ArticlePDF Available

A randomized, open-label, comparative, two-period crossover trial on preference, efficacy, and safety profiles of a prefilled, disposable pen with lispro insulin u-100 versus concentrated lispro insulin u-200 in patients with type 2 diabetes mellitus: a possible contribution to increase adherence

Authors:

Abstract and Figures

BACKGROUND. Incorrect insulin administration techniques may greatly affect metabolic control in T2DM people. The aim of our study was to compare glycemic control associated with a concentrated insulin analog preparation (U-200 lispro) in people with T2DM to the one observed with standard U-100 lispro. METHODS. 126 patients with T2DM were enrolled. Half of them were randomized to U-100 lispro, half to U-200 and after 12 weeks they were switched to the other preparation for 12 weeks. At the end a questionnaire was also administered to investigate patient preference. RESULTS. No significant variation in fasting blood glucose, HbA1c, severe or mild hypoglycemic rate and daily fast-acting insulin analog dose was observed with U-100 lispro while U-200 lispro treatment was associated with a significant improvement of all the above mentioned parameters and with around 20% decrease in insulin requirement. Moreover patients’ answers to the questionnaire pointed out a higher preference for U-200 lispro for continuing treatment due to fewer difficulties completing injection. DISCUSSION. The explanation of better metabolic results with the U-200 device might be the lower inner piston inertia and volume and shorter duration of a complete injection. CONCLUSIONS. The use of U-200 lispro might improve treatment adherence and metabolic control.
Content may be subject to copyright.
Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=ieds20
Expert Opinion on Drug Safety
ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20
A randomized, open-label, comparative, crossover
trial on preference, efficacy, and safety profiles
of lispro insulin u-100 versus concentrated lispro
insulin u-200 in patients with type 2 diabetes
mellitus: a possible contribution to greater
treatment adherence
Sandro Gentile, Alessandra Fusco, Sara Colarusso, Marco Piscopo, Maria
Rosaria Improta, Marco Corigliano, Emilia Martedi, Domenica Oliva,
Antonietta Santorelli, Rosa Simonetti, Armando Giammarco, Caterina
Colella, Luigia Miretto, Alessandra D’Alessandro, Viviana Russo, Giuseppina
Guarino, Giampiero Marino, Gerardo Corigliano & Felice Strollo
To cite this article: Sandro Gentile, Alessandra Fusco, Sara Colarusso, Marco Piscopo, Maria
Rosaria Improta, Marco Corigliano, Emilia Martedi, Domenica Oliva, Antonietta Santorelli, Rosa
Simonetti, Armando Giammarco, Caterina Colella, Luigia Miretto, Alessandra D’Alessandro, Viviana
Russo, Giuseppina Guarino, Giampiero Marino, Gerardo Corigliano & Felice Strollo (2018): A
randomized, open-label, comparative, crossover trial on preference, efficacy, and safety profiles
of lispro insulin u-100 versus concentrated lispro insulin u-200 in patients with type 2 diabetes
mellitus: a possible contribution to greater treatment adherence, Expert Opinion on Drug Safety,
DOI: 10.1080/14740338.2018.1453495
To link to this article: https://doi.org/10.1080/14740338.2018.1453495
Accepted author version posted online: 22
Mar 2018.
Published online: 18 Apr 2018.
Submit your article to this journal
View related articles View Crossmark data
ORIGINAL RESEARCH
A randomized, open-label, comparative, crossover trial on preference, efficacy, and
safety profiles of lispro insulin u-100 versus concentrated lispro insulin u-200 in
patients with type 2 diabetes mellitus: a possible contribution to greater treatment
adherence
Sandro Gentile
a
, Alessandra Fusco*
b
, Sara Colarusso
c
, Marco Piscopo
d
, Maria Rosaria Improta
e
, Marco Corigliano
b
,
Emilia Martedi
f
, Domenica Oliva
g
, Antonietta Santorelli
h
, Rosa Simonetti
d
, Armando Giammarco
c
, Caterina Colella
f
,
Luigia Miretto
h
, Alessandra DAlessandro
i
, Viviana Russo
a
, Giuseppina Guarino
a
, Giampiero Marino
a
,
Gerardo Corigliano
b
and Felice Strollo
j
a
Department of Clinical and Experimental Medicine, Università della Campania Luigi Vanvitelli, Napoli, Italy;
b
AID, Diabetes Unit, Napoli, Italy;
c
AID, Diabetes Unit, Benevento, Italy;
d
AID, Diabetes Unit, Nola, Italy;
e
AID, Diabetes Unit, Castellammare, Italy;
f
AID, Diabetes Unit, Portici, Italy;
g
AID, Diabetes Unit, Cava de Tirreni, Italy;
h
AID, Diabetes Unit, Caserta, Italy;
i
Gastroenterologia, AOU Federico II, Napoli, Italy;
j
Istituto San Raffaele
Termini, Endocrinology Unit, Roma, Italy
ABSTRACT
Background: Several outstanding pharmacological advances making innovative drugs sophisticated-
devices available during the last few years. Nevertheless too many patients still disappointingly fail to
meetthe metabolic targets suggested by current guidelines. Incorrect insulin administration techniques
may greatly affect metabolic control in T2DM people. The aim of our study was to compare glycemic
control associated with a concentrated insulin analog preparation (U-200 lispro) in people with T2DM to
the one observed with standard U-100 lispro. The secondary endpoint of our study was patients
preference and performance ratings of U-200 lispro.
Methods: 126 patients with T2DM were enrolled. They were also assessed for limited joint mobility
syndrome (LJMS),defined as limitation in at least two anatomical areas of the dominant upper extre-
mity. After a 4-weekstructured insulin injection education period. Half of them were randomized to
U-100 lispro, half to U-200 and after 12 weeks they were switched to the other preparation for
12 weeks. At the end a questionnaire was also administered to investigate patient preference.
Results: No significant variation in fasting blood glucose, HbA1c, severe or mild hypoglycemic rate and
daily fast-acting insulin analog dose was observed with U-100 lispro while U-200 lispro treatment was
associated with a significant improvement of all the above mentioned parameters and with around 20%
decrease in insulin requirement. Moreover patientsanswers to the questionnaire pointed out a higher
preference for U-200 lispro for continuing treatment due to fewer difficulties completing injection.
Discussion: The explanation of better metabolic results with the U-200 device might be the lower inner
piston inertia and volume and shorter duration of a complete injection.
Conclusions: Checking for LJIMS before insulin prescription could be adopted as a standard practi-
ceaimed at choosing the most suitable device for patient's specific characteristics and abilities. The use
of U-200 lispro might improve treatment adherence and metabolic control. This would also result
intocost reduction by saving about half the amount of pens per year and of time spent to both fill
prescriptionand dump the pharmacy.
