Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes Assessed by Continuous Glucose Monitoring

Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes Assessed by... Abstract Context Recurrent hypoglycemia promotes impaired awareness, resulting in an increased risk for asymptomatic hypoglycemia. However, there are no firm data on the frequency of hypoglycemia in daily life needed to initiate this vicious cycle or the role of asymptomatic hypoglycemia. Objective To explore the association between hypoglycemic exposure and proportion of asymptomatic hypoglycemia and relation to risk for severe hypoglycemia. Design Prospective observational trial. Setting Outpatient clinic. Patients One hundred fifty-three unselected patients with type 1 diabetes mellitus (T1D). Intervention Six days of blinded continuous glucose monitoring and recording of hypoglycemia symptoms. Main Outcome Measure Proportion of asymptomatic hypoglycemic events (glucose level ≤70 mg/dL). Results Patients were grouped by the number of hypoglycemic events during the recording period (group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events), and fractions of asymptomatic events were calculated. Across the four groups, the fraction of asymptomatic hypoglycemia increased: 57% in group 1, 61% in group 2, 65% in group 3, and 80% in group 4 (P < 0.001). Higher fraction of asymptomatic hypoglycemia was positively associated with risk for severe hypoglycemia (incidence rate ratio, 1.3; 95% confidence interval, 1.1 to 1.5; P = 0.003). Group 4 consisted of patients characterized by classic risk factors of severe hypoglycemia (longer duration of diabetes, lower hemoglobin A1c, and more frequent impaired awareness of hypoglycemia). Conclusions Patients with T1D with hypoglycemic rates corresponding to daily exposure had an increased fraction of asymptomatic events, which was positively associated with risk for severe hypoglycemia; therefore, such patients deserve particular attention in clinical practice. Hypoglycemia is the main side effect of insulin therapy and can be disruptive and life-threatening in the daily life of persons with type 1 diabetes (T1D). Hypoglycemia can be classified as symptomatic or asymptomatic (silent) according to presence of warning symptoms. Furthermore, episodes of hypoglycemia are classified as severe if the patient needs assistance from another person to restore glucose levels to normal (1). In T1D, hormonal counter-regulatory responses to hypoglycemia are often impaired. The glucagon response usually becomes blunted in the years after diagnosis, and the catecholamine responses may be impaired along the course of disease, leading to counter-regulatory failure with reduced endogenous glucose production during hypoglycemia. Therefore, warning symptoms of hypoglycemia are important for patients to detect and self-treat, thereby avoiding severe hypoglycemia. Antecedent episodes of hypoglycemia are known to blunt the catecholamine and symptomatic responses to hypoglycemia at subsequent episodes (2, 3). Thus, recurrent hypoglycemia promotes the syndrome of impaired awareness of hypoglycemia with loss of warning symptoms in T1D. Impaired awareness of hypoglycemia is, in turn, known to increase the risk for severe hypoglycemia (4, 5). It is presumed that asymptomatic hypoglycemia is also implicated in this vicious cycle of recurrent hypoglycemia leading to impaired awareness (6), but the exact manner by which events of asymptomatic hypoglycemia contribute to the cycle and the pathogenesis of impaired awareness is unclear. Asymptomatic hypoglycemia seems to be an important component in the syndrome of impaired awareness of hypoglycemia, as supported by two studies reporting that patients with impaired hypoglycemia awareness have the same frequency of mild symptomatic hypoglycemia but a higher rate of both asymptomatic hypoglycemia and severe hypoglycemia than patients with normal hypoglycemia awareness (7, 8). However, there are no firm data on the frequency of daily-life hypoglycemia needed to initiate this cycle or on the exact role of asymptomatic hypoglycemia. Therefore, using continuous glucose monitoring (CGM), we performed this study to investigate (1) the association between rate of hypoglycemic exposure and proportion of asymptomatic hypoglycemic events, (2) the association between the proportion of asymptomatic hypoglycemia and state of hypoglycemia awareness, and (3) the association between the proportion of asymptomatic hypoglycemia and the risk for severe hypoglycemia in T1D. Materials and Methods Participants A cohort of patients with T1D attending the diabetes outpatient clinic at Nordsjællands Hospital in Hillerød, Denmark, was recruited. All included participants were adults (age >18 years) with T1D for ≥1 year. Patients with end-stage renal disease, concomitant malignant disease, or pregnancy were excluded from participation in the study. The study was approved by the Regional Committee on Biomedical Research Ethics (H-15002715) and the Danish Data Protection Agency, and written informed consent was obtained from all participants before they entered the study. Participants filled in a detailed questionnaire regarding self-estimated state of awareness according to the methods of Gold et al. (8), Clarke et al. (9), and Pedersen-Bjergaard et al. (10), which are all validated methods for assessment of hypoglycemia awareness (11). Furthermore, number of events of severe hypoglycemia in the preceding year was reported and defined as events with need of assistance from another person to actively restore glucose level to normal (1). Information about participants’ history of diabetes, treatment, and late diabetic complications were also requested or extracted from the participants’ medical records as appropriate. Hemoglobin A1c (HbA1c; Tosoh G8 HPLC Analyzer; Tosoh Bioscience Inc., San Francisco, CA) and C-peptide (Advia Centaur XP; Siemens Medical Solutions Diagnostics Inc., Los Angeles, CA) were measured, and participants with undetectable C-peptide levels (<20 pmol/L) were classified as C-peptide–negative. Study setting All participants underwent 6 days of blinded continuous interstitial glucose (IG) monitoring. The CGM system used in this study was iPro®2 CGMs using Enlite™ Glucose Sensors (Medtronic MiniMed, Northridge, CA) [overall mean absolute relative difference of 13.9% and 18.4% in the hypoglycemic range; sensitivity of 79.5% and positive predictive value of 83.8% for hypoglycemia (12)]. The CGMs were calibrated with blood glucose meter measurements (Contour®XT meter using Contour®NEXT test strips; Bayer, Basel, Switzerland) as recommended by the manufacturer (four times daily). While the monitoring was performed, participants carried out their daily life and treatment of diabetes as usual. During the monitoring period, the participants were instructed to fill in a diary about symptoms of hypoglycemia. We classified hypoglycemia as IG concentration below two threshold glucose values: ≤70 mg/dL [3.9 mmol/L (IG70)] and ≤54 mg/dL [3.0 mmol/L (IG54)] for ≥15 minutes (13–15) and recovery when the IG concentration had been continuously above the threshold for ≥20 minutes (13, 14). Asymptomatic hypoglycemia was defined as an event of hypoglycemia without self-reported symptoms of hypoglycemia in the diary. Statistical analyses Because