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1.
Comparison of the Pharmacokinetic and Pharmacodynamic Relationship of Ipragliflozin Between Patients With Type 1 and Type 2 Diabetes Mellitus.
Toyoshima, J, Saito, M, Kaibara, A, Isaka, H, Sakatani, T
Clinical therapeutics. 2020;(9):1787-1798.e3
Abstract
PURPOSE To characterize the pharmacokinetic and pharmacodynamic (PK/PD) relationship of ipragliflozin in Japanese patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and to determine the appropriate dose regimen for a Phase III study of ipragliflozin in Japanese patients with T1DM. METHODS The PK (AUC24h of plasma ipragliflozin) and PD (renal glucose clearance) properties in patients with T1DM and T2DM were assessed in 2 independent clinical pharmacologic studies of ipragliflozin. The same maximum efficacy (Emax) model described the PK/PD relationship in patients with T1DM and T2DM. Changes in fasting plasma glucose (FPG) in T1DM patients were simulated by applying a previously established FPG model for ipragliflozin in patients with T2DM. FINDINGS Data from 42 patients with T1DM and 28 patients with T2DM were used. Comparable AUC24h of plasma ipragliflozin and similar dose dependency were observed on day 14 between patients with T1DM and those with T2DM. Decreases in renal glucose clearance were comparable regardless of the ipragliflozin dose in both groups of patients. The estimated mean Emax and AUC24h producing 50% of Emax (EX50) were 45.1 mL/min (95% CI, 37.0-53.2 mL/min) and 2160 ng·h/mL (95% CI, 929-3390 ng·h/mL), respectively, in all patients with T1DM and T2DM. Observed FPG in patients with T1DM was reproduced well by the simulation from the previously established FPG model. IMPLICATIONS The PK/PD properties for ipragliflozin were comparable between patients with T1DM and T2DM, suggesting no substantial difference in PK/PD relationships in both patient populations. The dose regimen used for patients with T2DM was also recommended for a Phase III study in Japanese patients with T1DM. ClinicalTrials.gov identifiers: NCT01023945 and NCT02529449.
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2.
Weight-based carbohydrate treatment of hypoglycaemia in people with Type 1 diabetes using insulin pump therapy: a randomized crossover clinical trial.
McTavish, L, Corley, B, Weatherall, M, Wiltshire, E, Krebs, JD
Diabetic medicine : a journal of the British Diabetic Association. 2018;(3):339-346
Abstract
AIM: To test whether weight-based treatment is more effective than usual care in people with Type 1 diabetes receiving continuous subcutaneous insulin infusion therapy with regard to both hypoglycaemia and avoiding excessive rebound hyperglycaemia. METHODS Children and adults on continuous subcutaneous insulin infusion were enrolled into a study with a crossover design. Each episode of hypoglycaemia (defined as capillary glucose <4.0 mmol/l) was randomly assigned one of two treatment protocols using glucose tablets: either 0.3 g/kg body weight or usual treatment with 15 g (adults) or 10 g (children) for capillary glucose levels 3-3.9 mmol/l or twice these doses for capillary glucose levels <3 mmol/l. All participants received each treatment in random order for up to 10 hypoglycaemic episodes. Glucose levels were re-tested 10 min after treatment, with a repeat dose if still <4 mmol/l. RESULTS Of the 37 participants enrolled, 35 (aged 6-68 years) completed the study. Twenty-four participants completed all treatment episodes, while 10 participants had <10 hypoglycaemic episodes and two withdrew without data. The mean glucose difference between weight-based and usual treatment after 10 min was 0.33 mmol/l (95% CI 0.005 to 0.66; P=0.047) in adults and 0.45 (95% CI 0.18 to 0.72; P=0.001) in children. The odds ratios for resolution of hypoglycaemia at 10 min with a single treatment using weight-based compared with usual treatment were 3.12 (95% CI 1.38 to 7.02; P=0.0070) in adults and 2.61 (95% CI 1.19 to 5.74; P=0.017) in children. CONCLUSIONS Weight-based treatment using 0.3 g/kg glucose was more effective for symptomatic hypoglycaemia in children and adults with Type 1 diabetes who were using continuous subcutaneous insulin infusion than treatment based on current international recommendations.
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3.
Coronary artery calcifications and diastolic dysfunction versus visceral fat area in type 1 diabetes: VISCERA study.
