMT), in patients with T2DM. METHODS: A total of 66 patients with T2DM admitted from March 10, 2015 to June 20, 2017 in the Department of Endocrinology, Beijing Hospital were randomized to receive twice-daily exenatide or aspartate 70/30 insulin for 52 weeks. The primary endpoint was change from baseline in CIMT, and secondary endpoints included changes at week 52 from baseline in body weight, glycemic markers, lipid metabolism markers, blood pressure, C-reactive protein, fibrinogen, 8-hydroxydeoxyguanosine, irisin, and brain natriuretic peptide. RESULTS: Exenatide more significantly reduced the CIMT from baseline compared with insulin after 52 weeks, with a mean difference of - 0.14 mm (95% interval confidence: - 0.25, - 0.02; P = 0.016). Weight and body mass index were both significantly reduced in the exenatide group over 52 weeks. Exenatide reduced total lipoprotein and low-density lipoprotein cholesterol levels more significantly than insulin at weeks 16 and 40. Correlation analyses showed that CIMT was positively correlated with low-density lipoprotein cholesterol. CONCLUSIONS: Twice-daily exenatide could prevent atherosclerosis progression in patients with T2DM over a 52-week treatment period compared with insulin therapy. Trial registration Chinese Clinical Trial Registry ChiCTR-1800015658.

A Randomized Trial Evaluating the Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec With or Without Metformin, in Adults With Type 2 Diabetes (ONSET 9).

OBJECTIVE: To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp), both with insulin degludec with or without metformin, in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen. RESEARCH DESIGN AND METHODS: This multicenter, double-blind, treat-to-target trial randomized participants to faster aspart (n = 546) or IAsp (n = 545). All available information, regardless of treatment discontinuation or use of ancillary treatment, was used for evaluation of effect. RESULTS: Noninferiority for the change from baseline in HbA1c 16 weeks after randomization (primary end point) was confirmed for faster aspart versus IAsp (estimated treatment difference [ETD] -0.04% [95% CI -0.11; 0.03]; -0.39 mmol/mol [-1.15; 0.37]; P < 0.001). Faster aspart was superior to IAsp for change from baseline in 1-h postprandial glucose (PPG) increment using a meal test (ETD -0.40 mmol/L [-0.66; -0.14]; -7.23 mg/dL [-11.92; -2.55]; P = 0.001 for superiority). Change from baseline in self-measured 1-h PPG increment for the mean over all meals favored faster aspart (ETD -0.25 mmol/L [-0.42; -0.09]); -4.58 mg/dL [-7.59; -1.57]; P = 0.003). The overall rate of treatment-emergent severe or blood glucose (BG)-confirmed hypoglycemia was statistically significantly lower for faster aspart versus IAsp (estimated treatment ratio 0.81 [95% CI 0.68; 0.97]). CONCLUSIONS: In combination with insulin degludec, faster aspart provided effective overall glycemic control, superior PPG control, and a lower rate of severe or BG-confirmed hypoglycemia versus IAsp in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen.

[Spice intoxication and hyperglycemia]. / Intoxicación por Spice e hiperglucemia.

We present a case of intoxication by synthetic cannabinoids (SC). SC are substances of abuse with effects similar to Marijuana but with a different chemical structure, which avoids its detectability by regular drug tests, making diagnosis difficult. Among the possible side effects of their use is hyperglycemia. Their presence should be suspected in cases of hyperglycemia that cannot be explained by any other cause, especially in young patients presenting another clinical picture suggestive of SC consumption such as agitation, confusional symptoms or psychosis; the patient should be questioned about their use. It is important that the diabetic population knows the side effects of synthetic cannabinoids to avoid their consumption, as it is a sector of the population especially vulnerable to the consequences of their use.

Faster Compared With Standard Insulin Aspart During Day-and-Night Fully Closed-Loop Insulin Therapy in Type 1 Diabetes: A Double-Blind Randomized Crossover Trial.

OBJECTIVE: We evaluated the safety and efficacy of day-and-night fully closed-loop insulin therapy using faster (Faster-CL) compared with standard insulin aspart (Standard-CL) in young adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: In a double-blind, randomized, crossover trial, 20 participants with type 1 diabetes on insulin pump therapy (11 females, aged 21.3 ± 2.3 years, HbA1c 7.5 ± 0.5% [58.5 ± 5.5 mmol/mol]) underwent two 27-h inpatient periods with unannounced afternoon moderate-vigorous exercise and unannounced/uncovered meals. We compared Faster-CL and Standard-CL in random order. During both interventions, the fuzzy-logic control algorithm DreaMed GlucoSitter was used. Glucose sensor data were analyzed by intention-to-treat principle with the difference (between Faster-CL and Standard-CL) in proportion of time in range 70-180 mg/dL (TIR) over 27 h as the primary end point. RESULTS: The proportion of TIR was similar for both arms: 53.3% (83% overnight) in Faster-CL and 57.9% (88% overnight) in Standard-CL (P = 0.170). The proportion of time in hypoglycemia <70 mg/dL was 0.0% for both groups. Baseline-adjusted interstitial prandial glucose increments 1 h after meals were greater in Faster-CL compared with Standard-CL (P = 0.017). The gaps between measured plasma insulin and estimated insulin-on-board levels at the beginning, at the end, and 2 h after the exercise were smaller in the Standard-CL group (P = 0.029, P = 0.003, and P = 0.004, respectively). No severe adverse events occurred. CONCLUSIONS: Fully closed-loop insulin delivery using either faster or standard insulin aspart was safe and efficient in achieving near-normal glucose concentrations outside postprandial periods. The closed-loop algorithm was better adjusted to the standard insulin aspart.