this was an exploratory study, no power calculation was made. Standard descriptive statistics were used to characterize participants. In those cases in which the distribution of data was skewed, medians and ranges are presented in addition to means and standard deviations. The participants were grouped by number of hypoglycemic events during the recording period: group 0, no events; group 1, one event; group 2, two to three events; group 3, four to six events; group 4: seven or more events. Fraction of asymptomatic events was calculated in each group, and parametric (χ2 test and t test) and nonparametric (Mann-Whitney or Kruskal-Wallis test) statistics were used to compare groups as appropriate. Participants with no events (group 0) were excluded from the analyses. We used the generalized estimating equation to assess the influence of risk factors on the risk for hypoglycemia so we could take into account patients who experienced more than one episode of hypoglycemia during the recording period. The logarithm of the recording period was used as offset in the model. A log-linear negative binomial regression model was used because this model takes into account the skewed distribution of episodes of hypoglycemia. The factors included in the analyses were fraction of asymptomatic hypoglycemia (per 10% increase), awareness of hypoglycemia, age (per 1-year increment), sex, C-peptide status, duration of diabetes (per 10 years), and HbA1c (per 10 mmol/mol). We used the SPSS software package, version 22.0 (IBM, Armonk, NY) to analyses, and level of statistical significance was chosen as a P < 0.05 (two-sided). Results Participant characteristics are shown in Table 1. Data on CGM recording were obtained from all 153 participants, and the total duration of recording was 22,621 hours, resulting in 22,500 hours of valid recording (99.5%) corresponding to 6.1 ± 0.9 (mean ± standard deviation) days of recording/participant. Table 1. Baseline Participant Characteristics Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Values are expressed as mean ± standard deviation, median (range), or number (percentage). Abbreviations: CSII, continuous subcutaneous insulin infusion; DCCT, Diabetes Control and Complications Trial; IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Table 1. Baseline Participant Characteristics Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Values are expressed as mean ± standard deviation, median (range), or number (percentage). Abbreviations: CSII, continuous subcutaneous insulin infusion; DCCT, Diabetes Control and Complications Trial; IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Fraction of asymptomatic hypoglycemia Threshold IG70 At threshold IG70, 767 events of hypoglycemia were recorded by the 153 participants, resulting in an overall rate of hypoglycemia of 5.8 ± 4.7 events/patient-week, which corresponds to 10.1 ± 11.3 (median, 6.1; range, 0 to 65) hours in hypoglycemia/patient-week. The incidence of asymptomatic hypoglycemia was 4.3 ± 4.2 events/patient-week, corresponding to 7.9 ± 10.4 (median, 3.8; range, 0 to 65) hours in asymptomatic hypoglycemia/patient-week. Of the 153 participants, 133 (87%) had at least one event of hypoglycemia during the recording period, and these 133 participants are included in the following analyses. The overall fraction of asymptomatic hypoglycemia was 68% at threshold IG70. Across the four groups (Table 2), the fraction of asymptomatic hypoglycemia increased: 57% in group 1, 61% in group 1, 65% in group 2, and 80% in group 4 (threshold IG70). Figure 1(a) displays the increase in rate of hypoglycemia from group 1 to group 4, separated by symptomatic and asymptomatic rates. Table 2. Participants With T1D per Number of Hypoglycemic Events (IG70 and IG54) Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. View Large Table 2. Participants With T1D per Number of Hypoglycemic Events (IG70 and IG54) Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. View Large Figure 1. View largeDownload slide Rates of asymptomatic and symptomatic hypoglycemia according to number of hypoglycemic events/patient-week in participants with type 1 diabetes. (a) 133 participants at threshold IG ≤ 70 mg/dL. (b) 106 participants at threshold IG ≤ 54 mg/dL. Participants with no events of hypoglycemia are excluded from the analyses. Dark gray circles: rate of asymptomatic hypoglycemia (events/patient-week); light gray squares: rate of symptomatic hypoglycemia (events/patient-week). SEM, standard error of the mean. Figure 1. View largeDownload slide Rates of asymptomatic and symptomatic hypoglycemia according to number of hypoglycemic events/patient-week in participants with type 1 diabetes. (a) 133 participants at threshold IG ≤ 70 mg/dL. (b) 106 participants at threshold IG ≤ 54 mg/dL. Participants with no events of hypoglycemia are excluded from the analyses. Dark gray circles: rate of asymptomatic hypoglycemia (events/patient-week); light gray squares: rate of symptomatic hypoglycemia (events/patient-week). SEM, standard error of the mean. In univariate analyses, possible conventional risk factors of severe hypoglycemia were not significantly associated with severe hypoglycemia in this study. However, a high fraction of asymptomatic hypoglycemia was positively associated with the rate of severe hypoglycemia in the preceding 1-year period [incidence rate ratio (IRR), 1.3; 95% confidence interval (CI), 1.1 to 1.5; P = 0.003), whereas a high fraction of symptomatic hypoglycemia was negatively associated with the rate of severe hypoglycemia in the preceding 1-year period (IRR, 0.8; 95% CI, 0.7 to 0.9; P = 0.003). Adjustment for hypoglycemia awareness in the analyses did not change the results. Threshold IG54 At threshold IG54, 319 events of hypoglycemia were recorded by the 153 participants, resulting in an overall rate of hypoglycemia of 2.4 ± 3.1 events/patient-week, which corresponds to 3.8 ± 6.5 (median, 1.2; range, 0 to 43) hours with hypoglycemia/patient-week. The incidence of asymptomatic hypoglycemia was 1.8 ± 2.7 events/patient-week, corresponding to 3.0 ± 6.0 (median, 0.4; range, 0 to 43) hours with asymptomatic hypoglycemia/patient-week. Of the 153 participants, 133 (87%) had at least one event of hypoglycemia during the recording period, and these 133 participants were included in the following analyses (IG54). At threshold IG54, the overall fraction of asymptomatic hypoglycemia was 71%. The fraction increased across the four groups: 64% in group 1, 70% in group 2, 75% in group 3, and 87% in group 4. Furthermore, the rate of asymptomatic episodes of hypoglycemia increased from 0.6 ± 0.8 asymptomatic episodes/patient-week in group 1 to 1.6 ± 1.0, 4.3 ± 1.8, and 8.9 ± 2.8 asymptomatic episodes/patient-week in groups 2, 3, and 4, respectively. The rate of symptomatic hypoglycemia increased less (rates of symptomatic hypoglycemia in groups 1, 2, 3, and 4 were 0.6, 1.0, 1.1, and 1.7 episodes/patient-week, respectively) [Fig. 1(b)]. Also at threshold IG54, there was a trend toward an association between higher fraction of asymptomatic hypoglycemia and increased risk for severe hypoglycemia, but it was not statistically significant (IRR, 1.1; 95% CI, 1.0 to 1.2; P = 0.076). Characteristics of group 4 vs groups 1 through 3 The characteristics of group 4 having hypoglycemic events (threshold