De Block, CEM, Shivalkar, B, Goovaerts, W, Brits, T, Carpentier, K, Verrijken, A, Van Hoof, V, Parizel, PM, Vrints, C, Van Gaal, LF
Journal of diabetes and its complications. 2018;(3):271-278
Abstract
AIMS: Type 1 diabetic patients (T1DM) experience a higher cardiovascular disease and mortality risk than controls. We investigated whether visceral adipose tissue (VAT) contributes to coronary artery calcifications (CAC) and cardiac dysfunction in T1DM. METHODS A cross-sectional study of 118 T1DM patients without a history of cardiovascular disease (men/women: 68/50, age 46±12years, HbA1c 7.6±0.9%, BMI 25.8±4.1kg/m2) was conducted. CAC and VAT were measured using a CT scan. CAC was scored using the Agatston method. Cardiac functional abnormalities were assessed by echocardiography. RESULTS CAC scored ≥10 in 42% of patients. Systolic function was normal in all, but diastolic dysfunction was present in 75%. Forty-six percent had VAT≥100cm2. CAC score≥10 occurred more often in subjects with VAT≥100cm2 (54% vs 31%; p=0.01). Age (OR=1.10; p<0.0001), diabetes duration (OR=1.10; p=0.008), gender (OR=4.28; p=0.016), LDL-cholesterol (OR=1.03; p=0.009) and metabolic syndrome (OR=5.79; p=0.005) were independently associated with a CACS≥10. Subjects with CACS≥10 were more prone to have diastolic dysfunction (84 vs 54%; p=0.03). Factors independently associated with diastolic dysfunction were age (OR=1.11; p=0.002), waist circumference (OR=1.10; p=0.016) and VAT (OR=0.99; p=0.035). CONCLUSIONS Excess VAT in T1DM, present in 46%, is associated with diastolic dysfunction and CAC, present in respectively 75% and 42% of patients. Timely detection might improve future cardiovascular risk.
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4.
Faster-acting insulin aspart provides faster onset and greater early exposure vs insulin aspart in children and adolescents with type 1 diabetes mellitus.
Fath, M, Danne, T, Biester, T, Erichsen, L, Kordonouri, O, Haahr, H
Pediatric diabetes. 2017;(8):903-910
Abstract
BACKGROUND Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with additional excipients (L-arginine and niacinamide). In adults, faster aspart provides faster onset and greater early exposure and action vs IAsp. AIM: This randomized, double-blind, 2-period crossover trial investigated the pharmacological properties of faster aspart vs IAsp in 12 children (6-11 years), 13 adolescents (12-17 years), and 15 adults (18-64 years) with type 1 diabetes mellitus. METHODS Subjects received 0.2 U/kg subcutaneous dosing (mean of 8.3, 12.8, and 15.6 U, respectively) immediately prior to a standardized meal (17.3 g carbohydrate/100 mL; amount adjusted by body weight). RESULTS Consistently across age groups, onset of appearance occurred approximately twice-as-fast (5-7 minutes earlier) and early exposure (AUCIAsp,0-30min ; area under the IAsp curve from 0 to 30 minutes) was greater (by 78%-147%) for faster aspart vs IAsp, with no treatment differences in total exposure (AUCIAsp,0-t ) or maximum concentration (C max ). Two-hour postmeal plasma glucose excursion was reduced for faster aspart vs IAsp (although only reaching statistical significance in children). In accordance with the absolute dose administered for each age group, AUCIAsp,0-t for faster aspart was lower in children (estimated ratio children/adults [95% confidence interval]: 0.59 [0.50;0.69], P < .001) and adolescents (0.78 [0.67;0.90], P = .002) vs adults. No age group differences were seen in C max (0.91 [0.70;1.17], P = .445, and 0.99 [0.77;1.26], P = .903). The age effect on AUCIAsp,0-t and C max did not differ statistically significantly between treatments. Faster aspart and IAsp were well-tolerated. CONCLUSION The current findings in children and adolescents suggest a potential for faster aspart to improve postprandial glycemia over current rapid-acting insulins also in younger age groups. http://ClinicalTrials.gov identifier: NCT02035371.
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5.
Comparison of Two Continuous Glucose Monitoring Systems, Dexcom G4 Platinum and Medtronic Paradigm Veo Enlite System, at Rest and During Exercise.
