Readily releasable ß cells with tight Ca2+-exocytosis coupling dictate biphasic glucose-stimulated insulin secretion.

Biphasic glucose-stimulated insulin secretion (GSIS) is essential for blood glucose regulation, but a mechanistic model incorporating the recently identified islet ß cell heterogeneity remains elusive. Here, we show that insulin secretion is spatially and dynamically heterogeneous across the islet. Using a zinc-based fluorophore with spinning-disc confocal microscopy, we reveal that approximately 40% of islet cells, which we call readily releasable ß cells (RRßs), are responsible for 80% of insulin exocytosis events. Although glucose up to 18.2 mM fully mobilized RRßs to release insulin synchronously (first phase), even higher glucose concentrations enhanced the sustained secretion from these cells (second phase). Release-incompetent ß cells show similarities to RRßs in glucose-evoked Ca2+ transients but exhibit Ca2+-exocytosis coupling deficiency. A decreased number of RRßs and their altered secretory ability are associated with impaired GSIS progression in ob/ob mice. Our data reveal functional heterogeneity at the level of exocytosis among ß cells and identify RRßs as a subpopulation of ß cells that make a disproportionally large contribution to biphasic GSIS from mouse islets.

Real-world study of the concomitant use of biphasic insulin aspart 30/70 with GLP-1 receptor agonist versus first-generation basal insulin with GLP-1 receptor agonist in type 2 diabetes.

AIMS: Combining insulin with a glucagon-like peptide-1 receptor agonist (GLP-1RA) to treat type 2 diabetes (T2D) is common. While many studies have investigated concomitant therapy with basal insulin+GLP-1RA, few have reported on premixed insulin+GLP-1RA. We aimed to address this gap using data from the Clinical Practice Research Datalink Aurum database in England. METHODS: This retrospective cohort study with propensity score matching assessed glycaemic levels and other clinical outcomes in people with T2D, comparing biphasic insulin aspart 30/70 (BIAsp 30) + GLP-1RA with basal insulin (insulin detemir/glargine U100) + GLP-1RA (from 2006 to 2021). RESULTS: In total, 4770 eligible people were identified; 1511 had a BIAsp 30 + GLP-1RA regimen and were propensity score-matched to an equal number receiving basal+GLP-1RA. There was no significant difference in glycated haemoglobin (HbA1c) reduction between cohorts at 6 months (p = 0.15), with a decrease of -1.07 (95% CI: -1.16; -0.98) %-points (-11.7 mmol/mol [95% CI: -12.7; -10.7]) in the BIAsp 30 + GLP-1RA cohort, versus -0.97 (95% CI: -1.07; -0.88) %-points (-10.6 mmol/mol [95% CI: -11.7; -9.6]) in the basal+GLP-1RA cohort. Body mass index (BMI) decreased by -0.35 kg/m2 (95% CI: -0.52;-0.18) at 6 months with BIAsp 30 + GLP-1RA, versus -0.72 kg/m2 (95% CI: -0.90;-0.54) with basal+GLP-1RA (p = 0.003). BMI was influenced by the initiation sequence of GLP-1RA in relation to insulin (p < 0.0001). Hypoglycaemia rates were low and not significantly different between cohorts. CONCLUSIONS: Combining BIAsp 30 + GLP-1RA provides glycaemic control with no significant difference to that of propensity score-matched people receiving basal insulin+GLP-1RA, with no increase in hypoglycaemia risk or weight gain.

Bioequivalence of Reference and Biosimilar Preparations of Premixed Biphasic Insulin Aspart: A Comparative Clamp Study.

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. This was a phase 1, randomized, double-blind, 2-sequence, 2-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. 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. The safety profiles of both drugs were also comparable.

Real-world study of ethnic differences in glycaemic control and clinical characteristics among insulin-naïve people with type 2 diabetes initiating biphasic insulin aspart 30/70: A retrospective, observational cohort study in England.