IG70) on a daily basis were compared with the pooled data of groups 1 to 3 having less hypoglycemia and a lower proportion of asymptomatic hypoglycemia (Table 3). Group 4 consisted of participants with longer duration of diabetes, lower HbA1c, and more frequently impaired awareness of hypoglycemia (assessed by the Hillerød and Clarke methods but not by the Gold method) as compared with groups 1 to 3. Age, sex, diabetes complications, and the proportion of C-peptide–negative participants did not differ between groups 1 through 3 and group 4. Table 3. Comparison of Groups 1 Through 3 With Group 4 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. Abbreviation: IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Table 3. Comparison of Groups 1 Through 3 With Group 4 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. Abbreviation: IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Fraction of asymptomatic hypoglycemia and state of awareness of hypoglycemia At threshold IG70, the fraction of asymptomatic hypoglycemia was higher in participants with impaired awareness and unawareness than in participants with normal awareness assessed by the Hillerød method [aware/impaired/unaware (percentage asymptomatic hypoglycemia): 63%/69%/90%; P = 0.01]. When the method of Clarke to assess state of awareness, we also found a higher fraction of asymptomatic hypoglycemia in participants with reduced awareness as compared with aware participants [aware/reduced awareness (percentage asymptomatic hypoglycemia): 63%/85%; P = 0.01], but not when using the Gold et al. method [aware/impaired awareness (percentage asymptomatic hypoglycemia): 67%/74%; P = 0.25]. As shown in Fig. 2, the overall rate of hypoglycemia tended to increase slightly but insignificantly (Hillerød method: P = 0.06; Gold method: P = 0.4; Clarke method: P = 0.1) with decreasing state of awareness. With decreasing awareness, the rate of asymptomatic hypoglycemia increased significantly as assessed by the Hillerød and Clarke methods (Hillerød method: P = 0.04; Gold method: P = 0.3; Clarke method: P = 0.01) and the rate of symptomatic hypoglycemia decreased according to the Hillerød method but not when assessed by the Clarke and Gold methods (Hillerød method: P = 0.03; Gold method: P = 0.4; Clarke method: P = 0.2). Figure 2. View largeDownload slide Rate of asymptomatic and symptomatic hypoglycemia in 153 participants with type 1 diabetes according to state of awareness assessed by three methods: Pedersen-Bjergaard et al. (10), Gold et al. (8), and Clarke et al. (9) (threshold IG ≤ 70 mg/dL). Figure 2. View largeDownload slide Rate of asymptomatic and symptomatic hypoglycemia in 153 participants with type 1 diabetes according to state of awareness assessed by three methods: Pedersen-Bjergaard et al. (10), Gold et al. (8), and Clarke et al. (9) (threshold IG ≤ 70 mg/dL). Discussion In a cohort of people with T1D, we found that three quarters of all episodes of hypoglycemia were asymptomatic. This finding supports findings in earlier studies in children and adolescents (16, 17). To examine the association between the total occurrence of hypoglycemic events and the proportion of asymptomatic hypoglycemia, we subdivided the participants into four groups according to total number of hypoglycemic events during the recording period (excluding the 13% of the participants with no hypoglycemic episodes during the observation period of ∼6 d/participant). The participants with a hypoglycemic rate corresponding to daily exposure to hypoglycemia (group 4) had a fraction of asymptomatic hypoglycemia of 80%, which is considerably higher than that in participants with less frequent hypoglycemic events. This is consistent with earlier studies showing that antecedent hypoglycemia blunts the response to subsequent episodes of hypoglycemia during the next 24 hours (3) but no longer (18). These participants with daily exposure to hypoglycemia were characterized by longer duration of diabetes, lower HbA1c, and more frequent impaired awareness of hypoglycemia than participants with a rate of hypoglycemia corresponding to less than daily exposure, which are factors known to imply a risk of hypoglycemia (5, 13, 19, 20). The increasing rate of hypoglycemia in the four groups was largely due to an increase in number of asymptomatic events of hypoglycemia rather than of symptomatic events. Thus, when the participants are exposed to hypoglycemia on a daily basis, the rate and fraction of asymptomatic hypoglycemia increase markedly, whereas the rate and fraction of symptomatic episodes are almost unchanged. This is consistent with our finding of an increasing proportion of asymptomatic hypoglycemia with decreasing awareness of hypoglycemia. Almost all (90%) of the hypoglycemic events were asymptomatic in participants with unawareness. Such a high proportion of asymptomatic hypoglycemia in patients with reduced awareness is of concern and supports our finding that higher fraction of asymptomatic hypoglycemia is the only significant predictor of severe hypoglycemia independent of state of hypoglycemia awareness. However, the lack of other significant risk factors of severe hypoglycemia could be explained by the low rate of severe hypoglycemia, thereby possibly making our cohort a low-risk cohort and making it difficult to assess the potential risk factors with sufficient statistical power. In a clinical setting, the positive association between higher proportion of asymptomatic hypoglycemia and risk for severe hypoglycemia raises the possibility of assessing patients’ risk for severe hypoglycemia by determining the patients’ proportion of asymptomatic hypoglycemia with CGM. The positive association was found at threshold IG70, which may indicate that hypoglycemia defined at this threshold also contributes to the vicious cycle of recurrent hypoglycemia and impaired awareness as well as the clinically important events of hypoglycemia, recently redefined as glucose values <54 mg/dL (15). Our findings are in line with two previous studies exploring the relationship between state of hypoglycemia awareness and the frequency of symptomatic and asymptomatic hypoglycemia (7, 8). Both studies used open daytime self-monitored blood glucose to determining the rate of hypoglycemia and found that the frequency of asymptomatic hypoglycemia was fourfold (8) and sevenfold (7) higher in persons with T1D and impaired awareness as compared with persons with normal awareness at threshold IG54. However, the frequency of symptomatic hypoglycemia was the same and not related to state of awareness (7). In our study applying blinded CGM, the total amount of hypoglycemia tended to increase slightly as state of awareness decreased, but the increase was not statistically significant. However, the increase in proportion of asymptomatic hypoglycemia as state of awareness decreased was statistically significant and shows that it is an association. This is consistent with studies reporting decreased hormonal and symptomatic response to recurrent hypoglycemia (2, 3). However, it remains to be shown whether the association is causal. In conclusion, persons with T1D with hypoglycemic rates corresponding to daily exposure to hypoglycemia have an increased fraction of asymptomatic events. These persons are also at increased risk for severe hypoglycemia