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BACKGROUND: Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This phase 3 study aimed to assess the efficacy and safety of efsitora compared with insulin degludec (degludec) in adults with type 1 diabetes. METHODS: This randomised, 52-week, parallel-design, open-label, treat-to-target non-inferiority study conducted at 82 global health-care centres, randomly assigned (1:1) adults (ie, those aged ≥18 years) with type 1 diabetes glycated haemoglobin A1c (HbA1c) 7·0-10·0% (53·0-85·8 mmol/mol) to efsitora (n=343) or, degludec (n=349), both in combination with insulin lispro. The primary endpoint was the change in HbA1c from baseline to week-26 (non-inferiority margin=0·4%). The trial was registered at ClinicalTrials.gov (NCT05463744) and is completed. FINDINGS: Between Aug 12, 2022, and May 7, 2024, of 893 participants enrolled, 692 (77%) participants were randomly assigned to once-weekly efsitora or once-daily degludec, and 623 (90%) participants completed the study. Mean HbA1c decreased from 7·88% (62·66 mmol/mol) at baseline to 7·41% (57·5 mmol/mol) at week 26 with efsitora and from 7·94% (63·3 mmol/mol) at baseline to 7·36% (56·9 mmol/mol) at week 26 with degludec. Mean HbA1c change from baseline to week 26 was -0·51% with efsitora and -0·56% with degludec (estimated treatment difference 0·052%, 95% CI -0·077 to 0·181; p=0·43), confirming a non-inferiority margin of 0·4% for efsitora compared with degludec. Rates of combined level 2 (<54 mg/dL [3·0 mmol/L]) or level 3 severe hypoglycaemia were higher with efsitora compared with degludec (14·03 vs 11·59 events per patient year of exposure; estimated rate ratio 1·21, 95% CI 1·04 to 1·41; p=0·016) during weeks 0-52, with the highest rates during weeks 0-12. Severe hypoglycaemia incidence was higher with efsitora (35 [10%] of 343) versus degludec (11 [3%] of 349) during weeks 0-52. Overall incidence of treatment-emergent adverse events was similar across treatment groups. One death not related to the study treatment occurred in the degludec group. INTERPRETATION: In adults with type 1 diabetes, once-weekly efsitora showed non-inferior HbA1c reduction compared with daily insulin degludec. Higher rates of combined level 2 or level 3 hypoglycaemia and greater incidence of severe hypoglycaemia in participants treated with efsitora compared with participants treated with degludec might suggest the need for additional evaluation of efsitora dose initiation and optimisation in people with type 1 diabetes. FUNDING: Eli Lilly and Company.

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Increased intracranial pressure (ICP) ≥15 mmHg is associated with adverse neurological outcomes, but needs invasive intracranial monitoring. Using the publicly available MIMIC-III Waveform Database (2000-2013) from Boston, we developed an artificial intelligence-derived biomarker for elevated ICP (aICP) for adult patients. aICP uses routinely collected extracranial waveform data as input, reducing the need for invasive monitoring. We externally validated aICP with an independent dataset from the Mount Sinai Hospital (2020-2022) in New York City. The AUROC, accuracy, sensitivity, and specificity on the external validation dataset were 0.80 (95% CI, 0.80-0.80), 73.8% (95% CI, 72.0-75.6%), 73.5% (95% CI 72.5-74.5%), and 73.0% (95% CI, 72.0-74.0%), respectively. We also present an exploratory analysis showing aICP predictions are associated with clinical phenotypes. A ten-percentile increment was associated with brain malignancy (OR = 1.68; 95% CI, 1.09-2.60), intracerebral hemorrhage (OR = 1.18; 95% CI, 1.07-1.32), and craniotomy (OR = 1.43; 95% CI, 1.12-1.84; P < 0.05 for all).

