The IDEAL (Insulin therapy DE-intensificAtion with iglarLixi) Randomised Controlled Trial-Study Design and Protocol.

INTRODUCTION: Multiple daily injection insulin regimen (MDI) represents the most intensive insulin regimen used in the management of people with type 2 diabetes (PwT2D). Its efficacy regarding glycaemic control is counterbalanced by the increased risk of hypoglycaemia, frequently observed tendency to weight gain and necessity for frequent glucose monitoring. Recent introduction of novel antidiabetic medications with pleiotropic effects reaching far beyond the reduction of glycaemia (HbA1c), such as the glucagon-like peptide 1 receptor agonist (GLP-1 RA), has significantly widened the therapeutic options available for management of T2D. Consequently, there is currently a substantial number of PwT2D for whom the MDI regimen was initiated at a time when no other options were available. Yet, in present times, these individuals could benefit from simplified insulin regimens ideally taking advantage of the beneficial effects of the novel classes of antidiabetic medications. iGlarLixi (Suliqua®) is a once-daily fixed-ratio combination of basal insulin analogue glargine 100 U/ml and a GLP-1 RA lixisenatide. METHODS: Insulin therapy DE-intensificAtion with iglarLixi (IDEAL) is a six-centre, open-label, parallel-group, active comparator, phase IV randomised controlled trial with a 24-week active treatment period examining the efficacy and safety of MDI regimen de-intensification with once-daily administration of iGlarLixi versus MDI regimen continuation in PwT2D on a backgroud therapy with metformin ± sodium-glucose cotransporter 2 inhibitor. PLANNED OUTCOMES: The primary objective is to compare the effects of MDI therapy de-intensification with iGlarLixi versus MDI regimen continuation regarding glycaemic control (HbA1c). Secondary objectives include detailed evaluation of the effects of MDI regimen de-intensification with iGlarLixi on glycaemic control using standardised continuous glucose monitoring (CGM) metrics and self-monitoring of plasma glucose. Furthermore, body weight and body composition analysis, quality of life and safety profile are evaluated. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT04945070.

Consistent glycaemic efficacy and safety of concomitant use of iGlarLixi and sodium-glucose co-transporter-2 inhibitor therapy for type 2 diabetes: A patient-level pooled analysis of three randomised clinical trials.

AIMS: Sodium glucose co-transporter 2 inhibitors (SGLT2is) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with proven cardio- and reno-protective benefits are recommended in people with type 2 diabetes (T2D) at high risk of cardiovascular disease, chronic kidney disease, and/or heart failure. This pooled analysis compared efficacy and safety outcomes of iGlarLixi with or without SGLT2is in people with T2D. METHODS: This post hoc analysis evaluated outcomes in participants who were receiving an SGLT2i when initiating iGlarLixi (SGLT2i users) and those who were not (SGLT2i non-users) in a pooled dataset from three trials: LixiLan-G (advancing from a GLP-1 RA), SoliMix and LixiLan ONE CAN (advancing from basal insulin). RESULTS: Baseline characteristics were generally similar between 219 users and 746 non-users. Least squares mean changes in HbA1c from baseline to Week 26 were similar for users (-1.2 % [95 % confidence intervals: -1.4 %, -1.1 %]) and non-users (-1.2 % [-1.2 %, -1.1 %]). Changes in body weight, fasting glucose and post-prandial glucose were similar between groups, as were hypoglycaemic events. CONCLUSIONS: Pooled results from three studies of adults with T2D demonstrated that iGlarLixi provided similar clinically meaningful improvements in glycaemic control without increased hypoglycaemia risk, regardless of concomitant use of SGLT2is.

Effects of age and disease duration on the efficacy and safety of iGlarLixi in Asian people with type 2 diabetes: A post hoc analysis of the LixiLan-O-AP and LixiLan-L-CN trials.

