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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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Mediation of the association of smoking and microvascular complications by glycemic control in type 1 diabetes.
Braffett, BH, Rice, MM, Young, HA, Lachin, JM
PloS one. 2019;(1):e0210367
Abstract
Studies have demonstrated the adverse effects of smoking on the risk of microvascular complications; however, few have also examined the potential mediating effects of glycemic control. Using data from the Diabetes Control and Complications Trial (DCCT 1983-1993), we describe the acute and long-term risks of smoking on glycemic control and microvascular complications in a well-characterized cohort of participants with type 1 diabetes. The DCCT recorded self-reported smoking behaviors, glycemic exposure based on HbA1c, and complications status. Generalized linear mixed models were used to assess whether time-dependent measurements of smoking predict HbA1c levels. Cox proportional hazard models were used to assess time-dependent smoking exposures as predictors of retinopathy and nephropathy. During a mean of 6.5 years of follow-up, current smokers had consistently higher HbA1c values and were at a higher risk of retinopathy and nephropathy compared with former and never smokers. These risk differences were attenuated after adjusting for HbA1c suggesting that the negative association of smoking on glycemic control is partially responsible for the adverse association of smoking on the risk of complications in type 1 diabetes. These findings support the potential for a beneficial effect of smoking cessation on complications in type 1 diabetes.
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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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Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial.
Lablanche, S, Vantyghem, MC, Kessler, L, Wojtusciszyn, A, Borot, S, Thivolet, C, Girerd, S, Bosco, D, Bosson, JL, Colin, C, et al
The lancet. Diabetes & endocrinology. 2018;(7):527-537
Abstract
BACKGROUND Islet transplantation is indicated for patients with type 1 diabetes with severe hypoglycaemia or after kidney transplantation. We did a randomised trial to assess the efficacy and safety of islet transplantation compared with insulin therapy in these patients. METHODS In this multicentre, open-label, randomised controlled trial, we randomly assigned (1:1) patients with type 1 diabetes at 15 university hospitals to receive immediate islet transplantation or intensive insulin therapy (followed by delayed islet transplantation). Eligible patients were aged 18-65 years and had severe hypoglycaemia or hypoglycaemia unawareness, or kidney grafts with poor glycaemic control. We used computer-generated randomisation, stratified by centre and type of patient. Islet recipients were scheduled to receive 11 000 islet equivalents per kg bodyweight in one to three infusions. The primary outcome was proportion of patients with a modified β-score (in which an overall score of 0 was not allocated when stimulated C-peptide was negative) of 6 or higher at 6 months after first islet infusion in the immediate transplantation group or 6 months after randomisation in the insulin group. The primary analysis included all patients who received the allocated intervention; safety was assessed in all patients who received islet infusions. This trial is registered with ClinicalTrials.gov, number NCT01148680, and is completed. FINDINGS Between July 8, 2010, and July 29, 2013, 50 patients were randomly assigned to immediate islet transplantation (n=26) or insulin treatment (n=24), of whom three (one in the immediate islet transplantation group and two in the insulin therapy group) did not receive the allocated intervention. Median follow-up was 184 days (IQR 181-186) in the immediate transplantation group and 185 days (172-201) in the insulin therapy group. At 6 months, 16 (64% [95% CI 43-82]) of 25 patients in the immediate islet transplantation group had a modified β-score of 6 or higher versus none (0% [0-15]) of the 22 patients in the insulin group (p<0·0001). At 12 months after first infusion, bleeding complications had occurred in four (7% [2-18]) of 55 infusions, and a decrease in median glomerular filtration rate from 90·5 mL/min (IQR 76·6-94·0) to 71·8 mL/min (59·0-89·0) was observed in islet recipients who had not previously received a kidney graft and from 63·0 mL/min (55·0-71·0) to 57·0 mL/min (45·5-65·1) in islet recipients who had previously received a kidney graft. INTERPRETATION For the indications assessed in this study, islet transplantation effectively improves metabolic outcomes. Although studies with longer-term follow-up are needed, islet transplantation seems to be a valid option for patients with severe, unstable type 1 diabetes who are not responding to intensive medical treatments. However, immunosuppression can affect kidney function, necessitating careful selection of patients. FUNDING Programme Hospitalier de Recherche Clinique grant from the French Government.
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Clinical characteristics of type 2 diabetes patients with discordance between HbA1c and fasting plasma glucose in the real world: An analysis of the ORBIT study.