ARTICLE HISTORY
Received 4 December 2017
Accepted 6 March 2018
KEYWORDS
Lispro U-200; insulin; device;
diabetes; adherence
1. Introduction
There is strong evidence that poor glycemic control is strongly
associated with micromacro-vascular complications in type 2
diabetic subjects (T2DM) [1]. In fact, despite several outstand-
ing pharmacological advances making innovative drugs avail-
able during the last few years along with sophisticated
devices, increasingly thin needles and insulin analogs with
improved pharmacokinetic (PK) profiles, too many patients
still disappointingly fail to catch up with the metabolic targets
provided for by current guidelines.
Many reasons may explain their failure, including the inner
complexity of diabetes treatment, too many drugs and related
side effects, therapeutic inertia, and, last but not least, patient
nonadherence [2]. In particular, incorrect insulin administra-
tion techniques and pen misuse [3] may greatly affect meta-
bolic control in T2DM people on multiple daily injections
(MDIs). In fact all this reflects day-to-day clinical experience
rather than the outcome of a thorough scientific analysis. That
is why we did a survey of all T2DM outpatients using pens for
MDI referred to our Diabetes Unit in the last two weeks, sum-
ming up to 367 people, by asking them the following simple
CONTACT Alessandra Fusco alefusc@yahoo.it
*
AID: Italian Diabetes Association (Outpatient Diabetes Centers)
EXPERT OPINION ON DRUG SAFETY, 2018
https://doi.org/10.1080/14740338.2018.1453495
© 2018 Informa UK Limited, trading as Taylor & Francis Group
questions: (i) Do you wait 1020 s without releasing the pressure
on the plunger at the end of injection before removing the
needle from the skin? (ii) Does the plunger get all the way
back to its initial lifted position at the end of injection? (46%
people admitted it did not). Seventy-two percent patients
gave a negative answer to the first question. When asked to
explain why they failed to wait, 69% put the blame on diffi-
culties at handling the pen and/or limited power to fully
complete the injection and wait for several seconds after
that; 18% placed responsibility with missed education; and
13% claimed they had either forgotten or underestimated
this rule. From this short survey two main issues arose: educa-
tional deficiencies, which represent a well-known therapeutic
weakness, and hand problems due to frequently observed
muscle-skeletal alterations. In fact the guidelines we recently
issued were meant at improving supporting diabetes team-
work with respect to education [4] and hand defects have also
been described in depth in diabetes literature [5].
A recent study [6] compared the accuracy, precision, and
handling of the three most commonly used pens, KwikPen
(KP), FlexPen (FP), and Solostar (SS), by establishing that the
three devices are similar for accuracy but KP performs better in
terms of ergonomics and strength required for complete injec-
tion. In this context concentrated insulin preparations, which
just recently became available and are easier-to-handle per se,
could have a positive impact on personal feelings about injec-
tions and improve metabolic control accordingly through
enhanced treatment adherence.
U-200 lispro insulin (from now on referred to as lispro) has
the same PK profile as U-100 lispro despite being concen-
trated twice as much [7]. This implies no dosage changes
when shifting from one to the other as in fact bio-equivalence
carries along dose equivalence. However, it is immediately
apparent that people halve their injected volume when shift-
ing from U-100 to U-200 lispro 30 units a day, thus achieving a
remarkable advantage in terms of force applied to the plunger
during injection independent of and in addition to improved
device engineering. Moreover, under standardized experimen-
tal conditions a significantly lower thrust has been recently
reported as required by U-200 than with U-100 lispro KP
utilization [8]. All of these aspects might further improve
patientsexperience during injection.
The aim of the study was to evaluate glycemic control
associated with U-200 as compared to U-100 lispro in people
with T2DM over a 12-week observation period. As a secondary
endpoint we analyzed patientspreference and ratings of the
U-200 lispro device.
2. Subjects and methods
This observational study was conducted in one single Diabetes
Unit in real-life conditions, and the protocol was approved by
the Ethics Committees of Campania University Luigi
Vanvitelli, Naples, Italy. We collected information only from
patients preliminarily signing their informed consent to anon-
ymous data utilization for clinical evaluations aimed at dia-
betes community health and quality-of-life improvement [9].
The study conformed to the Helsinki Declaration.
In total, 150 consecutive patients with T2DM were enrolled.
All of them had been using pen devices for at least 12 months
and were on three daily prandial insulin injections of a U-100
fast-acting insulin analog at a 44 ± 10 U mean dose plus a basal
analog. Patients with previous cardiovascular events, serious
renal, hepatic, or cancer diseases were excluded from the
study along with pregnant women or women in their fertile
age not using contraceptives. The remaining 126 patients
entered the study: their general features are reported in Table 1.
In the 4-week enrollment period (T-4 to T0), in compliance
with the usual national NHS reimbursement rules and without
any external financial support, all patients were prescribed
U-100 lispro as the only fast-acting product. In order to avoid
far too obvious confounding factors to affect our results, a
structured educational intervention was implemented aiming
at eliminating the risk of technical errors, improper pen utiliza-
tion, and accidental injections in lipohypertrophy (LH) affected
skin areas. In particular, participants were trained to use 4 mm/
32G needles, to dispose of them after use, to consistently rotate
injection sites while accurately skipping LH areas, and, according
to the current best injection technique guidelines, to hold the
pen plunger for 1020 s before extracting the needle from the
skin [10]. At T0 patients were randomized to U-100 lispro KP
[n=63 subjects as starting control group (SCG)] or to U-200 lispro
KP [63 subjects as starting intervention group (SIG)] and were
followed over a 12-week period (T0T12). At T12, patients under
U-100 were shifted to U-200 lispro KP and vice versa, and
followed for further 12 weeks (T12T24). For the sake of clarity,
the SCG was treated with U-100 during the first 12 weeks and
with U-200 in the following period (T12T24), the reverse
applied to the SIG, so that all patients experienced both analogs
for a total of 24 weeks and had the same chance to perceive
volume, injection duration, and glide force differences during
the two time frames. Compared to the U-100 lispro Kwickpen
device, the one for U-200 lispro underwent only a volume-
relatedcalibration system modification to allow the same insulin
doses to be injected, and in fact, as stated by theNational Drug
Administration Agency (AIFA) no dose adaptation is required
when changing from U-100 KPto U-200 KP (10). Indeed the most
relevant difference between U-200 and U-100 KP is volume
reduction,which requires less time and effort to complete the
injection (6) and is therefore better suited to people ofmiddle-
advanced age, especially those suffering from keiro-arthropathy.
Single doses of fast acting insulin and basal insulin were
increased or reduced of about 2 units every 2-4days to keep
the fasting glucose between 90 to 130 mg per dL (5 to 7.21
mmol per L) or < 180 mg per dL(9.99 mmol per L), according
to ADA criteria 2010 (12). The diagnosis of type 2 diabetes was
made/confirmed at each participating DC according to criteria
defined by the American Diabetes Association (ADA)
Standards of Medical Care in Diabetes 2017 [11].