AIM: To evaluate the effect of age and disease duration on the efficacy and safety of iGlarLixi versus insulin glargine 100 units/ml (iGlar) or lixisenatide (Lixi) alone in Asian people with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (LixiLan-O-AP) or basal insulin ± oral antidiabetic drugs (LixiLan-L-CN). MATERIALS AND METHODS: In this post hoc analysis, the glycated haemoglobin (HbA1c) changes were assessed from baseline to week 24 (LixiLan-O-AP) or 30 (LixiLan-L-CN) in subgroups defined by baseline age (<65, ≥65 years) and duration of T2D. The proportion who achieved the composite of HbA1c <7% (<53.0 mmol/mol) without weight gain and without symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L) and the incidences of hypoglycaemia and gastrointestinal disorders were also analysed. RESULTS: HbA1c reductions were consistently greater with iGlarLixi versus iGlar or Lixi across all subgroups, including participants aged ≥65 years and those with T2D for ≥15 or ≥20 years. Greater proportions of participants achieved HbA1c <7% (<53.0 mmol/mol) without weight gain or hypoglycaemia with iGlarLixi versus iGlar or Lixi, regardless of age or T2D duration. Hypoglycaemia incidence was similar with iGlarLixi versus iGlar across most subgroups; the incidence of gastrointestinal disorders was lower with iGlarLixi versus Lixi in all subgroups. CONCLUSIONS: iGlarLixi showed consistent efficacy and safety across all age and disease duration subgroups in Asian people with uncontrolled T2D, including older individuals and those with longstanding disease.

Impact of X-Ray Exposure From Computed Tomography on Wearable Insulin Delivery Devices.

BACKGROUND: To investigate the impact of radiation exposure from a computed tomography (CT) scanner on the functional integrity of a wearable insulin delivery system. METHODS: A total of 160 Omnipods and four personal diabetes managers (PDMs) were evenly divided into four groups: (1) control group (no radiation exposure), (2) typical radiation exposure group, (3) 4× typical radiation exposure group, and (4) scatter radiation group. Pods were attached to an anthropomorphic torso phantom on the abdomen (direct irradiation) or shoulder (scatter radiation) region. A third-generation dual-source CT scanner was used to scan the pods using either a typical exposure (used for routine CT abdominal study of a median size patient) or 4× typical exposure. A manufacturer-recommended 20-step functionality test was performed for all 160 Omnipods. RESULTS: The radiation dose (measured in volume CT Dose index) was 16 mGy for a typical exposure, and 64 mGy for 4× typical exposure. The scatter radiation is less than 0.1 mGy. All Pods passed the functionality test except one pod in the scatter radiation group, which sounded an alarm due to occlusion. The blockage to the fluid was due to a kink in the soft cannula, a mechanical issue not caused by the radiation exposure. CONCLUSIONS: This study suggests X-ray exposure levels used in radiological imaging procedures do not negatively impact the functional integrity of Omnipods. This finding may support the potential for the manufacturer to remove the warning that patients should remove the Pod for X-ray imaging procedures, which will have a huge impact on patient care.

iGlarLixi provides a higher derived time-in-range versus insulin glargine 100 U/mL or lixisenatide in Asian Pacific people with type 2 diabetes: A post hoc analysis.