Shu, H, Lu, J, Zhang, P, Zhu, D, Li, X, Ji, J, Zhao, F, Ji, L
Diabetes/metabolism research and reviews. 2018;(4):e2977
Abstract
BACKGROUND We aimed to determine the clinical characteristics of type 2 diabetes patients on basal insulin therapy with inadequate glucose control due to discordance between glycated haemoglobin (HbA1c ) and fasting plasma glucose (FPG) in the real world. METHODS This was a retrospective analysis of data from the ORBIT study in China. Clinical characteristics of patients with discordance between HbA1c and FPG at baseline and at the end of 6 months of follow-up were analysed using multinomial logistic regression in 4 study groups divided by HbA1c and FPG. RESULTS Overall, of 6721 patients initiated on basal insulin, 853 achieved HbA1c < 7% but FPG ≥ 7 mmol/L (group 2), while 997 had FPG < 7 mmol/L but HbA1c ≥ 7% (group 3) at the end of follow-up. Patients in group 3 had a longer duration of type 2 diabetes compared with those in group 2 (7.22 ± 5.30 vs 6.00 ± 4.80 y, P < .05). Patients on glargine (32.90%) or detemir (36.88%) treatment accounted for a higher proportion of patients with both HbA1c and FPG controlled than those on neutral protamine Hagedorn therapy (23.45%; P < .05). Per the multinomial logistic analysis, higher frequency of self-monitoring of blood glucose (SMBG) and use of glargine or detemir therapy were significantly inversely associated with risk of discordance between HbA1c and FPG, while dose of insulin was a risk factor for discordance at the end of follow-up (all P < .05). CONCLUSIONS Patients treated with insulin analogues (glargine or detemir), instead of neutral protamine Hagedorn, and with more frequent SMBG are more likely to exhibit concordance between HbA1c and FPG.
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Effect of Continuous Glucose Monitoring on Glycemic Control, Acute Admissions, and Quality of Life: A Real-World Study.
Charleer, S, Mathieu, C, Nobels, F, De Block, C, Radermecker, RP, Hermans, MP, Taes, Y, Vercammen, C, T'Sjoen, G, Crenier, L, et al
The Journal of clinical endocrinology and metabolism. 2018;(3):1224-1232
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CONTEXT Randomized controlled trials evaluating real-time continuous glucose monitoring (RT-CGM) patients with type 1 diabetes (T1D) show improved glycemic control, but limited data are available on real-world use. OBJECTIVE To assess impact of RT-CGM in real-world settings on glycemic control, hospital admissions, work absenteeism, and quality of life (QOL). DESIGN Prospective, observational, multicenter, cohort study. PARTICIPANTS A total of 515 adults with T1D on continuous subcutaneous insulin infusion (CSII) therapy starting in the Belgian RT-CGM reimbursement program. INTERVENTION Initiation of RT-CGM reimbursement. MAIN OUTCOME MEASURE Hemoglobin A1c (HbA1c) evolution from baseline to 12 months. RESULTS Between September 1, 2014, and December 31, 2016, 515 adults entered the reimbursement system. Over this period, 417 (81%) patients used RT-CGM for at least 12 months. Baseline HbA1c was 7.7 ± 0.9% (61 ± 9.8 mmol/mol) and decreased to 7.4 ± 0.8% (57 ± 8.7 mmol/mol) at 12 months (P < 0.0001). Subjects who started RT-CGM because of insufficient glycemic control showed stronger decrease in HbA1c at 4, 8, and 12 months compared with patients who started because of hypoglycemia or pregnancy. In the year preceding reimbursement, 16% of patients were hospitalized for severe hypoglycemia or ketoacidosis in contrast to 4% (P < 0.0005) the following year, with decrease in admission days from 54 to 18 per 100 patient years (P < 0.0005). In the same period, work absenteeism decreased and QOL improved significantly, with strong decline in fear of hypoglycemia. CONCLUSION Sensor-augmented pump therapy in patients with T1D followed in specialized centers improves HbA1c, fear of hypoglycemia, and QOL, whereas work absenteeism and admissions for acute diabetes complications decreased.
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Adherence to a lifestyle program for youth with type 2 diabetes and its association with treatment outcome in the TODAY clinical trial.
Berkowitz, RI, Marcus, MD, Anderson, BJ, Delahanty, L, Grover, N, Kriska, A, Laffel, L, Syme, A, Venditti, E, Van Buren, DJ, et al
Pediatric diabetes. 2018;(2):191-198
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OBJECTIVE To assess the association of proxies of behavioral adherence to the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) lifestyle program with changes in glycemic control and obesity in a multi-ethnic sample of youth with type 2 diabetes. METHODS The TODAY clinical trial included an intensive lifestyle intervention to promote weight reduction. Adherence was assessed with measures of attendance at intervention sessions and rates of self-monitoring of diet and physical activity by participants and their caregivers. The relation between participant characteristics and consistency of proxies of adherence were examined across 3 phases of intervention. RESULTS A total of 234 TODAY youth were randomized to the lifestyle program. Overall rate of session attendance was approximately 60% of planned sessions. Participants with an adequate dose of session attendance (≥75% attended) did not differ from those who attended <75% of sessions in glycemic control, but did have significantly greater reductions in percent overweight compared with those who attended fewer than 75% of sessions. Rates of self-monitoring were low and additional analysis was not possible. CONCLUSIONS Rates of session attendance were moderate in a lifestyle program for youth with type 2 diabetes, but levels of self-monitoring, considered a key lifestyle change behavior, were low. Glycemic control was not significantly associated with session attendance but reductions in percent overweight were. Given the salience of program attendance and self-monitoring to lifestyle weight management established in other populations, future research is needed to understand, develop, and promote strategies and interventions targeting weight loss to achieve improved glycemic control in youth diagnosed with type 2 diabetes.