Taleb, N, Emami, A, Suppere, C, Messier, V, Legault, L, Chiasson, JL, Rabasa-Lhoret, R, Haidar, A
Diabetes technology & therapeutics. 2016;(9):561-7
Abstract
BACKGROUND Despite technological advances, the accuracy of continuous glucose monitoring (CGM) systems may not always be satisfactory with rapidly changing glucose levels, as is notable during exercise. We compare the performance of two current and widely used CGM systems, Dexcom G4 Platinum (Dexcom) and Medtronic Paradigm Veo Enlite system (Enlite), during both rest and exercise in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Paired sensor and plasma glucose (PG) values (total of 431 data pairs for Dexcom and 425 for Enlite) were collected from 17 adults (37.3 ± 13.6 years) with T1D. To evaluate and compare the accuracy of sensor readings, criteria involving sensor bias (sensor minus PG levels), absolute relative difference (ARD), and percentage of readings meeting International Organization for Standardization (ISO) criteria were considered. RESULTS Both Dexcom and Enlite performed equally well during the rest period, with respective mean/median biases of -0.12/-0.02 mmol/L versus -0.18/-0.40 (P = 0.78, P = 0.66) mmol/L and ARDs of 13.77/13.34% versus 12.38/11.95% (P = 0.53, P = 0.70). During exercise, sensor bias means/medians were -0.40/-0.21 mmol versus -0.26/-0.24 mmol/L (P = 0.67, P = 0.62) and ARDs were 22.53/15.13% versus 20.44/14.11% (P = 0.58, P = 0.68) for Dexcom and Enlite, respectively. Both sensors demonstrated significantly lower performance during exercise; median ARD comparison at rest versus exercise for both Dexcom and Enlite showed a P = 0.02. More data pairs met the ISO criteria for Dexcom and Enlite at rest, 73.6% and 76.9% compared with exercise 48.2% and 53.9%. CONCLUSION Dexcom and Enlite demonstrated comparable overall performances during rest and physical activity. However, a lower accuracy was observed during exercise for both sensors, necessitating a fine-tuning of their performance with physical activity.
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6.
Reduction in short-acting insulin requirement accompanies improved glycemic control with basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes.
Rosenstock, J, Blevins, TC, Bergenstal, RM, Morrow, LA, Qu, Y, Jacober, SJ
Journal of diabetes. 2016;(1):166-9
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7.
Significant retinopathy in young-onset type 2 vs. type 1 diabetes: a clinical observation.
Song, SH
International journal of clinical practice. 2016;(10):853-860
Abstract
OBJECTIVE Little is known about the burden of severe retinal disease between young-onset type 2 (T2D) and type 1 diabetes (T1D). This study assessed the prevalence of significant retinopathy in young-onset T2D vs. T1D and its predictive factors. METHODS This was a cross-sectional study. Subjects with T1D and T2D diagnosed below age 40 were identified from diabetes eye screening register. Preproliferative, proliferative, maculopathy changes and/or previous laser photocoagulation treatment were considered to have significant retinopathy (SigDR). RESULTS A total of 1306 subjects were identified, of whom 842 and 464 had T1D and T2D, respectively. The mean age of diagnosis was significantly lower in T1D subjects (T1D vs. T2D; 20.1 ± 10.3 vs. 32.1 ± 6.0 years, p < 0.0005). Although the T2D cohort had shorter diabetes duration (T1D vs. T2D; 20.8 ± 13.0 vs. 13.7 ± 9.0 years, p < 0.0005), the overall prevalence of SigDR was similar to T1D (T1D vs. T2D; 21.6 vs. 20.9%, p = NS). After adjusting for diabetes duration, the T2D cohort experienced significantly higher prevalence of this complication than T1D after 10 years duration. The age threshold beyond which the T2D cohort began to experience greater burden of SigDR was approximately 50 years. The prevalence of any retinopathy after 15 years duration was 75-80% for both young-onset cohort. Risk factors for SigDR (older age, diabetes duration, systolic BP, HbA1c and creatinine) were similar in both young-onset diabetes cohort with poor glycaemic control being the strongest variable. Lower age of T2D diagnosis was not a predictive factor. CONCLUSIONS Irrespective of diabetes type, subjects with young-onset diabetes possessed high lifetime risk for retinopathy. However, young-onset T2D cohort was more susceptible to severe retinal disease with substantial burden of this complication by the fifth decade of life.
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8.
A pilot study to examine the tolerability and device preference in type 1 diabetes of insulin aspart administered by InsuJet compared with subcutaneous injection.
