Article

Hypoglycemia in People with Type 2 Diabetes and CKD

Iram Ahmad,1 Leila R. Zelnick ,2,3 Zona Batacchi ,2,4 Nicole Robinson,2 Ashveena Dighe,2,3
Jo-Anne E. Manski-Nankervis,5 John Furler,5 David N. O’Neal,6 Randie Little,7 Dace Trence,4 Irl B. Hirsch,4
Nisha Bansal,2,3 and Ian H. de Boer2,3,8

Abstract
Background and objectives Among people with diabetes mellitus, CKD may promote hypoglycemia through
altered clearance of glucose-lowering medications, decreased kidney gluconeogenesis, and blunted counter- 1
Division of
regulatory response. We conducted a prospective observational study of hypoglycemia among 105 individuals Endocrinology,
with type 2 diabetes treated with insulin or a sulfonylurea using continuous glucose monitors. Banner-MD Anderson
Cancer Center,
Design, setting, participants & measurements We enrolled 81 participants with CKD, defined as eGFR,60 ml/min Gilbert, Arizona;
2
per 1.73 m2, and 24 control participants with eGFR$60 ml/min per 1.73 m2 frequency-matched on age, duration of Kidney Research
Institute, 3Division of
diabetes, hemoglobin A1c, and glucose-lowering medications. Each participant wore a continuous glucose Nephrology, and
monitor for two 6-day periods. We examined rates of sustained level 1 hypoglycemia (,70 mg/dl) and level 2 4
Division of
hypoglycemia (,54 mg/dl) among participants with CKD. We then tested differences compared with control Metabolism,
participants as well as a second control population (n=73) using Poisson and linear regression, adjusting for age, Endocrinology, and
Nutrition, University
sex, and race. of Washington,
Seattle, Washington;
Results Over 890 total days of continuous glucose monitoring, participants with CKD were observed to have 5
Department of
255 episodes of level 1 hypoglycemia, of which 68 episodes reached level 2 hypoglycemia. Median rate of General Practice,
hypoglycemic episodes was 5.3 (interquartile range, 0.0–11.7) per 30 days and mean time spent in hypoglycemia University of
Melbourne, Carlton,
was 28 (SD 37) minutes per day. Hemoglobin A1c and the glucose management indicator were the main clinical Victoria, Australia;
correlates of time in hypoglycemia (adjusted differences 6 [95% confidence interval, 2 to 10] and 13 [95% confidence 6
Department of
interval, 7 to 20] fewer minutes per day per 1% higher hemoglobin A1c or glucose management indicator, Medicine, St Vincent’s
respectively). Compared with control populations, participants with CKD were not observed to have significant Hospital Melbourne,
University of
differences in time in hypoglycemia (adjusted differences 4 [95% confidence interval, 212 to 20] and 212 Melbourne, Fitzroy,
[95% confidence interval, 229 to 5] minutes per day). Victoria, Australia;
7
Department of
Conclusions Among people with type 2 diabetes and moderate to severe CKD, hypoglycemia was common, Pathology and
particularly with tighter glycemic control, but not significantly different from groups with similar clinical Anatomical Sciences,
University of Missouri,
characteristics and preserved eGFR. Columbia, Missouri;
CJASN 14: 844–853, 2019. doi: https://doi.org/10.2215/CJN.11650918 and 8Puget Sound
Veterans Affairs
Health Care System,
Seattle, Washington
Introduction wellbeing and self-care, and hypoglycemia can limit
Hypoglycemia is an important cause of morbidity and the implementation of intensive glycemic control, Correspondence: Dr.
mortality for people with diabetes mellitus. It causes which is the cornerstone of preventing diabetes com- Iram Ahmad, Division
symptoms related to the counter-regulatory response, of Endocrinology,
plications (1).
Banner-MD Anderson
including sympathetic activation, and leads to inca- CKD may increase the risk of hypoglycemia. With Cancer Center, 2940 E.
pacitation that requires assistance from others or reduced GFR, kidney gluconeogenesis and clearance Banner Gateway Drive,
causes accidents (1). Severe hypoglycemia is associated of insulin and other glucose-lowering medications are Gilbert, AZ, 85234.
with increased risks of cardiovascular events and reduced, and the counter-regulatory response to hy- Email: Iram.Ahmad@
bannerhealth.com
mortality (2–4), and asymptomatic hypoglycemia has poglycemia may be blunted (9–11). In the ACCORD
been associated with systemic inflammation and ox- trial, severe hypoglycemia requiring assistance was
idative stress (5–7). In the Action to Control Cardio- more common in participants with a lower eGFR or
vascular Risk in Diabetes (ACCORD) trial, participants higher urine albumin excretion (12), and the excess
with type 2 diabetes assigned to an intensive glycemic mortality observed when targeting intensive glycemic
target experienced higher rates of severe hypoglyce- control was most pronounced among participants with
mia and a higher mortality rate than those assigned CKD at baseline (13). CKD has also been associated
to a conventional glycemic target; although not with severe hypoglycemia in other studies (4,14), but
proven, many have speculated that hypoglycemia the full burden of hypoglycemia among people with
mediated this increased mortality (3,8). In addition, type 2 diabetes and CKD, including asymptomatic
fear of hypoglycemia can adversely affect patient episodes, is not well defined.