According to the ADA guidelines, severe hypoglycemia was
defined as a hypoglycemic episode leading to unconscious-
ness or requiring assistance by a third person or with a blood
glucose 70 mg/dL range (3.9 mmol/l); symptomatic hypogly-
cemia was defined as the onset of one or more of the follow-
ing symptoms that resolved with the ingestion of food or
sugary drinks: palpitations, tremors, sweating, shakiness, irrit-
ability, difficulty concentrating, dizziness, hunger, blurred
2S. GENTILE ET AL.
vision, confusion, tachycardia, or difficulty moving without loss
of consciousness [11]. All participants systematically moni-
tored their glucose levels through officially certified and per-
iodicallyteam-verified meters according to an ongoing daily
rotating method involving a pre- and a 2-hourpostprandialfin-
ger prick at breakfast, lunch or dinner. They were instructed to
perform further glucosechecks when hypoglycaemic symp-
toms occurred.
Limited joint mobility, syndrome (LJMS), defined as limitation
in at least two anatomical areas of the dominant upper extre-
mity, was defined/diagnosed as previously described [1214].
At the end of the study, general biochemical parameters
and HbA1c were evaluated along with eventually occurring
changes in insulin dosage, hypoglycemic rate, and analog
preference in terms of pen handling, required effort, and
ease of use. The latter was investigated through the following
simple dichotomic questions:
(1) Is the effort required to push the plunger down the
same with U-100 as with U-200 KP?
(2) In case of a negative answer, which of the two pens
requires more effort?
(3) Have you always been able to complete the injection
with the U-100 KP and wait 1020 s before removing
the needle from the skin?
(4) In case of a negative answer, did your partial injections
account for more than 50%?
(5) Have you always been able to complete the injection
with the U-200 KP and wait 1020 s before removing
the needle from the skin?
(6) In case of a negative answer, did your partial injections
account for more than 50%?
(7) If you had to go on with either U-100 KP or U-200 KP,
which one would you choose?
The questionnaire was preliminarily validated in 260
randomly selected subjects from 13 DCUs (20 subject-
sper DCU) who had been on KP U-200 for at least 6
months after U-100 KP utilization. They had comple-
tedthe written questionnaire after reading it at least
twice and asked the health care team for explanations
asneeded. Those unable to read or autonomously
understand questions for any reasons were excluded.
Lipohypertrophy (LH) was looked for and identified
within the injection sites according to the method
wepreviously described in detail (17).
3. Statistical analysis
The estimated sample size for this study was 100 subjects to
have a power of 93.4% and to yield a p<0.05significant result
at least. To compensate for possible drop-outs we decided to
increase our sample size to150 subjects and, out of those
initially selected, 126 were found to meet all inclusion criteria
andrandomized as described within the text. Patientscharac-
teristics are reported as mean ± standard deviation (SD) for
continuous variables or percentages for categorical variables.
Severe or symptomatic hypoglycemic episodes were eval-
uated through Poisson regression models and expressed as
incidence rates and their 95% confidence intervals.
Two-factor analysis of variance (ANOVA) for repeated mea-
sures was carried out on the SAS Program (Release 9.4, SAS
Institute, Cary, NC, USA) and p-values <0.05 were accepted as
statistically significant. Eventually occurring carry-over effects
were not expected to be present due to both the extremely
short half-life of lispro and the relatively brief treatment
phases but carry-over effects were also ruled out after verify-
ing that no significant differences could be found between
U-100 KP results after 12 and 24 treatment weeks.
The KruskalWallis test (a non-parametric one-way ANOVA)
was used to explore the questionnaire for (i) factor analysis, (ii)
comprehensibility, (iii) convergent validity, and (iv) internal
consistency when answering to items belonging to the same
scale. p-Values <0.05 were accepted for statistical significance.
4. Results
All enrolled subjects completed the study. No general or local
adverse reactions were observed. As shown in Table 1, only
41.5% of patients was on U-100 lispro KP before enrollment,
Table 1. Descriptive features of the patients at enrollment period (from T-4 to
T0).
Variable
Subjects
(n=126)
Female, n(%) 72 (54.2)
Age (years), M±SD (range) 65.5 ± 6.0 (5971)
BMI (kg/m
2
), M±SD (range) 28.9 ± 3.3 (26.633.4)
Diabetes duration (years), M±SD (range) 8.6 ± 2.1 (39)
SBP (M±SD, mmHg) 133.3 ± 6.7
DBP (M±SD, mmHg) 81.5 ± 7.3
Users of KwikPen (%) 41.5
Users of other pen (%) 60.7
Needle length/gauge users (%)
4 mm/32G 12
5 mm/32G 16
6 mm/30G 64
8 mm/30G 10
Mean dose of fast insulin analog U-100 (IU, M+SD) 44 ± 10
Mean dose of basal insulin glargine 20 ± 8
Lipohypertrophy (%) 67
Fasting glucose (mg/dl) 149.5 ± 18.4
HbA1c (%) 8.2 ± 1.0
S hypos (n/12 weeks; M+SD) 6.1 ± 2.2
M hypos (n/12 weeks; M+SD) 18 ± 4
Total cholesterol (mg/dl) 189.5 ± 22.6
HDL cholesterol (mg/dl) 43.3 ± 3.2
LDL cholesterol (mg/dl) 106.5 ± 12.6
Triglycerides (mg/dl) 168.4 ± 41.3
Creatinine (mg/dl) 0.9 ± 0.7
eGFR (ml/min/1.73m
2
) 90.3 ± 17.9
Smokers (%) 39
Lipid-lowering treatment (%) 68
Antihypertensive treatment (%) 72
Aspirin (%) 36
Complications (n)43
Retinopathy BG (%) 11.5
Nephropathy (%) 9.1
Autonomic neuropathy (%) 10.3
Peripheral neuropathy (%) 11.4
Limited joint mobility syndrome, n(%) 61 (48.4)
Data are expressed as mean + SD or as nand percent rate in case of categorical
variables: 43 subjects had more than a single diabetes complication and
61 had limited joint mobility syndrome. SBP: systolic blood pressure;
DBP: diastolic blood pressure; S hypos: severe hypoglycemias; M hypos: mild
hypoglycemias; HDL: high density lipoprotein; LDL: low density lipoprotein;
eGFR: estimated glomerular filtration rate; NHS: national health service; BG:
background.
EXPERT OPINION ON DRUG SAFETY 3
and different needles were used not in line with correct injec-
tion technique guidelines [4,10]. In addition, 61 participants
(48%) suffered from LJMS and, as evidence of inappropriate
adherence to therapy, and 56 (44%) were found to have LH at
the injection sites.
In Table 2, the results of U-200 and U-100 lispro adminis-
tration are compared in both treatment periods. The SCG was
treated with U-100 during the first 12 weeks and with U-200 in
the following period (T12T24), the reverse applies to the SIG.
