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1.
Closed-loop insulin delivery in adults with type 1 diabetes in real-life conditions: a 12-week multicentre, open-label randomised controlled crossover trial.
Benhamou, PY, Franc, S, Reznik, Y, Thivolet, C, Schaepelynck, P, Renard, E, Guerci, B, Chaillous, L, Lukas-Croisier, C, Jeandidier, N, et al
The Lancet. Digital health. 2019;(1):e17-e25
Abstract
BACKGROUND Closed-loop insulin delivery systems are expected to become a standard treatment for patients with type 1 diabetes. We aimed to assess whether the Diabeloop Generation 1 (DBLG1) hybrid closed-loop artificial pancreas system improved glucose control compared with sensor-assisted pump therapy. METHODS In this multicentre, open-label, randomised, crossover trial, we recruited adults (aged ≥18 years) with at least a 2 year history of type 1 diabetes, who had been treated with external insulin pump therapy for at least 6 months, had glycated haemoglobin (HbA1c) of 10% or less (86 mmol/mol), and preserved hypoglycaemia awareness. After a 2-week run-in period, patients were randomly assigned (1:1) with a web-based system in randomly permuted blocks of two, to receive insulin via the hybrid closed-loop system (DBLG1; using a machine-learning-based algorithm) or sensor-assisted pump therapy over 12 weeks of free living, followed by an 8-week washout period and then the other intervention for 12 weeks. The primary outcome was the proportion of time that the sensor glucose concentration was within the target range (3·9-10·0 mmol/L) during the 12 week study period. Efficacy analyses were done in the modified intention-to-treat population, which included all randomly assigned patients who completed both 12 week treatment periods. Safety analyses were done in all patients who were exposed to either of the two treatments at least once during the study. This trial is registered with ClinicalTrials.gov, number NCT02987556. FINDINGS Between March 3, 2017, and June 19, 2017, 71 patients were screened, and 68 eligible patients were randomly assigned to the DBLG1 group (n=33) or the sensor-assisted pump therapy group (n=35), of whom five dropped out in the washout period (n=1 pregnancy; n=4 withdrew consent). 63 patients completed both 12 week treatment periods and were included in the modified intention-to-treat analysis. The proportion of time that the glucose concentration was within the target range was significantly higher in the DBLG1 group (68·5% [SD 9·4] than the sensor-assisted pump group (59·4% [10·2]; mean difference 9·2% [95% CI 6·4 to 11·9]; p<0·0001). Five severe hypoglycaemic episodes occurred in the DBLG1 group and three episodes occurred in the sensor-assisted pump therapy group, which were associated with hardware malfunctions or human error. INTERPRETATION The DBLG1 system improves glucose control compared with sensor-assisted insulin pumps. This finding supports the use of closed-loop technology combined with appropriate health care organisation in adults with type 1 diabetes. FUNDING French Innovation Fund, Diabeloop.
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Clinical pharmacology study of ipragliflozin in Japanese patients with type 1 diabetes mellitus: A phase 2, randomized, placebo-controlled trial.
Kaku, K, Isaka, H, Toyoshima, J, Sakatani, T
Diabetes, obesity & metabolism. 2019;(6):1445-1454
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Abstract
AIM: To evaluate the pharmacodynamics, pharmacokinetics, and safety of the novel oral sodium-glucose co-transporter-2 inhibitor, ipragliflozin, in Japanese patients with type 1 diabetes mellitus. MATERIALS AND METHODS We conducted a multicentre, double-blind, placebo-controlled, parallel-group study. Patients were randomized to receive 25, 50, or 100 mg/day ipragliflozin or placebo for 2 weeks. Key pharmacokinetic endpoints included area under the concentration-time curve 24 hours postdose (AUC24h ), maximum plasma concentration (Cmax ), and renal clearance. Key pharmacodynamic endpoints included 24-hour urinary glucose excretion, mean plasma glucose AUC0-24h , and mean renal glucose clearance. Changes in total, basal, and bolus insulin dosages were recorded. Adverse events (AEs) were monitored for safety. RESULTS Dose-dependent increases were observed in AUC24h and Cmax on days 1 and 14 for 25-, 50-, and 100-mg ipragliflozin. The mean plasma glucose AUC0-24h was lower than that of placebo and the mean renal glucose clearance increased in a dose-dependent manner from baseline, but remained unchanged in the placebo group. The mean (standard deviation) change from baseline in total daily insulin dose was greater in the ipragliflozin 25-, 50-, and 100-mg groups (-14.77 ± 14.04%, -18.40 ± 12.49% and -19.25 ± 16.77%, respectively), than placebo (-4.51 ± 16.28%). Most AEs were mild in severity; no patients discontinued the study because of treatment-emergent AEs. CONCLUSIONS The pharmacokinetic and pharmacodynamic properties of ipragliflozin in Japanese patients with type 1 diabetes mellitus were confirmed. Increases in urinary glucose excretion lead to dose-dependent decreases in plasma glucose. Concomitant insulin dose decreased with ipragliflozin treatment. No clinically relevant safety concerns were identified.
