Eric Renard

Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Bolus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial

BACKGROUND Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes. METHODS In an open-label, treat-to-target, non-inferiority trial, undertaken at 79 sites (hospitals and centres) in six countries, adults (aged ≥18 years) with type 1 diabetes (glycated haemoglobin [HbA(1c)] ≤10% [86 mmol/mol]), who had been treated with basal-bolus insulin for at least 1 year, were randomly assigned in a 3:1 ratio, with a computer-generated blocked allocation sequence, to insulin degludec or insulin glargine without stratification by use of a central interactive response system. The primary outcome was non-inferiority of degludec to glargine, assessed as a reduction in HbA(1c) after 52 weeks, with the intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00982228. FINDINGS Of 629 participants, 472 were randomly assigned to insulin degludec and 157 to insulin glargine; all were analysed in their respective treatment groups. At 1 year, HbA(1c) had fallen by 0·40% points (SE 0·03) and 0·39% points (0·07), respectively, with insulin degludec and insulin glargine (estimated treatment difference -0·01% points [95% CI -0·14 to 0·11]; p<0·0001 for non-inferiority testing) and 188 (40%) and 67 (43%) participants achieved a target HbA(1c) of less than 7% (<53 mmol/mol). Rates of overall confirmed hypoglycaemia (plasma glucose <3·1 mmol/L or severe) were similar in the insulin degludec and insulin glargine groups (42·54 vs 40·18 episodes per patient-year of exposure; estimated rate ratio [degludec to glargine] 1·07 [0·89 to 1·28]; p=0·48). The rate of nocturnal confirmed hypoglycaemia was 25% lower with degludec than with glargine (4·41 vs 5·86 episodes per patient-year of exposure; 0·75 [0·59 to 0·96]; p=0·021). Overall serious adverse event rates (14 vs 16 events per 100 patient-years of exposure) were similar for the insulin degludec and insulin glargine groups. INTERPRETATION Insulin degludec might be a useful basal insulin for patients with type 1 diabetes because it provides effective glycaemic control while lowering the risk of nocturnal hypoglycaemia, which is a major limitation of insulin therapy. FUNDING Novo Nordisk.

Artificial Pancreas: Past, Present, Future

The artificial pancreas (AP), known as closed-loop control of blood glucose in diabetes, is a system combining a glucose sensor, a control algorithm, and an insulin infusion device. AP developments can be traced back 50 years to when the possibility for external blood glucose regulation was established by studies in individuals with type 1 diabetes using intravenous glucose measurement and infusion of insulin and glucose. After the pioneering work by Kadish (1) in 1964, expectations for effectively closing the loop were inspired by the nearly simultaneous work of five teams reporting closed-loop control results between 1974 and 1978: Albisser et al. (2), Pfeiffer et al. (3), Mirouze et al. (4), Kraegen et al. (5), and Shichiri et al. (6). In 1977, one of these realizations (3) resulted in the first commercial device—the Biostator (7; Fig. 1), followed by another inpatient system, the Nikkiso STG-22 Blood Glucose Controller, now in use in Japan (8). FIG. 1. The Biostator (courtesy of William Clarke, University of Virginia). Although the intravenous route of glucose sensing and insulin infusion is unsuitable for outpatient use, these devices proved the feasibility of external glucose control and stimulated further technology development. Figure 2 presents key milestones in the timeline of AP progress. FIG. 2. Key milestones in the timeline of AP progress. EU, Europe; IP, intraperitoneal; NIH, National Institutes of Health; SC, subcutaneous. In 1979, landmark studies by Pickup et al. (9) and Tamborlane et al. (10) showed that the subcutaneous route was feasible for continuous insulin delivery. Three years later, Shichiri et al. (11) tested a prototype of a wearable AP, which was further developed in subsequent studies (12,13). In the late 1980s, an implantable system was introduced using intravenous glucose sensing and intraperitoneal insulin infusion (14). This technology was further developed, leading to clinical trials and …

Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes: The RealTrend study

OBJECTIVE To compare the improvements in glycemic control associated with transitioning to insulin pump therapy in patients using continuous glucose monitoring versus standard blood glucose self-monitoring. RESEARCH DESIGN AND METHODS The RealTrend study was a 6-month, randomized, parallel-group, two-arm, open-label study of 132 adults and children with uncontrolled type 1 diabetes (A1C ≥8%) being treated with multiple daily injections. One group was fitted with the Medtronic MiniMed Paradigm REAL-Time system (PRT group), an insulin pump with integrated continuous subcutaneous glucose monitoring (CGM) capability, with instructions to wear CGM sensors at least 70% of the time. Conventional insulin pump therapy was initiated in the other group (continuous subcutaneous insulin infusion [CSII] group). Outcome measures included A1C and glycemic variability. RESULTS A total of 115 patients completed the study. Between baseline and trial end, A1C improved significantly in both groups (PRT group −0.81 ± 1.09%, P < 0.001; CSII group −0.57 ± 0.94%, P < 0.001), with no significant difference between groups. When the 91 patients who were fully protocol-compliant (including CGM sensor wear ≥70% of the time) were considered, A1C improvement was significantly greater in the PRT group (P = 0.004) (PRT group −0.96 ± 0.93%, P < 0.001; CSII group −0.55 ± 0.93%, P < 0.001). Hyperglycemia parameters decreased in line with improvements in A1C with no impact on hypoglycemia. CONCLUSIONS CGM-enabled insulin pump therapy improves glycemia more than conventional pump therapy during the first 6 months of pump use in patients who wear CGM sensors at least 70% of the time.

Fully Integrated Artificial Pancreas in Type 1 Diabetes: Modular Closed-Loop Glucose Control Maintains Near Normoglycemia

Integrated closed-loop control (CLC), combining continuous glucose monitoring (CGM) with insulin pump (continuous subcutaneous insulin infusion [CSII]), known as artificial pancreas, can help optimize glycemic control in diabetes. We present a fundamental modular concept for CLC design, illustrated by clinical studies involving 11 adolescents and 27 adults at the Universities of Virginia, Padova, and Montpellier. We tested two modular CLC constructs: standard control to range (sCTR), designed to augment pump plus CGM by preventing extreme glucose excursions; and enhanced control to range (eCTR), designed to truly optimize control within near normoglycemia of 3.9–10 mmol/L. The CLC system was fully integrated using automated data transfer CGM→algorithm→CSII. All studies used randomized crossover design comparing CSII versus CLC during identical 22-h hospitalizations including meals, overnight rest, and 30-min exercise. sCTR increased significantly the time in near normoglycemia from 61 to 74%, simultaneously reducing hypoglycemia 2.7-fold. eCTR improved mean blood glucose from 7.73 to 6.68 mmol/L without increasing hypoglycemia, achieved 97% in near normoglycemia and 77% in tight glycemic control, and reduced variability overnight. In conclusion, sCTR and eCTR represent sequential steps toward automated CLC, preventing extremes (sCTR) and further optimizing control (eCTR). This approach inspires compelling new concepts: modular assembly, sequential deployment, testing, and clinical acceptance of custom-built CLC systems tailored to individual patient needs.

Dupuytren's disease, carpal tunnel syndrome, trigger finger, and diabetes mellitus

A comparative prospective study of 120 adult diabetics (60 insulin dependent, 60 non-insulin dependent) and 120 non-diabetic adults as controls showed significantly higher incidence of Dupuytrens disease, limited joint motion, carpal tunnel syndrome, and flexor tenosynovitis in the diabetic population. Of the diabetic patients one third had a mild non-progressive form of Dupuytrens disease, which commonly involved the long and ring rays. Limited joint motion was noted in a third of diabetics, and carpal tunnel syndrome was observed in 15-25%, and flexor tenosynovitis in about a fifth. Limited joint motion co-existed with Dupuytrens disease in 57% of insulin-dependent diabetics. Diabetic polyneuropathy was found in two thirds of insulin-dependent diabetics and in one third of non-insulin dependent diabetics. All these hand changes were more marked in insulin-dependent diabetics and they showed a positive correlation with increasing age of the patient, duration of the diabetes, and the presence of a microangiopathy.

Multinational Study of Subcutaneous Model-Predictive Closed-Loop Control in Type 1 Diabetes Mellitus: Summary of the Results