Therefore, all patients experienced both analogs and had the
same chance to perceive volume, injection duration, and glide
force differences during the two time frames. No significant
variation in fasting blood glucose, HbA1c, severe or mild
hypoglycemic rate, and daily fast-acting insulin analog dose
was observed at the end of either U-100 lispro treatment
period. On the opposite, U-200 lispro treatment was asso-
ciated with a significant improvement of all the above-men-
tioned parameters compared to both baseline and the end of
each U-100 lispro utilization period (see also Figure 1 for
HbA1c changes). The 61 subjects with Limited joint mobility
syndrome reported the greatest subjective improvements
with U-200 compared to U-100. The around 20% decrease in
insulin requirement during any U-200 administration period is
of particular interest too.
Patientsanswers concerning feelings on U-100 and U-200
lispro utilization (Figure 1) pointed out that the latter required
less effort during injection. Moreover, 79% patients reported
difficulty completing injection in over 50% U-100 lispro shots
as compared to 12% of those using U-200 lispro. Finally, 79%
claimed to prefer U-200 lispro for continuing treatment.
5. Discussion
This spontaneous uncontrolled study evaluated changes
occurring in main metabolic parameters after shifting from a
12-week U-100 lispro treatment regimen to a further 12-week
utilization of the double-concentrated, half-volume U-200 lis-
pro. In order to avoid obvious method-related biases, all
patients were asked to use the same device and needle
(4 mm/32G) and to follow injection guidelines concerning
needle rotation and systematic avoidance of LH areas. As a
consequence of that all participants experienced U-100 KP and
Table 2. Comparison of metabolic parameters between intervention periods with either lispro U-200 or lispro U-100.
Overall
Lispro
U-100
Lispro
U-200
Lispro
U-100
Lispro
U-200
Baseline T0 T12 T12 T24 T24
Fasting glucose (mg/dl) 149.5 ± 18.4 145.5 ± 14.3 118.5 ± 12.4* 161.2 ± 14.3 110.5 ± 13.6°
HbA1c (%) 8.2 ± 1.0 7.9 ± 1.1 7.2 ± 0.7** 8.0 ± 0.9 7.1 ± 0.7°°
S hypos (n/12 weeks; M±SD) 6.1 ± 2.2 5.2 ± 1.1 0.2 ± 0.1* 5.1 ± 0.8 0.2 ± 0.1°
M hypos (n/12 weeks; M+SD) 18.2 ± 4.1 15.4 ± 2.1 4.2 ± 0.3* 15.8 ± 3.4 0.4 ± 0.1
Mean daily dose of fast insulin analog U-100 (IU, M+SD) 44 ± 10 45 ± 11 37 ± 10*° 43 ± 11 36 ± 9°*
Mean daily dose of basal insulin analog U-100 (IU, M
+SD)
20 ± 8 21 ± 9 17 ± 8 21 ± 6 18 ± 5
* *p<0.01 and **p<0.05 vs. baseline vs. T12/U100; ° p< 0.01 and °° p< 0.05 vs. baseline vs. T12/U-100, and T24/U-100.
S hypos = severe hypoglycemias; M hypos = mild hypoglycemias.
0
20
40
60
80
100
Yes No U-100 U-200 Yes No More Less Yes No More Less U-100 U-200
1234567
Question N.
%
Figure 1. Patients answers to the seven question on KP U-100 and KP U-200.
Questions: 1. Is the effort required to push the plunger down the same with U-100 as with U-200 KP?; 2. In case of a negative answer, which of the two pens requires less effort?; 3. Have you
always been able to complete the injection with the U-100 KP and wait 1020 s before removing the needle from the skin?; 4. In case of a negative answer, did your partial injections account for
more or less than 50%?; 5. Have you always been able to complete the injection with the U-200 KP and wait 1020 s before removing the needle from the skin?; 6. In case of a negative answer,
did your partial injections account for more or less than 50%?; 7. If you had to go on with either U-100 KP or U-200 KP, which one would you choose?
4S. GENTILE ET AL.
4mm/32G needles during the 4-week enrollment period, i.e.
before being randomized to U-100 or U-200 KP.
Metabolic results clearly indicate a better performance of
U-200 vs. U-100 lispro, and, interestingly enough, the need to
reduce daily U-200 lispro dosage by 20%. In fact we might
have described those changes in terms of U/kg ratio according
to the most currently accepted concept by also taking into
account BMI and individual insulin resistance, but some rea-
sons discouraged such choice this time. Indeed the answers to
our questionnaire clearly showed that virtually all patients
found the effort associated with U-200 KP utilization to be
lower and that 79% U-100 KP users could complete less than
50% injections. It was therefore impossible for us to assess the
exact amount of insulin injected by people on U-100.
Conversely, 88% U-200 KP users stated they managed to
complete the overall injection process including the expected
time interval between needle insertion and withdrawal. Thus
participants spontaneously clustered into 2 groups: (i) U-100
KP users, 79% of whom only partially injected insulin doses
displayed on the pen counter and (ii) U-200 KP users 88% of
whom fully injected the chosen dose instead. Dose description
in terms of U/Kg would therefore turn out to be misleading in
79% people on U-100 and in only 12% people on U-200. This
in fact made us avoid reporting doses as U/kg. Since the two
insulin preparations have exactly the same PK and pharmaco-
dynamic profiles [7], the explanation of this phenomenon
should be sought elsewhere.
A possible explanation can come from injection modalities
as most patients stated that the ability to perform injections
was very different with the two analogs. Indeed the analysis of
patientsanswers concerning feelings about U-100 and U-200
KP utilization (Figure 1) was very instructive: everyone recog-
nized that the U-200 device required less injection effort, and
79% reported difficulty completing injection in over 50%
U-100 lispro shots. This might reflect the fact that, based on
previous studies [6,1517], volume reduction asks for less
force to be applied to the pen piston. According to the same
questionnaire results, 79% also claimed to prefer U-200 KP for
continuing treatment.
In fact, when the injection is not completed, a lower dose is
administered than scheduled. On the contrary, an easier to
handle device, due to its lower inner piston inertia and injec-
tion volume, as well as a shorter performance duration actu-
ally grants good metabolic results while reducing the insulin
doses. The latter result, which also entails improved treatment
adherence, does not cause any surprise when realizing that
higher insulin amounts are provided by full injections, while
incomplete shots make patients continuously increase doses
in order to attain an apparently ever moving forward target.
This explanation is well in agreement with the high rate of
LJMS we found strongly affecting our patientsability to han-
dle a pen and push the injecting piston all the way down.
Major limitations of our study were the short duration of
real-life observation, the smallnumberofpatientsinvolved,
and the inner inseparable effects of U-200 device technol-
ogy and reduced injection volume. Nevertheless, in our
hands U-200 lispro significantly reduced hypoglycemic epi-
sodes, fasting blood glucose, HbA1c, and daily insulin
requirement within only 12 weeks and such impressive
metabolic results provide objective support to subjective
patient ratings.