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Dietary protein affects both the dose and pattern of insulin delivery required to achieve postprandial euglycaemia in Type 1 diabetes: a randomized trial.
Evans, M, Smart, CEM, Paramalingam, N, Smith, GJ, Jones, TW, King, BR, Davis, EA
Diabetic medicine : a journal of the British Diabetic Association. 2019;(4):499-504
Abstract
AIM: To quantify the insulin requirement for a high-protein meal compared with a low-protein meal, controlling for carbohydrate and fat content. METHODS In this crossover study, young people with Type 1 diabetes were randomized to consume a high- (60 g) or low-protein meal (5 g), each containing 30 g carbohydrate and 8 g fat. A variation of the insulin clamp technique was used to determine the insulin requirements to maintain euglycaemia for the following 5 h. RESULTS A total of 11 participants (mean ± sd age 16.5 ± 2.7 years, HbA1c 52 ± 8.7 mmol/mol [6.9 ± 0.8%], diabetes duration 6.9±5.1 years) completed the study. The mean insulin requirements for the high-protein meal were higher than for the low-protein meal [10.3 (CI 8.2, 12.57) vs 6.7 units (CI 4.7, 8.8); P=0.001], with inter-individual requirements ranging from 0.9 to six times the low-protein meal requirement. Approximately half the additional insulin [1.1 units/h (CI 0.5, 1.8; P=0.001)] was given in the first 2 h, compared with an additional 0.5 units/h (CI -0.2, 1.2; P=0.148) in the second 2 h and 0.1 units (CI -0.6, 0.8; P=0.769) in the final hour. CONCLUSIONS A high-protein meal requires ~50% more insulin to maintain euglycaemia than a low-protein meal that contains the same quantity of carbohydrate. The majority is required within the first 2 h. Inter-individual differences exist in insulin requirements for dietary protein.
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Pharmacokinetics, Pharmacodynamics, and Modulation of Hepatic Glucose Production With Insulin Glargine U300 and Glargine U100 at Steady State With Individualized Clinical Doses in Type 1 Diabetes.
Porcellati, F, Lucidi, P, Candeloro, P, Cioli, P, Marinelli Andreoli, A, Curti, G, Bolli, GB, Fanelli, CG
Diabetes care. 2019;(1):85-92
Abstract
OBJECTIVE This study characterized the pharmacokinetics (PK), pharmacodynamics (PD), and endogenous (hepatic) glucose production (EGP) of clinical doses of glargine U300 (Gla-300) and glargine U100 (Gla-100) under steady-state (SS) conditions in type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS T1DM subjects (N = 18, age 40 ± 12 years, T1DM duration 26 ± 12 years, BMI 23.4 ± 2 kg/m2, A1C 7.19 ± 0.52% [55 ± 5.7 mmol · mol-1-1]) were studied after 3 months of Gla-300 or Gla-100 (evening dosing) titrated to fasting euglycemia (random, crossover) with the euglycemic clamp using individualized doses (Gla-300 0.35 ± 0.08, Gla-100 0.28 ± 0.07 units · kg-1). RESULTS Plasma free insulin concentrations (free immunoreactive insulin area under the curve) were equivalent over 24 h with Gla-300 versus Gla-100 (point estimate 1.11 [90% CI 1.03; 1.20]) but were reduced in the first 6 h (0.91 [90% CI 0.86; 0.97]) and higher in the last 12 h postdosing (1.38 [90% CI 1.21; 1.56]). Gla-300 and Gla-100 both maintained 24 h euglycemia (0.99 [90% CI 0.98; 1.0]). The glucose infusion rate was equivalent over 24 h (1.03 [90% CI 0.88; 1.21]) but was lower in first (0.77 [90% CI 0.62; 0.95]) and higher (1.53 [90% CI 1.23; 1.92]) in the second 12 h with Gla-300 versus Gla-100. EGP was less suppressed during 0-6 h but more during 18-24 h with Gla-300. PK and PD within-day variability (fluctuation) was 50% and 17% lower with Gla-300. CONCLUSIONS Individualized, clinical doses of Gla-300 and Gla-100 resulted in a similar euglycemic potential under SS conditions. However, Gla-300 exhibited a more stable profile, with lower variability and more physiological modulation of EGP compared with Gla-100.