844 Copyright © 2019 by the American Society of Nephrology www.cjasn.org Vol 14 June, 2019
CJASN 14: 844–853, June, 2019
We conducted a prospective study to examine the
incidence and severity of hypoglycemia among people
with type 2 diabetes and moderate to severe CKD. The
study featured use of continuous glucose monitoring
(CGM) for up to 12 days per participant to detect all
episodes of hypoglycemia, including those that were
not clinically apparent, and quantify glycemic variabil-
ity, which correlates with risk of hypoglycemia (15). We
aimed to describe the occurrence of hypoglycemia in this
population and hypothesized that hypoglycemia was more
frequent in the target population than control populations
with type 2 diabetes and normal eGFR.
Materials and Methods
Study Design
The Continuous Glucose Monitoring to Assess Glycemia
in CKD (CANDY) study was a prospective, observational,
cohort study designed to examine hypoglycemia and
glycemic variability and to evaluate the performance of
biomarkers of mean glycemia among people with type
2 diabetes and moderate to severe CKD (Supplemental
Figure 1). Participants were enrolled between August 7,
2015 and July 12, 2017. Each participant wore a blinded
CGM device for two nonconsecutive 6-day periods sepa-
rated by approximately 2 weeks (to ensure that glycemia
was not influenced by transient environmental factors).
Clinical data were collected at the initial study visit, and
blood and spot urine samples were collected at the end of
each CGM period. Follow-up was concluded at the end of
the second CGM period. The study was approved by
Institutional Review Boards of the University of Washington
and the Puget Sound Veterans Affairs Health Care System,
and each participant granted written informed consent.
Deidentified data will be shared in accordance with policies
for human trial participants when mutually agreeable to
requestors and investigators.
Study Population
Participants were recruited from three health care sys-
tems in Seattle, Washington: the University of Washington
and associated clinics, Harborview Medical Center, and the
Puget Sound Veterans Affairs Health Care System. Patients
with a clinical diagnosis of type 2 diabetes treated with
sulfonylurea or insulin (agents known to cause hypogly-
cemia) were eligible. Exclusion criteria included age ,18
years, history of kidney transplant, dialysis treatment,
pregnancy, current use of clinical CGM, current therapy
for cancer or with erythropoietin, and inability to speak
English.
We first recruited participants with moderate to severe
CKD (eGFR of 6 to ,60 ml/min per 1.73 m2). We then
recruited CANDY control participants (with eGFR$60 ml/min
per 1.73 m2) from the same source population, frequency-
matching on the distributions of age, duration of diabetes,
hemoglobin A1c, and glucose-lowering medication use of
participants with CKD. Of the 149 consented, 105 completed
the study. Nine participants were found to meet exclu-
sion criteria after consent was obtained, 13 declined to
participate, and 17 were lost to follow-up. One participant
completed the study, but the data from the CGM was
insufficient for analysis.
Hypoglycemia in People with DM2 and CKD, Ahmad et al. 845
Participants in the INITIATION trial (Australian New Zealand
Clinical Trials Registry identifier: ACTRN12610000797077) with
eGFR$60 ml/min per 1.73 m2 were included as additional
controls to provide an additional comparator group that
used identical CGM devices. The INITIATION study was a
clinical trial of people with type 2 diabetes who initiated
insulin therapy for unsatisfactory glycemic control in Victoria,
Australia (16,17). Participants were randomly assigned to self-
monitored blood glucose or blinded CGM to guide insulin
titration. We used CGM data from the end of the INITIATION
trial (24 weeks after insulin initiation), when most participants
were taking insulin (as in the CANDY trial).
CGM
The Medtronic iPro2 Professional blinded CGM and Enlite
sensor (Medtronic, Northridge, CA) were used to monitor
glycemia. With this equipment, blood glucose concentrations
are calculated from interstitial glucose levels and recorded
every 5 minutes, with a detection range of 40–400 mg/dl.
Trained research coordinators placed each CGM device and
provided each participant with instructions regarding CGM
maintenance and care. Each participant was also provided
with a Freestyle Lite glucose meter (Abbott, Alameda, CA)
to check self-monitored fingerstick capillary blood glucose
at least twice a day to calibrate the CGM.
Study physicians evaluated each CGM report by hand
for quality control, excluding periods of time with evidence
of CGM malfunction or marked (.30%) dyssynchrony
between CGM and fingerstick glucose values. Participants
were blinded to all CGM data until they completed the
study, at which time CGM reports were provided to them
and their clinical provider. In 18 instances, a pattern of
recurrent severe hypoglycemia was identified after a par-
ticipant’s first CGM period, and results of that period were
disclosed to the participant and provider midway through
the study to promote safety.
Outcomes
Thresholds used to define level 1 (,70 mg/dl) and level 2
hypoglycemia (,54 mg/dl) were taken from an international
consensus on use of CGM (15). A discrete hypoglycemia
episode was declared only when three consecutive measure-
ments met the diagnostic threshold, and participants were not
considered at risk for a recurrent episode until three consec-
utive normal values $70 mg/dl were observed; alternative
definitions were explored in sensitivity analyses. Each hypo-
glycemia episode was confirmed by a study physician
through hand review of CGM data and participant logs.
Other glycemia metrics evaluated included time in range
(70–180 mg/dl), time in hypoglycemia (,70 mg/dl), time
above range (.180 mg/dl), coefficient of variation (SD
divided by mean of all CGM glucose concentrations, a
preferred metric of glycemic variability), SD and
interquartile range of all CGM glucose concentrations
(alternative variability metrics), and the glucose manage-
ment indicator (GMI) (a measure of mean blood glucose
calculated from all CGM glucose concentrations) (15,18).
Clinical Data
Race, ethnicity, education, general health, smoking, and
past medical history were defined by self-report. Medications
were inventoried with assistance from electronic health
846 CJASN
records. Many participants used multiple glucose-lowering
medications; all participants studied were required by
design to use insulin, a sulfonylurea, or both. Insulin usage
was categorized by type of insulin, frequency of dosing, and
duration of effect: long- or intermediate-acting only, mixed
insulin (a combination of intermediate- and short-acting
insulin), basal bolus (use of a long- or intermediate-acting
plus a separate short-acting insulin), or no insulin. The mean
of two eGFR measurements was calculated from creatinine
(measured at two separate study visits) traceable to isotope
dilution mass spectrometry (IDMS) using the CKD Epide-
miology Collaboration equation (19). Hemoglobin A1c was
measured by HPLC at the University of Missouri, conform-
ing to National Glycohemoglobin Standardization Program
(NGSP) standards, from whole blood collected at the end of
each CGM period; the mean of the two values was used for
analyses. During CGM, participants were asked to keep a log
of medication use, physical activity, and meals, although
logging was not strictly enforced and most logs appeared
incomplete.
Statistical Analyses
Incidence rates were calculated as number of events
divided by total valid observation time at risk, scaled to
episodes per 30 days. For times in, below, and above range,
each glucose concentration was presumed to count for
5 minutes. We graphically quantified the burden of hypogly-
cemia as the number of minutes during which hypoglycemia
occurred by time of day across participants. We compared
most hypoglycemia outcomes between CKD and control
groups via the two-sample t test, assuming nonequal
variance; differences in hypoglycemia rates between CKD
and controls were compared via Poisson regression. Correlates
of time below range were examined using linear regression
with robust Huber–White SEM, adjusting for age, sex,
and race. Differences in time below range and coefficient of
variation between groups were additionally adjusted for
mean CGM blood glucose. All analyses were performed
using the R statistical computing environment version
3.4.0. A two-tailed P value ,0.05 was taken as evidence of
statistical significance in all analyses.
Results
Participant Characteristics
The 81 analyzed participants with CKD had a mean (SD)
age of 69 (10) years, diabetes duration of 20 (11) years, body
mass index of 33.8 (5.7) kg/m2, eGFR of 38 (14) ml/min per
1.73 m2, and hemoglobin A1c of 7.7% (1.4%) (Table 1); 74%
were white, 51% had a college education, 89% used insulin
(mainly basal bolus regimens), 21% used sulfonylureas,
and 36% used other glucose-lowering medications (mainly
biguanides and GLP1 receptor agonists). In comparison,
CANDY control participants had overlapping but
slightly lower distributions of age and duration of diabetes
and a similar distribution of glucose-lowering medication
use (by design). Control subjects from the INITIATION
trial were younger (mean age 59 [SD 10] years), with a
shorter duration of diabetes (mean 10 [SD 6] years)
and more use of long-without short-acting insulin
(by INITIATION design), biguanides, and dipeptidyl
peptidase-4 inhibitors.
Hypoglycemia in CKD
Over 890 total days of CGM, participants with CKD were
observed to have 255 episodes of hypoglycemia, including
68 episodes of level 2 hypoglycemia (Table 2). None of
the 255 episodes were reported by participants to require
assistance from others—the definition used to define se-
vere hypoglycemia in many large studies. A representative
participant report of 6 days of CGM monitoring with three
episodes of hypoglycemia is shown in Figure 1.
Hypoglycemia was most frequent from 1 to 8 AM (Figure 2).
Mean duration of hypoglycemic episodes was 100 (SD 56)
minutes, and mean nadir glucose was 58 (SD 4) mg/dl. Median
rate of hypoglycemic episodes was 5.3 (interquartile range, 0.0–
11.7) per 30 days, and mean time spent in hypoglycemia was
28 (SD 37) minutes per day. When the number of consecutive
measurements required to define an episode ranged from 1 to
6, median rate of hypoglycemic episodes varied from 4.8 to
7.3 per 30 days (Supplemental Table 1). In additional sensi-
tivity analyses, hypoglycemia incidence rates and time in
hypoglycemia were similar to or lower than observed in
primary analyses when 17 participants using acetaminophen
or paracetamol were excluded or when the second observation
period was excluded for 18 participants who were informed of
CGM results after the first observation period (for safety
concerns) (Supplemental Tables 2 and 3).
Hemoglobin A1c and GMI were the main clinical correlates
of time in hypoglycemia. Each 1% higher hemoglobin A1c
was associated with 6 minutes less hypoglycemia per day,
and each 1% higher GMI was associated with 13 minutes less
hypoglycemia per day (Figure 3, Table 3). The correlation of
GMI with time in hypoglycemia (r=20.39; P,0.001) was
numerically stronger than that of hemoglobin A1c with time
in hypoglycemia (r=20.25; P=0.01). Older age, insulin dosage,
and usage of insulin were nominally associated with lower
coefficient of variation (Supplemental Table 4).
Comparisons by CKD Status
Hypoglycemia occurred most commonly during the
night for participants with and without CKD, although
CANDY participants with CKD appeared qualitatively to
have a stronger predominance of nighttime hypoglycemia
and less evening or postprandial hypoglycemia than
controls (Figure 2). Within the CANDY study, hypoglyce-
mia rates and other glycemia metrics were generally similar
for participants with and without CKD (Table 2), and
there was no clear relationship between eGFR and time in
hypoglycemia (Figure 3). For INITIATION control partic-
ipants, mean blood glucose concentration was lower,
unadjusted hypoglycemia rate and time in hypoglycemia
were higher, and time in hyperglycemia was lower than for
CANDY participants with CKD (Table 2). Adjusting for
mean CGM glucose, participants with CKD were not
observed to have significant differences in time in hypo-
glycemia: 4 (95% confidence interval [95% CI], 212 to 20)
minutes per day compared with CANDY controls, and 212
(95% CI, 229 to 5) minutes per day compared with
INITIATION controls. Similarly, adjusting for mean CGM
glucose, participants with CKD were not observed to have
significant differences in glucose coefficient of variation:
1.5% (95% CI, 21.6% to 4.6%) compared with CANDY
controls, and 21.1% (95% CI, 23.3% to 1.1%) mg/dl compared
with INITIATION controls.
CJASN 14: 844–853, June, 2019 Hypoglycemia in People with DM2 and CKD, Ahmad et al. 847