RESUMEN

AIMS: To investigate contributions of changes in fasting plasma glucose (FPG) and postprandial glucose (PPG) to changes in hemoglobin A1c (HbA1c) and time-in-range (TIR, 70-180 mg/dL) in people with type 1 diabetes (T1D) and type 2 diabetes (T2D) treated with multiple daily injections (MDI) of insulin lispro (rapid/ultra-rapid formulations). METHODS: Multivariate regression models were used to quantify the contributions of FPG and PPG reductions to change in HbA1c and TIR using data from the PRONTO-T1D (N = 1222) and PRONTO-T2D (N = 673) clinical trials. TIR was derived from 10-point self-monitored blood glucose (SMBG) profiles overall, as well as from continuous glucose monitoring (CGM) in the PRONTO-T1D CGM substudy (n = 269/1222). RESULTS: A 1 mmol/L FPG reduction corresponded with a 0.09-0.12 % (95 % confidence interval [CI] 0.06-0.15 %) HbA1c reduction in PRONTO-T1D and 0.17-0.26 % (95 % CI 0.13-0.30 %) in PRONTO-T2D (both p < 0.0001). A 1 mmol/L PPG reduction corresponded with a 0.05-0.09 % (95 % CI 0.01-0.12 %) HbA1c reduction in PRONTO-T1D (p < 0.001) and 0.10-0.15 % (95 % CI 0.05-0.19 %) in PRONTO-T2D (p < 0.0001). Reductions in FPG and PPG were significantly associated with increased TIR whether derived from SMBG (7.87-12.95 % [95 % CI 6.81-14.23 %]; all p < 0.0001) or CGM (3.35-4.18 % [95 % CI 2.11-5.39 %]; all p < 0.05). CONCLUSIONS: FPG and PPG significantly impact HbA1c and TIR. Balanced management of both FPG and PPG is important to achieve glycemic goals for people with diabetes on MDI insulin therapy. CLINICAL TRIALS REGISTRATION: PRONTO-T1D ClinicalTrials.gov identifier: NCT03214367; PRONTO-T2D ClinicalTrials.gov Identifier: NCT03214380.

Asunto(s)

Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hemoglobina Glucada , Glucemia , Hipoglucemiantes/uso terapéutico , Automonitorización de la Glucosa Sanguínea/métodos , Insulina/uso terapéutico , Glucosa , Ayuno

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INTRODUCTION: To assess time in range (TIR) (70-180 mg/dL) with postprandial glucose (PPG)-focused titration of ultra rapid lispro (URLi; Lyumjev®) in combination with insulin degludec in people with type 1 diabetes (T1D). METHODS: This phase 2, single-group, open-label, exploratory study was conducted in 31 participants with T1D on multiple daily injection therapy. Participants were treated with insulin degludec and Lispro for an 11-day lead-in and then URLi for a 46-day treatment period consisting of 35-day titration and 11-day endpoint maintenance period. Glucose targets for the titration period were PPG < 140 mg/dL or < 20% increase from premeal, fasting glucose 80-110 mg/dL, and overnight excursion ± 30 mg/dL or less. Participants used the InPen™ bolus calculator and Dexcom G6 continuous glucose monitoring (CGM). RESULTS: Primary endpoint mean TIR (70-180 mg/dL) with URLi during the maintenance period was 70.2%. TIR (70-180 mg/dL) and times below/above range were not significantly different with URLi (maintenance) versus lispro (lead-in). HbA1c decreased from 7.1% at screening to 6.8% at endpoint (least squares mean [LSM] change from baseline, - 0.36%; P < 0.001). Fructosamine and 1,5-anhydroglucitol improved (P < 0.001). Mean hourly glucose using CGM was reduced from 8:00 AM to 4:00 PM with URLi. Overall highest PPG excursion across meals was significantly reduced at URLi endpoint compared with lispro lead-in (mean 56.5 vs 72.4 mg/dL; P < 0.001). Insulin-to-carbohydrate ratio (U/X g) was reduced (more insulin given) at breakfast at URLi endpoint vs lead-in (LSM 9.0 vs 9.7 g; P = 0.002) and numerically decreased at other meals. Total daily insulin dose (TDD) was higher at URLi endpoint compared with lispro lead-in (mean 50.2 vs 47.0 U; P = 0.046) with similar prandial/TDD ratio (mean 52.1% vs 51.2%). There were no severe hypoglycemia events during the study. CONCLUSIONS: URLi in a basal-bolus regimen focusing on PPG targets demonstrated improved overall glycemic control and reduced PPG excursions without increased hypoglycemia in participants with T1D. TRIAL REGISTRATION: ClinicalTrial.gov, NCT04585776.