AIM: To evaluate the efficacy of iGlarLixi in the Asian Pacific (AP) population with type 2 diabetes (T2D) using derived time-in-ranges calculated from seven-point self-measured blood glucose. METHODS: Two phase III trials were analysed. LixiLan-O-AP was performed in insulin-naive T2D patients (n = 878) randomized to iGlarLixi, glargine 100 units/mL (iGlar) or lixisenatide (Lixi). LixiLan-L-CN was performed in insulin-treated T2D patients (n = 426) randomized to iGlarLixi or iGlar. Changes in derived time-in-ranges from baseline to end-of-treatment (EOT) and estimated treatment differences (ETDs) were analysed. The proportions of patients achieving 70% or higher derived time-in-range (dTIR), 5% or higher dTIR improvement, and the composite triple target (≥ 70% dTIR, < 4% derived time-below-the-range [dTBR] and < 25% derived time-above-the-range [dTAR]) were calculated. RESULTS: The changes from baseline to EOT in dTIR with iGlarLixi were greater versus iGlar (ETD1 : 11.45% [95% CI, 7.66% to 15.24%]) or Lixi (ETD2 : 20.54% [95% CI, 15.74% to 25.33%]) in LixiLan-O-AP, and versus iGlar (ETD: 16.59% [95% CI, 12.09% to 21.08%]) in LixiLan-L-CN. In LixiLan-O-AP, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT with iGlarLixi were 77.5% and 77.8%, respectively, higher than with iGlar (61.1% and 75.3%) or Lixi (47.0% and 53.0%). In LixiLan-L-CN, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT were 71.4% and 59.8% with iGlarLixi, greater than with iGlar (45.4% and 39.5%). More patients achieved the triple target with iGlarLixi compared with iGlar or Lixi. CONCLUSION: iGlarLixi achieved greater improvements in dTIR parameters versus iGlar or Lixi in insulin-naïve and insulin-experienced AP people with T2D.

Improvements in Glycemic Outcomes in 4738 Children, Adolescents, and Adults with Type 1 Diabetes Initiating a Tubeless Insulin Management System.

INTRODUCTION: Despite recent advances in diabetes technology, most people living with type 1 diabetes mellitus (T1D) are unable to meet glycemic targets. Real-world evidence can provide insight into outcomes achieved with specific treatment devices when used in clinical practice. The aim of this study was to analyze real-world outcomes collected from a large cohort of people living with T1D and initiating treatment with the Omnipod DASH System. METHODS: In this retrospective observational study, real-world outcomes were analyzed from a database of information collected from people with T1D initiating the Omnipod DASH System. Information in the database was either taken directly from the patient's medical record or self-reported if medical records were unavailable. The primary outcome was change in glycated hemoglobin (HbA1c) from baseline (before initiation) to 3 months after initiation. Secondary outcomes were changes in total daily dose of insulin (TDD) and self-reported frequency of hypoglycemic events (< 70 mg/dL). Results are separated for the adult (≥ 18 years, N = 3341) and pediatric (< 18 years, N = 1397) cohorts. RESULTS: The change in HbA1c from baseline was - 0.9 ± 1.6% ( - 10 ± 18 mmol/mol; p < 0.0001) in adults and - 0.9 ± 2.0% ( - 10 ± 22 mmol/mol; p < 0.0001) in the pediatric cohort. For those previously using multiple daily injections, HbA1c decreased by - 1.0 ± 1.7% ( - 11 ± 19 mmol/mol) in adults and - 1.0 ± 2.1% ( - 11 ± 23 mmol/mol) in the pediatric cohort (both p < 0.0001). Hypoglycemic events decreased in adults from 2.9 to 1.3 episodes per week ( - 1.6 ± 3.2 events/week; p < 0.0001), and in the pediatric cohort from 2.8 to 1.5 episodes per week ( - 1.3 ± 2.7 events/week; p < 0.0001). In adults, TDD decreased by 19.9% (p < 0.0001), and it remained stable in the pediatric cohort (p > 0.05). CONCLUSIONS: Real-world outcomes from this large cohort of people initiating therapy with the Omnipod DASH System showed significant improvement in HbA1c and a substantial reduction in hypoglycemic events after 3 months of use.

The SAGE study: Global observational analysis of glycaemic control, hypoglycaemia and diabetes management in T1DM.