Table 1. Characteristics of participants in two studies using continuous glucose monitoring to assess hypoglycemia and glycemic
variability

CANDY Study INITIATION Study

Characteristic
CKD, n=81 Control Participants, n=24 Control Participants, n=73

Demographics
Age (years) 69 (10) 64 (10) 59 (10)
Men 52 (64) 15 (62) 43 (59)
Race/ethnicity
White 60 (74) 20 (83) NA
Black 12 (15) 2 (8) NA
Other 9 (11) 2 (8) NA
Hispanic ethnicity 8 (10) 3 (12) NA
Highest level of education
High school 22 (27) 7 (29) NA
Trade school 17 (21) 7 (29) NA
College 23 (28) 7 (29) NA
Graduate school 19 (23) 3 (12) NA
Health history
General health
Excellent/very good 14 (17) 8 (33) NA
Good 26 (32) 8 (33) NA
Fair or poor 41 (51) 8 (33) NA
Current smoking 2 (2) 3 (12) NA
History of myocardial infarction 13 (16) 1 (4) NA
History of heart failure 18 (22) 1 (4) NA
History of stroke 12 (15) 1 (4) 2 (3)
Duration of diabetes 20 (11) 16 (8) 10 (6)
Medication use
Insulina 72 (89) 21 (88) 73 (100)
Long- or intermediate-acting only 22 (27) 4 (17) 73 (100)
Mixed insulin 4 (5) 0 (0) 1 (1)
Basal bolus 46 (57) 17 (71) 0 (0)
No insulin 9 (11) 3 (12) 0 (0)
Insulin dose, units/kg per d 0.56 (0.43) 0.65 (0.49)
Insulin secretagogues 18 (22) 5 (21) 50 (68)
Sulfonylureas 17 (21) 5 (21) 50 (68)
Meglitinides 1 (1) 0 (0) 0 (0)
Other glucose-lowering agentsb 29 (36) 18 (75) 65 (89)
DPP-4 inhibitors 3 (4) 0 (0) 17 (23)
GLP-1 agonists 11 (14) 5 (21) 1 (1)
Biguanides 18 (22) 14 (58) 63 (86)
SGLT-2 inhibitors 1 (1) 5 (21) 0 (0)
TZDs 0 (0) 0 (0) 6 (8)
a Glucosidase inhibitor 0 (0) 0 (0) 2 (3)
Antihypertensive medications 77 (95) 21 (88) 50 (68)
ACEi/ARBs 60 (74) 21 (88) 50 (68)
b Blockers 38 (47) 5 (21) 10 (14)
Lipid-lowering medications 75 (93) 20 (83) 47 (64)
Statins 75 (93) 20 (83) 47 (64)
Acetaminophen 13 (16) 2 (8) 2 (3)
Physical characteristics
Body mass index, kg/m2 33.8 (5.7) 32.4 (6.2) 33.5 (6.2)
Systolic BP, mm Hg 132 (21) 136 (17) NA
Diastolic BP, mm Hg 72 (13) 78 (12) NA
Laboratory values
eGFR, ml/min per 1.73 m2 38 (14) 83 (11) 77 (8)
Urine ACR, mg/g 132 (8) 26 (7) NA
Hemoglobin A1c, % 7.8 (1.4) 7.6 (1.1) 7.4 (0.9)

