Content uploaded by Jeffrey Jackson
Author content
All content in this area was uploaded by Jeffrey Jackson on Mar 25, 2022
Content may be subject to copyright.
https://doi.org/10.1177/1932296820972719
Journal of Diabetes Science and Technology
2022, Vol. 16(2) 401 –407
© 2020 Diabetes Technology Society
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/1932296820972719
journals.sagepub.com/home/dst
Original Article
Introduction
Managing patients with type 2 diabetes (T2D) who require
high-dose insulin to achieve glycemic control is challenging
using conventional treatment options; as insulin doses
increase with disease progression, concerns regarding weight
gain, hypoglycemia, regimen complexity, increased number
or volume of injections, and cost become apparent.1 Flexible
intensive insulin therapy is generally achieved either by
972719DSTXXX10.1177/1932296820972719Journal of Diabetes Science and TechnologyMa et al.
research-article2020
1Eli Lilly and Company, Indianapolis, IN, USA
2ProSciento Incorporated, Chula Vista, CA, USA
3Indiana University School of Medicine/IU Health, Indianapolis, IN, USA
4Insulet Corporation, Acton, MA, USA
Corresponding Author:
Xiaosu Ma, PhD, Eli Lilly and Company Global Headquarters Lilly
Corporate Center, Indianapolis, IN 46285, USA.
Email: ma_xiaosu@lilly.com
Pharmacokinetics and Pharmacodynamics
of Human Regular U-500 Insulin
Administered via Continuous
Subcutaneous Insulin Infusion Versus
Subcutaneous Injection in Adults With
Type 2 Diabetes and High-Dose Insulin
Requirements
Xiaosu Ma, PhD1, Charles T. Benson, MD1, Randy Prescilla, PhD1,
Shuyu Zhang, MS1, Helle Linnebjerg, PhD1,
Elizabeth S. LaBell, BS1, Linda A. Morrow, MD2,
Jeffrey A. Jackson, MD1,3, Alex Nguyen, RD, CDE4, Liza L. Ilag, MD1,
Jennal L. Johnson, MS1, and Derek Leishman, PhD1
Abstract
Introduction: Human regular U-500 insulin (U-500R) is approved for subcutaneous (SC) injection in patients with diabetes
requiring >200 units/day of insulin. Here, pharmacokinetic and pharmacodynamic (PK/PD) profiles following U-500R
administered by continuous subcutaneous insulin infusion (CSII) and SC injection in adults with type 2 diabetes (T2D) on
high-dose insulin were studied.
Methods: In this randomized, crossover, euglycemic clamp study, patients received a 100-unit bolus of U-500R via SC
injection or CSII with basal infusion using a U-500R specific pump. PK parameters were estimated using non-compartmental
methods. PD estimates were derived from the glucose infusion rate during the euglycemic clamp procedure.
Results: When corrected for the basal infusion, the PK profiles for the 100-unit bolus of U-500R were similar for CSII and
SC injection. Without correction for basal infusion, PK and PD profiles showed a greater insulin concentration and effect
when U-500R was administered via CSII compared to SC injection, primarily due to basal insulin infusion for CSII. The ratio
of geometric least squares AUC0-tlast means SC:CSII (90% CI) is 0.857 (0.729, 1.01) with correction (mean AUC0-tlast: 5230
pmol*L/h [SC injection] and 6070 pmol*L/h [CSII, with correction]) and 0.424 (0.361, 0.499) without correction (mean
AUC0-tlast: 12300 pmol*L/h [CSII, without correction]). Median time-to-peak insulin concentration was six hours (range 0.5-8
hours) via SC injection and five hours (0.5-12 hours) via CSII.
Conclusions: In adults with T2D on high-dose insulin, U-500R PK/PD parameters were similar for a 100-unit bolus when
given by SC injection or CSII via a U-500R pump.