AIMS: To describe glycaemic control and diabetes management in adults with type 1 diabetes (T1DM), in a real-life global setting. MATERIALS AND METHODS: Study of Adults' GlycEmia (SAGE) was a multinational, multicentre, single visit, noninterventional, cross-sectional study in adult patients with T1DM. Data were collected at a single visit, analysed according to predefined age groups (26-44, 45-64 and ≥65 years) and reported across different regions. The primary endpoint was the proportion of participants achieving HbA1c  less than 7.0 % in each age group. Secondary endpoints included incidence of hypoglycaemia, severe hypoglycaemia and severe hyperglycaemia leading to diabetic ketoacidosis (DKA) and therapeutic management of T1DM. RESULTS: Of 3903 included participants, 3858 (98.8%) were eligible for the study. Overall, 24.3% (95% confidence interval [CI]: 22.9-25.6) of participants achieved the glycaemic target of HbA1c  less than 7.0 %, with more participants achieving this target in the 26-44 years group (27.6% [95% CI: 25.5-29.8]). Target achievement was highest in Eastern and Western Europe, and lowest in the Middle East. The incidence of hypoglycaemia and of severe hyperglycaemia leading to DKA tended to decrease with age, and varied across regions. Age and regional differences were observed in therapeutic management, including types of device/insulin usage, frequency of insulin dose adjustment and technology usage. CONCLUSIONS: Glycaemic control remains poor in adults with T1DM globally. Several areas of treatment may be optimised to improve outcomes, including supporting patient self-management of insulin therapy, increasing use of technologies such as CGM, and greater provision of healthcare support.

Lower risk of severe hypoglycaemia with insulin glargine 300 U/mL versus glargine 100 U/mL in participants with type 1 diabetes: A meta-analysis of 6-month phase 3 clinical trials.

Severe hypoglycaemia (SH) remains a challenge to people with type 1 diabetes (T1DM), and new-generation basal insulins may improve patient outcomes. This post hoc meta-analysis explored the risk of SH with insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in a pooled population with T1DM from three randomized, multicentre, 6-month similarly designed phase 3 trials: EDITION 4, EDITION JP 1 and EDITION JUNIOR. Endpoints included incidence and time to first occurrence of SH. Among 629 and 626 participants randomized to Gla-300 and Gla-100, respectively, glycated haemoglobin reductions were similar. Fewer participants experienced ≥1 SH event with Gla-300 (6.2%) than with Gla-100 (9.3%). From baseline to month 6, the risk of a first SH event was lower with Gla-300: hazard ratio 0.65 [95% confidence interval (CI) 0.44-0.98; stratified log-rank test P = 0.038]. SH event rates were numerically lower with Gla-300 versus Gla-100 from baseline to month 6 [relative risk (RR) 0.80 (95% CI 0.49-1.29); P = 0.356] and baseline to week 8 [RR 0.73 (95% CI 0.37-1.44); P = 0.369]. Thus, Gla-300 demonstrated similar glycaemic control with lower risk of SH versus Gla-100, particularly during the titration period.

Differential glycaemic control with basal insulin glargine 300 U/mL versus degludec 100 U/mL according to kidney function in type 2 diabetes: A subanalysis from the BRIGHT trial.

AIMS: Chronic kidney disease (CKD) challenges diabetes management and is associated with increased cardiovascular morbidity and mortality. We examined whether clinical outcomes with insulin glargine 300 U/mL (Gla-300) and insulin degludec 100 U/mL (IDeg-100) are affected by renal function in a prespecified subgroup analysis from the BRIGHT trial. MATERIALS AND METHODS: BRIGHT (NCT02738151) was a multicentre, open-label, randomized, active-controlled, two-arm, parallel-group, 24-week study in insulin-naïve uncontrolled type 2 diabetes (T2D). Participants were randomized 1:1 to evening Gla-300 (n = 466) or IDeg-100 (n = 463) and stratified based on baseline estimated glomerular filtration rate (eGFR) for this analysis. RESULTS: Heterogeneity of treatment effect across renal function subgroups was observed (P = .02), reflecting a greater mean glycated haemoglobin (HbA1c) reduction from baseline to week 24 with Gla-300 versus IDeg-100 in the eGFR <60 mL/min/1.73 m2 subgroup (least squares mean difference: -0.43% [95% confidence interval: -0.74% to -0.12%]), while there were no differences in hypoglycaemia incidence or rates over 24 weeks in that subgroup. HbA1c reductions were similar between treatments in the other eGFR subgroups. However, heterogeneity was observed for annualized rates of anytime (24 hours) or nocturnal (00:00-05:59 hours) confirmed hypoglycaemia (≤70 mg/dL [≤3.9 mmol/L]) over 24 weeks showing less hypoglycaemia with Gla-300 versus IDeg-100 in the ≥90 mL/min/1.73 m2 . CONCLUSIONS: Kidney function seems to affect the glucose-lowering effects of Gla-300 versus IDeg-100 in insulin-naïve T2D. Greater HbA1c reductions with Gla-300 without increase in hypoglycaemia risk, were observed in patients with eGFR <60 mL/min/1.73 m2 .