Considering the high number of people with diabetes with
educational deficiencies [18,19] or functional limitations, the
use of concentrated insulin preparations like U-200 lispro may
contribute to improving treatment adherence and, conse-
quently, metabolic control. Therefore, checking for LJIMS
before insulin prescription could be adopted as a standard
practice aimed at choosing the most suitable device for
patientsspecific characteristics and abilities. A further eco-
nomic advantage is also expected from concentrated insulin
devices as halved volumes might save about half the amount
of pens per year and of time spent to both fill prescription and
dump the pharmacy. In conclusion, the most relevant positive
aspect of this study is represented by the almost total pre-
ference of concentrated insulin, because it enhances patients
performance during the insulin injection and consequently
improves the metabolic control and the risk of hypoglycemia,
thus contributing to improving the quality of life of patients
and reducing the costs.
Acknowledgments
We thank the Associazione Medici Diabetologi (AMD) for its support. The
components of Italian Study Group on Injection Techniques are also
acknowledged for critical reading and approval of the manuscript:
Stefano De Riu, Nicoletta De Rosa, Giorgio Grassi, Gabriella Garrapa,
Laura Tonutti, Katja Speese, Lia Cucco, Maria Teresa Branca, Amodio Botta
Funding
The study was supported by the AID Private Italian Diabetes Association
(Outpatient Diabetes Centers)
Ethical standard. This study was conducted in conformance with
good clinical practice standards. The study was led in accordance with
the Declaration of Helsinki 1975, as revised in 2008, and was approved by
the Ethics Committee.
Human and animal rights. All procedures were in accordance with
the ethical standards of the responsible committee on human experimen-
tation (institutional and national).
Informed consent. Written informed consent was obtained from all
participants before enrollment.
Declaration of interest
The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the manuscript
apart from those disclosed. Peer reviewers on this manuscript have no
relevant financial or other relationships to disclose. The authors declare no
conflicts of interest.
Author Contributions
SG and FS planned and wrote the manuscript after critically interpreting
the results of the database analysis performed by TDC, GM, AF, GC and
GG. SC, MP, SI, MC, EM, DO, AS, RS, AG, CC, LM, ADA and VR validated the
questionnaire, participated in the critical review of the manuscript and
approved its final version. All authors meet the International Committee of
Medical Journal Editors (ICMJE) criteria for authorship for this article, take
responsibility for the integrity of the work as a whole, and have given final
approval to the version to be published.
EXPERT OPINION ON DRUG SAFETY 5
References
1. Zoungas S, Arima H, Gerstein HC, et al. Collaborators on Trials of
Lowering Glucose (CONTROL) group. Effects of intensive glucose con-
trol on microvascular outcomes in patients with type 2 diabetes: a meta-
analysis of individual participant data from randomized controlled trials.
Lancet Diabetes Endocrinol. 2017;pii: S2213-8587(17)301043.
DOI:10.1016/S2213-8587(17)30104-3. Last Accessed 2017 Dec 1.
2. Gentile S, Ceriello A, Pipicelli G, et al. Type 2 diabetes mellitus
treatment habits in a specialized care setting: the START-DIAB
study. Med J Nutrition Metab. 2017;10(2):165179.
3. Gentile S, Strollo F, De Rosa N, et al. Injection-related local side
effects in the treatment of diabetes mellitus: a methodological
approach and possible solutions. consensus statement of AMD-
OSDI study group on injection technique. Diabetic Complications.
2016. Available from: www.smgebooks.com
4. Frid AH, Kreugel G, Grassi G, et al. New insulin delivery recommen-
dations. Mayo Clin Proc. 2016;91:12311255.
5. Papanas N, Maltezos E. The diabetic hand: a forgotten complica-
tion? J Diabetes Complications. 2010;24(3):154162.
6. Tenore GC. Accuratezza della dose, facilità duso e preferenza del
paziente: risultati di uno studio di simulazione che ha comparato
tre penne pre-riempite con analoghi rapidi dellinsulina. Beyond
Glycemia. 2016; Available from: http://www.beyondglycemia.com/
la-rivista/articolo/accuratezza-della-dose-facilita-d-uso-e-prefer
enza-del-paziente-risultati-di-uno-studio-di-simulazione-che-ha-
comparato-.aspx?sKey=gian%20carlo%20tenore
7. AIFA (Italian Drug Agency) Nota Informativa Importante su
Humalog KwikPen (25/05/2016). [cited 2017 Dec 1]. Available
from: http://www.agenziafarmaco.gov.it/content/nota-informativa-
importante-su-humalog-kwikpen-25052016
8. Rees TM, Lennartz AH, Ignaut DA. A comparison of glide force
characteristics between 2 prefilled insulin lispro pens. J Diabetes
Sci Technol. 2015;9(2):316319.
9. Gruppo di studio ANNALI AMD. AMD Annals: a model of contin-
uous monitoring and improvement of the quality of diabetes care].
Epidemiol Prev. 2011;35(1):1826. AIFA: Agenzia Italiana del
Farmaco. Nota Informativa Importante su Humalog KwikPen
Available from: http://www.agenziafarmaco.gov.it/content/aifa-
nota-informativa-importante-su-humalog-kwikpen; (date of last
consultation: 27 February 2018)
10. Gentile S, Grassi G, Armentano V, et al. AMD-OSDI consensus on
injection techniques for people with diabetes mellitus. Med Clin
Rev. 2016;2(3):34. American Diabetes Association. Standards of
medical care in diabetes 2010. Diabetes Care. 2010;33(suppl 1):
S11S61. Available from: http://www.imedpub.com/
11. American Diabetes Association Standards of Medical Care in
Diabetesd 2017. 6. Glycemic targets. Diabetes Care. 2017;40
(Suppl. 1): S48S56. DOI:10.2337/dc17-S009.
12. Shinabarger NI. Limited joint mobility in adults with diabetes mel-
litus. Phys Ther. 1987;67(2):215218.
13. Shah KM, Ruth Clark B, McGill JB, et al. Shoulder limited joint
mobility in people with diabetes mellitus. Clin Biomech (Bristol,
Avon). 2015 Mar;30(3):308313. Epub 2015 Jan 6. DOI:10.1016/j.
clinbiomech.2014.12.013.
14. Gentile S, Guarino G, Giancaterini A, et al. Italian Injection
Technique Study Group. A suitable palpation technique allows to
identify skin lipohypertrophic lesions in insulin-treated people with
diabetes. SpringerPlus. 2016;5:563. DOI:10.1186/s40064-016-1978-y.
15. Rissler J, Jørgensen C, Rye Hansen M, et al. Evaluation of the
injection force dynamics of a modified prefilled insulin pen.
Expert Opin Pharmacother. 2008;9(13):22172222.
16. Asakura T, Seino H, Kageyama M, et al. Evaluation of injection force of
three insulin delivery pens. Expert Opin Pharmacother. 2009;10
(9):13891393.