AIMS: This study investigated the ethnic differences in glycaemic levels and clinical characteristics among insulin-naïve people with type 2 diabetes (T2D) initiating biphasic insulin aspart 30/70 (BIAsp 30) in primary practice in England. MATERIALS AND METHODS: Retrospective, observational cohort study utilizing data from the Clinical Practice Research Datalink Aurum database, including White, South Asian, Black and Chinese insulin-naïve adults with T2D, initiating BIAsp 30. The index date was that of the first BIAsp 30 prescription. Endpoints included change in glycated haemoglobin (HbA1c) and body mass index (BMI) 6 months post index. RESULTS: In total, 11 186 eligible people were selected (9443 White, 1116 South Asian, 594 Black, 33 Chinese). HbA1c decreased across all subgroups 6 months post index: estimated %-point changes [95% CI of -2.32 (-2.36; -2.28) (White); -1.91 (-2.02; -1.80) (South Asian); -2.55 (-2.69; -2.40) (Black); and -2.64 (-3.24; -2.04) (Chinese)]. The BMI increased modestly 6 months post index in all subgroups [estimated changes (95% CI) kg/m2 : White, 0.92 (0.86; 0.99); South Asian, 0.60 (0.41; 0.78); Black, 1.41 (1.16; 1.65); and Chinese, 0.32 (-0.67; 1.30)]. In the overall population, hypoglycaemic event rates increased from 0.92 events per 100 patient-years before the index to 3.37 events per 100 patient-years post index; event numbers were too low to be analysed by subgroup. CONCLUSIONS: Among insulin-naïve people with T2D initiating BIAsp 30, clinically meaningful HbA1c reductions in all ethnicities were observed. Some ethnic groups had larger reductions than others, but differences were small. In all groups, small BMI increases were seen, with small differences observed between groups. Hypoglycaemia rates were low.

Mixed insulin can improve control of prednisolone-induced hyperglycaemia.

BACKGROUND: Hyperglycaemia is a common side effect of prednisolone, although there are no widely accepted guidelines for the management of glucocorticoid-induced hyperglycaemia (GIH). Our institution uses mixed insulin in a pre-breakfast or pre-breakfast and pre-lunch regimen, with the rationale that this profile of insulin action matches the physiological effect of prednisolone on blood glucose levels (BGLs). AIM: Evaluate the use of the mixed insulin (NovoMix30) in a pre-breakfast or pre-breakfast and pre-lunch regimen as management for GIH in a tertiary hospital setting. METHOD: We retrospectively evaluated all inpatients coprescribed prednisolone ≥7.5 mg and NovoMix30 for at least 48 hours over a 19-month period. BGLs were evaluated with repeated-measures analysis within four time periods across the day, beginning from the day prior to NovoMix30 administration. RESULTS: A total of 53 patients were identified. NovoMix30 significantly reduced BGLs in the morning (mean 12.7 ± 4.5 vs. 9.2 ± 3.9 mmol/L, P < 0.001), afternoon (mean 13.6 ± 3.8 vs. 11.9 ± 3.8 mmol/L, P = 0.001) and evening (12.1 ± 3.8 vs. 10.8 ± 3.8 mmol/L, P = 0.01). With uptitration of insulin over 3 days, 43% of all BGLs were within the target range, compared with 23% on day 0 (P < 0.001). The final median dose of NovoMix30 was 0.15 (0.10-0.22) units/kg bodyweight, or 0.40 (0.23-0.69) units/mg of prednisolone, which is lower than our hospital guideline recommends. One overnight hypoglycaemic event was observed. CONCLUSION: Mixed insulin as a pre-breakfast or pre-breakfast and pre-lunch regimen can target the hyperglycaemic pattern induced by prednisolone and minimise overnight hypoglycaemia. However, higher doses of insulin than those used in our study are likely required for optimal BGL control.

Regimen comprising GLP-1 receptor agonist and basal insulin can decrease the effect of food on glycemic variability compared to a pre-mixed insulin regimen.

BACKGROUND: Increasing evidence suggests that glucagon-like peptide 1 (GLP-1) receptor agonists (RA) can stabilize glycemic variability (GV) and interfere with eating behavior. This study compared the impact of insulin, GLP-1 RA, and dietary components on GV using professional continuous glucose monitoring (CGM). METHODS: Patients with type 2 diabetes underwent CGM before and after switching from a twice-daily pre-mixed insulin treatment regimen to a GLP-1 RA (liraglutide) plus basal insulin regimen. The dietary components were recorded and analyzed by a certified dietitian. The interactions between the medical regimen, GV indices, and nutrient components were analyzed. RESULTS: Sixteen patients with type 2 diabetes were enrolled in this study. No significant differences in the diet components and total calorie intake between the two regimens were found. Under the pre-mixed insulin regimen, for increase in carbohydrate intake ratio, mean amplitude of glucose excursion (MAGE) and standard deviation (SD) increased; in contrast, under the new regimen, for increase in fat intake ratio, MAGE and SD decreased, while when the protein intake ratio increased, the coefficient of variation (CV) decreased. The impact of the food intake ratio on GV indices disappeared under the GLP-1 RA regimen. After switching to the GLP-1 RA regimen, the median MAGE, SD, and CV values decreased significantly. However, the significant difference in GV between the two regimens decreased during the daytime. CONCLUSION: A GLP-1 RA plus basal insulin regimen can stabilize GV better than a regimen of twice-daily pre-mixed insulin, especially in the daytime, and can diminish the effect of food components on GV.