Long-Term Intranasal Insulin Aspart: A Profile of Gene Expression, Memory, and Insulin Receptors in Aged F344 Rats.

Intranasal insulin is a safe and effective method for ameliorating memory deficits associated with pathological brain aging. However, the impact of different formulations and the duration of treatment on insulin's efficacy and the cellular processes targeted by the treatment remain unclear. Here, we tested whether intranasal insulin aspart, a short-acting insulin formulation, could alleviate memory decline associated with aging and whether long-term treatment affected regulation of insulin receptors and other potential targets. Outcome variables included measures of spatial learning and memory, autoradiography and immunohistochemistry of the insulin receptor, and hippocampal microarray analyses. Aged Fischer 344 rats receiving long-term (3 months) intranasal insulin did not show significant memory enhancement on the Morris water maze task. Autoradiography results showed that long-term treatment reduced insulin binding in the thalamus but not the hippocampus. Results from hippocampal immunofluorescence revealed age-related decreases in insulin immunoreactivity that were partially offset by intranasal administration. Microarray analyses highlighted numerous insulin-sensitive genes, suggesting insulin aspart was able to enter the brain and alter hippocampal RNA expression patterns including those associated with tumor suppression. Our work provides insights into potential mechanisms of intranasal insulin and insulin resistance, and highlights the importance of treatment duration and the brain regions targeted.

Fast-Acting Insulin Aspart: A Review of its Pharmacokinetic and Pharmacodynamic Properties and the Clinical Consequences.

Fast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) with two added excipients, L-arginine and niacinamide, to ensure formulation stability with accelerated initial absorption after subcutaneous administration compared with previously developed rapid-acting insulins. The pharmacokinetic/pharmacodynamic properties of faster aspart have been characterised in clinical pharmacology trials with comparable overall methodology. In subjects with type 1 (T1D) or type 2 (T2D) diabetes, the serum IAsp concentration-time and glucose-lowering effect profiles are left-shifted for faster aspart compared with IAsp. In addition, faster aspart provides earlier onset, doubling of initial exposure, and an up to 2.5-fold increase in initial glucose-lowering effect within 30 min of subcutaneous injection, as well as earlier offset of exposure and effect. Similar results have been shown using continuous subcutaneous insulin infusion (CSII). The improved pharmacological properties of faster aspart versus IAsp are consistent across populations, i.e. in the elderly, children, adolescents and the Japanese. Thus, the faster aspart pharmacological characteristics more closely resemble the mealtime insulin secretion in healthy individuals, giving faster aspart the potential to further improve postprandial glucose control in subjects with diabetes. Indeed, change from baseline in 1-h postprandial glucose increment is in favour of faster aspart versus IAsp when used as basal-bolus or CSII treatment in phase III trials in subjects with T1D or T2D. This review summarises the currently published results from clinical pharmacology trials with faster aspart and discusses the potential clinical benefits of faster aspart compared with previous rapid-acting insulin products.

Efficacy and Safety of Insulin Aspart Biosimilar SAR341402 Versus Originator Insulin Aspart in People with Diabetes Treated for 26 Weeks with Multiple Daily Injections in Combination with Insulin Glargine: A Randomized Open-Label Trial (GEMELLI 1).

Background: This study compared the efficacy, safety, and immunogenicity of insulin aspart biosimilar/follow-on biologic product SAR341402 (SAR-Asp) with originator insulin aspart-NovoLog®/NovoRapid® (NN-Asp) in people with type 1 diabetes (T1D) or type 2 diabetes (T2D) treated with multiple daily injections in combination with insulin glargine (Lantus®; Gla-100). Materials and Methods: This 6-month, randomized, open-label, phase 3 study (NCT03211858) enrolled 597 people with T1D (n = 497) or T2D (n = 100). Participants were randomized 1:1 to mealtime SAR-Asp (n = 301) or NN-Asp (n = 296) in combination with Gla-100. The primary objective was to demonstrate noninferiority (by 0.3% margin in the intent-to-treat population) of SAR-Asp versus NN-Asp in HbA1c change from baseline to week 26. Immunogenicity was also assessed in terms of anti-insulin aspart antibody (AIA) status (positive/negative) and titers during the study. Results: HbA1c was similarly improved in both treatment groups (SAR-Asp -0.38%; NN-Asp -0.30%); the least squares mean difference at week 26 for SAR-Asp minus NN-Asp was -0.08% (95% confidence interval: -0.192 to 0.039), thus meeting the criteria for noninferiority between SAR-Asp and NN-Asp and inverse noninferiority of NN-Asp versus SAR-Asp. Changes in fasting plasma glucose and seven-point self-monitored plasma glucose profile, including postprandial glucose excursions, and insulin dosages were similar in both groups at week 26. Safety and tolerability, including AIA responses (incidence, prevalence), hypoglycemia, and adverse events (including hypersensitivity events and injection site reactions), were similar between groups. Conclusions: SAR-Asp demonstrated effective glycemic control with a similar safety and immunogenicity profile to NN-Asp in people with diabetes treated for 26 weeks.