17. Owens DR. Study to compare the injection force required for the
following insulin pen devices: lilly disposable pen, Novo FlexPen,
and Solostar. J Diabetes SCI Tech. 2007;1:A134.
18. Clapham L. Injection technique education and follow-up: the key to
ensuring optimal glycaemic control. J Diabetes Nurs. 2015;19:152
155.
19. Blanco M, Hernández MT, Strauss KW, et al. Prevalence and risk
factors of lipohypertrophy in insulin-injecting patients with dia-
betes. Diabetes Metab. 2013;39(5):445453.
6S. GENTILE ET AL.
... 62 Lispro is available as U-100 and U-20 0, with U-20 0 being formulated in twice as much concentration as U-100. 63 Aspart Insulin aspart comes in various forms (in solution administered subcutaneously, in solution cartridge administered subcutaneously, and in solution pen-injector administered subcutaneously). In each form of insulin aspart, two available brands (Fiasp and Novolog) and a generic are present, in which the onsets of action, times to peak, duration of action, and half-lives differ from one another. ...
Article
The discovery of insulin by Banting and Best marked 100 years in 2021, and it was a life-saving treatment modality for type II diabetes mellitus (T2DM). Insulin is a natural hormone that has been used extensively in T2DM patients since its discovery. Currently, insulin analogs are also available in different formulations for T2DM management, overcoming the limitations of human insulin with better safety and side effect profiles. The insulin analogs like the rapid-acting analogs (Aspart, lispro, glulisine), the long-acting basal analogs (Glargine, detemir), the ultra-long acting (Insulin degludec), and the premixed insulin analog formulations (75% Neutral protamine lispro, 25% lispro; 50% neutral protamine lispro, 50% lispro; 70% protamine aspart, 30% aspart) have been prepared through genetic engineering while preserving the basic insulin profile. A large number of studies have demonstrated their clinical effects on glycated hemoglobin test (HbA1c) in achieving glycemic control and thereby lowering the microvascular and macrovascular complications of T2DM with less traditional side effects of regular human insulin, mainly the risk of hypoglycemia, postprandial glycemic excursions, and weight gain. This review explores the currently available insulin analogs, their clinical implications, pharmacokinetics (PK), pharmacodynamics (PD), safety profile, and cost-effectiveness. We also discuss the future developments in the management of T2DM, especially the scientific advancements surrounding the novel insulin formulations, including the biosimilar insulin, and the innovative insulin delivery methods, such as oral and inhaled insulin.
... Despite these limitations, the study analyzed sufficient data on the profile of patients with T1D and T2D in a short period of time and from a large number of centers. Although randomized clinical trials are essential to analyze specific aspects of drug efficacy and safety [17], observational studies such as this are complementary and reveal the real-world patterns of patient characteristics and treatments. Future real-world studies should be conducted focusing on glycemic outcomes and changes in patient satisfaction, quality of life, and adherence to the treatment following IL200 initiation. ...
Article
Full-text available
Introduction: Insulin lispro 200 U/ml (IL200) is a rapid-acting concentrated insulin used for the treatment of adults with diabetes requiring daily doses of > 20 units of rapid-acting insulin. The aim of this study was to describe the clinical/demographic and treatment characteristics of patients who initiated insulin IL200 therapy in Spain in a real-world setting (PROFILE-IL200). Methods: This retrospective observational study based on the IQVIA database included adult (≥ 18 years) patients with type 1 (T1D) or type 2 (T2D) diabetes who initiated IL200 between June 2015 and December 2019. Demographic and clinical characteristics were analyzed descriptively. Results: Main characteristics for the T1D/T2D groups (N = 65/167) were as follows: male, 63.1/55.7%; mean (standard deviation [SD]) age, 46.5 (15.5)/62.6 (12.8) years; time since first diabetes record, 6.6 (4.2)/7.9 (2.9) years; body mass index (BMI), 30.9 (5.8)/33.1 (5.5) kg/m2; glycated hemoglobin, 8.3 (2.1)/8.8 (1.8)%; and diabetes-associated comorbidity, 55.4/92.8%. Among patients with T1D/T2D and a prior diagnosis (N = 54/164), 96.3/90.2% had received previous insulin (rapid insulin in 81.5/62.2%), and 13.0/97.6% had received previous noninsulin antihyperglycemic therapy. The mean (SD) total insulin dose before IL200 initiation for T1D/T2D was 98.0 (73.9)/95.2 (59.8) U/day; IL200 was initiated at a dose of 56.3 (43.8)/51.5 (34.3) U/day, with basal insulin in 86.2/83.2% of the patients. IL200 was first prescribed by an endocrinologist or a primary care physician in 48.7% and 46.6% of patients, respectively. Conclusions: PROFILE-IL200 described the profile of patients treated with IL200 in clinical practice in Spain. Patients were middle-aged, with poor glycemic control, high BMI and associated comorbidities, and received high doses of insulin at IL200 initiation.
... However, the preferences of physicians and patients regarding treatment options can differ substantially. While the aforementioned studies [6,17,20] provided information on patient preference toward IL200, little is known about how physicians prescribed IL200. This physicians' survey-based study aimed to describe the characteristics of average IL200 patients and the importance of patients' clinical factors and behavioral aspects when prescribing IL200. ...
Article
Full-text available
Objective To understand physicians’ reasons for prescribing Insulin Lispro 200 units/ml (IL200) and their experience with IL200 treatment in Germany. Methods The survey consisted of 28 questions on physician’s profile, average IL200 patients’ characteristics and rationales for prescribing IL200. Questions were rated on a scale of 0 (‘not at all important’/‘strongly disagree’) to 4 (‘absolutely important’/‘strongly agree’). Results The surveyed physicians had a mean (SD) experience of 18.1 (7.0) years managing diabetes, consulted an average of 226.8 patients with diabetes/month and prescribed IL200 to 56.1% of their patients on mealtime insulin (MTI). About 80.0% of IL200 patients had type 2 diabetes mellitus, were overweight/obese, and received >20 units/day of MTI. More than 70.0% of physicians rated patient’s insulin dose, pattern of self-measured glucose levels, hemoglobin A1c (HbA1c) (clinical); adherence, hypoglycemia knowledge, motivation to improve lifestyle, desire to reduce injection volume and emotional struggle with controlling HbA1c (behavioral) as ‘very important’/‘absolutely important’ factors when prescribing IL200. Conclusion Physicians considered IL200 a promising treatment option that reduces the injection burden for patients on MTI. Physicians adopted a patient-centered perspective by aligning IL200 prescribing decisions with each patient’s medical needs and non-clinical preferences, with an aim to encourage treatment adherence through resorting to IL200’s advantageous attributes.
... Compared to insulin lispro 100, insulin lispro 200 showed also significant improvements in variability of fasting glucose, HbA1c, hypoglycemic rate and satisfaction with therapy. At the same time, 20 % insulin could be saved [143]. ...
