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Diabetes Research
and Clinical Practice
journa l home page: www.e lse vier.com/locate/diabres

Insulin regimens and glycemic control in different


parts of Europe over 4 years after starting insulin in
people with type 2 diabetes: Data from the CREDIT
non-interventional study

Lawrence Blonde a,*, Michel Marre b, Maya Vincent c, Sandrine Brette d, Valerie Pilorget c,
Nicholas Danchin e, Giacomo Vespasiani f, Philip Home g
a
Ochsner Medical Center, Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology,
New Orleans, LA, USA
b
Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique des Hopitaux de Paris, INSERM U 695, Universite Paris 7, Paris, France
c
Sanofi, Paris, France
d
Lincoln, Boulogne-Billancourt, France
e
Division of Coronary Artery Disease and Intensive Cardiac Care, Universite Paris 5, Paris, France
f
Diabetology and Metabolic Disorders Centre, Madonna del Soccorso Hospital, San Benedetto del Tronto, Italy
g
Institute of Cellular Medicine Diabetes, Newcastle University, Newcastle upon Tyne, United Kingdom

A R T I C L E I N F O A B S T R A C T

Article history: Aims: A number of insulin regimens are used in type 2 diabetes. This analysis aims to bet-
Received 8 July 2016 ter understand the evolution of insulin therapy in different regions of Europe.
Received in revised form Methods: Data from people starting any insulin were collected in eastern Europe (EEur:
24 March 2017 Croatia, Russia, Ukraine), northern Europe (NEur: Finland, Germany, UK) and southern Eur-
Accepted 21 August 2017 ope (SEur: France, Italy, Portugal, Spain). Retrospective data on starting insulin and
Available online 31 August 2017 prospective follow-up data were extracted from clinical records.
Results: At 4 years, 1699 (76.0%) of 2236 eligible people had data. EEur participants were
mostly female, younger and had shorter diabetes duration on starting insulin, yet had high-
Keywords:
est baseline HbA1c and more micro-/macrovascular disease. A majority (60%64%) in all
CREDIT
regions started on basal insulin alone, declining to 30%38% at 4 years, with most switching
Non-interventional study
to basal + mealtime insulin regimen (24%40%). Higher baseline (28%) and 4-year use (34%)
Insulin regimens
of premix insulin was observed in NEur. Change in HbA1c (SD) ranged from 1.2 (2.1)% ( 13
Glucose-lowering mediations
[23] mmol/mol) in NEur to 2.4 (2.0)% ( 26 [22] mmol/mol) in EEur. Weight change ranged
Glycemic control
from +1.9 (8.3) kg in NEur to +3.2 (7.0) kg in SEur. Overall documented hypoglycemia ranged
Hypoglycemia
from 0.3 (1.3) to 1.3 (4.4) events/person/6-months (NEur vs. EEur, respectively) and was
stable with time. Severe hypoglycemia rates remained low.
Conclusion: When starting insulin, HbA1c and prevalence of complications were higher in
EEur. Regional differences exist in choice of insulin regimens in Europe. However, people
starting insulin improved and sustained their glycemic control regardless of regional differ-
ences or insulin regimens used.
2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author at: Ochsner Medical Center, Department of Endocrinology, 1514 Jefferson Highway, New Orleans, LA 70121,
USA.
E-mail address: lblonde@ochsner.org (L. Blonde).
http://dx.doi.org/10.1016/j.diabres.2017.08.016
0168-8227/ 2017 The Authors. Published by Elsevier Ireland Ltd.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
diabetes research and clinical practice 1 3 3 ( 2 0 1 7 ) 1 5 0 1 5 8 151