The efficacy and safety of GP40081 (insulin aspart biphasic 30) compared with NovoMix® 30 in Type 2 diabetes patients.

Aim: To evaluate the safety and efficacy of insulin Aspart-Mix biosimilar candidate GP40081 (GP-Asp30) compared with NovoMix® 30 (NN-Asp30). Materials & methods: In a randomized open-label, active-controlled, 26-week non-inferiority clinical trial 264 patients with Type 2 diabetes mellitus were randomized 1:1 to receive once-daily GP-Asp30 or NN-Asp30. The primary safety end point was the immune response rate. Efficacy outcomes were a mean change in HbA1c (primary), frequency of achieving a glycemic g fasting plasma glucose levels, 7-point glucose profiles, and insulin doses. Results: The immune response developed in 10/126 (8%) participants in the GP-Asp30 group and in 10/125 (8%) participants in the NN-Asp30 group (p = 1.000). The mean difference in HbA1c change between groups was 0.12 (95%CI [-0.14, 0.38]). Other secondary efficacy and safety outcomes weren't statistically different between the two groups. Conclusion: GP-Asp30 demonstrated similar safety and efficacy compared with NN-Asp30 and may be considered a biosimilar insulin.

Cost-effectiveness of insulin degludec/insulin aspart versus biphasic insulin aspart in Chinese population with type 2 diabetes.

Objective: To evaluate the long-term cost effectiveness of insulin degludec/insulin aspart (IDegAsp) vs. biphasic insulin aspart 30 (BIAsp 30) for the treatment of people with type 2 diabetes mellitus (T2DM) inadequately managed on basal insulin in China. Methods: The CORE (the Center for Outcomes Research) Diabetes Model, which has been published and verified, was used to simulate disease progression and calculate the total direct medical costs, life years (LYs) and quality-adjusted life years (QALYs) over 30 years, from the perspective of Chinese healthcare system. The patient demographic information and clinical data needed for the model were gathered from a phase III treat-to-target clinical trial (NCT02762578) and other Chinese cohort studies. Medical costs on treating diabetes were calculated based on clinical trial and local sources. The diabetes management and complications costs were derived from published literature. A discounting rate of 5% was applied to both health and cost outcomes. And one-way and probabilistic sensitivity analyses were carried out to test the reliability of the results. Results: Compared with BIAsp 30, treatment with IDegAsp was associated with an incremental benefit of 0.001 LYs (12.439 vs. 12.438) and 0.280 QALYs (9.522 vs. 9.242) over a 30-year time horizon, and increased CNY (Chinese Yuan) 3,888 (390,152 vs. 386,264) for total costs. IDegAsp was cost-effective vs. BIAsp 30 therapy with an incremental cost-effectiveness ratio of CNY 13,886 per QALY gained. Results were robust across a range of sensitivity analyses. Conclusion: Compared with BIAsp 30, IDegAsp was a cost-effective treatment option for people with T2DM with inadequate glycemic management on basal insulin in China.