Article
Full-text available
Background: There are limited data on the real-world evidence of Humalog 200 units/ml KwikPen (U-200) insulin. We assessed the use of U-200 insulin in UK routine clinical practice to provide information on clinical characteristics, treatment satisfaction and short-term clinical outcomes. Methods: Nine patients with type 2 diabetes who initiated U-200 in secondary care and a further 12 identified from primary care electronic database were enrolled. A treatment satisfaction questionnaire was administered to the 19 secondary care patients. Follow-up data on clinical parameters were collected at 3 and 6 months following initial U-200 insulin administration and the data were used to assess changes in clinical outcomes from baseline. Results: Secondary care patients had a mean age 60 ± 11 years, mean HbA1c of 8.6% ± 1.3% and a mean BMI of 39.7 ± 5.3 kg/m² at baseline. Primary care database patients had a mean age 57 ± 13 years, mean HbA1c 10.3% ± 1.7 and a mean BMI 42.3 ± 3.8 kg/m². The nine participants’ responses to the questionnaire suggested a high preference for U-200 over a previous mealtime insulin pen (PMIP). On average, the patients agreed that U-200 was quicker to inject, had a better controlled home blood glucose reading and less discomfort at the injection site compared to a PMIP. Patients were willing to continue with their U-200 treatment. No significant HbA1c reduction was observed at 3 months in the secondary care group (−0.5%), but marked significant reduction in HbA1c was seen at 3 months in the primary care dataset to (−2.8%; p < .0004). There was also some suggestion of weight loss in both the secondary and primary care groups. Conclusion: Humalog U-200 insulin users were comprised mainly of older patients with diabetes complications and high HbA1c levels at the time of U-200 initiation. Overall, U-200 improved patients’ satisfaction with diabetes treatment and short-term metabolic outcomes.
Article
Full-text available
BACKGROUND: Early optimized lifestyle and medication treatment can reduce the burden of type 2 diabetes mellitus (T2DM). Although Diabetologists take care of most Italian people withT2DMand are the only allowed to prescribe innovative drugs, still half T2DM patients are poorly controlled. AIMS: To verify specialists’ propensity to reach individualized glycemic goals by treating to target newly referred people with T2DM having HbA1c levels >7% (>53 mmol/mol). MATERIALS AND METHODS: 2536 poorly controlled, orally treated T2DM from all over Italy were evaluated and followed up for 6 months for appropriate nutritional and pharmacologic treatment in a specialized setting and diabetologists filled in a questionnaire on supposed reasons behind patients’ poor metabolic control and on their own therapeutic choices. RESULTS: At the first visit only 71.8% people underwent slight treatment adaptations (through a slight reduction of secretagogue utilization accompanied, to a lesser extent, by some increase in incretin prescription (from 13.4% to 33.5%; p < 001) and by de novo insulin administration (3.8%). Specialists stated three major reasons for poor control as observed at referral. Two of them, i.e. disease per se (secondary failure) and patients’ attitude (poor adherence), were high-rated, while the other one, addressing clinicians’ responsibility, was only marginally accounted for despite most diabetes specialists still going on with secretagogues all the time. Detailed results are provided within the text.
Article
Full-text available
Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes.
Article
Full-text available
Background Lipohypertrophy (LH) is a major complication of subcutaneous insulin treatment brought about by multiple overlapping injections and/or needle reuse. It is responsible for unacceptable glucose oscillations due to a high rate of hypoglycaemic episodes and rebound glucose spikes. Skin ultrasound scans (USS), the gold standard for its detection, is too expensive for screening purposes. AimsTo define a structured method allowing health professionals (HPs) to identify LH lesions as inexpensively and correctly as possible. Methods Out of 129 insulin-treated people with diabetes identified by USS as having LH lesions, only 40 agreed to participate in the study (24 females, age 54 ± 15 years, daily insulin dosage 57 ± 12 IU). Each was blindly examined by four well trained and four non-trained HPs according to a standard method involving repeated well codified maneuvers. ResultsA specific training allowed inexperienced HPs to acquire high diagnostic accuracy in identifying LH lesions independent of site, size, shape, and even BMI. This kind of training also allowed to reach a 97 % consistency rate among HPs as compared to USS, while the lack of training was associated with a wide variability and inconsistency of identification results. Conclusions Diabetes teams should follow systematically the simple procedure reported in this paper for the diagnosis of LH and try to get it further implemented and progressively refined in large scale studies. This would have a major impact on patient education in terms of (1) correct injection technique and (2) ability to identify lesions early enough to prevent poor metabolic outcome.
Article
Full-text available
Objective: in recent years, several initiatives have been launched by the Associazione medici diabetologi (AMD) in the context of a national quality improvement program. These activities include: identification of specific indicators of quality of diabetes care, development of a software to calculate such indicators by using routine clinical data, creation of a network of diabetes clinics and analysis and publication of the results in ad hoc reports (AMD Annals). Through the best performer approach, each centre could compare its own performance not only with the theoretical targets suggested by existing guidelines, but also with the results achieved by the best centres operating within the same healthcare system. We evaluated whether the involvement of diabetes clinics into the AMD Annals initiative improved the quality of care over 4 years. Design: a controlled before and after study was performed to compare data collected from 2004 to 2007 by two groups of centres: group A included centres that had been involved in the project since the first edition of AMD Annals; group B included centres only involved in the last edition. Setting and participants: overall, 124 diabetes clinics provided data on over 100,000 type 2 diabetes patients/year seen from 2004 to 2007. Main outcome measures: process indicators included the proportion of patients with at least one measurement of HbA1c, blood pressure and lipid profile during the previous 12 months. Intermediate outcomes included percentages of patients with levels of HbA1c <= 7%, blood pressure <= 130/85 mmHg and LDL-cholesterol <100 mg/dl (favourable indicators), and the percentages of patients with levels of HbA1c >= 9%, blood pressure >= 140/90 mmHg and LDL-cholesterol >= 130 mg/dl (unfavourable indicators). Percentages of patients treated with insulin, two or more antihypertensive agents, and statins were also evaluated A multilevel analysis adjusted forage, gender, diabetes duration, and clustering effect was applied to investigate the changes in the indicators between the two groups of centres during 4 years. Results: lipid profile monitoring increased more in group A (+62% from 2004 to 2007) than in group B (+2.4%), while HbA1c and blood pressure monitoring did not change over time in both groups. As for the outcomes considered, the percentage of patients with HbA1c <= 7% increased by 6% in group A and by 1.3% in group B, while the proportion of patients achieving the blood pressure target increased in group A (+6.4%), but not in group B (-1.4%). A reduction in the percentage of patients with blood pressure >= 140/90 mmHg was found in group A (-7.3%) but not in group B (-0.9%). Marked improvements in the proportion of patients with LDL-cholesterol at target were documented in both groups (group A: +10.5%; group 13: +12.2%.) The proportion of patients treated with insulin increased in group A only (+5.8%), while the use of statins grew by 20% in both groups. The proportion of individuals treated with two or more antihypertensive drugs increased by 3.6% in group A and by 1.6% in group B. Conclusion: the AMD Annals approach can be considered as a case model fin. pall, improvement activities in chronic diseases and a tool to evaluate the level of adoption/acceptance of guidelines in clinical practice. The considerable success documented was obtained without allocation of extra resources or financial incentives but simply through a physician-led effort made possible by the commitment of the specialists involved.