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Effects of DPP-4 inhibitor linagliptin and GLP-1 receptor agonist liraglutide on physiological response to hypoglycaemia in Japanese subjects with type 2 diabetes: A randomized, open-label, 2-arm parallel comparative, exploratory trial.
Yabe, D, Eto, T, Shiramoto, M, Irie, S, Murotani, K, Seino, Y, Kuwata, H, Kurose, T, Seino, S, Ahrén, B, et al
Diabetes, obesity & metabolism. 2017;(3):442-447
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Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose-dependent insulinotropic polypeptide (GIP) action, but not that of glucagon-like peptide-1 (GLP-1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP-4 inhibitor linagliptin on glucagon and other counter-regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP-1 receptor agonist liraglutide in a multi-centre, randomized, open-label, 2-arm parallel comparative, exploratory trial. Three-step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2-week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5 mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2-week treatment. Changes in other counter-regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2-week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.
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[Hypoglycaemia in patients with type 1 and type 2 diabetes mellitus on insulin therapy. Results of the global HAT study in Argentina].
Costa Gil, JE, Linari, MA, Pugnaloni, N, Zambon, FG, Pérez Manghi, F, Rezzónico, M, ,
Medicina. 2017;(6):449-457
Abstract
We describe the results of the HAT study in 433 Argentinean patients with type 1 diabetes (T1D) and 823 with type 2 diabetes (T2D). HAT was an international non-interventional study assessing severe and non-severe hypoglycaemia in patients with T1D and T2D under insulin treatment through a two-part self-assessment questionnaire (retrospective and prospective). The annual incidence of at least one hypoglycaemic episode was 46 episode/patient/year in T1D and 14.2 in T2D (retrospective), 96.5 and 24.6 episode/patient/year in T1D and T2D, respectively (prospective). Hypoglycaemia affected quality of life (on a scale of 0-10 for fear of hypoglycaemia: 60% in T1D and 37.6% in T2D scored 5 to 10), daily life, occupational or academic performance (2.1% with T1D and 3.2% with T2D did not attend to their work after hypoglycaemia), and induced an increased use of health resources (T1D: 66.1% increased glucose monitoring, 60.5% food intake, 51% consultations, 3.5% hospital admissions; 60.5% reduced insulin and 20.9% exercises; T2D increased 46.2% glucose monitoring, 43.8% consultations, 38.6% food intake, 24.1% reduced and 13.9% skipped the insulin dose and 14.3% suspended exercises). Greater numbers of episodes were recorded in the prospective period. An instrument to assess hypoglycaemia in clinical practice and strategies to reduce their risk are required. It is also important to ask about the episodes and reinforce the education of patients and close relatives on hypoglycaemia prevention and treatment.
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Predictive Hyperglycemia and Hypoglycemia Minimization: In-Home Evaluation of Safety, Feasibility, and Efficacy in Overnight Glucose Control in Type 1 Diabetes.
Spaic, T, Driscoll, M, Raghinaru, D, Buckingham, BA, Wilson, DM, Clinton, P, Chase, HP, Maahs, DM, Forlenza, GP, Jost, E, et al
Diabetes care. 2017;(3):359-366
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OBJECTIVE The objective of this study was to determine the safety, feasibility, and efficacy of a predictive hyperglycemia and hypoglycemia minimization (PHHM) system compared with predictive low-glucose insulin suspension (PLGS) alone in overnight glucose control. RESEARCH DESIGN AND METHODS A 42-night trial was conducted in 30 individuals with type 1 diabetes in the age range 15-45 years. Participants were randomly assigned each night to either PHHM or PLGS and were blinded to the assignment. The system suspended the insulin pump on both the PHHM and PLGS nights for predicted hypoglycemia but delivered correction boluses for predicted hyperglycemia on PHHM nights only. The primary outcome was the percentage of time spent in a sensor glucose range of 70-180 mg/dL during the overnight period. RESULTS The addition of automated insulin delivery with PHHM increased the time spent in the target range (70-180 mg/dL) from 71 ± 10% during PLGS nights to 78 ± 10% during PHHM nights (P < 0.001). The average morning blood glucose concentration improved from 163 ± 23 mg/dL after PLGS nights to 142 ± 18 mg/dL after PHHM nights (P < 0.001). Various sensor-measured hypoglycemic outcomes were similar on PLGS and PHHM nights. All participants completed 42 nights with no episodes of severe hypoglycemia, diabetic ketoacidosis, or other study- or device-related adverse events. CONCLUSIONS The addition of a predictive hyperglycemia minimization component to our existing PLGS system was shown to be safe, feasible, and effective in overnight glucose control.