Keywords
continuous subcutaneous insulin infusion, high-dose insulin, pharmacodynamics, pharmacokinetics, type 2 diabetes, U-500
regular insulin
402 Journal of Diabetes Science and Technology 16(2)
multiple daily injections (MDIs) or continuous subcutaneous
insulin infusion (CSII). Currently approved/marketed CSII
insulin pumps are designed for U-100 insulin; however,
patients with high-dose insulin requirements who use more
concentrated insulin formulations may benefit from CSII,
which potentially offers improvements in comfort and adher-
ence through reduced burden of multiple injections and
improved glycemic control.2
Human regular U-500 insulin (Humulin-R U-500;
U-500R) is five times as concentrated as human regular
U-100 insulin (U-100R) and is approved in the USA and
Canada for subcutaneous (SC) injection in patients with dia-
betes mellitus requiring more than 200 units of insulin per
day to improve glycemic control.3 Pharmacokinetic (PK) and
pharmacodynamic (PD) data have shown that the overall
exposure and action of U-500R insulin after SC injections
were similar to those of U-100R insulin but with a blunted
peak concentration and action profiles and a longer duration
of action, suggesting that U-500R has both basal and pran-
dial activity. This supports the use of U-500R to be used as
insulin monotherapy.3,4 In patients with T2D and inadequate
glycemic control on high doses of U-100 insulin, switching
to U-500R has been suggested to improve glycemic control
and insulin adherence and reduce cost.1,5-7 Studies have dem-
onstrated U-500R treatment in this population to be effica-
cious and safe with fewer injections, usually two-three times
daily prior to meals.8 U-500R by CSII using a U-100 pump
has also been studied and shown to be safe and effective.9,10
The recent VIVID study directly compared the efficacy and
safety of U-500R given by SC injection to U-500R given by
an investigational U-500-specific pump (Omnipod® U-500
Insulin Management System, Insulet Corp., Acton, MA) in
patients with T2D requiring high-dose insulin.11 The VIVID
study demonstrated that both methods of U-500R effectively
lowered HbA1c with CSII having a greater reduction associ-
ated with a minimal increase in insulin, albeit with more noc-
turnal hypoglycemia with CSII than MDI.
The PK/PD properties of U-500R given by SC injection
have been studied in healthy obese participants4 and in
patients with T2D;12 however, data from administration of
U-500R via CSII in patients with T2D are lacking. Information
about PK/PD profiles following bolus via an insulin pump
versus injection is of interest considering that approximately
25% of patients with T2D who receive U-500R are treated
off-label with CSII.6 An insulin pump delivers a CSII for
long-term glycemic control and eliminates the need for mul-
tiple injections.13 There are no data from euglycemic clamp
PK/PD studies comparing U-500R administered via CSII to
U-500 via MDI in T2D patients with high-dose insulin
requirements. The use of U-500R in an insulin pump is under
investigation and not currently approved by regulators, but
may be a viable option in the future.11
The purpose of this study was to determine PK/PD pro-
files following the administration of a 100-unit bolus dose of
U-500R insulin using an investigational version of the novel,
specifically designed Omnipod U-500 Insulin Management
System versus a single injection in adults with T2D and
high-dose insulin requirements.
Materials and Methods
Study Design
This was a single-center, open-label, randomized, euglyce-
mic clamp study (Supplemental Figure 1, NCT02588950) in
patients (N=11) with T2D treated with high-dose insulin. The
randomized crossover design allowed each patient to act as
his/her own control, thus potentially decreasing variability
and other confounding factors.
Patients
Eligible patients with T2D were ≥18 to <75 years of age
with hemoglobin A1c (HbA1c) 7.5%-11.5% inclusive, body
mass index (BMI) ≥27 kg/m2, and with high-dose insulin
requirements. High-dose insulin was defined as using U-100,
U-200, and/or U-300 insulin with a total daily dose (TDD)
≥150 units or at least one dose of >100 units as part of an
MDI regimen with a TDD ≤3.0 units/kg. Patients were cur-
rently using U-100, U-200, and/or U-300 insulin analog as
basal, premixed, and/or basal-bolus therapy delivered with
pens and/or syringe and vial (but excluding CSII/insulin
infusion pumps in the preceding three months).
Sample Size
Target enrollment was 32 patients with 24 completers
expected. Based on an assumption of an intra-subject vari-
ability estimate of 20% for tmax, the sample size of 24 com-
pleted subjects would provide approximately 90% coverage
probability that the half width of the 90% confidence interval
(CI) for the ratio of geometric means for tmax would be within
0.116 in the log scale, which corresponds to approximately
12% of the geometric mean ratio estimate in the natural scale.