1. Introduction nephropathy, retinopathy and/or peripheral neuropathy.


Macrovascular disease was defined as having myocardial
Insulin therapy is generally started when people with type 2 infarction, stable angina, severe unstable angina leading
diabetes on oral therapies can no longer attain the recom- to hospitalization, heart failure, stroke, transient ischemic
mended targets for blood glucose control. Various types of attack, peripheral vascular disease, myocardial revascular-
insulin have been recommended [13], with some authorities ization, peripheral revascularization and/or lower limb
sanctioning basal or premix, while others emphasize basal amputation. High blood pressure was defined as
insulin only. Mealtime insulin alone is occasionally recom- 130/80 mmHg.
mended when starting insulin as is a mealtime + basal insulin Starting insulin regimens were classified as basal, basal
regimen [4]. Evidence on the relative efficacy of insulin regi- + mealtime, mealtime, premix and other, where other was a
mens has been provided in randomized clinical trials [5,6], mix of these. There was no fixed study visit schedule, and
but these trials may not be representative of the people and insulin choice, dosage, titration and concomitant oral agent
clinical environments found in routine clinical practice. Some therapy were according to usual local practice. Data were
of the challenges of generalizability intrinsic to randomized gathered from routine clinical practice from people starting
trials may be overcome in non-interventional observational any insulin in E Europe (Croatia, Russia, Ukraine), N Europe
studies, and they may be a bridge toward more routine clini- (Finland, Germany, United Kingdom) and S Europe (France,
cal settings [4]. Italy, Portugal, Spain).
The Cardiovascular Risk Evaluation in People With Type 2 Physicians were asked to report updated data every
Diabetes on Insulin Therapy (CREDIT) study, an interna- 6 months. Data at 1, 2, 3 and 4 years represent those ascer-
tional, 4-year, non-interventional, longitudinal study, was tained 918, 1830, 3042, and 4254 months after starting
designed to evaluate, in routine clinical practice, the rela- insulin, respectively. Glucose control was assessed by HbA1c,
tionship between blood glucose control and cardiovascular fasting plasma glucose (FPG) and postprandial plasma glu-
events in people beginning any insulin and to provide cose (PPPG). HbA1c is presented in both National Glycohe-
insight into current medical practice in people with type 2 moglobin Standardization Program and International
diabetes using insulin [7]. The study was conducted in Federation of Clinical Chemistry units, locally measured
Canada, Japan and 10 countries in Europe from December [11,12]. FPG and PPPG are reported as either laboratory- or
2006 to May 2012. Baseline data and 1- and 4-year blood self-monitored glucose values. PPPG values were obtained
glucose-related results have been reported in detail for the approximately 2 h post-meal. Documented symptomatic
overall population [710]. hypoglycemia, nocturnal hypoglycemia and severe hypo-
The aim of the current study was to dissect out some of the glycemia were assessed retrospectively over the 6 months
differences in clinical practice when starting insulin in differ- prior to the follow-up visit date. Symptomatic hypoglycemia
ent parts of Europe, specifically in terms of the population was an event with clinical symptoms confirmed by blood
starting insulin, insulin regimens used, and concomitant ther- glucose 3.9 mmol/l. Nocturnal hypoglycemia was hypo-
apies, and resultant outcome. We hoped to gain a better glycemia that occurred while the patient was asleep, after
understand of the diversity of clinical behavior and perhaps bed-time and before getting up in the morning. Severe hypo-
shed light on the reasons for some of the differences. To main- glycemia was an event that required assistance of another
tain reasonable pools of data, we report blood glucose-related person and either confirmed blood glucose <2.0 mmol/l or
outcomes at 4 years in study-defined regions of eastern (E), prompt recovery after oral carbohydrate, intravenous glu-
northern (N) and southern (S) Europe, concentrating on char- cose or glucagon administration. Changes of insulin regi-
acteristics when starting insulin, choice of insulin regimen, men, other glucose-lowering medications and body weight
evolution of insulin therapy and metabolic outcomes. change were assessed.

2. Materials and methods 2.1. Statistical methods

The CREDIT study design, site/participant selection pro- Analyses were performed with SAS software, version 9.2
cess and participant baseline characteristics have been (Cary, NC, USA). All data are reported and analyzed using
reported previously [7]. Ethical approval was obtained descriptive statistics. All data (when starting insulin and
for all study sites. Study conduct adhered to data collec- yearly data) are presented for each regional population. The
tion standards for clinical trials, according to the Declara- percentage and 95% CIs of participants on individual insulin
tion of Helsinki. All participants gave written informed regimens are presented for each regional population. Com-
consent prior to enrollment. Men and women aged parative statistical testing was not performed because of the
>40 years with type 2 diabetes were eligible if they had likelihood of some degree of allocation bias, avoiding the dan-
started any insulin regimen >1 month and <12 months ger of spurious statistically significant findings with the high
prior to study entry and had an HbA1c measurement numbers of people studied.
within 3 months before beginning insulin. Data when
starting insulin were collected retrospectively from 3. Results
clinical records and included micro-/macrovascular dis-
ease and high blood pressure as well as starting insulin A total of 2236 (74.6%) of the 2999 eligible participants were
regimen. Microvascular disease was defined as having from Europe: 735 from E Europe, 460 from N Europe and
152 diabetes research and clinical practice 1 3 3 ( 2 0 1 7 ) 1 5 0 1 5 8