and are characterized by presence of multiple risk factors for severe hypoglycemia. The proportion of asymptomatic hypoglycemia events increases as hypoglycemia awareness decreases; however, the overall rate of hypoglycemia only tends to increase slightly as awareness decreases. In clinical practice, these persons at high risk for hypoglycemia deserve particular attention and efforts to reduce the frequency and fraction of asymptomatic hypoglycemia because such episodes may contribute to the vicious cycle of recurrent hypoglycemia leading to impaired awareness and a greater risk for severe hypoglycemia in T1D. Abbreviations: Abbreviations: CGM continuous glucose monitoring CI confidence interval HbA1c hemoglobin A1c IG interstitial glucose IG54 interstitial glucose values ≤54 mg/dL IG70 interstitial glucose values ≤70 mg/dL IRR incidence rate ratio T1D type 1 diabetes mellitus Acknowledgments The authors thank the participants and the staff at the research unit at Nordsjællands Hospital for their important contributions. Financial Support: This work was supported in part by unrestricted research grants from Nordsjællands Hospital, Denmark (M.M.H.), the Danish Medical Research Grant (M.M.H.), and Toyota-Fonden, Denmark (M.M.H.). Author Contributions: All authors participated in the study design. M.M.H. acquired and analyzed the data, wrote and revised the manuscript, and contributed to the discussion. H.U.A., B.T., and U.P.-B. reviewed and edited the manuscript and contributed to the discussion. Disclosure Summary: H.U.A. owns stocks in Novo Nordisk and is on advisory boards for Novo Nordisk and Astra Zeneca. U.P.-B. has served on advisory boards for AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, and Novo Nordisk and has received lecture fees from AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, and Novo Nordisk. The remaining authors have nothing to disclose. References 1. Seaquist ER , Anderson J , Childs B , Cryer P , Dagogo-Jack S , Fish L , Heller SR , Rodriguez H , Rosenzweig J , Vigersky R . Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society . Diabetes Care . 2013 ; 36 ( 5 ): 1384 – 1395 . Google Scholar CrossRef Search ADS PubMed 2. Veneman T , Mitrakou A , Mokan M , Cryer P , Gerich J . Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia . Diabetes . 1993 ; 42 ( 9 ): 1233 – 1237 . Google Scholar CrossRef Search ADS PubMed 3. Dagogo-Jack SE , Craft S , Cryer PE . Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia . J Clin Invest . 1993 ; 91 ( 3 ): 819 – 828 . Google Scholar CrossRef Search ADS PubMed 4. ter Braak EW , Appelman AM , van de Laak M , Stolk RP , van Haeften TW , Erkelens DW . Clinical characteristics of type 1 diabetic patients with and without severe hypoglycemia . Diabetes Care . 2000 ; 23 ( 10 ): 1467 – 1471 . Google Scholar CrossRef Search ADS PubMed 5. Pedersen-Bjergaard U , Pramming S , Heller SR , Wallace TM , Rasmussen AK , Jørgensen HV , Matthews DR , Hougaard P , Thorsteinsson B . Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection . Diabetes Metab Res Rev . 2004 ; 20 ( 6 ): 479 – 486 . Google Scholar CrossRef Search ADS PubMed 6. Choudhary P , Geddes J , Freeman JV , Emery CJ , Heller SR , Frier BM . Frequency of biochemical hypoglycaemia in adults with type 1 diabetes with and without impaired awareness of hypoglycaemia: no identifiable differences using continuous glucose monitoring . Diabet Med . 2010 ; 27 ( 6 ): 666 – 672 . Google Scholar CrossRef Search ADS PubMed 7. Schopman JE , Geddes J , Frier BM . Frequency of symptomatic and asymptomatic hypoglycaemia in type 1 diabetes: effect of impaired awareness of hypoglycaemia . Diabet Med . 2011 ; 28 ( 3 ): 352 – 355 . Google Scholar PubMed 8. Gold AE , MacLeod KM , Frier BM . Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia . Diabetes Care . 1994 ; 17 ( 7 ): 697 – 703 . Google Scholar CrossRef Search ADS PubMed 9. Clarke WL , Cox DJ , Gonder-Frederick LA , Julian D , Schlundt D , Polonsky W . Reduced awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic frequency and associated symptoms . Diabetes Care . 1995 ; 18 ( 4 ): 517 – 522 . Google Scholar CrossRef Search ADS PubMed 10. Pedersen-Bjergaard U , Pramming S , Thorsteinsson B . Recall of severe hypoglycaemia and self-estimated state of awareness in type 1 diabetes . Diabetes Metab Res Rev . 2003 ; 19 ( 3 ): 232 – 240 . Google Scholar CrossRef Search ADS PubMed 11. Høi-Hansen T , Pedersen-Bjergaard U , Thorsteinsson B . Classification of hypoglycemia awareness in people with type 1 diabetes in clinical practice . J Diabetes Complications . 2010 ; 24 ( 6 ): 392 – 397 . Google Scholar CrossRef Search ADS PubMed 12. Keenan DB , Mastrototaro JJ , Zisser H , Cooper KA , Raghavendhar G , Lee SW , Yusi J , Bailey TS , Brazg RL , Shah RV . Accuracy of the Enlite 6-day glucose sensor with guardian and Veo calibration algorithms . Diabetes Technol Ther . 2012 ; 14 ( 3 ): 225 – 231 . Google Scholar CrossRef Search ADS PubMed 13. UK Hypoglycaemia Study Group . Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration . Diabetologia . 2007 ; 50 ( 6 ): 1140 – 1147 . CrossRef Search ADS PubMed 14. Bay C , Kristensen PL , Pedersen-Bjergaard U , Tarnow L , Thorsteinsson B . Nocturnal continuous glucose monitoring: accuracy and reliability of hypoglycemia detection in patients with type 1 diabetes at high risk of severe hypoglycemia . Diabetes Technol Ther . 2013 ; 15 ( 5 ): 371 – 377 . Google Scholar CrossRef Search ADS PubMed 15. International Hypoglycaemia Study Group . Glucose concentrations of less than 3.0 mmol/l (54 mg/dl) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes . Diabetologia [ published correction appears in Diabetologia. 2017;60(2):377 ]. 2017 ; 60 ( 1 ): 3 – 6 . CrossRef Search ADS PubMed 16. Wiltshire EJ , Newton K , McTavish L . Unrecognised hypoglycaemia in children and adolescents with type 1 diabetes using the continuous glucose monitoring system: prevalence and contributors . J Paediatr Child Health . 2006 ; 42 ( 12 ): 758 – 763 . Google Scholar CrossRef Search ADS PubMed 17. Boland E , Monsod T , Delucia M , Brandt CA , Fernando S , Tamborlane WV . Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes . Diabetes Care . 2001 ; 24 ( 11 ): 1858 – 1862 . Google Scholar CrossRef Search ADS PubMed 18. George E , Marques JL , Harris ND , Macdonald IA , Hardisty CA , Heller SR . Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM . Diabetes Care . 1997 ; 20 ( 8 ): 1293 – 1298 . Google Scholar CrossRef Search ADS PubMed 19. The Diabetes Control and Complications Trial Research Group . Hypoglycemia in the Diabetes Control and Complications Trial . Diabetes . 1997 ; 46 ( 2 ): 271 – 286 . CrossRef Search ADS PubMed 20. Pedersen-Bjergaard U , Agerholm-Larsen B , Pramming S , Hougaard P , Thorsteinsson B . Activity of angiotensin-converting enzyme and risk of severe hypoglycaemia in type 1 diabetes mellitus . Lancet . 2001 ; 357 ( 9264 ): 1248 – 1253 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Clinical Endocrinology and Metabolism Oxford University Press

Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes Assessed by Continuous Glucose Monitoring

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Endocrine Society
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Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
D.O.I.