Despite protocol amendments (eg, allowing patients with
lower insulin doses, increasing BMI range, and permitting
concomitant antihyperglycemic medications) and significant
participant recruiting efforts, the study was terminated early
due to difficulties recruiting this population. When the study
was terminated, 11 patients were enrolled and followed
through study completion. During a post-study analysis, a
sample size of 11 subjects would provide at least 90% cover-
age probability such that the half-width of the 90% CI for the
ratio of geometric means for tmax would be within 20% of the
geometric mean ratio estimate in the natural scale.
Treatment
All patients received U-500R administered by a single 100-
unit bolus SC injection and CSII through randomized
Ma et al. 403
crossover design. For CSII administration, U-500R bolus
dose was administered via the investigational U-500 pump,
which took approximately 13 to 14 minutes. The U-500
pump was programmed to reflect dosage in clinical practice,
and a 12-hour basal 4.25 units/hour U-500R infusion was
administered overnight prior to the 100-unit U-500R bolus,
then continued at the same basal infusion rate during the
24-hour euglycemic clamp procedure following the bolus
dose. For SC injection, U-500R was administered as a single
injection at the beginning of the euglycemic clamp proce-
dure. As U-500R CSII administration typically includes both
basal infusion rates through the day and bolus doses at meal-
times, the data provided a good representation for this par-
ticular treatment regimen. On the other hand, when U-500R
is given as MDI, it is typically dosed either twice- (BID) or
thrice-daily (TID) SC, as it has demonstrated both prandial
and basal activity.3,4,7 The inclusion of a basal insulin infu-
sion in the CSII arm only, but not in the SC injection arm,
allowed us to assess the PK and PD of U-500R for both
administration methods in the real-world dosing paradigm.
Patients were permitted to take their pre-study oral antihy-
perglycemic agents (eg, metformin, pioglitazone, and/or sul-
fonylureas) at pre-study doses throughout the study, except
on clamp assessment days. Any previous insulin was discon-
tinued prior to starting study treatment.
Euglycemic Glucose Clamp Procedure
Patients fasted for 12 hours prior to the euglycemic clamp
initiation (Day 1) until completion of the 24-hour clamp pro-
cedure (Day 2). Pre-study insulin was taken at approximately
the same time each day prior to and between each visit and
was stopped at least 15 hours prior to clamp initiation to
allow washout and prevent insulin carryover. Overnight, all
subjects had their plasma glucose (PG) stabilized, using an
insulin lispro and/or glucose drip, to a target fasting PG con-
centration of 120 mg/dL (6.7 mmol/L) (with an acceptable
range of 100 to 130 mg/dL). During the euglycemic glucose
clamp, the glucose infusion rate (GIR) was adjusted every
minute to maintain PG within ±5% of 120 mg/dL (6.7
mmol/L), the predetermined glucose target value for the
individual participant. GIR was documented throughout the
24 hours. The euglycemic clamp procedure was performed
using a Biostator®, which is an automated clamp device.
Thus, blood glucose concentrations were kept constant while
GIR varied; the varying GIR reflected the PD activity of
insulin. All measurable GIR data (the sum of the GIR from
the Biostator and the GIR from the external pump) were
included in the PD analysis.
Pharmacokinetics/Pharmacodynamics
Serum samples were collected and analyzed for immunore-
active insulin (IRI) using a validated ELISA method. This
method measured the total concentration of endogenous
insulin as well as exogenous biosynthetic insulin after pre-
treatment with polyethylene glycol to remove anti-insulin
antibodies. Time-matched C-peptide concentrations were
also collected and used to correct serum IRI concentrations
for endogenous insulin production.