COVID-19 and diabetic ketoacidosis: A case series at an urban district hospital in South Africa.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with an increased prevalence and mortality from diabetic ketoacidosis (DKA) globally. With limited access to specialised care, most patients with DKA in South Africa are managed at district hospital level. This study describes the profile of patients admitted to a district hospital in South Africa with DKA and COVID-19 and examines associated risk factors encountered. METHODS: This was a case series of all patients presenting to a district hospital with DKA and COVID-19 infection between July 2020 and July 2021. Data extracted included patients' demographic profiles, biochemical results, comorbidities and clinical outcomes. RESULTS: The median age of the 10 patients admitted during the study period was 39 years old (±12), six of whom were male. The hemoglobin A1c (HbA1c) values on admission ranged from 9.7 to 13.8. Five of the patients had pre-existing type 2 diabetes mellitus (DM). Four of the known DM patients were on metformin only, and one was on biphasic insulin. Three patients had other pre-existing comorbidities, two patients with hypertension and one with human immunodeficiency virus (HIV). Three patients demised, two of whom were hypoxic on admission. CONCLUSION: Diabetic ketoacidosis appears more commonly in COVID-19 infected patients with type 2 DM and at a young age. Suboptimal glycaemic control was associated with DKA, and hypoxia was a strong predictor for mortality. Treatment inertia was evident in the known DM group, who were on monotherapy despite persistent hyperglycaemia. Greater vigilance is required to detect ketosis in type 2 DM and intensify therapy to improve glycaemic control.

Improved patient-reported outcomes with iGlarLixi versus premix BIAsp 30 in people with type 2 diabetes in the SoliMix trial.

AIM: To assess patient-reported outcomes (PROs) in the SoliMix trial, which compared the efficacy and safety of iGlarLixi versus BIAsp 30 in people with type 2 diabetes (T2D). MATERIALS AND METHODS: SoliMix (EudraCT: 2017-003370-13), a 26-week, open-label study, randomized (1:1) 887 adults with T2D and HbA1c ≥7.5%-≤10.0% (≥58-≤86 mmol/mol) on basal insulin plus oral antihyperglycaemic drugs (OADs) to once-daily iGlarLixi or twice-daily premix insulin, BIAsp 30. PROs were assessed using the Treatment-Related Impact Measure Diabetes (TRIM-D) and Global Treatment Effectiveness Evaluation (GTEE) questionnaires. RESULTS: Over 26 weeks, iGlarLixi showed greater improvement from baseline versus BIAsp 30 in total TRIM-D score (least squares mean difference [95% confidence interval]: 5.08 [3.69, 6.47]; effect size: 0.32) and in each TRIM-D domain, with the greatest differences seen in diabetes management (8.47 [6.11, 10.84]) and treatment burden (6.95 [4.83, 9.07]). GTEE scores showed a greater proportion of participants and physicians rated a complete or marked improvement of diabetes control with iGlarLixi (80.5%, 82.8%) versus BIAsp 30 (63.3%, 65.1%) at week 26. Post hoc analyses showed that after adjusting for HbA1c, body weight and hypoglycaemia outcomes, iGlarLixi continued to show greater improvements in TRIM-D total scores versus BIAsp 30. CONCLUSIONS: In addition to better glycaemic control, weight benefit and less hypoglycaemia, once-daily iGlarLixi provided improved diabetes management, treatment burden and perceived effectiveness versus twice-daily premix BIAsp 30, further supporting iGlarLixi as an advanced treatment option in people with suboptimally controlled T2D on basal insulin plus OADs.

Hypoglycaemia events with iGlarLixi versus premix biphasic insulin aspart 30 (BIAsp 30) in people with type 2 diabetes advancing from basal insulin: An analysis of the SoliMix trial.

AIMS: To explore details of the incidence and rates of daytime and nocturnal hypoglycaemia, levels of hypoglycaemia, and relationship to glycated haemoglobin (HbA1c), when comparing iGlarLixi versus premixed biphasic insulin aspart 30 (BIAsp 30) in the SoliMix randomized controlled trial. MATERIALS AND METHODS: This exploratory analysis of SoliMix used logistic regression and negative binomial regression analyses to assess between-treatment differences in the incidence and rates of hypoglycaemia by time of day. A negative binomial model was used to derive estimated annualized hypoglycaemia rates as a function of HbA1c. RESULTS: iGlarLixi was associated with lower incidence and rates of American Diabetes Association Level 2 (<54 mg/dL [<3.0 mmol/L]) hypoglycaemia during both night and day versus BIAsp 30. Incidence and rates of Level 1 (<70 to ≥54 mg/dL [<3.9 to ≥3.0 mmol/L]) hypoglycaemia were also mostly shown to be reduced with iGlarLixi versus BIAsp 30. Severe (Level 3) events were too few for analysis (n = 3). iGlarLixi was associated with lower modelled event rates of Level 2 and Level 1 hypoglycaemia over a wide range of HbA1c levels versus BIAsp 30. CONCLUSIONS: These results show that the lower HbA1c levels and weight benefit seen with iGlarLixi versus premixed BIAsp 30 in people with type 2 diabetes advancing their basal insulin therapy in the SoliMix trial are also accompanied by a lower risk of hypoglycaemia at any time of day and across a broad range of HbA1c levels.