Article
Background: Intensive glucose control is understood to prevent complications in adults with type 2 diabetes. We aimed to more precisely estimate the effects of more intensive glucose control, compared with less intensive glucose control, on the risk of microvascular events. Methods: In this meta-analysis, we obtained de-identified individual participant data from large-scale randomised controlled trials assessing the effects of more intensive glucose control versus less intensive glucose control in adults with type 2 diabetes, with at least 1000 patient-years of follow-up in each treatment group and a minimum of 2 years average follow-up on randomised treatment. The prespecified and standardised primary outcomes were kidney events (a composite of end-stage kidney disease, renal death, development of an estimated glomerular filtration rate <30 mL/min per 1?73m(2), or development of overt diabetic nephropathy), eye events (a composite of requirement for retinal photocoagulation therapy or vitrectomy, development of proliferative retinopathy, or progression of diabetic retinopathy), and nerve events (a composite of new loss of vibratory sensation, ankle reflexes, or light touch). We used a random-effects model to calculate overall estimates of effect. Findings: We included four trials (ACCORD, ADVANCE, UKPDS, and VADT) with 27?049 participants. 1626 kidney events, 795 eye events, and 7598 nerve events were recorded during the follow-up period (median 5?0 years, IQR 4?5-5?0). Compared with less intensive glucose control, more intensive glucose control resulted in an absolute difference of -0?90% (95% CI -1?22 to -0?58) in mean HbA1c at completion of follow-up. The relative risk was reduced by 20% for kidney events (hazard ratio 0?80, 95% CI 0?72 to 0?88; p<0?0001) and by 13% for eye events (0?87, 0?76 to 1?00; p=0?04), but was not reduced for nerve events (0?98, 0?87 to 1?09; p=0?68). Interpretation: More intensive glucose control over 5 years reduced both kidney and eye events. Glucose lowering remains important for the prevention of long-term microvascular complications in adults with type 2 diabetes. Funding: None.
Article
OBJECTIVE in recent years, several initiatives have been launched by the Associazione medici diabetologi (AMD) in the context of a national quality improvement program.These activities include: identification of specific indicators of quality of diabetes care, development of a software to calculate such indicators by using routine clinical data, creation of a network of diabetes clinics and analysis and publication of the results in ad hoc reports (AMD Annals). Through the best performer approach, each centre could compare its own performance not only with the theoretical targets suggested by existing guidelines, but also with the results achieved by the best centres operating within the same healthcare system.We evaluated whether the involvement of diabetes clinics into the AMD Annals initiative improved the quality of care over 4 years. DESIGN a controlled before and after study was performed to compare data collected from 2004 to 2007 by two groups of centres: group A included centres that had been involved in the project since the first edition of AMD Annals; group B included centres only involved in the last edition. SETTING AND PARTICIPANTS overall, 124 diabetes clinics provided data on over 100,000 type 2 diabetes patients/year seen from 2004 to 2007. MAIN OUTCOME MEASURES process indicators included the proportion of patients with at least one measurement of HbA1c, blood pressure and lipid profile during the previous 12 months. Intermediate outcomes included percentages of patients with levels of HbA1c ≤ 7%, blood pressure ≤ 130/85 mmHg and LDL-cholesterol <100 mg/dl (favourable indicators), and the percentages of patients with levels of HbA1c ≥ 9%, blood pressure ≥ 140/90 mmHg and LDL-cholesterol ≥ 130 mg/dl (unfavourable indicators). Percentages of patients treated with insulin, two or more antihypertensive agents, and statins were also evaluated. A multilevel analysis adjusted for age, gender, diabetes duration, and clustering effect was applied to investigate the changes in the indicators between the two groups of centres during 4 years. RESULTS lipid profile monitoring increased more in group A (+6.2% from 2004 to 2007) than in group B (+2.4%), while HbA1c and blood pressure monitoring did not change over time in both groups. As for the outcomes considered, the percentage of patients with HbA1c ≤ 7% increased by 6% in group A and by 1.3%in group B, while the proportion of patients achieving the blood pressure target increased in group A (+6.4%), but not in group B (-1.4%). A reduction in the percentage of patients with blood pressure ≥ 140/90 mmHg was found in group A (-7.3%) but not in group B (-0.9%). Marked improvements in the proportion of patients with LDL-cholesterol at target were documented in both groups (group A: +10.5%; group B: +12.2%.) The proportion of patients treated with insulin increased in group A only (+5.8%), while the use of statins grew by 20%in both groups.The proportion of individuals treated with two or more antihypertensive drugs increased by 3.6% in group A and by 1.6% in group B. CONCLUSION the AMD Annals approach can be considered as a case model for quality improvement activities in chronic diseases and a tool to evaluate the level of adoption/acceptance of guidelines in clinical practice. The considerable success documented was obtained without allocation of extra resources or financial incentives but simply through a physician-led effort made possible by the commitment of the specialists involved.
Article
Best practice injection technique is critical to ensure optimal glycaemic control and prevent lipohypertrophy in people with diabetes who inject insulin. This article examines a case study to show that preventing lipohypertrophy with correct injection technique will also encourage better glycaemic stability. Injection site rotation and not re-using needles are shown to help in the prevention of lipohypertrophy. People should not accept lipohypertrophy as a given consequence of using injectable therapy, and rather focus on correct injection technique to reduce risk. Diabetes healthcare professionals have a duty to thoroughly check an individual's injection technique and inform and re-educate where applicable. Healthcare practitioners should be vigilant as people using injectable therapies may not always notice important changes.
Article
Glide force, average glide force, and glide force variability of the insulin lispro 200 units/mL pen (Eli Lilly and Company, Indianapolis, IN, USA) were compared to the Humalog® KwikPen® 100 units/mL pen (hereafter, KwikPen; Eli Lilly and Company, Indianapolis, IN, USA). Data were collected on 2 doses, 2 injection speeds, and 2 needle types. Insulin lispro 200 units/mL pen showed significantly lower maximum glide force, average glide force, and glide force variability than the KwikPen across all combinations of dose size, dose speed, and needle type. The lower glide force observed with the insulin lispro 200 units/mL pen offers another treatment option for patients with type 1 or type 2 diabetes who require greater than 20 units of mealtime insulin daily. © 2015 Diabetes Technology Society.
Article
Limited joint mobility at the shoulder is an understudied problem in people with diabetes mellitus. The purpose of this study was to determine the differences in shoulder kinematics between a group with diabetes and those without diabetes.