Fully closed-loop insulin delivery improves glucose control of inpatients with type 2 diabetes receiving hemodialysis

Inpatient diabetes management of those on hemodialysis poses a major challenge. In a post hoc analysis of a randomized controlled clinical trial, we compared the efficacy of fully automated closed-loop insulin delivery vs. usual care in patients undergoing hemodialysis while in hospital. Compared to control patients receiving conventional subcutaneous insulin therapy, those patients receiving closed-loop insulin delivery significantly increased the proportion of time when a continuous glucose monitor was in the target range of 5.6-10.0 mmol/l by 37.6 percent without increasing the risk of hypoglycemia. Thus, closed-loop insulin delivery offers a novel way to achieve effective and safe glucose control in this vulnerable patient population. Inpatient diabetes management of those on hemodialysis poses a major challenge. In a post hoc analysis of a randomized controlled clinical trial, we compared the efficacy of fully automated closed-loop insulin delivery vs. usual care in patients undergoing hemodialysis while in hospital. Compared to control patients receiving conventional subcutaneous insulin therapy, those patients receiving closed-loop insulin delivery significantly increased the proportion of time when a continuous glucose monitor was in the target range of 5.6-10.0 mmol/l by 37.6 percent without increasing the risk of hypoglycemia. Thus, closed-loop insulin delivery offers a novel way to achieve effective and safe glucose control in this vulnerable patient population. see commentary on page 540 see commentary on page 540 The prevalence of diabetes is increasing globally, as is the number of people with diabetes requiring hemodialysis.1Kramer A. Pippias M. Noordzij M. et al.The European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2015: a summary.Clin Kidney J. 2018; 11: 108-122Crossref PubMed Scopus (146) Google Scholar, 2Lu Y. Stamm C. Nobre D. et al.Changing trends in end-stage renal disease patients with diabetes.Swiss Med Wkly. 2017; 147: w14458PubMed Google Scholar Glucose management in this population imposes challenges on both patients and health care professionals. End-stage renal disease and hemodialysis predispose these patients to both hypo- and hyperglycemia,3Abe M. Kalantar-Zadeh K. Haemodialysis-induced hypoglycaemia and glycaemic disarrays.Nat Rev Nephrol. 2015; 11: 302-313Crossref PubMed Scopus (90) Google Scholar which are associated with adverse medical outcomes.4Umpierrez G.E. Isaacs S.D. Bazargan N. et al.Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes.J Clin Endocrinol Metab. 2002; 87: 978-982Crossref PubMed Scopus (1580) Google Scholar, 5Turchin A. Matheny M.E. Shubina M. et al.Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward.Diabetes Care. 2009; 32: 1153-1157Crossref PubMed Scopus (341) Google Scholar The situation is aggravated when patients are admitted to the hospital due to acute illness.6Gianchandani R.Y. Neupane S. Heung M. Hypoglycemia in hospitalized hemodialysis patients with diabetes: an observational study.J Diabetes Sci Technol. 2018; 12: 33-38Crossref PubMed Scopus (10) Google Scholar Optimal insulin dosing regimens are difficult to establish given the altered glucose metabolism and insulin kinetics in this population.7Sobngwi E. Enoru S. Ashuntantang G. et al.Day-to-day variation of insulin requirements of patients with type 2 diabetes and end-stage renal disease undergoing maintenance hemodialysis.Diabetes Care. 2010; 33: 1409-1412Crossref PubMed Scopus (40) Google Scholar, 8Sudha M.J. Salam H.S. Viveka S. Udupa A.L. Assessment of changes in insulin requirement in patients of type 2 diabetes mellitus on maintenance hemodialysis.J Nat Sci Biol Med. 2017; 8: 64-68Crossref PubMed Scopus (10) Google Scholar Hence, glucose management may be better facilitated by an algorithm-driven insulin therapy, also known as closed-loop insulin delivery or artificial pancreas, which is an emerging therapeutic approach combining continuous glucose monitoring with insulin pump therapy to achieve a more physiological means of replacing insulin.9Bally L. Thabit H. Hovorka R. Closed-loop for type 1 diabetes—an introduction and appraisal for the generalist.BMC Med. 2017; 15: 14Crossref PubMed Scopus (25) Google Scholar The role of the control algorithm is to continuously modulate insulin delivery based on real-time sensor glucose values, thereby responding to the inherent variability of insulin requirements. The closed-loop system used in the present study incorporates a control algorithm that is initialized based on the subject’s body weight and estimated total daily insulin dose, and calculates the required insulin infusion rate, aiming at a target glucose level between 5.8 and 7.2 mmol/l by continuously adapting model parameters.10Hovorka R. Canonico V. Chassin L.J. et al.Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes.Physiol Meas. 2004; 25: 905-920Crossref PubMed Scopus (918) Google Scholar We hypothesized that fully closed-loop insulin delivery improves glycemic control without increasing the risk of hypoglycemia in inpatients with type 2 diabetes undergoing hemodialysis. Here, we report a post hoc analysis in 17 such inpatients who took part in a randomized parallel-design study.11Bally L. Thabit H. Hartnell S. et al.Closed-loop insulin delivery for glycemic control in noncritical care.N Engl J Med. 2018; 379: 547-556Crossref PubMed Scopus (109) Google Scholar The aim of the original study (n = 136) was to assess the efficacy and safety of fully automated closed-loop insulin delivery in comparison with conventional insulin therapy at non–critical care units irrespective of underlying pathophysiology. Baseline characteristics were comparable between closed-loop versus control subjects, with mean values as follows: 77% versus 63% male; age 73 years (SD: 8) versus 67 years (SD: 10); body mass index 31.2 kg/m2 (SD: 6.5) versus 32.8 kg/m2 (SD: 6.9); glycated hemoglobin 7.1% (SD: 0.6) versus 6.9% (SD: 1.5); diabetes duration 25 years (SD: 13) versus 28 years (SD: 7); total daily insulin dose 42 U/24 h (SD: 25–55) versus 44 U/24 h (SD: 30–69). At recruitment, none of the closed-loop and 4 of the control participants received adjunctive anti-diabetic treatment (all dipeptidyl peptidase–4 inhibitors, with one patient additionally receiving metformin and the other glucagon-like peptide GLP-1 receptor agonist therapy). Participants were followed for up to 8.0 days (SD: 3.1) and 7.7 days (SD: 4.8) in the closed-loop and control groups, respectively, and they underwent 4.2 (SD: 1.5) and 3.6 (SD: 2.5) hemodialysis sessions (both differences nonsignificant). The proportion of time spent in the target glucose range, which was between 5.6 and 10 mmol/l, was significantly greater in the closed-loop group compared with the control group (69.0% SD: 12.0 vs. 31.5% SD: 13.5, respectively; difference 37.6% SD: 6.2; 95% confidence interval 24.4 to 50.8; P 10 mmol/l) was significantly lower in the closed-loop group (difference 37.2% SD: 9.2; 95% confidence interval 17.7 to 56.9; P = 0.001), whereas the time spent at concentrations lower than the target range (20 mmol/l) events based on capillary glucose were detected, respectively, in 1 control and in none of the closed-loop patients, and in 1 closed-loop and 2 control patients, although none of them had concomitant ketonemia.Table 1Primary and secondary endpoints during the entire studyStudy endpointClosed-loop (n = 9)Control (n = 8)P valueTime spent at glucose level in mmol/l (%) 5.6–10.0aPrimary endpoint.69.0 (12.0)31.5 (13.5)1020.1 (9.8)57.4 (25.7)0.001 <5.610.9 (4.5)11.1 (14.1)0.96 <3.00.0 (0.0, 0.2)0.0 (0.0, 0.6)0.82Mean glucose (mmol/l)8.1 (0.6)11.0 (2.3)0.003SD of glucose (mmol/l)2.3 (0.5)3.6 (1.2)0.012CV of glucose (%)28.4 (4.9)32.3 (8.5)0.26Between days CV of glucose (%)13.4 (3.7)21.8 (7.3)0.008AUCDay <3.0 mmol/l (mg/dl × min)0.0 (0.0, 2.1)0.0 (0.0, 8.8)0.89Total daily insulin dose (U/24 h)40.7 (25.7)50.3 (20.6)0.42AUCDay, area under the curve for a glucose concentration of <3.0 mmol/l per 24-hour period; CV, coefficient of variation.Data are given as mean (SD), or median (interquartile range).a Primary endpoint. Open table in a new tab AUCDay, area under the curve for a glucose concentration of <3.0 mmol/l per 24-hour period; CV, coefficient of variation. Data are given as mean (SD), or median (interquartile range). Increasing evidence shows that closed-loop insulin delivery is superior to conventional insulin treatment in different target groups, such as children, adolescents, pregnant women with type 1 diabetes, and more recently, inpatients with type 2 diabetes.11Bally L. Thabit H. Hartnell S. et al.Closed-loop insulin delivery for glycemic control in noncritical care.N Engl J Med. 2018; 379: 547-556Crossref PubMed Scopus (109) Google Scholar, 12Tauschmann M. Thabit H. Bally L. et al.Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, 12-week randomised trial.Lancet. 2018; 392: 1321-1329Abstract Full Text Full Text PDF PubMed Scopus (220) Google Scholar, 13Stewart Z.A. Wilinska M.E. Hartnell S. et al.Closed-loop insulin delivery during pregnancy in women with type 1 diabetes.N Engl J Med. 2016; 375: 644-654Crossref PubMed Scopus (140) Google Scholar Glucose management in hospitalized patients undergoing hemodialysis is particularly challenging, and until now, whether a control algorithm can accommodate their specific requirements has been unclear. For the first time, we have shown here that a fully automated closed-loop system clearly improves glucose control in this vulnerable population. The closed-loop system increased time in the glycemic target range (5.6–10.0 mmol/l) throughout a 24-hour period by 37.6%, compared with control (additional 9 hours). The difference in time spent with target glycemia between closed-loop and control