Entries are mean (SD) for continuous variables or n (%) for categorical variables, except geometric mean (SD) for urine ACR. Missing data
in CANDY: history of stroke (n=2), duration of diabetes (n=4), urine ACR (n=3), hemoglobin A1c (n=1). Missing data in INITIATION:
eGFR (n=7), hemoglobin A1c (n=1). CANDY, Continuous Glucose Monitoring to Assess Glycemia in Chronic Kidney Disease;
NA, not available; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT-2, sodium-glucose cotransporter 2;
TZD, thiazolidinedione; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin-2 receptor blocker; ACR, albumin-to-
creatinine ratio.
a
Insulin usage was categorized by type of insulin, frequency of dosing and duration of effect: long- or intermediate-acting only, mixed
insulin (a combination of intermediate- and short-acting insulin), basal bolus (use of a long- or intermediate-acting plus a separate short-
acting insulin), or no insulin.
b
Many participants used multiple glucose-lowering medications; all were required by design to use insulin, a sulfonylurea, or both.
848 CJASN

Table 2. Glycemia metrics assessed using continuous glucose monitoring

CANDY Study INITIATION Study

Metric
P
CKD, n=81 Controls, n=24 End of Study, n=73 P Valueb
Valuea

Observation time
Total time, d 890 276 1456
Average time per participant, d 11 (2.3) 12 (2.5) 6. (0.8)
Mean blood glucose, mg/dl 170 (40.0) 158 (30.4) 154 (30.4)
Glucose management indicator, % 7.4 (1.0) 7.1 (0.7) 7.0 (0.7)
Level 1 hypoglycemia, <70 mg/dl
No. of events 255 80 220
No. (%) of participants with at least one event 56 (69) 16 (67) 51 (70)
Duration of episode, min 100 (56) 116 (86) 0.51 104 (76) 0.76
Nadir glucose, mg/dl 58 (4) 55 (7) 0.16 59 (6) 0.13
Rate, episodes per 30 d 5.3 (0.0–11.7) 5.9 (0.0–10.9) 0.97 10.1 (0.0–18.5) 0.01
Level 2 hypoglycemia, <54 mg/dl
No. of events 68 25 78
No. (%) of participants with at least one event 34 (42) 11 (46) 27 (37)
Time in range
Time in hypoglycemia, min ,70 mg/dl per d 28 (37) 29 (36) 0.93 49 (71) 0.02
10 PM–10 AM 23 (32) 22 (29) 39 (63)
10 AM–10 PM 5 (11) 7 (13) 10 (21)
Time ,54 mg/dl 6 (12) 9 (15) 13 (29)
Time in range, min 70–180 mg/dl per d 886 (325) 998 (312) 0.14 985 (268) 0.03
Time above range, min .180 mg/dl per d 526 (337) 414 (316) 0.14 406 (275) 0.01
Glycemic variability
SD of glucose readings, mean (SD) 52 (14) 46 (15) 0.11 49 (14) 0.22
IQR of glucose readings, mean (SD) 72 (23) 63 (24) 0.15 69 (24) 0.56
CV% of glucose readings, mean (SD) 31 (6) 29 (7) 0.36 32 (8) 0.27

Data are displayed as n (%), mean (SD), or median (IQR). CANDY, Continuous Glucose Monitoring to Assess Glycemia in Chronic
Kidney Disease; IQR, interquartile range; CV, coefficient of variation.
a
P value compares CANDY participants with CKD with CANDY controls.
b
P value compares CANDY participants with CKD with INITATION study controls.

Discussion blood glucose often reached low concentrations (mean 58

Hypoglycemia detected by CGM was quite common in [SD 4] mg/dl, 27% of episodes ,54 mg/dl), and early
this clinic-based study of people with long-standing type 2 morning was the highest-risk time of day, presumably
diabetes and moderate to severe CKD. Hypoglycemia during sleep, which is consistent with prior studies of type 1
episodes were often long (mean 100 minutes [SD 56]), and type 2 diabetes without CKD. Hemoglobin A1c and the

12am 1 2 3am 4 5 6am 7 8 9am 10 11 12pm 1 2 3pm 4 5 6pm 7 8 9pm 10 11 12am

mg/dL Avg 141 mg/dL 117 mg/dL 136 mg/dL 224 mg/dL 236 mg/dL 208 mg/dL 187 mg/dL 146 mg/dL
400

350

300

250

200

150
140
100
70
50

Thu Dec 3 Fri Dec 4 Sat Dec 5 Sun Dec 6 Mon Dec 7 Tue Dec 8 Wed Dec 9 AVG Target Meal Marker

Figure 1. | Representative visual report of hypoglycemia glycemia observed for a study participant over 6 days of CGM. Each line represents
blood glucose concentration tracked for 1 day, from midnight to midnight. The manufacturer-suggested target range of 70–150 mg/dl is shown
as a tan band. Over 6 days, this participant experienced three episodes of level 1 hypoglycemia (,70 mg/dl), including one episode of level
2 hypoglycemia (,54 mg/dl), all starting between 3 and 6 AM. AVG, average.
CJASN 14: 844–853, June, 2019 Hypoglycemia in People with DM2 and CKD, Ahmad et al. 849

CANDY CKD participants (N = 81)

Hypoglycemia (total minutes)

2500

1500

500

00:00 04:00 08:00 12:00 16:00 20:00 00:00

Time of day

CANDY control participants (N = 24)

800
Hypoglycemia (total minutes)

600

400

200

00:00 04:00 08:00 12:00 16:00 20:00 00:00

Time of day

INITIATION control participants (N = 78)

Hypoglycemia (total minutes)

2500

1500

500

00:00 04:00 08:00 12:00 16:00 20:00 00:00

Time of day

Figure 2. | Time spent in hypoglycemia (<70 mg/dl) according to time of day. Hypoglycemia was most frequent from 1 to 8 AM.