RESUMEN

INTRODUCTION: To evaluate time in range metrics and HbA1c in people with type 2 diabetes (T2D) treated with ultra rapid lispro (URLi) using continuous glucose monitoring (CGM) for the first time in this population. METHODS: This was a Phase 3b, 12-week, single-treatment study in adults with T2D on basal-bolus multiple daily injection (MDI) therapy using basal insulin glargine U-100 along with a rapid-acting insulin analog. Following a 4-week baseline period, 176 participants were newly treated with prandial URLi. Participants used unblinded CGM (Freestyle Libre). Primary endpoint was time in range (TIR) (70-180 mg/dl) during the daytime period at Week 12 compared to baseline with gated secondary endpoints of HbA1c change from baseline and 24-h TIR (70-180 mg/dl). RESULTS: Improved glycemic control was observed at Week 12 versus baseline including mean daytime TIR (change from baseline [Δ] 3.8%; P = 0.007), HbA1c (Δ - 0.44%; P < 0.001), and 24-h TIR (Δ 3.3%; P = 0.016) with no significant difference in time below range (TBR). After 12 weeks, there was a statistically significant decrease in postprandial glucose incremental area under curve, overall, across all meals, within 1 h (P = 0.005) or 2 h (P < 0.001) after the start of a meal. Basal, bolus, and total insulin dose were intensified with increased bolus/total dose ratio at Week 12 (50.7%) versus baseline (44.5%; P < 0.001). There were no severe hypoglycemia events during the treatment period. CONCLUSIONS: In people with T2D, URLi in an MDI regimen was efficacious with improved glycemic control including TIR, HbA1c, and postprandial glucose without increased hypoglycemia/TBR. CLINICAL TRIAL REGISTRATION NUMBER: NCT04605991.

RESUMEN

INTRODUCTION: Ultra-rapid lispro (URLi) is a new prandial insulin lispro formulation. In the PRONTO-T2D study, URLi, in a basal-bolus regimen with glargine or degludec, was non-inferior to lispro (Humalog®) for HbA1c reduction and superior for postprandial glucose (PPG) control. We evaluated the efficacy and safety of URLi compared to lispro in younger versus older patients in PRONTO-T2D. METHODS: PRONTO-T2D was a phase 3, 26-week, double-blind, treat-to-target study in people with type 2 diabetes. In this sub-group analysis, we compared URLi to lispro on the change from baseline  in HbA1c and rate of level 2 hypoglycemia (< 54 mg/dl) in patients aged < 65 (N = 406) and ≥ 65 years (N = 267). RESULTS: At baseline, patients < 65 versus ≥ 65 years had mean age of 54.9 versus 69.2 years and duration of diabetes 14.6 versus 19.4 years. Mean HbA1c at screening and randomization was 8.35 and 7.34%, respectively, in patients < 65 years, and 8.21 and 7.23%, respectively, in patients ≥ 65 years. At endpoint, mean HbA1c with URLi versus lispro was 6.92 versus 6.90%, respectively, in patients < 65 years and 6.89 versus 6.79%, respectively, in patients ≥ 65 years. URLi significantly reduced 1- and 2-h PPG excursions with a standardized meal test in both age groups: between-treatment differences at 1-h postmeal for younger and older patients was - 9.8 and - 15.1 mg/dl, respectively; and at 2-h postmeal, - 18.7 and - 15.1 mg/dl, respectively, all p < 0.05. Severe and nocturnal hypoglycemia were similar between groups. The relative rate (URLi/Humalog) of level 2 hypoglycemia was lower in older versus younger patients, with a significant treatment-by-age interaction observed. No differential treatment effects were noted for insulin dose, weight, and fasting and maximum glucose after the meal test. CONCLUSIONS: URLi, in a basal-bolus regimen, resulted in endpoint HbA1c < 7% and significantly lower PPG excursions compared to lispro in both age groups, with reduced level 2 hypoglycemia in older versus younger patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03214380.

RESUMEN

AIM: Magnet ingestion has become more frequent in children as magnetic toys and jewellery have been popularised, with the potential to cause significant morbidity. Our aim was to describe our experience at a tertiary paediatric surgical centre. METHODS: Retrospective review of patients admitted with multiple magnet ingestion (January 2011-December 2020). Division into an intervention group and conservative group. Comparisons included demographics, number of magnets and clinical outcomes. Data analysis with a Student's t-test and ROC Curve, P value of <0.05 was significant. RESULTS: A total of 23 patients were identified with a total of 150 magnets ingested. The majority required an intervention for magnets retrieval (15/23, 65.2%), 11/15 (73.3%) surgical and 4/15 (26.7%) endoscopic. In the surgery group, 6/11 (54%) presented with an initial perforation and 1/11 (9.1%) an entero-enteric fistula. One patient (9.1%) had a multi-site anastomotic leak post-operatively. The conservative group had a significantly lower median number of ingested magnets (2 (2-6) vs. 7 (2-40), P = 0.03) and median length of stay (1 (1-4) vs. 7 (1-24), P = 0.03). ROC curve analysis revealed ingestion of >3 magnets had a sensitivity of 86.7% (95% CI: 62.1-97.6%) and specificity of 87.5% (95% CI: 53.0-99.4%) for requiring an intervention. CONCLUSION: This series highlights a significant morbidity in children with a higher incidence of intervention following ingestion of more than three magnets. There is a strong requirement for the creation and adherence to new legislature involving industry standards.