10.1210/jc.2018-00142
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Abstract

Abstract Context Recurrent hypoglycemia promotes impaired awareness, resulting in an increased risk for asymptomatic hypoglycemia. However, there are no firm data on the frequency of hypoglycemia in daily life needed to initiate this vicious cycle or the role of asymptomatic hypoglycemia. Objective To explore the association between hypoglycemic exposure and proportion of asymptomatic hypoglycemia and relation to risk for severe hypoglycemia. Design Prospective observational trial. Setting Outpatient clinic. Patients One hundred fifty-three unselected patients with type 1 diabetes mellitus (T1D). Intervention Six days of blinded continuous glucose monitoring and recording of hypoglycemia symptoms. Main Outcome Measure Proportion of asymptomatic hypoglycemic events (glucose level ≤70 mg/dL). Results Patients were grouped by the number of hypoglycemic events during the recording period (group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events), and fractions of asymptomatic events were calculated. Across the four groups, the fraction of asymptomatic hypoglycemia increased: 57% in group 1, 61% in group 2, 65% in group 3, and 80% in group 4 (P < 0.001). Higher fraction of asymptomatic hypoglycemia was positively associated with risk for severe hypoglycemia (incidence rate ratio, 1.3; 95% confidence interval, 1.1 to 1.5; P = 0.003). Group 4 consisted of patients characterized by classic risk factors of severe hypoglycemia (longer duration of diabetes, lower hemoglobin A1c, and more frequent impaired awareness of hypoglycemia). Conclusions Patients with T1D with hypoglycemic rates corresponding to daily exposure had an increased fraction of asymptomatic events, which was positively associated with risk for severe hypoglycemia; therefore, such patients deserve particular attention in clinical practice. Hypoglycemia is the main side effect of insulin therapy and can be disruptive and life-threatening in the daily life of persons with type 1 diabetes (T1D). Hypoglycemia can be classified as symptomatic or asymptomatic (silent) according to presence of warning symptoms. Furthermore, episodes of hypoglycemia are classified as severe if the patient needs assistance from another person to restore glucose levels to normal (1). In T1D, hormonal counter-regulatory responses to hypoglycemia are often impaired. The glucagon response usually becomes blunted in the years after diagnosis, and the catecholamine responses may be impaired along the course of disease, leading to counter-regulatory failure with reduced endogenous glucose production during hypoglycemia. Therefore, warning symptoms of hypoglycemia are important for patients to detect and self-treat, thereby avoiding severe hypoglycemia. Antecedent episodes of hypoglycemia are known to blunt the catecholamine and symptomatic responses to hypoglycemia at subsequent episodes (2, 3). Thus, recurrent hypoglycemia promotes the syndrome of impaired awareness of hypoglycemia with loss of warning symptoms in T1D. Impaired awareness of hypoglycemia is, in turn, known to increase the risk for severe hypoglycemia (4, 5). It is presumed that asymptomatic hypoglycemia is also implicated in this vicious cycle of recurrent hypoglycemia leading to impaired awareness (6), but the exact manner by which events of asymptomatic hypoglycemia contribute to the cycle and the pathogenesis of impaired awareness is unclear. Asymptomatic hypoglycemia seems to be an important component in the syndrome of impaired awareness of hypoglycemia, as supported by two studies reporting that patients with impaired hypoglycemia awareness have the same frequency of mild symptomatic hypoglycemia but a higher rate of both asymptomatic hypoglycemia and severe hypoglycemia than patients with normal hypoglycemia awareness (7, 8). However, there are no firm data on the frequency of daily-life hypoglycemia needed to initiate this cycle or on the exact role of asymptomatic hypoglycemia. Therefore, using continuous glucose monitoring (CGM), we performed this study to investigate (1) the association between rate of hypoglycemic exposure and proportion of asymptomatic hypoglycemic events, (2) the association between the proportion of asymptomatic hypoglycemia and state of hypoglycemia awareness, and (3) the association between the proportion of asymptomatic hypoglycemia and the risk for severe hypoglycemia in T1D. Materials and Methods Participants A cohort of patients with T1D attending the diabetes outpatient clinic at Nordsjællands Hospital in Hillerød, Denmark, was recruited. All included participants were adults (age >18 years) with T1D for ≥1 year. Patients with end-stage renal disease, concomitant malignant disease, or pregnancy were excluded from participation in the study. The study was approved by the Regional Committee on Biomedical Research Ethics (H-15002715) and the Danish Data Protection Agency, and written informed consent was obtained from all participants before they entered the study. Participants filled in a detailed questionnaire regarding self-estimated state of awareness according to the methods of Gold et al. (8), Clarke et al. (9), and Pedersen-Bjergaard et al. (10), which are all validated methods for assessment of hypoglycemia awareness (11). Furthermore, number of events of severe hypoglycemia in the preceding year was reported and defined as events with need of assistance from another person to actively restore glucose level to normal (1). Information about participants’ history of diabetes, treatment, and late diabetic complications were also requested or extracted from the participants’ medical records as appropriate. Hemoglobin A1c (HbA1c; Tosoh G8 HPLC Analyzer; Tosoh Bioscience Inc., San Francisco, CA) and C-peptide (Advia Centaur XP; Siemens Medical Solutions Diagnostics Inc., Los Angeles, CA) were measured, and participants with undetectable C-peptide levels (<20 pmol/L) were classified as C-peptide–negative. Study setting All participants underwent 6 days of blinded continuous interstitial glucose (IG) monitoring. The CGM system used in this study was iPro®2 CGMs using Enlite™ Glucose Sensors (Medtronic MiniMed, Northridge, CA) [overall mean absolute relative difference of 13.9% and 18.4% in the hypoglycemic range; sensitivity of 79.5% and positive predictive value of 83.8% for hypoglycemia (12)]. The CGMs were calibrated with blood glucose meter measurements (Contour®XT meter using Contour®NEXT test strips; Bayer, Basel, Switzerland) as recommended by the