GMI were inversely correlated with time in hypoglycemia, Most published studies examining hypoglycemia in
confirming in this population that hypoglycemia is a trade- CKD have evaluated severe episodes requiring assistance
off for the benefits of intensive glycemic control. Counter from others, now termed level 3 hypoglycemia (14,15).
to our hypothesis, metrics of hypoglycemia and glycemic None of the observed episodes in our study required
variability were not significantly worse comparing partic- assistance from others, suggesting that hypoglycemia rates
ipants with CKD to two control populations. that come to the attention of health care providers reported
850 CJASN

enough to be eligible for ACCORD) who were assigned to

p = 0.20
Minutes of hypoglycemia, per day intensive glycemic control experienced 0.05 episodes of
level 3 hypoglycemia per year, on average, whereas we
150 observed 5.3 episodes of level 1 hypoglycemia per month
(12). We are unaware of other studies that have compre-
hensively evaluated hypoglycemia and glycemic variabil-
100 ity in moderate to severe CKD using CGM, and our data
are therefore important to define and describe the extent of
this problem. Other studies have suggested high rates of
50 hypoglycemia among patients treated with dialysis, al-
though direct comparisons are difficult because of differ-
ences in study populations and technology (20–27).
0 We observed no correlation of eGFR with hypoglycemia
<30 30-44 45-59 ≥ 60 among CANDY participants with CKD. It is possible that
CKD per se does not actually increase the risk of hypogly-
Estimated GFR (mL/min/1.73 m2)
cemia, or that CKD increases the likelihood that hypo-
glycemia events become clinically apparent (explaining
increased severe hypoglycemia requiring assistance in
p = 0.02 other studies) without altering the underlying rate of level
Minutes of hypoglycemia, per day

1 hypoglycemia. However, other aspects of study design

150 and population may also have influenced this result. In
CANDY, control participants were matched to partici-
pants with CKD on duration of diabetes and use of
100 glucose-lowering medications; if long-standing diabetes
(with resulting reduced residual b cell function) and
differential use of glucose-lowering medications are im-
50 portant causes of hypoglycemia in CKD, this design would
have reduced expected differences. In addition, the
CANDY control population was small and perhaps not
0 representative of uncomplicated type 2 diabetes in general.
Although the INITIATION trial was also a relevant control
<7.0 7.0-7.9 ≥ 8.0
population, particularly because of similarities in CGM
HbA1c (%)
technology, there are important differences that may
confound our comparison, including new use of insulin
p = 0.003 and better overall glycemic control.
Minutes of hypoglycemia, per day

Lower hemoglobin A1c and GMI were the only clinical

150
100
50
0 such as CKD (28,29). These results also suggest that mean
<7.0 7.0-7.9
GMI (%)
Figure 3. | Time spent in hypoglycemia was not related to eGFR and
inversely related to hemoglobin A1c and GMI. (A) Time spent in
hypoglycemia according to eGFR among all 106 study participants. (B)
Time spent in hypoglycemia according to hemoglobin A1c (HbA1c)
among 81 study participants with eGFR,60 ml/min per 1.73 m2. (C)
Time spent in hypoglycemia according to the GMI among 81 par-
ticipants with eGFR,60 ml/min per 1.73 m2.
in many studies markedly underestimate total episodes of
self-reported hypoglycemia. For example, ACCORD par-
ticipants with serum creatinine .1.3 mg/dl (but still low
risk factors we identified for hypoglycemia among partic-
ipants with CKD. Although mean blood glucose (reflected
by hemoglobin A1c) and glycemic variability are only
moderately correlated (15), our results confirm that better
overall glycemic control generally comes with a trade-off of
increased hypoglycemia risk. These results support rec-
ommendations of the American Diabetes Association to
individualize target hemoglobin A1c for patients with type
2 diabetes, taking into account hypoglycemia risk and
considering higher targets for patients with comorbidities
≥ 8.0 glycemia measured by CGM and expressed using the new
metric of GMI may reflect risk of hypoglycemia more
accurately than hemoglobin A1c (18), perhaps because of
limitations to the accuracy or precision of hemoglobin A1c
among people with diabetes and CKD.
The main strength of our study was the use of a state-of-
the-art CGM system to comprehensively ascertain hypo-
glycemia and glycemic variability in CKD for periods of
time sufficient to characterize usual glycemic patterns
(mean 11 [SD 2.3] days per participant). In addition, the
sample size with CKD was reasonably large, the population
included a range of moderate to severe CKD, and hemoglobin
A1c was measured using gold standard methods. Other
limitations included the observational design, which pre-
cludes conclusions regarding causality of associations, lack
CJASN 14: 844–853, June, 2019 Hypoglycemia in People with DM2 and CKD, Ahmad et al. 851

Table 3. Associations of clinical characteristics with time spent in hypoglycemia among 81 CANDY study participants with type 2
diabetes and CKD

Difference Adjusted Difference

Characteristic N Mean (SD), min/d
(95% CI), min/d (95% CI), min/d

Age, yr
,60 12 15 (19) 0 (Ref.) 0 (Ref.)
60–69 28 29 (38) 14 (23 to 32) 9 (26 to 24)
70–79 34 33 (43) 18 (1 to 36) 14 (22 to 31)
$80 7 19 (16) 4 (211 to 19) 23 (220 to 13)
eGFR, ml/min per 1.73 m2
45–59 28 25 (41) 0 (Ref.) 0 (Ref.)
30–44 30 39 (36) 14 (26 to 33) 9 (210 to 29)
,30 23 18 (30) 27 (226 to 12) 211 (226 to 5)
Hemoglobin A1c category
,7.0% 25 41 (46) 0 (Ref.) 0 (Ref.)
7.0%–7.9% 27 31 (38) 210 (232 to 13) 211 (231 to 9)
$8.0% 28 13 (19) 227 (247 to 29) 225 (242 to 27)
Hemoglobin A1c, per 1% increment 28 (213 to 23) 26 (210 to 22)
Glucose management indicator
,7.0% 28 44 (44) 0 (Ref.) 0 (Ref.)
7.0%–7.9% 39 24 (32) 220 (239 to 21) 215 (234 to 4)
$8.0% 14 6 (9) 238 (255 to 222) 229 (245 to 212)
GMI, per 1% increment 216 (223 to 29) 213 (220 to 27)
Insulin dose, units/kg per d
No insulin 9 7 (12) 0 (Ref.) 0 (Ref.)
0.01–0.5 38 33 (44) 26 (10 to 42) 14 (21 to 29)
0.51–1.0 23 27 (29) 19 (5 to 33) 9 (25 to 24)
.1.0 11 29 (36) 22 (0.4 to 44) 12 (213 to 36)
Insulin dosage, per 0.44 unit/kg per d increment 3 (27 to 13) 2 (29 to 13)
Duration of diabetes, yr
,10 8 20 (28) 0 (Ref.) 0 (Ref.)
10–19 30 19 (28) 21 (221 to 20) 24 (223 to 17)
$20 40 38 (43) 18 (24 to 40) 21 (21 to 43)
Body mass index
,30 21 27 (28) 0 (Ref.) 0 (Ref.)
30–34 33 31 (42) 4 (214 to 23) 9 (28 to 27)
35–39 18 17 (30) 210 (227 to 8) 27 (224 to 11)
$40 9 39 (48) 12 (220 to 44) 9 (214 to 31)
Medications
Insulin
None 9 7 (12) 0 (Ref.) 0 (Ref.)
Any 72 30 (38) 31 (2 to 61) 16 (213 to 45)
Insulin secretagogues
No 63 28 (33) 0 (Ref.) 0 (Ref.)
Yes 18 27 (49) 11 (221 to 44) 4 (228 to 35)
Other glucose-lowering agents
No 52 26 (34) 0 (Ref.) 0 (Ref.)
Yes 29 31 (43) 4 (212 to 19) 10 (25 to 26)