Asunto(s)

Cuerpos Extraños , Imanes , Niño , Ingestión de Alimentos , Cuerpos Extraños/cirugía , Humanos , Imanes/efectos adversos , Juego e Implementos de Juego , Estudios Retrospectivos

RESUMEN

OBJECTIVE: To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro in patients with type 2 diabetes on a basal-bolus insulin regimen. RESEARCH DESIGN AND METHODS: This was a phase 3, treat-to-target, double-blind 26-week study. After an 8-week lead-in to optimize basal insulin glargine or degludec in combination with prandial lispro treatment, patients were randomized to blinded URLi (n = 336) or lispro (n = 337) injected 0-2 min prior to meals. Patients could continue metformin and/or a sodium-glucose cotransporter 2 inhibitor. The primary end point was change in HbA1c from baseline to 26 weeks (noninferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions during a standardized meal test. RESULTS: HbA1c improved for both URLi and lispro, and noninferiority was confirmed: estimated treatment difference (ETD) 0.06% (95% CI -0.05; 0.16). Mean change in HbA1c was -0.38% for URLi and -0.43% for lispro, with an end-of-treatment HbA1c of 6.92% and 6.86%, respectively. URLi was superior to lispro in controlling 1- and 2-h PPG excursions: 1-h ETD, -0.66 mmol/L (95% CI -1.01, -0.30); 2-h ETD, -0.96 mmol/L (-1.41, -0.52). Significantly lower PPG excursions were evident from 0.5 to 4.0 h postmeal with URLi treatment. There were no significant treatment differences in rates of severe or documented hypoglycemia (<3.0 mmol/L). Incidence of overall treatment-emergent adverse events was similar between treatments. CONCLUSIONS: URLi compared with lispro in a basal-bolus regimen was confirmed to be noninferior for HbA1c and superior to lispro for PPG control in patients with type 2 diabetes.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina Glargina/administración & dosificación , Insulina Lispro/administración & dosificación , Insulina de Acción Prolongada/administración & dosificación , Anciano , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Quimioterapia Combinada , Estudios de Equivalencia como Asunto , Femenino , Hemoglobina Glucada/análisis , Hemoglobina Glucada/efectos de los fármacos , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Insulina Glargina/efectos adversos , Insulina Lispro/efectos adversos , Insulina de Acción Prolongada/efectos adversos , Masculino , Comidas , Metformina/administración & dosificación , Metformina/efectos adversos , Persona de Mediana Edad , Periodo Posprandial/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Resultado del Tratamiento

RESUMEN

BACKGROUND: There is limited evidence for the use of postoperative antibiotics for simple appendicitis (SA) in children. Our aim was to conduct a prospective double-blinded randomized controlled trial to investigate this after a laparoscopic appendicectomy. METHODS: Following ethical approval, children (≤16 years) undergoing appendicectomy were recruited at a single institution. Patients were randomized intraoperatively to receive either 2 postoperative intravenous doses of placebo or antibiotics (Abx). All patients received a dose of Abx at induction of anesthesia. Primary outcome was the incidence of postoperative wound infection (WI), and secondary outcome was the incidence of intra-abdominal abscess formation. Data are reported as number of cases (%), median (range), relative risk, and analyzed using Mann Whitney U test, Chi-square test, as appropriate, a P-value ≤0.05 was considered significant. RESULTS: A total of 304 patients were randomized. Sixty-one were subsequently excluded due to protocol violations or recruitment errors; therefore, 243 were included in the final analysis. One hundred twenty-two patients received placebo and 121 Intravenous Abx. There was no difference between the sex (50F/72 M vs 47F/74 M, P = 0.8), median age (12.4 vs 12.2 years, P = 0.5), and postoperative length of stay in a hospital (27.2 vs 25.6 hours, P = 0.7). There was also no difference in the preoperative blood results. A total of 9 WIs occurred: 8/122 (6.6%) placebo versus 1/121 (0.8%) Abx, P = 0.01 [relative risk for WI 7.9 (95% confidence interval: 1.0-62.4)]. There were no intra-abdominal abscess in either groups. CONCLUSIONS: This prospective randomized double blinded randomized controlled trial has revealed a significant decrease in WI rates by giving 2 postoperative intravenous doses of Abx, suggesting postoperative Abx are of benefit in SA.