1041 from S Europe (Supplemental Table 1). Of those 2236 par- 3.1. Insulin regimens
ticipants, 1699 (76.0%) had 4-year data. There were differences
in baseline characteristics between regions (Table 1). More Approximately 60%64% of participants in all three regions
participants from E Europe were female, younger and had initiated insulin with only a basal formulation, and use of this
shorter diabetes duration, yet had higher HbA1c and had at 4 years had declined in all to 30%38% of participants, with
more micro-/macrovascular disease when beginning insulin the biggest fall in N Europe (Fig. 1). A basal + mealtime regi-
than those from the other regions. In each region, the base- men had the greatest use at baseline in E Europe (15%) and
line characteristics of participants without 4-year data were had a slightly lower use in S Europe. However, there was a
similar to those of all participants in that region (Supplemen- marked increase in use of this regimen in all regions by
tal Table 2). 4 years, again most notably in E Europe (40% at 4 years), with
Across the regions, 73%100% of the 228 physicians were the least increase in N Europe. Premix insulin had the greatest
specialists (diabetologist/endocrinologist/internist) in an baseline use in N Europe (28%), expanding by 4 years to 34%,
urban location (68100%). The percentage of physicians with but with no change in E Europe (22% at both times) and little
their practice office-based, hospital-based or both was change (13%16%) in S Europe. Accordingly, participants in all
25.0%, 43.8% and 31.3% in E Europe; 40.0%, 52.5% and 7.5% regions appear to be moving primarily to a basal bolus regi-
in N Europe; and 48.9%, 16.8% and 34.3% in S Europe. Most men with time. Few participants in any region started on
physicians were males in N Europe (65.0%) and S Europe mealtime (2%5%) or other insulin regimens (0.4%6%), with
(55.1%), whereas 91.8% were female in E Europe. proportions remaining below 10% at 4 years. However, while

Table 1 Demographic and clinical characteristics when starting insulin by region in Europe.
E Europe (n = 735) N Europe (n = 460) S Europe (n = 1041)

Age, years 58 (8) 63 (11) 63 (11)


Female, n (%) 554 (75) 178 (39) 458 (44)
Body weight, kg 83.0 (15.5) 90.0 (19.4) 79.8 (16.7)
Body mass index, kg/m2 30.7 (5.4) 31.5 (6.3) 29.5 (5.9)
Duration of diabetes, years 8 (5) 9 (6) 13 (9)
1 microvascular disease, n (%) 633 (86) 291 (63) 571 (55)
1 macrovascular disease, n (%) 346 (47) 161 (35) 308 (30)
Prior diagnosis of high blood pressure, n (%) 574 (78) 350 (76) 684 (66)
Family history of premature CVD, n (%) 337 (46) 132 (29) 159 (15)
Physical exercise, n (%) 465 (63) 223 (49) 398 (38)
Never smoked/stopped smoking 1 year, n (%) 653 (89) 353 (77) 857 (82)
Other glucose-lowering medication, n (%)
1 547 (74) 359 (78) 743 (71)
1 320 (44) 178 (39) 315 (30)
2 220 (30) 159 (35) 339 (33)
3 7 (1) 22 (5) 89 (9)
Metformin 317 (43) 305 (66) 577 (55)
Sulfonylurea 417 (57) 200 (43) 445 (43)
Glinides 21 (3) 9 (2) 110 (11)
Thiazolidinediones 24 (3) 41 (9) 71 (7)
a-Glucosidase inhibitor 2 (0.3) 4 (0.9) 52 (5.0)
GLP-1 receptor agonist 0 (0) 0 (0) 0 (0)
DPP-4 inhibitor 0 (0) 2 (0.4) 0 (0)
Other 0 (0) 2 (0.4) 9 (0.9)
1 other long-term treatmenta, n (%) 631 (86) 424 (92) 851 (82)
HbA1c, % 9.7 (1.9) 9.1 (2.0) 9.3 (1.9)
HbA1c, mmol/mol 83 (21) 76 (22) 78 (21)
FPG, mmol/l 11.7 (3.1) 10.6 (3.4) 11.9 (3.9)
PPPG, mmol/l 13.7 (3.6) 14.3 (5.3) 13.7 (4.4)
Managing physician (n (%))
Primary care/generalist 0 (0.0) 107 (23.3) 141 (13.6)
Specialist 722 (100.0) 353 (76.7) 892 (86.4)
Type of practice (n (%))
Office-based 189 (26.6) 219 (47.6) 371 (35.9)
Hospital-based 335 (47.2) 210 (45.7) 392 (37.9)
Both 186 (26.2) 31 (6.7) 270 (26.1)
Mean (SD) or n (%).
a
Includes a-blockers, b-blockers, calcium channel blockers, diuretics, angiotensin II receptor blockers/ACE inhibitors, vasodilators (including
nitrates), statins, fibrates, antiplatelets and anticoagulants.
diabetes research and clinical practice 1 3 3 ( 2 0 1 7 ) 1 5 0 1 5 8 153