For PK analyses, blood samples were collected at the fol-
lowing timepoints: 0 (predose), and 0.5, 1, 2, 3, 4, 5, 6, 7, 8,
12, 16, and 24 hours post-dose. PK parameters were calcu-
lated using non-compartmental methods of analysis using
validated software (Phoenix WinNonlin Version 6.4,
Pharsight Corporation, USA). PK parameters were reported
for SC injection (100-unit bolus), CSII administration (100-
unit bolus + basal infusion), as well as CSII administration
(100-unit bolus alone). In order to calculate the PK param-
eter for the bolus dose component alone in the CSII arm, the
concentrations resulting from basal infusion were adjusted
from the total PK profile. If insulin concentrations from
basal infusion had reached steady state by the time of clamp
initiation, the insulin concentrations from basal infusion
could be subtracted using baseline insulin concentrations
(baseline corrected). However, it is likely that the insulin
concentrations due to U-500R basal infusion had not reached
steady-state after 12-hour fasting based on the half-life of
U-500R observed in the study, and the insulin concentra-
tions from basal infusion could still be increasing during the
clamp procedure. Therefore, in order to more accurately
account for the basal infusion, a one-compartment PK model
with first order absorption using data from U-500R SC
injection bolus treatment of 100 units was developed, and
the estimated post hoc PK parameters were then used to
simulate PK profiles following 4.25 units/hour basal infu-
sion for each individual and to correct for the basal infusion
concentrations using individual matched profiles (model
corrected, Supplemental Figure 2). PK profiles for the SC
injection period and the CSII period with and without basal
infusion were reported. Key PK parameters included maxi-
mum drug concentration (Cmax), area under the concentra-
tion versus time curve from time zero to time t, where t is the
last time point with a measurable concentration (AUC0-tlast),
area under the concentration time curve from time zero to 24
hours (AUC0-24), time to maximum drug concentration
(tmax), half-life associated with the terminal rate constant in
non-compartmental analysis (t1/2), and the last time point
with a measurable concentration (tlast).
For PD analyses (Supplemental Figure 2, panel 3), the
parameters were derived from the GIR over time during the
euglycemic clamp procedure as a measure of insulin effect.
A locally weighted scatterplot smoothing (LOESS) function
was applied to all individual GIR versus time profiles in each
treatment group using TIBCO Spotfire S+ (Version 8.2).
The fitted data for each participant were used to calculate the
PD parameters, such as the maximum GIR (Rmax), the total
amount of glucose infused over the duration of the clamp
procedure (Gtot0-24), the time of maximum GIR (tRmax), the
time of first non-zero value of GIR (tRonset), the time of last
404 Journal of Diabetes Science and Technology 16(2)
Table 1. Pharmacokinetic Parameters After Administration of 100-Unit Bolus of U-500R.
Parameter
Geometric mean (CV%)
SC injection (N = 11) CSII (N = 11)
CSII (model-
corrected) (N = 11)
Cmax, pmol/L 538 (47) 796 (51) 578 (66)
tmax, ha6.0 (0.5-8.0) 7.0 (0.5-12.0) 5.0 (0.5-12.0)
AUC0-tlast, pmol*h/L 5230 (35) 12300 (41) 6070 (70)
AUC0-24, pmol*h/L 5760 (33) 12300 (41) 6480 (66)
tlast, ha16.0 (16.0-24.0) 24.0 (24.0-24.0) 24.0 (16.0-24.0)
t1/2, hb5.83 (3.92-17.8)c10.8 (5.35-24.5)d4.71 (1.79-7.60)e
Abbreviations: AUC0-24, area under the concentration versus time curve from zero to 24 hours post-dose; AUC0-tlast, area under the concentration versus
time curve from time zero to time t, where t is the last time point with a measurable concentration; Cmax, maximum drug concentration; CSII, continuous
subcutaneous insulin infusion; CV%, percentage of coefficient of variation; N, number of patients; SC, subcutaneous; t1/2, half-life associated with the
terminal rate constant in non-compartmental analysis; tlast, last time point with a measurable concentration; tmax, time to maximum concentration;
U-500R, human regular U-500 insulin.
Pharmacokinetic parameters were estimated using C-peptide corrected insulin concentrations.
N = 11, unless indicated otherwise.
aMedian (min-max).
bGeometric mean (min-max).
cN = 9.
dN = 10.
eN = 8.
measurable GIR (tRlast), the time of 50% of maximum GIR
before Rmax (early tRmax50), and the time of 50% of maximum
GIR after Rmax (late tRmax50).
Statistical Methods
The values for AUC0-tlast, AUC0-24, Cmax, Rmax, and Gtot(0-24)
were log-transformed and analyzed by a linear mixed-effects
model with administration method, period, and sequence as
fixed effects and the patient as a random effect. The ratios of
geometric means and the 90% CI for the comparison of SC
injection and CSII were presented using back-transformed
difference in least squares means (LS mean) and 90% CI.
The time-action parameters (tmax, t1/2, tRmax, tRonset, tRlast, early
tRmax50, late tRmax50) were analyzed using the Wilcoxon signed-
rank test. Median differences between SC injection and CSII and
approximate 90% CIs for the difference were calculated.