GLP-1 receptor agonist use during hospitalisation: Better glycaemic control compared to premixed insulin.

INTRODUCTION: Glycaemic control associates with better outcomes for hospitalised patients. Whether GLP-1 receptor agonists (GLP-1 RA) are suitable and effective drugs for inpatients is unclear. METHODS: A retrospective, single centre, observational study using data from the electronic health record. Patients admitted using GLP-1 RA as outpatients, from 2016 to 2019, were identified. Outcomes were compared to those admitted using twice-daily (BD) mixed insulin. Capillary glucose, medication use, creatinine, and demographic data were collected. As drugs may be discontinued/not administered in hospital, days when GLP-1 RA was administered were 'GLP-1 RA active' and, for insulin, 'insulin active'. The primary comparison was rate of hypoglycaemia (<4 mmol/L) and severe hypoglycaemia (<3 mmol/L). A logistic regression model examined variables for hypoglycaemia. RESULTS: GLP-1 RA comprised n = 262 admissions and BD insulin n = 166. The 'insulin active' cohort (n = 957 patient days) had higher risk of hypoglycaemia than 'GLP-1 RA active' (n = 806 days); occurring on 14.7% of days; 95% confidence interval [CI] 12.6-17.1 versus 9.9% days; 95% CI 8.0-12.2; p = 0.002, and severe hypoglycaemia 4.0% of days (95% CI 2.8-5.4) versus 2.0% (95% CI 1.1%-3.2%; p = 0.005). Daily glucose (mean ± standard deviation) was 10.8 ± 5.2 mmol/L in insulin active versus 9.6 ± 4.7 mmol/L in GLP-1 RA active; p < 0.001. Insulin use, age, and acute admissions predicted hypoglycaemia. The odds ratio for hypoglycaemia was 2.15 times greater (95% CI, 1.14-4.08; p = 0.019) with insulin than with GLP-1 RA. CONCLUSIONS: GLP-1 RA provided better glycaemic control than BD mixed insulin and should be continued during hospitalisation unless there is a clear indication for cessation.

Elevated alanine aminotransferase is associated with biphasic insulin secretion in the healthy elderly Han Chinese population.

OBJECTIVE: To evaluate the relationship between alanine transaminase (ALT) level and biphasic insulin secretion (BPIS) in healthy elderly Han Chinese individuals. METHODS: This cross-sectional study enrolled healthy elderly participants aged ≥60 years that were part of a health examination programme. In order to explore the correlation and severity of the clinical condition, those with any possible confounding factors known to affect insulin secretion or liver function were excluded from the study. BPIS was calculated using an equation developed previously by this research team. RESULTS: This study enrolled 39 845 healthy elderly individuals (19 058 males and 20 787 females). Participants were stratified into four quartile groups according to their ALT level. In both males and females, the increasing ALT quartiles (ordinal variable) were associated with greater values of log-transformed first-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS). The correlation and the linear regression model showed that increasing ALT level was significantly correlated with higher log-transformed FPIS and SPIS. CONCLUSIONS: ALT was positively correlated with BPIS in a healthy elderly population in both men and women. Elevated ALT may serve as an indicating factor for developing metabolic syndrome and type 2 diabetes mellitus in healthy elderly individuals.

Modeling of Pharmacokinetic Profiles of Insulin Aspart and Biphasic Insulin Aspart 30/70.

This study includes modeling and simulation of insulin aspart pharmacokinetics (PK). The authors used PK data of biosimilar insulins-insulin aspart and biphasic insulin aspart 30/70-to develop a predictive population PK model for the insulins. The model was built via Monolix software, taking into account the weight-based dosing and the dose and body-weight effects on the parameters. The model-based simulations were performed using the R package mlxR for various administered doses and various ratios of insulin aspart forms for a better understanding of the insulin behavior. The optimal model was a 1-compartment model with a combination of zero- and first-order absorptions, with absorption lag for the soluble form of insulin aspart and first-order absorption for the insulin aspart protamine suspension. The assumption of identical behavior of 2 insulins at the distribution and elimination phases was made. The developed PK model was fitted successfully to the experimental data, and all fitted parameters displayed a moderate coefficient of variation. The PK model allows us to predict PK profiles for various doses and formulations of insulin aspart and can be used to improve the accuracy, safety, and ethics of novel clinical trials of insulin.