participants were prescribed basal insulin alone (61% vs 20%)


and basal + mealtime insulin (64% vs 33%) by office-based
physicians, whereas more were prescribed pre-mix insulin
by hospital-based physicians (63% vs 33%). In S Europe, more
participants were prescribed basal insulin alone (49% vs 22%)
and pre-mix insulin (36% vs 24%) by office-based physicians,
whereas more were prescribed basal + mealtime insulin
(68% vs 21%) and other insulin (55% vs 27%) by hospital-
based physicians. The percentage of participants prescribed
an insulin regimen by physicians with both an office- and
hospital-based practice ranged from 17%32% in E Europe;
2.5%11% in N Europe; and 18%40% in S Europe, with the
highest percentage observed with basal insulin alone in E Eur-
ope and N Europe and with pre-mix insulin in S Europe. Over-
all, similar results were observed when starting insulin.

3.2. Other glucose-lowering medications

Of the eligible participants starting insulin, 71%78% were


taking 1 other glucose-lowering medication across regions
(Table 1). The proportion of participants taking only one other
glucose-lowering medication when starting insulin ranged
from 30% in S Europe to 44% in E Europe, while a similar pro-
portion across regions were taking two other medications
(30%35%). Those taking 3 other glucose-lowering medica-
tions ranged from 1% in E Europe to 9% in S Europe. Met-
formin use was lower (43%) and sulfonylurea use greater
(57%) in E Europe than in the other regions; use of glucose-
lowering medications other than metformin or sulfonylurea
was limited in all regions.
Across regions at 4 years, 62%67% were taking 1 other
glucose-lowering medication (Table 2). Similar proportions
of participants were taking one (37%44%) or two (15%22%)
other glucose-lowering medication across regions, while
those taking 3 other medications ranged from 0.4% in E Eur-
ope to 8% in S Europe. Metformin use across regions at 4 years
Fig. 1 Evolution of basal, basal + mealtime and premix was similar to that when starting insulin, whereas sulfony-
insulin regimens over 4 years in E Europe (A), N Europe (B), lurea use across regions declined to 15%29%. Use of
and S Europe (C). Not shown are the least used insulin glucose-lowering medications other than metformin or sul-
regimens. Respectively, mealtime insulin was 2.2%, 3.9% fonylurea, while still low, did increase in all regions. This
and 5.3% (start) and 0.3%, 4.2% and 1.0% (4-year) in E Europe, increase was predominantly due to use of
N Europe and S Europe, and other insulin was 0.7%, 0.4% dipeptidylpeptidase-4 (DPP-4) inhibitors in E Europe and to
and 6.4% (start) and 1.3%, 0.6% and 8.9% (4-year). At 4 years, DPP-4 inhibitors and glucagon-like peptide-1 receptor (GLP-
no insulin was 0.3%, 7.2% and 4.4% in the respective 1R) agonists in N and S Europe.
regions.
3.3. Insulin dose