Safety
Safety parameters were listed and summarized using descrip-
tive statistics. The frequency of treatment-emergent adverse
events (AEs) was summarized by treatment and by preferred
term in Medical Dictionary for Regulatory Activities
(MedDRA) Version 18.0.
Results
Demographics
Patients with T2D (N = 11) participated in the study: eight
male and three female between the ages of 37 and 65 with a
mean (SD; range) HbA1c of 10.2% (1.08%; 8.9%-11.6%),
body weight of 121.6 kg (33.5, 78.5-175.7 kg), BMI of 39.6 kg/
m2 (8.6, 28.7-53.0 kg/m2), and with T2D disease duration of
12.5 years (6.9; 5.0-29 years; Supplemental Table 1), pre-study
insulin total daily dose 1.1-3.2 units/kg, and total daily insulin
dose of 154-410 units (mean = 229 U). Oral glucose-lowering
medications are given in Supplemental Table 2.
Pharmacokinetics
The tmax values (median [range]) after a 100-unit bolus of
U-500R were similar when administered via SC injection (six
hours [0.5-8 hours]) or CSII (five hours [0.5-12 hours]) with or
without model correction (Table 1; Figure 1). The time-course
profile of insulin concentration was higher with CSII com-
pared with SC injection due to the additional basal infusion for
CSII. However, after the CSII profile was corrected for the
4.25 units/hour basal infusion using the PK modeling method,
the profiles for SC injection and CSII for the 100-unit bolus
dose of U-500R were similar (Table 1, Figure 1), and the Cmax
and AUC0-tlast of a 100-unit bolus of U-500R were similar
between SC injection and CSII (Table 1). The AUC0-tlast was
5230 pmol*h/L with SC injection and 6070 pmol*h/L with
CSII. Geometric LS mean AUC0-24, AUC0-tlast, and Cmax were
approximately 11%, 14%, and 8% lower, respectively, follow-
ing SC administration compared with CSII; however, the dif-
ferences were not statistically significant with the 90% CI of
each ratio of LS means including 1 (Supplemental Table 3).
Pharmacodynamics
The GIR from the euglycemic clamp was consistent with the
PK profile (Table 2; Figure 1). tRmax after a 100-unit bolus of
U-500R was similar when administered via SC injection or
Ma et al. 405
CSII. There was no statistically significant difference in time-
action parameters such as tRmax, early tRmax50, or late tRmax50
between SC injection and CSII with the 90% CI for the differ-
ences all containing zero (Table 2). Rmax and Gtot were higher
with CSII as expected due to the basal infusion. The ratios of
GIR (Rmax and Gtot) between CSII and MDI were similar to
the ratios of the PK parameters (Cmax and AUC0-24).
Safety
There were no reported severe hypoglycemic events or serious
AEs, and no discontinuation due to AEs. AE frequency was
comparable between SC injection and CSII for all causalities.
Discussion
In patients with T2D, there have been very few studies per-
formed to understand the PK and PD for insulin administered
by CSII, even for U-100R insulin. Although the PK/PD char-
acteristics of U-500R by bolus SC injection were studied in
healthy obese participants,4 this is the first PK/PD study to
compare bolus SC injection with CSII administration of
U-500R in patients with T2D requiring high-dose insulin.
This study is also unique for U-500R to be given by an inves-
tigational U-500-specific pump (Omnipod U-500 Insulin
Management System).
Although the PK and PD profiles showed a greater insulin
concentration and effect following the 100-unit bolus with
CSII compared to SC injection, this was primarily due to the
additional basal infusion rate with CSII. After correction for
the basal infusion, the 100-unit bolus portion of the U-500R
resulted in similar time-action profiles for CSII and SC injec-
tion. In addition, the less than 15-minute onset of action
observed with bolus SC injection in this study of insulin
resistant patients with T2D was similar to that observed pre-
viously in obese healthy participants.4
A PK-model correction method was used to correct basal
infusion data using a model-predicted PK profile from
patients who were treated with 100-units of U-500R with
CSII. Serum insulin concentrations following CSII adminis-
tration were higher at 24-hours post-bolus dose (in contrast,
insulin concentrations following SC bolus administration
had returned to baseline), suggesting that after 12 hours of
continuous infusion, basal U-500R concentrations had not
yet reached steady state. Subtraction of the pre-bolus dose
concentrations before steady state could not, therefore, cor-
rect for the actual concentration of insulin contributed by the
basal infusion at each time point, as it continued to increase
during the euglycemic clamp period. An alternative method
of correction, subtracting individual predicted concentra-
tions of insulin contributed by the basal infusion of U-500R
at each time point based on PK modeling was therefore
applied. This model-correction method provided more accu-
rate profiles of the insulin concentrations after U-500R
administration by separating the concentration of basal infu-
sion from the 100-unit bolus dose. These findings indicate
that, after accounting for the contributions from the basal
insulin infusion, the PK profiles of U-500R given as bolus by
CSII or MDI are comparable at 100 units.