in nonhemodialysis patients of the main study11Bally L. Thabit H. Hartnell S. et al.Closed-loop insulin delivery for glycemic control in noncritical care.N Engl J Med. 2018; 379: 547-556Crossref PubMed Scopus (109) Google Scholar was 22.4%, indicating a trend toward a greater beneficial effect of the closed-loop system in the hemodialysis cohort. Hemodialysis patients in the control group spent less than one-third of the time in the target range, possibly due, at least in part, to fear of inducing hypoglycemia. A recent observational study in hospitalized dialysis patients with type 2 diabetes showed6Gianchandani R.Y. Neupane S. Heung M. Hypoglycemia in hospitalized hemodialysis patients with diabetes: an observational study.J Diabetes Sci Technol. 2018; 12: 33-38Crossref PubMed Scopus (10) Google Scholar that 1 in 5 (21.7%) individuals experienced glucose levels <3.0 mmol/l. Guidelines for inpatient diabetes care suggest14American Diabetes Association14. Diabetes care in the hospital: standards of medical care in diabetes—2018.Diabetes Care. 2018; 41: S144-S151Crossref PubMed Scopus (133) Google Scholar the use of a basal-bolus insulin regimen. However, implementation can be challenged by high within- and between-day variation in insulin requirements. An outpatient study using euglycemic clamp methodology showed that insulin requirements are reduced by 25% up to 24 hours after hemodialysis.7Sobngwi E. Enoru S. Ashuntantang G. et al.Day-to-day variation of insulin requirements of patients with type 2 diabetes and end-stage renal disease undergoing maintenance hemodialysis.Diabetes Care. 2010; 33: 1409-1412Crossref PubMed Scopus (40) Google Scholar Generalizability of this findings to an inpatient setting, however, may not be appropriate, especially in the context of variable daily dialysis schedules and concomitant acute illness.15Iyengar R. Franzese J. Gianchandani R. Inpatient glycemic management in the setting of renal insufficiency/failure/dialysis.Curr Diab Rep. 2018; 18: 75Crossref PubMed Scopus (13) Google Scholar Hence, a closed-loop system such as ours, which enables a finely tuned instantaneous glucose-responsive modulation of insulin delivery and continually adapts to changing insulin needs during the day and between days, may offer a more effective and safer diabetes therapy. One strength of the current study is the random allocation of treatment and the identification of a new target group who may be particularly likely to benefit from a closed-loop system. However, in the absence of randomized outcome trials, the long-term clinical benefits of maintaining effective glycemic control in hemodialysis patients have yet to be established. Findings from observational studies are inconsistent. Although the study with the longest follow-up showed a clear association between high glycated hemoglobin and all-cause mortality,16Triebswetter S. Gutjahr-Lengsfeld L.J. Schmidt K.R. et al.Long-term survivor characteristics in hemodialysis patients with type 2 diabetes.Am J Nephrol. 2018; 47: 30-39Crossref PubMed Scopus (3) Google Scholar this relationship was found to be either only in patients younger than 60 years17Adler A. Casula A. Steenkamp R. et al.Association between glycemia and mortality in diabetic individuals on renal replacement therapy in the U.K.Diabetes Care. 2014; 37: 1304-1311Crossref PubMed Scopus (26) Google Scholar or without support.18Williams M.E. Lacson E. Teng M. et al.Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival.Kidney Int. 2006; 70: 1503-1509Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar In addition to the unclear accuracy of measures of glycated hemoglobin in dialysis patients,19Peacock T.P. Shihabi Z.K. Bleyer A.J. et al.Comparison of glycated albumin and hemoglobin A(1c) levels in diabetic subjects on hemodialysis.Kidney Int. 2008; 73: 1062-1068Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar assessments can be challenged by hypoglycemia, which is similarly associated with adverse events.20Davis S.N. Duckworth W. Emanuele N. et al.Effects of severe hypoglycemia on cardiovascular outcomes and death in the Veterans Affairs Diabetes Trial.Diabetes Care. 2019; 42: 157-163Crossref PubMed Scopus (64) Google Scholar We acknowledge the limitation inherent in a subgroup analysis, such as small sample size and potential confounders that may limit the validity and generalizability of the results. However, our findings provide justification for evaluating further closed-loop insulin delivery use in inpatient and outpatient cohorts on maintenance dialysis. Diabetes management in inpatients with type 2 diabetes undergoing hemodialysis is complex and often results in suboptimal glucose control. Fully automated closed-loop insulin delivery resulted in significantly better glycemic control than did conventional therapy, without increasing the risk of hypoglycemia, thereby offering a novel treatment modality in this vulnerable population.