manufacturer (four times daily). While the monitoring was performed, participants carried out their daily life and treatment of diabetes as usual. During the monitoring period, the participants were instructed to fill in a diary about symptoms of hypoglycemia. We classified hypoglycemia as IG concentration below two threshold glucose values: ≤70 mg/dL [3.9 mmol/L (IG70)] and ≤54 mg/dL [3.0 mmol/L (IG54)] for ≥15 minutes (13–15) and recovery when the IG concentration had been continuously above the threshold for ≥20 minutes (13, 14). Asymptomatic hypoglycemia was defined as an event of hypoglycemia without self-reported symptoms of hypoglycemia in the diary. Statistical analyses Because this was an exploratory study, no power calculation was made. Standard descriptive statistics were used to characterize participants. In those cases in which the distribution of data was skewed, medians and ranges are presented in addition to means and standard deviations. The participants were grouped by number of hypoglycemic events during the recording period: group 0, no events; group 1, one event; group 2, two to three events; group 3, four to six events; group 4: seven or more events. Fraction of asymptomatic events was calculated in each group, and parametric (χ2 test and t test) and nonparametric (Mann-Whitney or Kruskal-Wallis test) statistics were used to compare groups as appropriate. Participants with no events (group 0) were excluded from the analyses. We used the generalized estimating equation to assess the influence of risk factors on the risk for hypoglycemia so we could take into account patients who experienced more than one episode of hypoglycemia during the recording period. The logarithm of the recording period was used as offset in the model. A log-linear negative binomial regression model was used because this model takes into account the skewed distribution of episodes of hypoglycemia. The factors included in the analyses were fraction of asymptomatic hypoglycemia (per 10% increase), awareness of hypoglycemia, age (per 1-year increment), sex, C-peptide status, duration of diabetes (per 10 years), and HbA1c (per 10 mmol/mol). We used the SPSS software package, version 22.0 (IBM, Armonk, NY) to analyses, and level of statistical significance was chosen as a P < 0.05 (two-sided). Results Participant characteristics are shown in Table 1. Data on CGM recording were obtained from all 153 participants, and the total duration of recording was 22,621 hours, resulting in 22,500 hours of valid recording (99.5%) corresponding to 6.1 ± 0.9 (mean ± standard deviation) days of recording/participant. Table 1. Baseline Participant Characteristics Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Values are expressed as mean ± standard deviation, median (range), or number (percentage). Abbreviations: CSII, continuous subcutaneous insulin infusion; DCCT, Diabetes Control and Complications Trial; IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Table 1. Baseline Participant Characteristics Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Characteristic Total Patients Patients With ≥1 Hypoglycemic Event Participants, n 153 133 Sex, men, n (%) 90 (59) 78 (59) Age, y 52 ± 14 52 ± 14 Duration of diabetes, y 22 ± 15 23 ± 15 C-peptide–negativea, n (%) 108 (71) 100 (75) Body mass index, kg/m2 26 ± 4 26 ± 4 Total insulin dose, U/d 47 ± 22 48 ± 22 Insulin therapy, n (%)  Analogs 123 (80) 109 (82)  Analog/human 22 (15) 20 (15)  Human 8 (5) 4 (3) Insulin treatment regimens, n (%)  1–3 daily injections 6 (4) 5 (4)  ≥4 daily injections 117 (76) 101 (76) CSII 30 (20) 27 (20) HbA1c  Per DCCT, % 8.0 ± 1.1 7.9 ± 1.1  Per IFCC, mmol/mol 64 ± 12 63 ± 12 Awareness, %  Gold et al. (8) (aware/reduced awareness) 80/20 80/20  Clarke et al. (9) (aware/unclassified/reduced awareness) 72/13/15 73/12/15  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 47/39/14 46/42/12 Events of severe hypoglycemia (per patient: last year) 0.3 ± 1.0 0.3 ± 1.0 0 (0–8) 0 (0–8) Events of mild hypoglycemia (per patient: last week) 1.9 ± 2.5 2.1 ± 2.6 1 (0–16) 1 (0–16) Values are expressed as mean ± standard deviation, median (range), or number (percentage). Abbreviations: CSII, continuous subcutaneous insulin infusion; DCCT, Diabetes Control and Complications Trial; IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Fraction of asymptomatic hypoglycemia Threshold IG70 At threshold IG70, 767 events of hypoglycemia were recorded by the 153 participants, resulting in an overall rate of hypoglycemia of 5.8 ± 4.7 events/patient-week, which corresponds to 10.1 ± 11.3 (median, 6.1; range, 0 to 65) hours in hypoglycemia/patient-week. The incidence of asymptomatic hypoglycemia was 4.3 ± 4.2 events/patient-week, corresponding to 7.9 ± 10.4 (median, 3.8; range, 0 to 65) hours in asymptomatic hypoglycemia/patient-week. Of the 153 participants, 133 (87%) had at least one event of hypoglycemia during the recording period, and these 133 participants are included in the following analyses. The overall fraction of asymptomatic hypoglycemia was 68% at threshold IG70. Across the four groups (Table 2), the fraction of asymptomatic hypoglycemia increased: 57% in group 1, 61% in group 1, 65% in group 2, and 80% in group 4 (threshold IG70). Figure 1(a) displays the increase in rate of hypoglycemia from group 1 to group 4, separated by symptomatic and asymptomatic rates. Table 2. Participants With T1D per Number of Hypoglycemic Events (IG70 and IG54) Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. View Large Table 2. Participants With T1D per Number of Hypoglycemic Events (IG70 and IG54) Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Variable Group 1 Group 2 Group 3 Group 4 IG70 Participants, n 21 28 31 53 No. of hypoglycemic events  Asymptomatic 12 42 100 417  Symptomatic 9 27 55 105 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.6 2.1 ± 1.5 3.9 ± 2.6 8.8 ± 3.4  Symptomatic 0.5 ± 0.6 1.2 ± 1.1 2.1 ± 1.7 2.2 ± 2.1 Fraction of asymptomatic hypoglycemia, % 57 61 65 80 IG54  Participants, n 40 35 19 12  No. of hypoglycemic events   Asymptomatic 19 50 68 95   Symptomatic 21 32 17 17 Rate (events/patient-week)  Asymptomatic 0.6 ± 0.8 1.6 ± 1.0 4.3 ± 1.8 8.9 ± 2.8  Symptomatic 0.6 ± 0.6 1.0 ± 0.9 1.1 ± 1.0 1.7 ± 2.4 Fraction of asymptomatic hypoglycemia, n 64 70 75 87 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. View Large Figure 1. View largeDownload slide Rates of asymptomatic and symptomatic hypoglycemia according to number of hypoglycemic events/patient-week in participants with type 1 diabetes. (a) 133 participants at