As the PK of U-500R has a prolonged tail, as shown in
this study and de la Peña et al,4 each time when adjusting
the basal insulin infusion rate, it takes 24 hours or more
before a new steady state is reached. When administered
with a pump, each meal bolus of U-500R may also stack up
on the basal insulin being infused. The consequences of
this stacking can potentially expose patients to more insu-
lin than is required. This risk of stacking is more likely in
the first few days of CSII when the insulin being adminis-
tered is still reaching steady state. Therefore, for patients
treated with CSII, physicians should be mindful of ongo-
ing basal infusion when interpreting blood glucose levels
and dose adjustment.
Another pilot study assessing U-500R characteristics was
published by Shrestha et al in a similar population of obese,
insulin-resistant patients with T2D (N = 12) with high-dose
insulin requirements.13 In that study, however, patients were
Figure 1. Pharmacokinetic and pharmacodynamic profiles. (a) PK
time course profile following a 100-unit bolus of U-500R insulin
by SC injection, CSII (before and after the profile was corrected
for the 4.25 units/hour basal infusion using PK modeling method)
and the simulated insulin profile from continuous basal infusion
for CSII. (b) PD profile as measured by GIR following a 100-U
bolus of U-500R insulin by SC injection and CSII.
CSII, continuous subcutaneous insulin infusion; GIR, glucose infusion rate;
PD, pharmacodynamic; PK, pharmacokinetic; SC, subcutaneous; U-500R,
human regular U-500 insulin (LY041001).
406 Journal of Diabetes Science and Technology 16(2)
overtly hyperglycemic and around 40 mg/dL higher than their
target glucose for clamp procedure. The GIR was adjusted
less frequently, only every 15-60 minutes. The tonset measured
by the GIR initiated during 0-4 hours was confounded by pro-
gressive decline in glucose over the first four hours when the
euglycemia target was not achieved, indicating that the tonset
should be earlier than that reported. The glucose concentra-
tions dropped quickly after U-500R administration with a rise
in insulin levels as early as the first measuring time point,
suggesting that the onset of action is faster. This does not sup-
port the authors’ assertion that U-500R should not be a pre-
meal bolus insulin with action one to two hours after meals to
prevent hyperglycemia.13 A quality euglycemic clamp study
should have a stable target glucose to enable the correct inter-
pretation of data, a situation not achieved in the Shrestha
study, thus confounding any interpretation of the GIR data.
Results from Shrestha et al12 differ from the finding of an
onset of action within less than 15 minutes observed in the
MDI arm of this study as well as in a previous study in healthy
obese patients with diabetes,4 wherein the GIR was adjusted
every minute and the glucose concentrations were kept in
euglycemic range during the entire clamp procedure.
A major limitation of this study is the small sample size
(due to the early termination of the study caused by slow
enrolment, despite the implementation of measures to
improve this), and the statistical inference should be inter-
preted with caution. Also, only the 100-U dose was studied
and patients enrolled in this study were on relatively lower
doses of insulin (TDD ≥150 units/day), compared with
high-dose insulin patients in a previously published study
(mean TDD 287.5 units/day).8 Last but not least, despite the
objective to study U-500R PK and PD under real-world dos-
ing paradigms, the extra steps of modeling correction to
characterize the insulin concentration profile following bolus
dose for CSII might have added uncertainty or bias into the
comparison, which needs to be addressed in future studies.
Conclusion
In adults with T2D and high-dose insulin requirements, the
time-action parameters were similar after administration of a
100-unit bolus dose of U-500R with an investigational
U-500R calibrated insulin pump (Omnipod U-500 System)
and SC injection. Data in the present report add to the scien-
tific knowledge regarding the PK and PD profiles of U-500R
delivered by either CSII or SC injection in patients with T2D
with high-dose insulin requirements and may further inform
clinicians regarding appropriate usage in this patient popula-
tion. U-500R delivered by CSII in a dedicated pump device
could be a viable option for patients requiring high doses of
insulin in the future.