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Antibacterianos/administración & dosificación , Apendicectomía/métodos , Apendicitis/cirugía , Laparoscopía/métodos , Infección de la Herida Quirúrgica/prevención & control , Cicatrización de Heridas/efectos de los fármacos , Apendicectomía/efectos adversos , Apendicitis/diagnóstico , Australia , Distribución de Chi-Cuadrado , Niño , Preescolar , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intravenosas , Laparoscopía/efectos adversos , Tiempo de Internación , Masculino , Estudios Prospectivos , Medición de Riesgo , Estadísticas no Paramétricas , Resultado del Tratamiento , Cicatrización de Heridas/fisiología

RESUMEN

BACKGROUND: There is ongoing debate concerning the use of peritoneal irrigation in the setting of complicated appendicitis (CA) in children. Our aim was to conduct a prospective randomized controlled trial for the treatment of CA during a laparoscopic appendicectomy in children. METHODS: Following ethical approval (REC10138B), pediatric patients (≤16 years old) were recruited from a single institution over a 3-year time period (2015-2018). Randomization occurred following intraoperative diagnosis of CA to either peritoneal lavage (PL) or suction only (SO). Primary outcome was the length of stay (LoS), and secondary outcomes were the presence of a postoperative intraabdominal abscess (IAA), wound infection (WI), or adhesive small bowel obstruction (ASBO). Data are reported as number of cases (%), median (range), odds ratio [OR] and analyzed using t-test and Fisher's exact test. A p-value ≤0.05 was considered significant. RESULTS: A total of 100 pediatric patients were recruited into the trial. Sixteen were excluded owing to either recruitment or protocol violations, and therefore a total of 86 underwent final analysis: 44 PL and 42 SO. There was no significant difference in the LoS: 5.7 (PL) vs 5.6 (SO) days, p = 0.75. Only 1 IAA occurred in the PL group: 1/44(2.3%) vs 0/42(0%), p = 1.0. There was 1 ASBOs in the PL group (2.3%, p = 1.0) and no WIs in either of the groups. CONCLUSION: This prospective randomized control trial has revealed equivalence in techniques for the treatment of complicated appendicitis. It has also revealed a low complication rate following pediatric LA with either PL or SO. TYPE OF STUDY: Randomized controlled trial. LEVEL OF EVIDENCE: Level I.

Asunto(s)

Apendicectomía/efectos adversos , Apendicectomía/métodos , Apendicitis/cirugía , Obstrucción Intestinal/etiología , Lavado Peritoneal , Absceso Abdominal/etiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Laparoscopía , Tiempo de Internación , Masculino , Oportunidad Relativa , Estudios Prospectivos , Succión , Infección de la Herida Quirúrgica/etiología , Adherencias Tisulares/etiología

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Automonitorización de la Glucosa Sanguínea/métodos , Glucemia/análisis , Diabetes Mellitus Tipo 1/sangre , Hemoglobina Glucada/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

BACKGROUND: For new insulin analogs with properties that vary from human insulin, defining activity in units of human insulin based on glycemic lowering efficacy may be challenging. Here we present a new method that can be used to quantify a unit dose of an experimental insulin when the traditional euglycemic clamp method is not adequate. METHODS: Joint modeling of insulin dose and the glycemic outcome variable hemoglobin A1c (HbA1c), where both were response variables, was used to evaluate insulin unit potency for basal insulin peglispro (BIL). The data were from the Phase 3 program for BIL, which included greater than 5500 patients with type 1 or type 2 diabetes who were treated for 26 or 52 weeks with BIL or a comparator insulin. Both basal-bolus and basal insulin only studies were included, and some type 2 diabetes patients were insulin-naïve. RESULTS: The analysis showed that 1 unit of BIL, composed of 9 nmol of active ingredient, had similar or slightly greater potency compared to 1 unit insulin glargine or NPH insulin for all populations. CONCLUSIONS: Despite some limitations, the joint modeling of HbA1c and insulin dose provides a reasonable approach to estimate the relative potency of a new basal insulin versus an established basal insulin.