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Insulin in Type 1 and Type 2 Diabetes-Should the Dose of Insulin Before a Meal be Based on Glycemia or Meal Content?
Krzymien, J, Ladyzynski, P
Nutrients. 2019;(3)
Abstract
The aim of this review was to investigate existing guidelines and scientific evidence on determining insulin dosage in people with type 1 and type 2 diabetes, and in particular to check whether the prandial insulin dose should be calculated based on glycemia or the meal composition, including the carbohydrates, protein and fat content in a meal. By exploring the effect of the meal composition on postprandial glycemia we demonstrated that several factors may influence the increase in glycemia after the meal, which creates significant practical difficulties in determining the appropriate prandial insulin dose. Then we reviewed effects of the existing insulin therapy regimens on glycemic control. We demonstrated that in most existing algorithms aimed at calculating prandial insulin doses in type 1 diabetes only carbohydrates are counted, whereas in type 2 diabetes the meal content is often not taken into consideration. We conclude that prandial insulin doses in treatment of people with diabetes should take into account the pre-meal glycemia as well as the size and composition of meals. However, there are still open questions regarding the optimal way to adjust a prandial insulin dose to a meal and the possible benefits for people with type 1 and type 2 diabetes if particular parameters of the meal are taken into account while calculating the prandial insulin dose. The answers to these questions may vary depending on the type of diabetes.
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Postprandial metabolic effects of fructose and glucose in type 1 diabetes patients: a pilot randomized crossover clinical trial.
Souto, DL, Lima, ÉDS, Dantas, JR, Zajdenverg, L, Rodacki, M, Rosado, EL
Archives of endocrinology and metabolism. 2019;(4):376-384
Abstract
OBJECTIVE To test the influence of oral fructose and glucose dose-response solutions in blood glucose (BG), glucagon, triglycerides, uricaemia, and malondialdehyde in postprandial states in type 1 diabetes mellitus (T1DM) patients. SUBJECTS AND METHODS The study had a simple-blind, randomized, two-way crossover design in which T1DM patients were selected to receive fructose and glucose solutions (75g of sugars dissolved in 200 mL of mineral-water) in two separate study days, with 2-7 weeks washout period. In each day, blood samples were drawn after 8h fasting and at 180 min postprandial to obtain glucose, glucagon, triglycerides, uric acid, lactate, and malondialdehyde levels. RESULTS Sixteen T1DM patients (seven men) were evaluated, with a mean age of 25.19 ± 8.8 years, a mean duration of disease of 14.88 ± 4.73 years, and glycated hemoglobin of 8.13 ± 1.84%. Fructose resulted in lower postprandial BG levels than glucose (4.4 ± 5.5 mmol/L; and 12.9 ± 4.1 mmol/L, respectively; p < 0.01). Uric acid levels increased after fructose (26.1 ± 49.9 µmol/L; p < 0.01) and reduced after glucose (-13.6 ± 9.5 µmol/L; p < 0.01). The malondialdehyde increased after fructose (1.4 ± 1.6 µmol/L; p < 0.01) and did not change after glucose solution (-0.2 ± 1.6 µmol/L; p = 0.40). Other variables did not change. CONCLUSIONS Fructose and glucose had similar sweetness, flavor and aftertaste characteristics and did not change triglycerides, lactate or glucagon levels. Although fructose resulted in lower postprandial BG than glucose, it increased uric acid and malondialdehyde levels in T1DM patients. Therefore it should be used with caution. ClinicalTrials.gov registration: NCT01713023.
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[A survey of various adjuvant treatments used against type 1 diabetes, focusing on SGLT2 inhibitors].