Reutens, AT, Balkau, B, Cohen, N
Diabetes technology & therapeutics. 2014;(4):235-40
Abstract
BACKGROUND Jet injectors allow needle-free insulin delivery. The study objective was to compare the tolerability and device preference of subcutaneous insulin aspart delivery by jet injector (InsuJet™; European Pharma Group, Schiphol-Rijk, The Netherlands) with pen injection in an open-label, randomized, crossover pilot study. SUBJECTS AND METHODS Ten participants with type 1 diabetes underwent two meal tolerance tests 1 week apart. Plasma glucose and serum insulin levels were sampled from 10 min preceding to 240 min after insulin aspart administration by InsuJet or FlexPen(®) (Novo Nordisk Pharmaceuticals Pty. Ltd., Baulkham Hills, NSW, Australia). Insulin dose was calculated using participants' insulin-to-carbohydrate ratios. Immediately after insulin administration, participants drank 500 mL of Ensure(®) (Abbott Australasia Pty. Ltd., Botany, NSW, Australia) (providing 2,240 kJ of energy, 18.6 g of protein, 96 g of carbohydrate, and 3 g of fat). RESULTS In this small pilot study, the devices were similar in glucose excursion (median [quartile 1, quartile 3], InsuJet vs. FlexPen, 9.4 [4.8, 12.8] vs. 8.1 [5.4, 10.6] mmol/L; P=0.43), in the area under the glucose concentration-time curve for 0-240 min corrected for baseline glucose level (InsuJet vs. FlexPen, 1,230 [623, 2,012] vs. 1,175 [91, 1,774] mmol · min/L; P=0.4), and in insulin absorption over the 240-min period. Devices were similar for participant preference and relative injection pain. CONCLUSIONS Subcutaneous jet injection of aspart insulin was well tolerated.
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9.
Standardizing corneal nerve fibre length for nerve tortuosity increases its association with measures of diabetic neuropathy.
Edwards, K, Pritchard, N, Vagenas, D, Russell, A, Malik, RA, Efron, N
Diabetic medicine : a journal of the British Diabetic Association. 2014;(10):1205-9
Abstract
AIMS: Recent studies on corneal markers have advocated corneal nerve fibre length as the most important measure of diabetic peripheral neuropathy. The aim of this study was to determine if standardizing corneal nerve fibre length for tortuosity increases its association with other measures of diabetic peripheral neuropathy. METHODS Two hundred and thirty-one individuals with diabetes with either predominantly mild or absent neuropathic changes and 61 control subjects underwent evaluation of diabetic neuropathy symptom score, neuropathy disability score, testing with 10-g monofilament, quantitative sensory testing (warm, cold, vibration detection) and nerve conduction studies. Corneal nerve fibre length and corneal nerve fibre tortuosity were measured using corneal confocal microscopy. A tortuosity-standardised corneal nerve fibre length variable was generated by dividing corneal nerve fibre length by corneal nerve fibre tortuosity. Differences in corneal nerve morphology between individuals with and without diabetic peripheral neuropathy and control subjects were determined and associations were estimated between corneal morphology and established tests of, and risk factors for, diabetic peripheral neuropathy. RESULTS The tortuosity-standardised corneal nerve fibre length variable was better than corneal nerve fibre length in demonstrating differences between individuals with diabetes, with and without neuropathy (tortuosity-standardised corneal nerve fibre length variable: 70.5 ± 27.3 vs. 84.9 ± 28.7, P < 0.001, receiver operating characteristic area under the curve = 0.67; corneal nerve fibre length: 15.9 ± 6.9 vs. 18.4 ± 6.2 mm/mm², P = 0.004, receiver operating characteristic area under the curve = 0.64). Furthermore, the tortuosity-standardised corneal nerve fibre length variable demonstrated a significant difference between the control subjects and individuals with diabetes, without neuropathy, while corneal nerve fibre length did not (tortuosity-standardised corneal nerve fibre length variable: 94.3 ± 27.1 vs. 84.9 ± 28.7, P = 0.028; corneal nerve fibre length: 20.1 ± 6.3 vs. 18.4 ± 6.2 mm/mm², P = 0.084). Correlations between corneal nerve fibre length and established measures of neuropathy and risk factors for neuropathy were higher when a correction was made for the nerve tortuosity. CONCLUSIONS Standardizing corneal nerve fibre length for tortuosity enhances the ability to differentiate individuals with diabetes, with and without neuropathy.
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10.
Evaluation of long-term treatment effect in a type 1 diabetes intervention trial: differences after stimulation with glucagon or a mixed meal.
Pozzilli, P, Raz, I, Peled, D, Elias, D, Avron, A, Tamir, M, Eren, R, Dagan, S, Cohen, IR
Diabetes care. 2014;(5):1384-91
Abstract
OBJECTIVE Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes. RESEARCH DESIGN AND METHODS A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson's correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (AUC). RESULTS The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74-0.9). However, the correlations between the AUC were much weaker (r = 0.39-0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4-11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose. CONCLUSIONS Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.