Similar glycaemic control and less hypoglycaemia during active titration after insulin initiation with glargine 300 units/mL and degludec 100 units/mL: A subanalysis of the BRIGHT study.

AIM: To further investigate glycaemic control and hypoglycaemia in BRIGHT, focusing on the titration period. MATERIALS AND METHODS: BRIGHT was a multicentre, open-label, randomized, active-controlled, two-arm, parallel-group, 24-week study in insulin-naïve patients with uncontrolled type 2 diabetes initiated on glargine 300 U/mL (Gla-300) (N = 466) or degludec (IDeg-100) (N = 463). Predefined efficacy and safety outcomes were investigated during the initial 12-week titration period. In addition, patients' characteristics and clinical outcomes were assessed descriptively, stratified by confirmed (≤3.9 mmol/L) hypoglycaemia incidence during the initial titration period. RESULTS: At week 12, HbA1c was comparable between Gla-300 (7.32%) and IDeg-100 (7.23%), with similar least squares (LS) mean reductions from baseline (-1.37% and - 1.39%, respectively; LS mean difference of 0.02; 95% confidence interval: -0.08 to 0.12). Patients who experienced hypoglycaemia during the initial titration period had numerically greater HbA1c reductions by week 12 than patients who did not (-1.46% vs. -1.28%), and higher incidence of anytime (24 hours; 73.3% vs. 35.7%) and nocturnal (00:00-06:00 hours; 30.0% vs. 11.9%) hypoglycaemia between weeks 13-24. CONCLUSIONS: The use of Gla-300 resulted in similar glycaemic control as IDeg-100 during the initial 12-week titration period of the BRIGHT study, when less anytime (24 hours) hypoglycaemia with Gla-300 versus IDeg-100 has been reported. Experiencing hypoglycaemia shortly after initiating Gla-300 or IDeg-100 may be associated with hypoglycaemia incidence in the longer term, potentially impacting glycaemic management.

Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment.

Type 2 diabetes mellitus (T2DM) has a high prevalence and incidence around the world. The complex pathophysiology mechanism is among the barriers for diabetes treatment. Type 2 diabetes patients have dysfunction in incretin hormones (as glucagon-like peptide-1 or GLP-1, and glucose-dependent insulinotropic polypeptide or GIP). By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, it is possible to slow the inactivation of GLP-1 and GIP, promoting blood glucose level reduction in a glucose-dependent manner. Linagliptin is a highly specific and potent inhibitor of DPP-4 that is currently indicated for the treatment of type 2 diabetes. Clinical studies with linagliptin demonstrated efficacy in reducing glycated hemoglobin (HbA1c) levels in type 2 diabetes patients, while maintaining a placebo-like safety and tolerability profile. Linagliptin has an interesting pharmacokinetic profile in terms of its predominantly non-renal elimination and the main implication of this characteristic is that no dose adjustment is necessary in patients with renal disease. Also, no dose adjustment is required in patients with hepatic insufficiency, as well in elderly or obese patients. This article will review the pharmacokinetic profile, efficacy data and safety aspects of linagliptin in type 2 diabetes patients.