Adjusted differences are adjusted for age, sex, and race. CANDY, Continuous Glucose Monitoring to Assess Glycemia in Chronic Kidney
Disease; 95% CI, 95% confidence interval; Ref., reference; GMI, glucose management indicator.

of high-quality data on patient-reported outcomes, and lack Acknowledgments

of data linking glycemic patterns to clinical outcomes.
Intervention studies are required to more rigorously eval-
uate the comparative effects of glucose-lowering medica-
tions (including newer basal insulins such as degludec and
U-300 glargine) and real-time, unblinded CGM on glycemia
in CKD. Unfortunately, self-reported data on symptoms
and other patient-reported effects of these episodes were not
uniformly well ascertained. Further investigation is needed
to determine how the broad range of hypoglycemic events
affects how patients with CKD feel and function, and also to
determine whether these episodes elicit a harmful patho-
physiologic response or increase the risk of adverse clinical
outcomes, such as cardiovascular events.
The Continuous Glucose Monitoring to Assess Glycemia in CKD study
was primarily supported by American Diabetes Association grant #4-15-
CKD-20.AdditionalfundingcamefromgrantsR01DK088762,R01087726,
and T32DK007247 from the National Institute of Diabetes and Digestive
and Kidney Diseases; a grant from Puget Sound Veterans Affairs Health
Care System; and an unrestricted grant from Northwest Kidney Centers.
Continuous glucose monitoring equipment and supplies were
donated by Medtronic, and self-monitored blood glucose equipment
and supplies were donated by Abbott.
Study sponsors had no role in designing the study, collecting
study data, or analyzing or presenting study results.
Because Dr. de Boer is a Deputy Editor of the CJASN, he was not
involved in the peer review process for this manuscript. Another
852 CJASN
editor oversaw the peer review and decision-making process for
this manuscript.
Disclosures
Dr. Bansal reports grants from Medtronic, during the conduct of
the study. Dr. de Boer reports nonfinancial support from Medtronic,
nonfinancial support from Abbott, during the conduct of the study;
personal fees from Boehringer-Ingelheim, personal fees from Iron-
wood, outside the submitted work. Dr. Hirsch reports grants from
Medtronic Diabetes, personal fees from Abbott Diabetes Care,
personal fees from Roche, personal fees from Bigfoot, personal fees
from Becton Dickinson, outside the submitted work. Dr. Manski-
Nankervis reports grants and other from MSD, personal fees and
other from Sanofi, nonfinancial support from Medtronic, nonfinancial
support from Abbott, other from Eli Lilly/Boehringer Ingelheim,
outside the submitted work. Dr. Trence reports other from Sanofi-
Aventis, other from Medtronic, outside the submitted work.
Dr. Ahmad, Dr. Batacchi, Ms. Dighe, Dr. Furler, Dr. Little, Dr. O’Neal,
Ms. Robinson, and Dr. Zelnick have nothing to disclose.
Supplemental Material
This article contains the following supplemental material
online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/
CJN.11650918/-/DCSupplemental.
Title Page
Supplemental Table 1. Hypoglycemia incidence using alternative
definitions of hypoglycemia.
Supplemental Table 2. Sensitivity analysis assessing glycemia
outcomes among CANDY and INITIATION participants who did
not report use of acetaminophen or paracetamol.
Supplemental Table 3. Sensitivity analysis assessing glycemia
outcomes in CANDY, excluding the second observation period for
18 CANDY participants (15 with CKD, three controls) who were
informed of their results from the first observation for safety.
Supplemental Table 4. Associations of clinical characteristics with
blood glucose coefficient of variation among 81 CANDY study
participants with type 2 diabetes and CKD.
Supplemental Figure 1. Consolidated Standards of Reporting
Trials (CONSORT) flow diagram of CANDY study.
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Received: September 27, 2018 Accepted: March 22, 2019
Published online ahead of print. Publication date available at
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Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Supplemental Table of Contents:

Title Page

Supplemental Table 1. Hypoglycemia incidence using alternative definitions of hypoglycemia

Supplemental Table 2. Sensitivity analysis assessing glycemia outcomes among CANDY and INITIATION
participants who did not report use of acetaminophen or paracetamol.

Supplemental Table 3. Sensitivity analysis assessing glycemia outcomes in CANDY, excluding the
second observation period for 18 CANDY participants (15 with chronic kidney disease, 3 control) who
were informed of their results from the first observation for safety.

Supplemental Table 4. Associations of clinical characteristics with blood glucose coefficient of

variation among 81 CANDY study participants with type 2 diabetes and chronic kidney disease

Supplemental Figure 1. CONSORT flow diagram of CANDY study

1
Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Title Page:

Chronic kidney disease and hypoglycemia in people with type 2 diabetes

Authors:

Iram Ahmad, MD, Division of Oncologic Endocrinology, Banner‐MD Anderson Cancer Center, Gilbert, AZ

Leila R. Zelnick, PhD, Kidney Research Institute and Division of Nephrology, University of Washington,
Seattle, WA

Zona Batacchi, MD, Kidney Research Institute and Division of Metabolism, Endocrinology, and Nutrition,
University of Washington, Seattle, WA

Nicole Robinson, BS, Kidney Research Institute, University of Washington, Seattle, WA

Ashveena Dighe, MS, MPH, Kidney Research Institute and Division of Nephrology, University of
Washington, Seattle, WA

Jo‐Anne E. Manski‐Nankervis, MBBS, Department of General Practice, University of Melbourne, Carlton,

Victoria, Australia

John Furler, MBBS, PhD, Department of General Practice, University of Melbourne, Carlton, Victoria,
Australia

David N. O’Neal, MD, University of Melbourne Department of Medicine, St Vincent’s Hospital

Melbourne, Fitzroy, Victoria, Australia

Randie Little, PhD, Department of Pathology and Anatomical Sciences, University of Missouri, Columbia,
MO

Dace Trence, MD, Division of Metabolism, Endocrinology, and Nutrition, University of Washington,
Seattle, WA

Irl B. Hirsch, MD, Division of Metabolism, Endocrinology, and Nutrition, University of Washington,
Seattle, WA