Background: In 2008–2009, the first multinational study was completed comparing closed-loop control (artificial pancreas) to state-of-the-art open-loop therapy in adults with type 1 diabetes mellitus (T1DM). Methods: The design of the control algorithm was done entirely in silico, i.e., using computer simulation experiments with N = 300 synthetic “subjects” with T1DM instead of traditional animal trials. The clinical experiments recruited 20 adults with T1DM at the Universities of Virginia (11); Padova, Italy (6); and Montpellier, France (3). Open-loop and closed-loop admission was scheduled 3–4 weeks apart, continued for 22 h (14.5 h of which were in closed loop), and used a continuous glucose monitor and an insulin pump. The only difference between the two sessions was that insulin dosing was performed by the patient under a physicians supervision during open loop, whereas insulin dosing was performed by a control algorithm during closed loop. Results: In silico design resulted in rapid (less than 6 months compared to years of animal trials) and cost-effective system development, testing, and regulatory approvals in the United States, Italy, and France. In the clinic, compared to open-loop, closed-loop control reduced nocturnal hypoglycemia (blood glucose below 3.9 mmol/liter) from 23 to 5 episodes (p < .01) and increased the amount of time spent overnight within the target range (3.9 to 7.8 mmol/liter) from 64% to 78% (p = .03). Conclusions: In silico experiments can be used as viable alternatives to animal trials for the preclinical testing of insulin treatment strategies. Compared to open-loop treatment under identical conditions, closed-loop control improves the overnight regulation of diabetes.

Improvement of HbA1c and Blood Glucose Stability in IDDM Patients Treated With Lispro Insulin Analog in External Pumps

OBJECTIVE To compare the efficacy of the short-acting insulin analog lispro (LP) with that of regular insulin in IDDM patients treated with an external pump. RESEARCH DESIGN AND METHODS Thirty-nine IDDM patients (age, 39.4 ± 1.5 years; sex ratio, 22M/17W; BMI, 24.4 ± 0.4 kg/m2; diabetes duration, 22.5 ± 1.6 years) who were treated by external pump for 5.1 ± 0.5 years were involved in an open-label, randomized, crossover multicenter study comparing two periods of 3 months of continuous subcutaneous insulin infusion with LP or with Actrapid HM, U-100 (ACT). Boluses were given 0–5 min (LP) or 20–30 min (ACT) before meals. Blood glucose (BG) was monitored before and after the three meals every day. RESULTS The decrease in HbA1c was more pronounced with LP than with ACT (−0.62 ± 0.13 vs. −0.09 ± 0.15%, P = 0.01). BG levels were lower with LP (7.93 ± 0.15 vs. 8.61 ± 0.18 mmol/l, P < 0.0001), particularly postprandial BG levels (8.26 ± 0.19 vs. 9.90 ± 0.20 mmol/l, P < 0.0001). Standard deviations of all the BG values (3.44 ± 0.10 vs. 3.80 ± 0.10 mmol/l, P = 0.0001) and of postprandial BG values (3.58 ± 0.10 vs. 3.84 ± 0.10 mmol/l. P < 0.02) were lower with LP. The rate of hypoglycemic events defined by BG < 3.0 mmol/l did not significantly differ between LP and ACT (7.03 ± 0.94 vs. 7.94 ± 0.88 per month, respectively), but the rate of occurrences of very low BG, defined as BG < 2.0 mmol/l, were significantly reduced with LP (0.05 ± 0.05 vs. 0.47 ± 0.19 per month, P < 0.05). At the end of the study, all but two (95%) of the patients chose LP for the extension phase. CONCLUSIONS When used in external pumps, LP provides better glycemic control and stability than regular insulin and does not increase the frequency of hypoglycemic episodes.

Closed-Loop Insulin Delivery Using a Subcutaneous Glucose Sensor and Intraperitoneal Insulin Delivery: Feasibility study testing a new model for the artificial pancreas

OBJECTIVE Attempts to build an artificial pancreas by using subcutaneous insulin delivery from a portable pump guided by an subcutaneous glucose sensor have encountered delays and variability of insulin absorption. We tested closed-loop intraperitoneal insulin infusion from an implanted pump driven by an subcutaneous glucose sensor via a proportional-integral-derivative (PID) algorithm. RESEARCH DESIGN AND METHODS Two-day closed-loop therapy (except for a 15-min premeal manual bolus) was compared with a 1-day control phase with intraperitoneal open-loop insulin delivery, according to randomized order, in a hospital setting in eight type 1 diabetic patients treated by implanted pumps. The percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was the primary end point. RESULTS During the closed-loop phases, the mean ± SEM percentage of time spent with blood glucose in the 4.4–6.6 mmol/l range was significantly higher (39.1 ± 4.5 vs. 27.7 ± 6.2%, P = 0.05), and overall dispersion of blood glucose values was reduced among patients. Better closed-loop glucose control came from the time periods excluding the two early postprandial hours with a higher percentage of time in the 4.4–6.6 mmol/l range (46.3 ± 5.3 vs. 28.6 ± 7.4, P = 0.025) and lower mean blood glucose levels (6.9 ± 0.3 vs. 7.9 ± 0.6 mmol/l, P = 0.036). Time spent with blood glucose <3.3 mmol/l was low and similar for both investigational phases. CONCLUSIONS Our results demonstrate the feasibility of intraperitoneal insulin delivery for an artificial β-cell and support the need for further study. Moreover, according to a semiautomated mode, the features of the premeal bolus in terms of timing and amount warrant further research.