Abbreviations
AEs, adverse events; AUC0-24, area under the concentration versus
time curve from zero to 24 hours postdose; AUC0-tlast, area under the
concentration versus time curve from time zero to time t, where t is
the last time point with a measurable concentration; BID, twice
daily; BMI, body mass index; CI, confidence interval; Cmax, maxi-
mum drug concentration; CSII, continuous subcutaneous insulin
infusion; CV%, percentage of coefficient of variation; early tRmax50,
time prior to tRmax when glucose infusion rate is half the maximum
glucose infusion rate; GIR, glucose infusion rate; Gtot(0-24), total
amount of glucose administered between time zero and 24 hours;
IRI, immunoreactive insulin; late tRmax50, time after tRmax when glu-
cose infusion rate is half the maximum glucose infusion rate;
LOESS, locally weighted scatterplot smoothing; LS, least squares;
MDI, multiple daily injections; MedDRA, Medical Dictionary for
Regulatory Activities; N, number of patients; PD, pharmacody-
namic; PK, pharmacokinetic; Rmax, maximum glucose infusion rate;
SC, subcutaneous; SC, subcutaneous; T2D, type 2 diabetes; t1/2,
half-life associated with the terminal rate constant in non-compart-
mental analysis; TID, thrice daily; tlast, last time point with a mea-
surable concentration; tonset, time of first positive glucose infusion
rate; tRmax, time of maximum glucose infusion rate; U-500R, human
regular U-500 insulin.
Table 2. Pharmacodynamic Parameters After Administration of 100-Unit Bolus of U-500R.
Parameter
Geometric mean [CV%] Ratio of geometric least
squares means
SC injection: CSII
(90% CI)
100-unit bolus of
U-500R SC injection
(N = 11)
100-unit bolus of
U-500R CSII
(N = 11)
Gtot(0-24), g 256 (35) 494 (23) 0.518 (0.458, 0.586)
Rmax, mg/min 368 (19) 486 (21) 0.753 (0.669, 0.847)
tRmax, h 8.50 (31) 8.53 (35) 0.900 (–1.60, 2.60)a
Early tRmax50, h 3.59 (44) 2.85 (28)b1.66 (–0.162, 4.14)a
Late tRmax50, h 15.3 (30) 18.5 (25)c−3.77 (–11.3, 1.81)a
tonset, h 0.178 (143) -
Abbreviations: CI, confidence interval; CSII, continuous subcutaneous insulin infusion; CV%, percentage coefficient of variation; early tRmax50, time prior
to tRmax when glucose infusion rate is half the maximum glucose infusion rate; Gtot(0-24), total amount of glucose administered between time zero and
24 hours; late tRmax50, time after tRmax when glucose infusion rate is half the maximum glucose infusion rate; N, number of patients; Rmax, maximum glucose
infusion rate; SC, subcutaneous; tonset, time of first positive glucose infusion rate; tRmax, time of maximum glucose infusion rate.
aMedian (median of differences SC-CSII [90% CI]).
bN = 7.
cN = 4.
Ma et al. 407
Acknowledgements
The authors would like to acknowledge Insulet Corporation for sup-
plying the pumps and training for the study and Gina Moore, Syneos
Health, for writing and editorial assistance.
Author Contributions
JLJ, XM, DL, HL, JAJ, LM participated in designing the study.
HL, XM, SZ, ESL, JJ, LLI, RP, AN, LM conducted experiments
and analyzed data.
All authors contributed to writing the manuscript.
All authors reviewed and edited this manuscript.
Preliminary results were presented at the American Diabetes
Association 78th Scientific Sessions, Orlando, FL, June 22-26,
2018.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Xiaosu Ma, Charles T. Benson, Shuyu Zhang, Helle
Linnebjerg, Elizabeth S. LaBell, Liza L. Ilag, Jennal L. Johnson,
and Derek Leishman are employees and stockholders of Eli Lilly
and Company. Jeffrey A. Jackson is a former employee and minor
stockholder of Eli Lilly and Company. Alex Nguyen is an employee
and stockholder of Insulet Corporation. Randy Prescilla is a former
employee of Eli Lilly and Company and an employee of Sanofi
Genzyme in Cambridge, MA. Linda Morrow is an employee and
stockholder of ProSciento, Inc.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: The
study was sponsored by Eli Lilly and Company.