threshold IG ≤ 70 mg/dL. (b) 106 participants at threshold IG ≤ 54 mg/dL. Participants with no events of hypoglycemia are excluded from the analyses. Dark gray circles: rate of asymptomatic hypoglycemia (events/patient-week); light gray squares: rate of symptomatic hypoglycemia (events/patient-week). SEM, standard error of the mean. Figure 1. View largeDownload slide Rates of asymptomatic and symptomatic hypoglycemia according to number of hypoglycemic events/patient-week in participants with type 1 diabetes. (a) 133 participants at threshold IG ≤ 70 mg/dL. (b) 106 participants at threshold IG ≤ 54 mg/dL. Participants with no events of hypoglycemia are excluded from the analyses. Dark gray circles: rate of asymptomatic hypoglycemia (events/patient-week); light gray squares: rate of symptomatic hypoglycemia (events/patient-week). SEM, standard error of the mean. In univariate analyses, possible conventional risk factors of severe hypoglycemia were not significantly associated with severe hypoglycemia in this study. However, a high fraction of asymptomatic hypoglycemia was positively associated with the rate of severe hypoglycemia in the preceding 1-year period [incidence rate ratio (IRR), 1.3; 95% confidence interval (CI), 1.1 to 1.5; P = 0.003), whereas a high fraction of symptomatic hypoglycemia was negatively associated with the rate of severe hypoglycemia in the preceding 1-year period (IRR, 0.8; 95% CI, 0.7 to 0.9; P = 0.003). Adjustment for hypoglycemia awareness in the analyses did not change the results. Threshold IG54 At threshold IG54, 319 events of hypoglycemia were recorded by the 153 participants, resulting in an overall rate of hypoglycemia of 2.4 ± 3.1 events/patient-week, which corresponds to 3.8 ± 6.5 (median, 1.2; range, 0 to 43) hours with hypoglycemia/patient-week. The incidence of asymptomatic hypoglycemia was 1.8 ± 2.7 events/patient-week, corresponding to 3.0 ± 6.0 (median, 0.4; range, 0 to 43) hours with asymptomatic hypoglycemia/patient-week. Of the 153 participants, 133 (87%) had at least one event of hypoglycemia during the recording period, and these 133 participants were included in the following analyses (IG54). At threshold IG54, the overall fraction of asymptomatic hypoglycemia was 71%. The fraction increased across the four groups: 64% in group 1, 70% in group 2, 75% in group 3, and 87% in group 4. Furthermore, the rate of asymptomatic episodes of hypoglycemia increased from 0.6 ± 0.8 asymptomatic episodes/patient-week in group 1 to 1.6 ± 1.0, 4.3 ± 1.8, and 8.9 ± 2.8 asymptomatic episodes/patient-week in groups 2, 3, and 4, respectively. The rate of symptomatic hypoglycemia increased less (rates of symptomatic hypoglycemia in groups 1, 2, 3, and 4 were 0.6, 1.0, 1.1, and 1.7 episodes/patient-week, respectively) [Fig. 1(b)]. Also at threshold IG54, there was a trend toward an association between higher fraction of asymptomatic hypoglycemia and increased risk for severe hypoglycemia, but it was not statistically significant (IRR, 1.1; 95% CI, 1.0 to 1.2; P = 0.076). Characteristics of group 4 vs groups 1 through 3 The characteristics of group 4 having hypoglycemic events (threshold IG70) on a daily basis were compared with the pooled data of groups 1 to 3 having less hypoglycemia and a lower proportion of asymptomatic hypoglycemia (Table 3). Group 4 consisted of participants with longer duration of diabetes, lower HbA1c, and more frequently impaired awareness of hypoglycemia (assessed by the Hillerød and Clarke methods but not by the Gold method) as compared with groups 1 to 3. Age, sex, diabetes complications, and the proportion of C-peptide–negative participants did not differ between groups 1 through 3 and group 4. Table 3. Comparison of Groups 1 Through 3 With Group 4 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. Abbreviation: IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Table 3. Comparison of Groups 1 Through 3 With Group 4 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Variable Groups 1–3 Group 4 P Value Age, y 50 ± 14 54 ± 13 0.15 Men, % 60 57 0.70 Duration of diabetes, y 20 ± 14 28 ± 14 0.002 C-peptide–negativea, % 70 83 0.21 HbA1c (per IFCC), mmol/mol 65 ± 12 60 ± 10 0.01 Retinopathy, n (%) 36 (45) 30 (57) 0.21 Nephropathy, n (%) 10 (13) 6 (11) 1.00 Peripheral neuropathy, n (%) 25 (31) 22 (42) 0.20 Autonomic neuropathy, n (%) 5 (6) 6 (11) 0.30 Macrovascular complications, n (%) 7 (9) 7 (13) 0.41 Awareness, %  Pedersen-Bjergaard et al. (10) (aware/impaired/unaware) 54/38/8 32/49/19 0.02  Gold et al. (8) (aware/reduced awareness) 85/15 74/26 0.1  Clarke et al. (9) (aware/unclassified/reduced awareness) 83/10/7 56/16/28 0.001 Fraction of asymptomatic hypoglycemia, % 61 80 0.04 Values are mean ± standard deviation, number (percentage), or percentage. Group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events. Participants with no events are excluded from the analyses. Abbreviation: IFCC, International Federation of Clinical Chemistry. a Undetectable: <20 pmol/L. View Large Fraction of asymptomatic hypoglycemia and state of awareness of hypoglycemia At threshold IG70, the fraction of asymptomatic hypoglycemia was higher in participants with impaired awareness and unawareness than in participants with normal awareness assessed by the Hillerød method [aware/impaired/unaware (percentage asymptomatic hypoglycemia): 63%/69%/90%; P = 0.01]. When the method of Clarke to assess state of awareness, we also found a higher fraction of asymptomatic hypoglycemia in participants with reduced awareness as compared with aware participants [aware/reduced awareness (percentage asymptomatic hypoglycemia): 63%/85%; P = 0.01], but not when using the Gold et al. method [aware/impaired awareness (percentage asymptomatic hypoglycemia): 67%/74%; P = 0.25]. As shown in Fig. 2, the overall rate of hypoglycemia tended to increase slightly but insignificantly (Hillerød method: P = 0.06; Gold method: P = 0.4; Clarke method: P = 0.1) with decreasing state of awareness. With decreasing awareness, the rate of asymptomatic hypoglycemia increased significantly as assessed by the Hillerød and Clarke methods (Hillerød method: P = 0.04; Gold method: P = 0.3; Clarke method: P = 0.01) and the rate of symptomatic hypoglycemia decreased according to the Hillerød method but not when assessed by the Clarke and Gold methods (Hillerød method: P = 0.03; Gold method: P = 0.4; Clarke method: P = 0.2). Figure 2. View largeDownload slide Rate of asymptomatic and symptomatic hypoglycemia in 153 participants with type 1 diabetes according to state of awareness