Nisha Bansal, MD, MAS, Kidney Research Institute and Division of Nephrology, University of Washington,
Seattle, WA

Ian H. de Boer, MD, MS, Kidney Research Institute and Division of Nephrology, University of Washington,
Seattle, WA

2
Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Supplemental Table 1. Hypoglycemia incidence using alternative definitions of hypoglycemia

CANDY Study INITIATION Study

Consecutive p‐value**
measurements <70
CKD Controls End of study
mg/dL required to p‐value*
(N = 81) (N = 24) (N = 78)
diagnosis
hypoglycemia
1 measurement
N events 312 96 233
N (%) participants with
at least 1 event 59 (73) 17 (71) 52 (71)
Duration of episode
(minutes) 91 (73) 100 (82) 0.69 96 (61) 0.68
Nadir glucose (mg/dL) 59 (4) 55 (8) 0.07 60 (5) 0.35
Rate (episodes per 30
days) 7.3 (0.0‐14.6) 5.9 (0.0‐13.6) 0.97 10.5 (0.0‐21.9) 0.04
2 measurements
N events 292 93 229
N (%) participants with
at least 1 event 57 (70) 17 (71) 52 (71)
Duration of episode
(minutes) 98 (74) 104 (89) 0.81 96 (61) 0.87
Nadir glucose (mg/dL) 58 (4) 55 (8) 0.10 60 (5) 0.08
Rate (episodes per 30
days) 5.3 (0.0‐13.0) 5.9 (0.0‐14.6) 0.92 10.5 (0.0‐18.5) 0.03
3 measurements
N events 255 80 220
N (%) participants with
at least 1 event 56 (69) 16 (67) 51 (70)
Duration of episode
(minutes) 100 (56) 116 (86) 0.51 104 (76) 0.76
Nadir glucose (mg/dL) 58 (4) 55 (7) 0.16 59 (6) 0.13
Rate (episodes per 30
days) 5.3 (0.0‐11.7) 5.9 (0.0‐10.9) 0.97 10.1 (0.0‐18.5) 0.01
6 measurements
N events 201 63 176
N (%) participants with
at least 1 event 52 (64) 15 (62) 48 (66)
Duration of episode
(minutes) 126 (59) 130 (80) 0.86 128 (88) 0.91
Nadir glucose (mg/dL) 55 (6) 52 (6) 0.12 57 (6) 0.17
Rate (episodes per 30
days) 4.8 (0.0‐10.1) 3.5 (0.0‐8.9) 0.97 8.7 (0.0‐14.3) 0.01
12 measurements
N events 129 42 120

3
Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

N (%) participants with

at least 1 event 49 (60) 14 (58) 42 (58)
Duration of episode
(minutes) 154 (67) 153 (83) 0.96 153 (85) 0.95
Nadir glucose (mg/dL) 53 (7) 50 (7) 0.19 54 (6) 0.38
Rate (episodes per 30
days) 2.5 (0.0‐6.0) 2.4 (0.0‐6.8) 0.86 4.5 (0.0‐13.1) 0.005

Glucose measurements were recorded by continuous glucose monitoring every 5 minutes. The number
of consecutive measurements <70 mg/dL required to define a discrete episode of hypoglycemia was
varied to assess impact of the definition on hypoglycemia incidence. The primary definition required at
least 3 consecutive measurements, or approximately 15 minutes (and at least 10 minutes). Participants
were required to have three consecutive measurements ≥70 mg/dL prior to being at risk for an
additional hypoglycemia episode, except when two measurements <70 mg/dL were required to
diagnose hypoglycemia (in which case two measurements ≥70 mg/dL were required prior to being at
risk for an additional hypoglycemia episode).

4
Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Supplemental Table 2. Sensitivity analysis assessing glycemia outcomes among CANDY and INITIATION
participants who did not report use of acetaminophen or paracetamol.

CANDY Study INITIATION Study

CKD Controls End of study p‐value**
p‐value*
(N = 68) (N = 22) (N = 71)
Observation time
Total time (days) 737.4 253.5 443
Average time per
participant (days) 10.8 (2.3) 11.5 (2.6) 6.2 (0.8)
Mean blood glucose
(mg/dL) 169.0 (38.0) 156.8 (31.5) 154.9 (30.3)
Level 1 hypoglycemia
(<70 mg/dL)
N events 218 64 210
N (%) participants with
at least 1 event 47 (69) 14 (64) 49 (69)
Duration of episode
(minutes) 96 (51) 118 (92) 0.42 106 (77) 0.47
Nadir glucose (mg/dL) 57 (4) 55 (8) 0.38 59 (6) 0.11
Rate (episodes per 30
days) 5.6 (0.0‐11.5) 3.7 (0.0‐8.9) 0.59 9.9 (0.0‐18.3) 0.02
Level 2 hypoglycemia
(<54 mg/dL)
N events 61 16 76
N (%) participants with
at least 1 event 31 (46) 9 (41) 26 (37)
Time in range
Time in hypoglycemia
(minutes <54 mg/dL
per day) 6 (12) 6 (12) 0.99 13 (29) 0.08
10PM – 10AM 5 (10) 5 (10) 11 (27)
10AM – 10PM 1 (5) 1 (4) 2 (7)
Time in hypoglycemia
(minutes <70 mg/dL
per day) 28 (38) 25 (36) 0.68 49 (72) 0.03
10PM – 10AM 23 (32) 19 (28) 39 (64)
10AM – 10PM 5 (12) 6 (12) 10 (21)
Time in range (minutes
70‐180 mg/dL per day) 888 (320) 1018 (319) 0.10 975 (266) 0.05
Time above range
(minutes >180 mg/dL
per day) 524 (333) 397 (325) 0.12 415 (273) 0.03
Glycemic variability
SD of glucose readings,
mean (SD) 51.8 (13.9) 43.9 (12.3) 0.02 49.6 (14.2) 0.36

5
Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

IQR of glucose
readings, mean (SD) 70.5 (21.4) 59.0 (19.5) 0.02 70.0 (23.3) 0.89
CV% of glucose
readings, mean (SD) 30.8 (6.0) 28.0 (5.7) 0.06 32.1 (7.6) 0.26
Cell contents are N (%), mean (SD), or median (IQR). SD = standard deviation; CV = coefficient of
variation. * p‐value compares CANDY participants with CKD to CANDY controls. ** p‐value compares
CANDY participants with CKD to INITATION study controls.

6
Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Supplemental Table 3. Sensitivity analysis assessing glycemia outcomes in CANDY, excluding the
second observation period for 18 CANDY participants (15 with chronic kidney disease, 3 control) who
were informed of their results from the first observation for safety.