Sjöholm, Å
Lakartidningen. 2019
Abstract
Insulin and its analogues have so far and for almost 100 years been the only officially approved treatment for type 1 diabetes in Europe. However, in clinical practice, various drugs against type 2 diabetes have sometimes been used off label as adjuvants to insulin for type 1 diabetes. Recently, the EMA approved the SGLT2 inhibitor dapagliflozin as an adjuvant treatment for type 1 diabetes in adults. This article is a survey of various adjuvant treatments used against type 1 diabetes, focusing on SGLT2 inhibitors and their pros and cons.
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Closed-loop management of inpatient hyperglycaemia.
Boughton, CK, Hovorka, R
British journal of hospital medicine (London, England : 2005). 2019;(11):665-669
Abstract
The prevalence of diabetes in the inpatient setting is increasing, and suboptimal glucose control in hospital is associated with increased morbidity and mortality. Attaining the recommended glucose levels is challenging with standard insulin therapy. Hypoglycaemia and hyperglycaemia are common and diabetes management in hospital can be a considerable workload burden for health-care professionals. Fully automated insulin delivery (closed-loop) has been shown to be safe, and achieves superior glucose control than standard insulin therapy in the hospital, including in those patients receiving haemodialysis and enteral or parenteral nutrition where glucose control can be particularly challenging. Evidence that the improved glucose control achieved using closed-loop systems can translate into improved clinical outcomes for patients is key to support widespread adoption of this technology. The closed-loop approach has the potential to provide a paradigm shift in the management of inpatient diabetes, particularly in the most challenging inpatient populations, and may reduce staff work burden and the health-care costs associated with inpatient diabetes.
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Low-Carb and Ketogenic Diets in Type 1 and Type 2 Diabetes.
Bolla, AM, Caretto, A, Laurenzi, A, Scavini, M, Piemonti, L
Nutrients. 2019;(5)
Abstract
Low-carb and ketogenic diets are popular among clinicians and patients, but the appropriateness of reducing carbohydrates intake in obese patients and in patients with diabetes is still debated. Studies in the literature are indeed controversial, possibly because these diets are generally poorly defined; this, together with the intrinsic complexity of dietary interventions, makes it difficult to compare results from different studies. Despite the evidence that reducing carbohydrates intake lowers body weight and, in patients with type 2 diabetes, improves glucose control, few data are available about sustainability, safety and efficacy in the long-term. In this review we explored the possible role of low-carb and ketogenic diets in the pathogenesis and management of type 2 diabetes and obesity. Furthermore, we also reviewed evidence of carbohydrates restriction in both pathogenesis of type 1 diabetes, through gut microbiota modification, and treatment of type 1 diabetes, addressing the legitimate concerns about the use of such diets in patients who are ketosis-prone and often have not completed their growth.
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SGLT2 inhibitors as adjunctive therapy for type 1 diabetes: balancing benefits and risks.
Taylor, SI, Blau, JE, Rother, KI, Beitelshees, AL
The lancet. Diabetes & endocrinology. 2019;(12):949-958
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Abstract
Sodium-glucose co-transporter-2 (SGLT2) inhibitors have several beneficial effects in patients with type 2 diabetes, including glucose lowering, weight loss, blood pressure lowering, and a reduced risk of major adverse cardiovascular events. To address high unmet medical need via improved glycaemic control, several clinical trials have been done to assess the efficacy and safety of SGLT2 inhibitors in combination with insulin therapy in patients with type 1 diabetes. In this Personal View, we summarise data from eight clinical trials of canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin in patients with type 1 diabetes. HbA1c-lowering efficacy was greatest at 8-12 weeks of therapy, but the magnitude of HbA1c lowering waned with longer duration of treatment (up to 52 weeks). Data are not yet available to establish for how long glycaemic efficacy could be sustained during long-term therapy in patients with type 1 diabetes. Moreover, SGLT2 inhibitor therapy induces serious adverse events, including a roughly six-times increased risk of diabetic ketoacidosis. The US Food and Drug Administration estimated that one additional case of ketoacidosis will occur for every 26 patient-years of exposure of patients with type 1 diabetes to sotagliflozin therapy. Assuming a case mortality of 0·4%, this estimate translates into 16 additional deaths per year per 100 000 patients with type 1 diabetes undergoing treatment. These considerations raise important questions about the risk-to-benefit profile of SGLT2 inhibitors when used as adjunctive therapy in patients with type 1 diabetes.