Asunto(s)

Glucemia/análisis , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hemoglobina Glucada/análisis , Hipoglucemiantes/administración & dosificación , Insulina/administración & dosificación , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Modelos Teóricos , Resultado del Tratamiento

RESUMEN

BACKGROUND: The association of glucose variability (GV) with other glycemic measures is emerging as a topic of interest. The aim of this analysis is to study the correlation between GV and measures of glycemic control, such as glycated hemoglobin (HbA1c) and daily mean glucose (DMG). METHODS: Data from 5 phase 3 trials were pooled into 3 analysis groups: type 2 diabetes (T2D) treated with basal insulin only, T2D treated with basal-bolus therapy, and type 1 diabetes (T1D). A generalized boosted model was used post hoc to assess the relationship of the following variables with glycemic control parameters (HbA1c and DMG): within-day GV, between-day GV (calculated using self-monitored blood glucose and fasting blood glucose [FBG]), hypoglycemia rate, and certain baseline characteristics. RESULTS: Within-day GV (calculated using standard deviation [SD]) was found to have a significant influence on endpoints HbA1c and DMG in all 3 patient groups. Between-day GV from FBG (calculated using SD), within-day GV (calculated using coefficient of variation), and hypoglycemia rate were found to significantly influence the endpoint HbA1c in the T2D basal-only group. CONCLUSIONS: Lower within-day GV was significantly associated with improvement in DMG and HbA1c. This finding suggests that GV could be a marker in the early phases of new antihyperglycemic therapy development for predicting clinical outcomes in terms of HbA1c and DMG.

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Glucemia , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Hemoglobina Glucada , Ensayos Clínicos Fase III como Asunto , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Estudios Retrospectivos

RESUMEN

Data on cytokeratin-18 (K-18) and enhanced liver fibrosis (ELF) score in insulin-treated diabetes patients with non-alcoholic fatty liver disease (NAFLD) are limited. This study analyzed phase III data comparing basal insulin peglispro (BIL) and insulin glargine in type 1 (T1D), and type 2 diabetes (T2D) (insulin-naïve and insulin-treated). Alanine aminotransferase (ALT), K-18, ELF scores and liver fat content (LFC), measured by MRI, were obtained longitudinally. Baseline K-18 (U/L) was higher in T2D (range: 207‒247) than T1D (range: 148‒183), correlated with ALT in all populations (r (range) 0.264‒0.637, p<0.05), but with LFC only in T2D (r (range) 0.474‒0.586, p<0.05). K-18 increased significantly from baseline in BIL-treated, but not glargine-treated patients. Change from baseline (CFB) K-18 was significantly correlated with CFB in ALT in BIL-treated T2D populations. Baseline ELF scores were higher in T2D (range: 9.12‒9.20) than T1D (range: 8.24‒8.36), correlated with ALT in T1D only (0.209, p<0.05), and not correlated with LFC in any population. ELF scores increased significantly from baseline in BIL-treated but not glargine-treated patients. There were no correlations between CFB in LFC and ELF score at week 52 in any treatment group/population. In all BIL-treated populations, CFB in ALT and CFB in ELF score at week 52 were positively correlated. These data characterize associations of K-18 and ELF score with ALT and LFC in insulin-treated patients with T1D and T2D. Hepatopreferential insulins may be associated with increased K-18 and ELF scores but mechanisms and clinical significance are unknown. ClinicalTrials.gov identifiers are NCT01481779, NCT01435616, NCT01454284 and NCT01582451.

Asunto(s)

Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/uso terapéutico , Queratina-18/sangre , Cirrosis Hepática/sangre , Adiposidad , Adulto , Demografía , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Cirrosis Hepática/complicaciones , Masculino

RESUMEN

AIM: To characterize the effects of hepato-preferential basal insulin peglispro (BIL) and insulin glargine on insulin resistance (lipoprotein insulin resistance index [LP-IR]) and inflammation (GlycA), and to explore the biological implications. METHODS: This substudy included 847 patients with Type 1 diabetes (T1D) or Type 2 diabetes (T2D) in four cohorts of the BIL development program. LP-IR and GlycA were measured before and after insulin treatment. Correlations between LP-IR, GlycA, clinical parameters and liver biomarkers were assessed. RESULTS: LP-IR and GlycA were higher in T2D than T1D. LP-IR increased in patients switched from basal insulins to BIL but not in insulin-naive patients. GlycA decreased in T2D patients treated with BIL and T1D patients treated with glargine. CONCLUSION: These exploratory analyses help to characterize differences in biological effects between BIL and glargine treatment.

