Fully Integrated Artificial Pancreas in Type 1 Diabetes

Modular Closed-Loop Glucose Control Maintains Near Normoglycemia

Marc Breton; Anne Farret; Daniela Bruttomesso; Stacey Anderson; Lalo Magni; Stephen Patek; Chiara Dalla Man; Jerome Place; Susan Demartini; Simone Del Favero; Chiara Toffanin; Colleen Hughes-Karvetski; Eyal Dassau; Howard Zisser; Francis J. Doyle III; Giuseppe De Nicolao; Angelo Avogaro; Claudio Cobelli; Eric Renard; Boris Kovatchev

Disclosures

Diabetes. 2012;61(9):2230-2237. 

In This Article

Results

Study 1: sCTR versus Open-loop CSII

Time spent in near normoglycemia increased significantly overall from 61.5 ± 5.2% (open-loop session) to 74.4 ± 3.9% (sCTR) (P = 0.01), with a maximal effect overnight (53.9 ± 7.8 vs. 74.1 ± 6.8%, P = 0.016). As would be expected by the design of sCTR, time spent in tight glycemic range (4.4–7.8 mmol/L) did not differ between the two admissions overall (34.9 ± 5.0 vs. 37.4 ± 5.4%, P = 0.66) or overnight (30.8 ± 0.7 vs. 32.7 ± 0.7%, P = 0.80) see Fig. 3.

Figure 3.

Primary outcomes of sCTR: Time in near normoglycemia (3.9–10 mmol/L), average glucose, intrasubject variability, and occurrence of hypoglycemia (hypo) during open- and closed-loop admissions, contrasted by overall and overnight periods. *P < 0.05. Open-loop CSII, gray bar; sCTR, black bar.

Improved glycemic control was achieved with simultaneous 2.7-fold reduction in hypoglycemia from a total of 27 hypoglycemic events during open loop to 10 events during sCTR, a reduction that corresponds to 1.08 ± 0.27 versus 0.4 ± 0.13 events/patient (P = 0.01) and to a significant reduction in the risk for hypoglycemia as indicated by the LBGI (1.51 ± 0.31 vs. 0.72 ± 0.18, P < 0.01). A particularly prominent sixfold reduction in hypoglycemia was observed overnight. Hypoglycemic events were most likely during exercise or within 3 h after dinner and almost never occurred on CLC during recovery (0.04 events/patient) and overnight (0.08 events/patient). Because the study protocol mandated treatment of hypoglycemia once it had occurred, the extent of the hypoglycemic events could not be assessed. Amount of treatment per hypoglycemic event was recorded and showed no difference between admission (each hypoglycemia event was treated with, respectively, 14.94 vs. 12.33 g carbohydrate, P = 0.58 independent sample t test).

Average glucose was not significantly reduced overall (8.82 ± 0.54 vs. 8.34 ± 0.28 mmol/L, P = 0.36) or overnight (9.44 ± 0.72 vs. 8.47 ± 0.39 mmol/L, P = 0.09), whereas a significant decrease in the overnight risk for hyperglycemia was observed, as indicated by the HBGI[9] (8.39 ± 1.85 to 4.35 ± 0.82, P = 0.014). Average glucose profiles and 25–75% quantiles for open-loop CSII versus sCTR are presented in Fig. 5 (upper panel).

Figure 4.

Primary outcomes of eCTR: Time in near normoglycemia (3.9–10 mmol/L) and tight control (4.4–7.78 mmol/L), average glucose, and intrasubject variability during open- and closed-loop admissions, contrasted by overall and overnight periods. *P < 0.05. Open-loop CSII, gray bar; eCTR, black bar.

Figure 5.

Mean (curves) and 25–75% quantiles (shaded areas) of plasma glucose for each algorithm comparing open-loop CSII and closed-loop admissions. Glycemic ranges are depicted by the bounds (plain: near normoglycemia; dotted: tight glucose control).

Glucose variability, as measured by the BG Risk Index,[9] was significantly reduced from 8.19 ± 1.19 to 5.05 ± 0.47 (P = 0.01), with maximum effect overnight (9.62 ± 1.66 vs. 4.9 ± 0.74, P < 0.01). Intrasubject variability (indicated by SD of BG, mmol/L) was significantly reduced overall (2.46 ± 0.21 vs. 1.87 ± 1.5, P = 0.02) and overnight (1.60 ± 0.22 vs. 1.05 ± 0.10, P = 0.02) (Traces are presented in Supplementary Fig. 1).