Real-Time Flash Glucose Monitoring Had Better Effects on Daily Glycemic Control Compared With Retrospective Flash Glucose Monitoring in Patients With Type 2 Diabetes on Premix Insulin Therapy.

Background and Aims: To compare the effects of real-time and retrospective flash glucose monitoring (FGM) on daily glycemic control and lifestyle in patients with type 2 diabetes on premix insulin therapy. Methods and Results: A total of 172 patients using premix insulin, with HbA1c ≥ 7.0% (56 mmol/mol), or the time below the target (TBR) ≥ 4%, or the coefficient of variation (CV) ≥36% during the screening period, were randomly assigned to retrospective FGM (n = 89) or real-time FGM group (n = 83). Another two retrospective or real-time 14-day FGMs were performed respectively, 1 month apart. Both groups received educations and medication adjustment after each FGM. Time in range (3.9~10.0 mmol/l, TIR) increased significantly after 3 months in the real-time FGM group (6.5%) compared with the retrospective FGM group (-1.1%) (p = 0.014). HbA1c decreased in both groups (both p < 0.01). Real-time FGMs increased daily exercise time compared with the retrospective group (p = 0.002). Conclusions: Real-time FGM with visible blood glucose improves daily glycemic control and diabetes self-care behaviors better than retrospective FGM in patients with type 2 diabetes on premix insulin therapy. Clinical Trial Registration: https://clinicaltrials.gov/NCT04847219.

Comparison of Prevailing Insulin Regimens at Different Time Periods in Hospitalized Patients: A Real-World Experience from a Tertiary Hospital.

BACKGROUND: Prevailing insulin regimens for glycemic control in hospitalized patients have changed over time. We aimed to determine whether the current basal-bolus insulin (BBI) regimen is superior to the previous insulin regimen, mainly comprising split-mixed insulin therapy. METHODS: This was a single tertiary center, retrospective observational study that included non-critically ill patients with type 2 diabetes mellitus who were treated with split-mixed insulin regimens from 2004 to 2007 (period 1) and with BBI from 2008 to 2018 (period 2). Patients from each period were analyzed after propensity score matching. The mean difference in glucose levels and the achievement of fasting and preprandial glycemic targets by day 6 of admission were assessed. The total daily insulin dose, incidence of hypoglycemia, and length of hospital stay were also evaluated. RESULTS: Among 244 patients from each period, both fasting glucose (estimated mean±standard error, 147.4±3.1 mg/dL vs. 129.4±3.2 mg/dL, P<0.001, day 6) and preprandial glucose (177.7±2.8 mg/dL vs. 152.8±2.8 mg/dL, P<0.001, day 6) were lower in period 2 than in period 1. By day 6 of hospital admission, 42.6% and 67.2% of patients achieved a preprandial glycemic target of <140 mg/dL in periods 1 and 2, respectively (relative risk, 2.00; 95% confidence interval, 1.54 to 2.59), without an increased incidence of hypoglycemia. Length of stay was shorter in period 2 (10.23±0.26 days vs. 8.70±0.26 days, P<0.001). CONCLUSION: BBI improved glycemic control in a more efficacious manner than a split-mixed insulin regimen without increasing the risk of hypoglycemia in a hospital setting.

Composite cardiovascular risk and BMI affected comparative profiles of BIAsp 30 + metformin vs BIAsp 30 monotherapy: a MERIT post-hoc analysis.

We assessed whether comparative efficacy and safety of biphasic insulin aspart 30 (BIAsp 30) plus metformin versus BIAsp 30 monotherapy differed for patients with type 2 diabetes mellitus (T2DM) inadequately controlled with oral antidiabetic drugs with different cardiovascular risk scores and different body mass indexes (BMI) by performing a post hoc analysis of the randomized controlled MERIT study. In the MERIT study, eligible patients were randomized 1:1 to receive BIAsp 30 plus metformin or BIAsp 30 for 16 weeks. Patients in the 2 treatment groups were classified into "low" and "high" risk subgroups based on their GloboRisk scores and into "BMI ≤ 26 kg/m2"and "BMI > 26 kg/m2" subgroups. Primary efficacy endpoint was between-treatments comparison of HbA1c changes from baseline for these 2 sets of subgroups. Between-treatments comparisons of secondary efficacy and safety endpoints were also performed. We found that BIAsp 30 plus metformin led to significantly higher percentage of high-risk patients achieving HbA1c target < 7% than BIAsp 30 monotherapy, with an overall comparable safety profile for high-risk patients. Meanwhile, for patients with BMI ≤ 26 kg/m2, compared with BIAsp 30 monotherapy, BIAsp 30 plus metformin led to significantly higher percentages of patients achieving HbA1c target (47.83% vs 28.17%, P = 0.0165) and composite target of HbA1c < 7% without hypoglycemia or weight gain (20.29% vs 6.85%, P = 0.0187) and have a slightly better safety profile. In conclusion, for T2DM patients at high CV risk or with BMI ≤ 26 kg/m2, BIAsp 30 plus metformin was preferable to BIAsp 30 monotherapy.