Safety of Outpatient Closed-Loop Control: First Randomized Crossover Trials of a Wearable Artificial Pancreas

OBJECTIVE We estimate the effect size of hypoglycemia risk reduction on closed-loop control (CLC) versus open-loop (OL) sensor-augmented insulin pump therapy in supervised outpatient setting. RESEARCH DESIGN AND METHODS Twenty patients with type 1 diabetes initiated the study at the Universities of Virginia, Padova, and Montpellier and Sansum Diabetes Research Institute; 18 completed the entire protocol. Each patient participated in two 40-h outpatient sessions, CLC versus OL, in randomized order. Sensor (Dexcom G4) and insulin pump (Tandem t:slim) were connected to Diabetes Assistant (DiAs)—a smartphone artificial pancreas platform. The patient operated the system through the DiAs user interface during both CLC and OL; study personnel supervised on site and monitored DiAs remotely. There were no dietary restrictions; 45-min walks in town and restaurant dinners were included in both CLC and OL; alcohol was permitted. RESULTS The primary outcome—reduction in risk for hypoglycemia as measured by the low blood glucose (BG) index (LGBI)—resulted in an effect size of 0.64, P = 0.003, with a twofold reduction of hypoglycemia requiring carbohydrate treatment: 1.2 vs. 2.4 episodes/session on CLC versus OL (P = 0.02). This was accompanied by a slight decrease in percentage of time in the target range of 3.9–10 mmol/L (66.1 vs. 70.7%) and increase in mean BG (8.9 vs. 8.4 mmol/L; P = 0.04) on CLC versus OL. CONCLUSIONS CLC running on a smartphone (DiAs) in outpatient conditions reduced hypoglycemia and hypoglycemia treatments when compared with sensor-augmented pump therapy. This was accompanied by marginal increase in average glycemia resulting from a possible overemphasis on hypoglycemia safety.

Closed-Loop Artificial Pancreas Using Subcutaneous Glucose Sensing and Insulin Delivery and a Model Predictive Control Algorithm: Preliminary Studies in Padova and Montpellier

New effort has been made to develop closed-loop glucose control, using subcutaneous (SC) glucose sensing and continuous subcutaneous insulin infusion (CSII) from a pump, and a control algorithm. An approach based on a model predictive control (MPC) algorithm has been utilized during closed-loop control in type 1 diabetes patients. Here we describe the preliminary clinical experience with this approach. In Padova, two out of three subjects showed better performance with the closed-loop system compared to open loop. Altogether, mean overnight plasma glucose (PG) levels were 134 versus 111 mg/dl during open loop versus closed loop, respectively. The percentage of time spent at PG > 140 mg/dl was 45% versus 12%, while postbreakfast mean PG was 165 versus 156 mg/dl during open loop versus closed loop, respectively. Also, in Montpellier, two patients out of three showed a better glucose control during closed-loop trials. Avoidance of nocturnal hypoglycemic excursions was a clear benefit during algorithm-guided insulin delivery in all cases. This preliminary set of studies demonstrates that closed-loop control based entirely on SC glucose sensing and insulin delivery is feasible and can be applied to improve glucose control in patients with type 1 diabetes, although the algorithm needs to be further improved to achieve better glycemic control. Six type 1 diabetes patients (three in each of two clinical investigation centers in Padova and Montpellier), using CSII, aged 36 ± 8 and 48 ± 6 years, duration of diabetes 12 ± 8 and 29 ± 4 years, hemoglobin A1c 7.4% ± 0.1% and 7.3% ± 0.3%, body mass index 23.2 ± 0.3 and 28.4 ± 2.2 kg/m2, respectively, were studied on two occasions during 22 h overnight hospital admissions 2–4 weeks apart. A Freestyle Navigator® continuous glucose monitor and an OmniPod® insulin pump were applied in each trial. Admission 1 used open-loop control, while admission 2 employed closed-loop control using our MPC algorithm.