Study 2: eCTR versus Open-loop CSII

We observed a significant decrease in the overall average plasma glucose (mmol/L) from 7.74 ± 0.44 (open-loop session) to 6.68 ± 0.28 (eCTR) (P < 0.01), with maximum effect reached overnight (7.71 ± 0.70 to 6.12 ± 0.38, P = 0.042). The decrease in the risk for hyperglycemia as indicated by the HBGI was marginal overall (3.63 ± 0.87 vs. 2.07 ± 0.74, P = 0.07) and during dinner and snack (3.83 ± 1.41 vs. 2.62 ± 0.62, P = 0.23) but significant overnight (3.67 ± 1.22 vs. 0.79 ± 0.34, P = 0.02).

The overall percent time in near normoglycemia increased significantly from 76.8 ± 5.0 to 90.1 ± 3.4% (P = 0.05), with maximal eCTR performance of 97.6 ± 2% achieved overnight (Fig. 4). Percent time in tight control (4.4–7.78 mmol/L) increased (but not significantly) overall from 47.2 ± 6.6 to 62.0 ± 5.2% (P = 0.09) and significantly overnight from 42.7 ± 11.2 to 79.3 ± 8.1% (P = 0.04). Glucose control was achieved without apparent increase in the risk of hypoglycemia (1.4 vs. 1.6 events/patient in open loop vs. eCTR, P = 0.43) as confirmed by the LBGI (overall: 0.62 ± 0.19 vs. 1.05 ± 0.23, P = 0.09; overnight: 0.88 ± 0.41 vs. 1.08 ± 0.58, P = 0.43). Hypoglycemic events were most likely during and after exercise and between dinner and snack (1.1 events/patient) but were less frequent overnight (0.4 events/patient).

Finally, using the BG Risk Index, we confirmed the improvement shown in percent time in target range: the index was significantly reduced overnight (4.37 ± 0.88 vs. 2.37 ± 0.67, P = 0.04) and marginally reduced overall (4.68 ± 0.76 vs. 3.26 ± 0.69, P = 0.41) and during dinner and snack (4.88 ± 1.24 vs. 3.84 ± 0.84, P = 0.25). Intrasubject variability (mmol/L) was marginally reduced overall (2.13 ± 0.21 vs. 1.81 ± 0.21, P = 0.27) but significantly reduced overnight (1.35 ± 0.14 vs. 0.84 ± 0.16, P = 0.045).

Average glucose profiles and 25–75% quantiles for open-loop CSII versus eCTR and sCTR are presented in Fig. 5 (Traces are presented in Supplementary Fig. 2).

Additional Comparisons

sCTR versus eCTR. Although direct comparison between sCTR and eCTR is not justified on all performance parameters because of their essential design differences, we can draw some conclusions comparing similar features and selecting similar populations (adult only). We used univariate ANOVA with CSII performance included as a covariate to compensate for interindividual differences for all continuous variables, except for hypoglycemia counts, which necessitated a nonparametric Mann-Whitney U test. This analysis led to the following conclusions: 1) eCTR and sCTR both increased time spent in near normoglycemia similarly (P = 0.21); 2) eCTR increased overnight time spent in tight glycemic control further, compared with sCTR (P = 0.036); 3) eCTR decreased mean BG further than sCTR overall (P = 0.012), but overnight comparison was not conclusive (P = 0.06); 4) eCTR and sCTR both decreased glycemic variability similarly (P = 0.46); and 5) the comparison of the occurrence of hypoglycemia in sCTR and eCTR was not conclusive (0.4 vs. 1.6 events/patient, Mann-Whitney U test, P = 0.11) and there was no difference in LBGI (P = 0.17).

Adults versus Adolescents The sCTR study included adolescents with worse control of diabetes as shown by their HbA1c levels and time in near normoglycemia (69.5 ± 4.6 vs. 50.2% ± 9.7, t test P = 0.047); no other significant differences were observed. In terms of system performance, we applied ANOVA analysis with open loop, as covariate for time in near normoglycemia, and tight control range; hypoglycemia occurrences were compared using Mann-Whitney U test. sCTR time in near normoglycemia compared with CSII did not show a significant difference between adolescents and adults (CSII 50.2 to sCTR 65.1% vs. CSII 69.5 to sCTR 81.7%, P = 0.13), but time in tight glycemic control was increased in the adult population and not in adolescents (CSII 30.1 to sCTR 21.3% vs. CSII 38.6 to sCTR 50.1%, P = 0.008). No difference in the occurrence of hypoglycemia was observed (0.82 to 0.27 vs. 1.29 to 0.5 events/admission, P = 0.37).

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