Efeito da drenagem abdominal na cicatrização de anastomoses colônicas: estudo experimental em ratos / The role of abdominal drain on colonic anastomosis healing: an experimental study in rats

A deiscência de anastomose é uma complicação importante nas cirurgias do aparelho digestivo. Vários fatores podem prejudicar o processo de cicatrização, entre eles, a presença de drenos na cavidade. O objetivo deste estudo foi avaliar a interferência da drenagem abdominal na cicatrização de anastomoses colônicas, em ratos. Quarenta ratos que foram distribuídos em 4 grupos, sendo submetidos à ressecção de segmento do colón, com anastomose local. Um grupo foi controle e nos demais foram colocados drenos de Látex, PVC e Silicone, respectivamente. O sacrifício ocorreu após 1 semana, quando foram avaliados os aspectos da cavidade abdominal (peritonite, aderências, deiscências e abscessos), a histologia e bioquímica (hidroxiprolina). No total, foram analisados, individualmente, 18 critérios: 4 macroscópicos, 13 microscópicos e 1 bioquímico. O grupo látex apresentou uma discrepância negativa em relação aos outros grupos. O grupo Controle (sem dreno) apresentou cicatrização positiva em relação aos outros grupos. Com base nos resultados, concluímos que a utilização de drenos (independente do material) seria um fator negativo para a cicatrização da anastomose. Entre os drenos, os de Látex interferiram negativamente na cicatrização quando comparado com os drenos de outros materiais.

Anastomosis dehiscence is a main complication of the gastrointestinal surgical procedures. Different factors might influence the healing process, including the presence of an abdominal drain. The aim of the present study was to evaluate the role of different abdominal drains, on the colonic anastomosis healing, in rats. Forty rats, all submitted to a colonic resection followed by a local anastomosis, were divided into 4 groups. Group I was the control. Groups II, III and IV received and abdominal drain constituted of latex, PVC or silicone, respectively. One week after, animals were killed and had their abdominal cavity inspected macroscopically (peritonitis, adhesions, dehiscence, and abscesses). The anastomotic regions were submitted to histological and biochemical evaluations. In total, 4 macroscopic, 13 histological and 1 biochemical criteria were evaluated and some of them did not show statistical differences between groups. Group II showed a negative outcome in comparison to the others. Control groups had a positive healing condition in comparison to the others. In conclusion, the abdominal drain, independently of the constituting material, is a negative factor which interferes with anastomosis healing, compared to controls. The latex drain showed the worse effect on healing, when compared to other drains.

Efeito da hipovolemia sobre a cicatrização de anastomoses colônicas: estudo experimental em ratos / Effect of the hypovolemia on the healing of colonic anastomosis: experimental study in rats

A cicatrização é o processo de reparo tecidual no qual o tecido lesado é substituído por tecido conjuntivo fibroso. A falha na cicatrização das feridas é um problema clínico significativo, sendo a deiscência de anastomose uma complicação importante em pós-operatórios de cirurgias do aparelho digestivo. Certas condições gerais podem prejudicar o processo de cicatrização, tais como a hipovolemia, comum de ocorrer em cirurgias de emergência prejudicando o metabolismo do colágeno. A hidroxiprolina está presente em concentrações elevadas no colágeno, sendo indispensável para a estabilidade da tríplice hélice da proteína. Neste estudo avaliamos a cicatrização de anastomoses colônicas em ratos na vigência de hipovolemia. Dividimos os animais em três grupos experimentais portadores de anastomose colônica, sendo dois deles com hipovolemia de 20por cento e 40por cento. Realizamos exame necroscópico para avaliação macroscópica da anastomose colônica e cavidade abdominal, ressecção do segmento com a anastomose para avaliação histopatológica e dosagem de hidroxiprolina. Observamos que o grupo com hipovolemia de 40por cento apresentou dados necroscópicos e histopatológicos de pior prognóstico do que o grupo controle. O grupo com hipovolemia de 20por cento diferiu em apresentar apenas três itens histopatológicos de pior prognóstico do que o grupo controle. Não houve diferença estatística na dosagem de hidroxiprolina entre os grupos analisados. Com estes dados pudemos concluir que a hemorragia aguda interfere nos mecanismos de cicatrização do cólon e causa uma maior morbi-mortalidade nestes animais.