Asunto(s)

Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Insulina Glargina/administración & dosificación , Resistencia a la Insulina , Lipoproteínas/sangre , Anciano , Biomarcadores/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action resulting from reduced peripheral effects. This report provides an integrated summary of lipid changes at 26 weeks with BIL and comparator insulins (glargine, NPH) from phase III studies in type 1 diabetes (T1D), insulin-naïve patients with type 2 diabetes (T2D), patients with T2D on basal insulin only and patients with T2D on basal-bolus therapy. BIL treatment had little effect on HDL cholesterol and LDL cholesterol in all patients. The effect of both BIL and glargine treatment on triglycerides (TG) depended on whether patients had been previously treated with insulin. When BIL replaced conventional insulin glargine or NPH treatments, increases in TG levels were observed. When BIL or comparator insulins were given for 26 weeks to insulin-naïve patients with T2D, TG levels were unchanged from baseline with BIL but decreased with either glargine or NPH. The decreased peripheral action of BIL may reduce suppression of lipolysis in peripheral adipose tissue resulting in increased free fatty acid delivery to the liver and, hence, increased hepatic TG synthesis and secretion.

Asunto(s)

Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Hipoglucemiantes/farmacología , Insulina Glargina/farmacología , Insulina Lispro/análogos & derivados , Insulina Isófana/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Lípidos/sangre , Polietilenglicoles/farmacología , Triglicéridos/sangre , Adulto , Anciano , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Esquema de Medicación , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/administración & dosificación , Insulina Glargina/administración & dosificación , Insulina Lispro/administración & dosificación , Insulina Lispro/farmacología , Insulina Isófana/administración & dosificación , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Estudios Retrospectivos

RESUMEN

Basal insulin peglispro (BIL) is a novel basal insulin with hepato-preferential action, resulting from reduced peripheral effects. This report summarizes hypoglycaemia data from five BIL phase III studies with insulin glargine as the comparator, including three double-blind trials. Prespecified pooled analyses (n = 4927) included: patients with type 2 diabetes (T2D) receiving basal insulin only, those with T2D on basal-bolus therapy, and those with type 1 diabetes (T1D). BIL treatment resulted in a 36-45% lower nocturnal hypoglycaemia rate compared with glargine, despite greater reduction in glycated haemoglobin (HbA1c) and higher basal insulin dosing. The total hypoglycaemia rate was similar in patients with T2D on basal treatment only, trended towards being higher (10%) in patients with T2D on basal-bolus treatment (p = .053), and was 15% higher (p < .001) with BIL versus glargine in patients with T1D, with more daytime hypoglycaemia in the T1D and T2D groups who were receiving basal-bolus therapy. In T1D, during the maintenance treatment period (26-52 weeks), the total hypoglycaemia rate was not significantly different. There were no differences in severe hypoglycaemia in the T1D or T2D pooled analyses. BIL versus glargine treatment resulted in greater HbA1c reduction with less nocturnal hypoglycaemia in all patient populations, higher daytime hypoglycaemia with basal-bolus therapy in the T1D and T2D groups, and an associated increase in total hypoglycaemia in the patients with T1D.

Asunto(s)

Ritmo Circadiano/efectos de los fármacos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemia/inducido químicamente , Hipoglucemia/epidemiología , Insulina Glargina/efectos adversos , Insulina Lispro/análogos & derivados , Polietilenglicoles/efectos adversos , Adulto , Anciano , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Femenino , Hemoglobina Glucada/efectos de los fármacos , Hemoglobina Glucada/metabolismo , Humanos , Insulina Glargina/administración & dosificación , Insulina Lispro/administración & dosificación , Insulina Lispro/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Estudios Retrospectivos

RESUMEN

OBJECTIVE: To evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA1c] ≤9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS: This 52-week, open-label, treat-to-target study randomized patients (mean HbA1c 7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin). RESULTS: At 26 weeks, reduction in HbA1c was superior with BIL versus glargine (-0.82% [-8.9 mmol/mol] vs. -0.29% [-3.2 mmol/mol]; least squares mean difference -0.52%, 95% CI -0.67 to -0.38 [-5.7 mmol/mol, 95% CI -7.3 to -4.2; P < 0.001); greater reduction in HbA1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks. CONCLUSIONS: BIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC.