CANDY Study
CKD Controls
p‐value*
(N = 81) (N = 24)
Observation time
Total time (days) 807.4 257.1
Average time per participant (days) 10.0 (3.0) 10.7 (3.0)
Mean blood glucose (mg/dL) 169.8 (40.3) 158.0 (30.5)
Level 1 hypoglycemia (<70 mg/dL)
N events 224 71
N (%) participants with at least 1 event 53 (65) 16 (67)
Duration of episode (minutes) 102 (62) 114 (88) 0.62
Nadir glucose (mg/dL) 58 (4) 55 (8) 0.21
Rate (episodes per 30 days) 5.2 (0.0‐12.0) 4.8 (0.0‐11.2) 0.99
Level 2 hypoglycemia (<54 mg/dL)
N events 58 21
N (%) participants with at least 1 event 33 (41) 10 (42)
Time in range
Time in hypoglycemia (minutes <70 mg/dL per day) 29 (39) 27 (36) 0.84
10PM – 10AM 24 (35) 19 (27)
10AM – 10PM 5 (12) 8 (15)
Time in range (minutes 70‐180 mg/dL per day) 883 (323) 1003 (313) 0.11
Time above range (minutes >180 mg/dL per day) 528 (337) 410 (318) 0.12
Glycemic variability
SD of glucose readings, mean (SD) 51.9 (13.8) 46.0 (15.3) 0.10
IQR of glucose readings, mean (SD) 71.7 (23.6) 63.9 (25.3) 0.18
CV% of glucose readings, mean (SD) 30.8 (6.2) 29.3 (6.9) 0.35
Cell contents are N (%), mean (SD), or median (IQR). SD = standard deviation; CV = coefficient of
variation. * p‐value compares CANDY participants with CKD to CANDY controls.

7
Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Supplemental Table 4. Associations of clinical characteristics with blood glucose coefficient of

variation among 81 CANDY study participants with type 2 diabetes and chronic kidney disease

Difference
Mean (SD), (95%CI), Adjusted difference
N minutes/day minutes/day (95%CI), minutes/day
Age (years)
<60 12 33.0 (7.1) 0 (Ref.) 0 (Ref.)
60‐69 28 29.9 (5.2) ‐3.1 (‐7.4, 1.2) ‐3.4 (‐7.4, 0.7)
70‐79 34 31.0 (6.2) ‐2.0 (‐6.3, 2.4) ‐1.7 (‐5.9, 2.6)
≥80 7 28.7 (4.4) ‐4.3 (‐9.2, 0.6) ‐5.0 (‐9.9, ‐0.1)
eGFR (mL/min/1.73m2)
45‐59 28 29.9 (6.7) 0 (Ref.) 0 (Ref.)
30‐44 30 32.3 (5.1) 2.4 (‐0.6, 5.4) 2.4 (‐0.3, 5.2)
<30 23 29.7 (5.7) ‐0.1 (‐3.4, 3.2) 0.1 (‐3.2, 3.4)
HbA1c category
<7.0% 25 29.9 (6.8) 0 (Ref.) 0 (Ref.)
7.0‐7.9% 27 31.6 (5.8) 1.7 (‐1.6, 5.1) 1.2 (‐2.1, 4.6)
≥8.0% 28 30.7 (5.3) 0.8 (‐2.4, 4.1) 0.2 (‐3.5, 3.9)
HbA1c, per 1% increment 0.2 (‐0.7, 1.1) 0.2 (‐0.7, 1.2)
GMI category
<7.0% 28 29.5 (5.1) 0 (Ref.) 0 (Ref.)
7.0‐7.9% 39 32.0 (6.7) 2.5 (‐0.3, 5.3) 3.1 (0.3, 5.9)
≥8.0% 14 29.6 (4.2) 0.1 (‐2.8, 2.9) 0.5 (‐2.2, 3.3)
GMI, per 1% increment ‐0.5 (‐1.7, 0.7) ‐0.3 (‐1.6, 1.0)
Insulin dose (units/kg/day)
No insulin 9 25.3 (3.7) 0 (Ref.) 0 (Ref.)
0.01 – 0.5 38 31.4 (5.3) 6.1 (3.2, 8.9) 5.2 (1.8, 8.6)
0.51 – 1.0 23 30.8 (6.9) 5.5 (1.9, 9.1) 4.8 (0.9, 8.8)
> 1.0 11 32.7 (5.2) 7.4 (3.7, 11.1) 6.6 (2.5, 10.8)
Insulin dosage, per SD (0.44)
increment 1.5 (0.4, 2.7) 1.4 (0.2, 2.7)
Duration of diabetes
< 10 years 8 28.4 (5.6) 0 (Ref.) 0 (Ref.)
10‐19 years 30 30.5 (5.3) 2.1 (‐2.0, 6.2) 1.0 (‐3.3, 5.3)
≥ 20 years 40 31.7 (6.4) 3.3 (‐0.8, 7.4) 3.9 (‐0.4, 8.2)
BMI
<30 21 30.4 (3.8) 0 (Ref.) 0 (Ref.)
30‐34 33 30.9 (7.1) 0.6 (‐2.3, 3.5) ‐0.2 (‐2.9, 2.5)
35‐39 18 31.3 (4.8) 1.0 (‐1.7, 3.7) 0.1 (‐2.9, 3.2)
≥40 9 29.6 (7.6) ‐0.7 (‐5.6, 4.2) ‐0.8 (‐6, 4.4)
Medications

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Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Insulin
None 9 25.3 (3.7) 0 (Ref.) 0 (Ref.)
Any 72 31.4 (5.8) 7.1 (3.4, 10.7) 5.9 (1.9, 9.9)
Insulin secretagogues
No 63 31.1 (5.9) 0 (Ref.) 0 (Ref.)
Yes 18 29.3 (6.0) 1.3 (‐1.9, 4.5) 0.8 (‐2.4, 4.0)
Other glucose lowering
agents
No 52 30.7 (6.1) 0 (Ref.) 0 (Ref.)
Yes 29 30.7 (5.7) ‐0.2 (‐2.8, 2.3) ‐0.5 (‐3.2, 2.1)
Adjusted differences are adjusted for age, sex, and race.

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Supplemental material is neither peer-reviewed nor thoroughly edited by CJASN. The authors alone are responsible for
the accuracy and presentation of the material.

Supplemental Figure 1. CONSORT flow diagram of CANDY study

Assessed for eligibility (n=2622)

Did not consent (n = 2472)

 Excluded (n=2370)
 Declined to participate (n=92)
 Lost to follow‐up (n=6)
 Unknown (n=4)

Consented (n=149)

Did not complete study (n=44)

 Excluded post consent (n=9)

 Declined/changed mind (n=13)
 Lost to follow up (n=17)
 Unknown (n=4)
 Insufficient CGM data (n=1)

Completed study (n=105)

10