assessed by three methods: Pedersen-Bjergaard et al. (10), Gold et al. (8), and Clarke et al. (9) (threshold IG ≤ 70 mg/dL). Figure 2. View largeDownload slide Rate of asymptomatic and symptomatic hypoglycemia in 153 participants with type 1 diabetes according to state of awareness assessed by three methods: Pedersen-Bjergaard et al. (10), Gold et al. (8), and Clarke et al. (9) (threshold IG ≤ 70 mg/dL). Discussion In a cohort of people with T1D, we found that three quarters of all episodes of hypoglycemia were asymptomatic. This finding supports findings in earlier studies in children and adolescents (16, 17). To examine the association between the total occurrence of hypoglycemic events and the proportion of asymptomatic hypoglycemia, we subdivided the participants into four groups according to total number of hypoglycemic events during the recording period (excluding the 13% of the participants with no hypoglycemic episodes during the observation period of ∼6 d/participant). The participants with a hypoglycemic rate corresponding to daily exposure to hypoglycemia (group 4) had a fraction of asymptomatic hypoglycemia of 80%, which is considerably higher than that in participants with less frequent hypoglycemic events. This is consistent with earlier studies showing that antecedent hypoglycemia blunts the response to subsequent episodes of hypoglycemia during the next 24 hours (3) but no longer (18). These participants with daily exposure to hypoglycemia were characterized by longer duration of diabetes, lower HbA1c, and more frequent impaired awareness of hypoglycemia than participants with a rate of hypoglycemia corresponding to less than daily exposure, which are factors known to imply a risk of hypoglycemia (5, 13, 19, 20). The increasing rate of hypoglycemia in the four groups was largely due to an increase in number of asymptomatic events of hypoglycemia rather than of symptomatic events. Thus, when the participants are exposed to hypoglycemia on a daily basis, the rate and fraction of asymptomatic hypoglycemia increase markedly, whereas the rate and fraction of symptomatic episodes are almost unchanged. This is consistent with our finding of an increasing proportion of asymptomatic hypoglycemia with decreasing awareness of hypoglycemia. Almost all (90%) of the hypoglycemic events were asymptomatic in participants with unawareness. Such a high proportion of asymptomatic hypoglycemia in patients with reduced awareness is of concern and supports our finding that higher fraction of asymptomatic hypoglycemia is the only significant predictor of severe hypoglycemia independent of state of hypoglycemia awareness. However, the lack of other significant risk factors of severe hypoglycemia could be explained by the low rate of severe hypoglycemia, thereby possibly making our cohort a low-risk cohort and making it difficult to assess the potential risk factors with sufficient statistical power. In a clinical setting, the positive association between higher proportion of asymptomatic hypoglycemia and risk for severe hypoglycemia raises the possibility of assessing patients’ risk for severe hypoglycemia by determining the patients’ proportion of asymptomatic hypoglycemia with CGM. The positive association was found at threshold IG70, which may indicate that hypoglycemia defined at this threshold also contributes to the vicious cycle of recurrent hypoglycemia and impaired awareness as well as the clinically important events of hypoglycemia, recently redefined as glucose values <54 mg/dL (15). Our findings are in line with two previous studies exploring the relationship between state of hypoglycemia awareness and the frequency of symptomatic and asymptomatic hypoglycemia (7, 8). Both studies used open daytime self-monitored blood glucose to determining the rate of hypoglycemia and found that the frequency of asymptomatic hypoglycemia was fourfold (8) and sevenfold (7) higher in persons with T1D and impaired awareness as compared with persons with normal awareness at threshold IG54. However, the frequency of symptomatic hypoglycemia was the same and not related to state of awareness (7). In our study applying blinded CGM, the total amount of hypoglycemia tended to increase slightly as state of awareness decreased, but the increase was not statistically significant. However, the increase in proportion of asymptomatic hypoglycemia as state of awareness decreased was statistically significant and shows that it is an association. This is consistent with studies reporting decreased hormonal and symptomatic response to recurrent hypoglycemia (2, 3). However, it remains to be shown whether the association is causal. In conclusion, persons with T1D with hypoglycemic rates corresponding to daily exposure to hypoglycemia have an increased fraction of asymptomatic events. These persons are also at increased risk for severe hypoglycemia and are characterized by presence of multiple risk factors for severe hypoglycemia. The proportion of asymptomatic hypoglycemia events increases as hypoglycemia awareness decreases; however, the overall rate of hypoglycemia only tends to increase slightly as awareness decreases. In clinical practice, these persons at high risk for hypoglycemia deserve particular attention and efforts to reduce the frequency and fraction of asymptomatic hypoglycemia because such episodes may contribute to the vicious cycle of recurrent hypoglycemia leading to impaired awareness and a greater risk for severe hypoglycemia in T1D. Abbreviations: Abbreviations: CGM continuous glucose monitoring CI confidence interval HbA1c hemoglobin A1c IG interstitial glucose IG54 interstitial glucose values ≤54 mg/dL IG70 interstitial glucose values ≤70 mg/dL IRR incidence rate ratio T1D type 1 diabetes mellitus Acknowledgments The authors thank the participants and the staff at the research unit at Nordsjællands Hospital for their important contributions. Financial Support: This work was supported in part by unrestricted research grants from Nordsjællands Hospital, Denmark (M.M.H.), the Danish Medical Research Grant (M.M.H.), and Toyota-Fonden, Denmark (M.M.H.). Author Contributions: All authors participated in the study design. M.M.H. acquired and analyzed the data, wrote and revised the manuscript, and contributed to the discussion. H.U.A., B.T., and U.P.-B. reviewed and edited the manuscript and contributed to the discussion. 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Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Mar 29, 2018

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