Advancing therapy with iGlarLixi versus premix BIAsp 30 in basal insulin-treated type 2 diabetes: Design and baseline characteristics of the SoliMix randomized controlled trial.

AIM: Premix insulin is commonly used in some regions of the world, despite the higher risk of hypoglycaemia and weight gain compared with basal insulin, based on the premise that it offers a simplified insulin regimen. iGlarLixi is a once-daily titratable fixed-ratio formulation that combines basal insulin glargine 100 units/mL (iGlar) and the GLP-1 RA, lixisenatide, which offers a single-injection option for treatment intensification, with improved HbA1c reductions, similar hypoglycaemia risk and more favourable bodyweight profiles over iGlar alone. This randomized controlled study directly compares, for the first time, treatment intensification with iGlarLixi versus premix insulin analogue biphasic insulin aspart 30 (BIAsp 30) in adults with T2D inadequately controlled on basal insulin in combination with one or two oral antihyperglycaemic drugs. MATERIALS AND METHODS: This was an open-label, active-controlled, comparative, parallel-group, multicentre, phase 3b study. In total, 887 adults with T2D uncontrolled on basal insulin were randomized to switch to either iGlarLixi once daily, or BIAsp 30 twice daily, for 26 weeks. RESULTS: Overall, 887 participants were enrolled (mean age 59.8 years, 50.2% female) from 89 centres in 17 countries. At baseline, 65.6% had a duration of T2D of 10 years or longer, and the mean HbA1c at baseline was 8.6%. CONCLUSIONS: The study directly compared the efficacy and safety of iGlarLixi versus BIAsp 30 in people with T2D uncontrolled on basal insulin and one or more oral antihyperglycaemic agents. These results provide robust clinical data that may inform clinicians in their therapeutic management of people with T2D uncontrolled on basal insulin requiring additional therapy.

A Glucose-Insulin Mixture Model and Application to Short-Term Hypoglycemia Prediction in the Night Time.

OBJECTIVE: Insulin-induced hypoglycemia is recognized as a critical problem for diabetic patients, especially at night. To give glucose prediction and advance warning of hypoglycemia of at least 30 minutes, various glucose-insulin models have been proposed. Recognizing the complementary nature of the models, this research proposes a Glucose-Insulin Mixture (GIM) model to predict the glucose values for hypoglycemia detection, by optimally fusing different models with its adjusted parameters to address the inter- and intra-individual variability. METHODS: Two types of classic glucose-insulin models, the Ruan model, with single-compartment glucose kinetics, and the Hovorka model, with two-compartment glucose kinetics, are selected as two candidate models. Based on Bayesian inference, GIM is introduced with quantified contributions from the models with the associated parameters. GIM is then applied to predict the glucose values and hypoglycemia events. RESULTS: The proposed model is validated by the nocturnal glucose data collected from 12 participants with type 1 diabetes. The GIM model has promising fitting of RMSE within 0.3465 mmol/L and predicting of RMSE within 0.5571 mmol/L. According to the literature, the hypoglycemia is defined as 3.9 mmol/L, and the GIM model shows good short-term hypoglycemia prediction performance with the data collected within the last hour (accuracy: 95.97%, precision: 91.77%, recall: 95.60%). In addition, the probability of hypoglycemia event in 30 minutes is inferred. CONCLUSION: GIM, by fusing various glucose-insulin models via Bayesian inference, has the promise to capture glucose dynamics and predict hypoglycemia. SIGNIFICANCE: GIM based short-term hypoglycemia prediction has potential clinical utility for timely intervention.