Ethics Approval
This study was conducted in accordance with consensus ethics prin-
ciples derived from international ethics guidelines, including the
Declaration of Helsinki and Council for International Organizations
of Medical Sciences International Ethical Guidelines, the International
Conference on Harmonization Good Clinical Practice Guideline
(E6), and applicable laws and regulations. All participants provided
their informed consent, and the protocol was approved by the Ethical
Review Board.
Data Availability Statement
Eli Lilly and Company provides access to all individual participant
data collected during the trial, after anonymization, with the excep-
tion of pharmacokinetic or genetic data. Data are available to request
six months after the indication studied has been approved in the US
and EU and after primary publication acceptance, whichever is later.
No expiration date of data requests is currently set once data are
made available. Access is provided after a proposal has been
approved by an independent review committee identified for this
purpose and after receipt of a signed data sharing agreement. Data
and documents, including the study protocol, statistical analysis
plan, clinical study report, and blank or annotated case report forms,
will be provided in a secure data sharing environment. For details on
submitting a request, see the instructions provided at www.vivli.org.
Supplemental Material
Supplemental material for this article is available online.
References
1. Lane WS, Cochran EK, Jackson JA, et al. High-dose insu-
lin therapy: is it time for U-500 insulin? Endocr Pract.
2009;15(1):71-79.
2. Sze D, Goldman J. Human regular 500 units/mL insulin ther-
apy: a review of clinical evidence and new delivery options.
Clin Diabetes. 2018;36(4):319-324.
3. Eli Lilly and Company. HUMULIN® R U-500 [Prescribing
Information]. Indianapolis: Eli Lilly and Company, 2018.
4. de la Peña A, Riddle M, Morrow LA, et al. Pharmacokinetics
and pharmacodynamics of high-dose human regular U-500
insulin versus human regular U-100 insulin in healthy obese
subjects. Diabetes care. 2011;34(12):2496-2501.
5. Eby EL, Wang P, Curtis BH, et al. Cost, healthcare resource
utilization, and adherence of individuals with diabetes using
U-500 or U-100 insulin: a retrospective database analysis. J
Med Econ. 2013;16(4):529-538.
6. Eby EL, Zagar AJ, Wang P, et al. Healthcare costs and adher-
ence associated with human regular U-500 versus high-
dose U-100 insulin in patients with diabetes. Endocr Pract.
2014;20(7):663-670.
7. Reutrakul S, Wroblewski K, Brown RL. Clinical use of U-500
regular insulin: review and meta-analysis. J Diabetes Sci
Technol. 2012;6(2):412-420.
8. Hood RC, Arakaki RF, Wysham C, Li YG, Settles JA, Jackson
JA. Two treatment approaches for human regular U-500 insu-
lin in patients with type 2 diabetes not achieving adequate
glycemic control on high-dose U-100 insulin therapy with or
without oral agents: a randomized, titration-to-target clinical
trial. Endocr Pract. 2015;21(7):782-793.
9. Lane WS. Use of U-500 regular insulin by continuous subcu-
taneous insulin infusion in patients with type 2 diabetes and
severe insulin resistance. Endocr Pract. 2006;12(3):251-256.
10. Lane WS, Weinrib SL, Rappaport JM, Hale CB, Farmer LK,
Lane RS. The effect of long-term use of U-500 insulin via con-
tinuous subcutaneous infusion on durability of glycemic con-
trol and weight in obese, insulin-resistant patients with type 2
diabetes. Endocr Pract. 2013;19(2):196-201.
11. Grunberger G, Bhargava A, Ly T, et al. Human regular U-500
insulin via continuous subcutaneous insulin infusion versus
multiple daily injections in adults with type 2 diabetes: the
VIVID study. Diabetes Obes Metab. 2020;22(3):434-441.
12. Shrestha RT, Kumar AF, Taddese A, et al. Duration and onset
of action of high dose U-500 regular insulin in severely insu-
lin resistant subjects with type 2 diabetes. Endocrinol Diabetes
Metab. 2018;1(4):e00041.
13. Pisano M. Overview of insulin and non-insulin delivery devices
in the treatment of diabetes. P T. 2014;39(12):866-876.