Asunto(s)

Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina Glargina/uso terapéutico , Insulina Lispro/uso terapéutico , Anciano , Glucemia , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/inducido químicamente , Masculino , Persona de Mediana Edad

RESUMEN

BACKGROUND: This report describes the performance of a wireless electronic diary (e-diary) system for data collection and enhanced patient-investigator interactions during intensive insulin management in diabetes clinical trials. MATERIALS AND METHODS: We implemented a customized electronic communication system featuring an e-diary and a Web portal in three global, randomized, controlled Phase 3 clinical trials testing basal insulin peglispro compared with insulin glargine, both combined with prandial insulin lispro, in patients with type 1 or type 2 diabetes mellitus (T1DM and T2DM, respectively). We collected data during 28 weeks of study e-diary use for the report. RESULTS: Patients (n=2,938) in 31 countries used e-diaries to transmit 2,439,087 blood glucose (BG) values, 96% of which were associated by the patient with a protocol time point during the 72-h response window. Of 208,192 hypoglycemia events captured, 96% had a BG value, and 95% had treatments and outcomes entered by patients within the 72-h window. Patients recorded administration of 1,964,477 insulin doses; 93% of basal insulin doses were adherent with the investigator prescription. Investigators adjusted 13 basal and 92 bolus insulin prescriptions per patient-year using the e-diary system. After 26 weeks of treatment and e-diary use in the combined study arms, hemoglobin A1c values decreased by 0.6% or 1.6% and fasting BG decreased by 7.8 or 28 mg/dL in patients with T1DM or T2DM, respectively. CONCLUSIONS: The e-diary system enabled comprehensive data collection and facilitated communication between investigators and patients for intensive insulin management in three global clinical trials testing basal insulins.

Asunto(s)

Automonitorización de la Glucosa Sanguínea/instrumentación , Diabetes Mellitus/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto/instrumentación , Telemetría/instrumentación , Adulto , Anciano , Glucemia/análisis , Automonitorización de la Glucosa Sanguínea/métodos , Diabetes Mellitus/sangre , Prescripción Electrónica/estadística & datos numéricos , Ayuno/sangre , Femenino , Hemoglobina Glucada/análisis , Humanos , Hipoglucemiantes/administración & dosificación , Insulina Glargina/administración & dosificación , Insulina Lispro/administración & dosificación , Insulina de Acción Prolongada/administración & dosificación , Masculino , Persona de Mediana Edad , Telemetría/métodos , Factores de Tiempo

RESUMEN

There is a paucity of literature describing metabolic and histological data in adult-onset autoimmune diabetes. This subgroup of diabetes mellitus affects at least 5% of clinically diagnosed type 2 diabetic patients (T2DM) and it is termed Latent Autoimmune Diabetes in Adults (LADA). We evaluated indexes of insulin secretion, metabolic assessment, and pancreatic pathology in clinically diagnosed T2DM patients with and without the presence of humoral islet autoimmunity (Ab). A total of 18 patients with at least 5-year duration of clinically diagnosed T2DM were evaluated in this study. In those subjects we assessed acute insulin responses to arginine, a glucose clamp study, whole-body fat mass and fat-free mass. We have also analyzed the pancreatic pathology of 15 T2DM and 43 control cadaveric donors, using pancreatic tissue obtained from all the T2DM organ donors available from the nPOD network through December 31, 2013. The presence of islet Ab correlated with severely impaired ß-cell function as demonstrated by remarkably low acute insulin response to arginine (AIR) when compared to that of the Ab negative group. Glucose clamp studies indicated that both Ab positive and Ab negative patients exhibited peripheral insulin resistance in a similar fashion. Pathology data from T2DM donors with Ab or the autoimmune diabetes associated DR3/DR4 allelic class II combination showed reduction in beta cell mass as well as presence of autoimmune-associated pattern A pathology in subjects with either islet autoantibodies or the DR3/DR4 genotype. In conclusion, we provide compelling evidence indicating that islet Ab positive long-term T2DM patients exhibit profound impairment of insulin secretion as well as reduced beta cell mass seemingly determined by an immune-mediated injury of pancreatic ß-cells. Deciphering the mechanisms underlying beta cell destruction in this subset of diabetic patients may lead to the development of novel immunologic therapies aimed at halting the disease progression in its early stage.

Asunto(s)

Autoinmunidad , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/metabolismo , Adulto , Anciano , Alelos , Autoanticuerpos/inmunología , Biomarcadores , Glucemia , Composición Corporal , Péptido C/metabolismo , Tamaño de la Célula , Diabetes Mellitus Tipo 2/genética , Femenino , Antígenos HLA-DR/genética , Antígenos HLA-DR/inmunología , Humanos , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/patología , Masculino , Persona de Mediana Edad , Donantes de Tejidos