7% had discontinued insulin in N Europe at 4 years, this was The mean (SD) total daily starting dose of insulin was lower in
true of 4% in S Europe but <1% in E Europe. Few in N Europe N Europe (0.20 [0.18] U/kg) than in E Europe (0.29 [0.19] U/kg)
started on a basal + mealtime insulin regimen (7%), while and S Europe (0.27 [0.18] U/kg in). However, the greatest
few in S Europe started on premix (13%). For participants with increase to the highest level at 4 years was in N Europe (0.64
4 years of data, 52% in E Europe, 63% in N Europe and 59% in S [0.46] U/kg), with lesser but similar changes in the other two
Europe remained on their starting regimen for all 4 years. regions (Table 2; Fig. 2).
More of these participants across regions (48%61%) remained
on basal insulin than any other regimen; in N Europe, 39% 3.4. Blood glucose control
also remained on premix.
At 4 years, more participants in E Europe were prescribed Mean (SD) HbA1c when starting insulin was highest in E
basal insulin alone (42% vs 26%), basal + mealtime insulin Europe (9.7 [1.9]%; 83 [21] mmol/mol) and lowest in N Europe
(43% vs 32%) and pre-mix insulin (62% vs 20%) by hospital- (9.1 [2.0]%; 76 [22] mmol/mol) (Fig. 2). However, by 4 years
based rather than office-based physicians. In N Europe, more this reversed, being the lowest in E Europe (7.3 [1.1]%; 56
154 diabetes research and clinical practice 1 3 3 ( 2 0 1 7 ) 1 5 0 1 5 8

Table 2 Glucose-lowering medications, insulin dose, glycemic control, body weight, and hypoglycemia at 4 years by region
in Europe.

E Europe N Europe S Europe

n (%) 676 (100) 334 (100) 689 (100)


Other glucose-lowering medication, n (%)
1 419 (62) 209 (63) 462 (67)
1 276 (41) 147 (44) 255 (37)
2 140 (21) 51 (15) 154 (22)
3 3 (0.4) 11 (3) 53 (8)
Metformin 305 (45) 187 (56) 366 (53)
Sulfonylurea 199 (29) 50 (15) 146 (21)
Glinides 16 (2) 5 (2) 91 (13)
Thiazolidinediones 20 (3) 3 (1) 23 (3)
a-Glucosidase inhibitor 0 (0) 2 (1) 25 (4)
GLP-1 receptor agonist 0 (0) 19 (6) 22 (3)
DPP-4 inhibitor 26 (4) 15 (4) 56 (8)
Other 0 (0) 1 (<1) 0 (0)
Insulin dose, U/kg
Start 0.29 (0.19) 0.20 (0.18) 0.27 (0.18)
4 year 0.58 (0.23) 0.64 (0.46) 0.52 (0.28)
HbA1c, % units
Start 9.7 (1.9) 9.1 (2.0) 9.3 (1.9)
4 year 7.3 (1.1) 7.9 (1.4) 7.7 (1.3)
Change 2.4 (2.0) 1.2 (2.1) 1.6 (2.0)
HbA1c, mmol/mol
Start 83 (21) 76 (22) 78 (21)
4 year 56 (12) 63 (15) 61 (14)
Change 26 (22) 13 (23) 17 (22)
FPG, mmol/l
Start 11.6 (2.9) 10.5 (3.1) 11.7 (3.7)
4 year 7.2 (1.8) 7.9 (2.6) 8.2 (2.7)
Change 4.5 (3.2) 2.5 (3.8) 3.5 (4.4)
PPPG, mmol/l
Start 13.6 (3.4) 13.7 (5.0) 14.0 (4.2)
4 year 8.7 (2.2) 10.5 (4.1) 9.6 (3.3)
Change 4.9 (3.7) 3.3 (5.4) 4.7 (5.0)
Documented symptomatic hypoglycemia
People with 1 event, n (%) 140 (21) 40 (12) 98 (14)
Overall rate (events/person/6 months) 1.34 (4.37) 0.35 (1.26) 0.92 (3.37)
Nocturnal rate (events/person/6 months) 0.33 (1.16) 0.07 (0.56) 0.17 (0.94)
Severe hypoglycemia
People with 1 event, n (%) 32 (5) 3 (1) 6 (1)
Overall event rate (events/person/6 months) 0.24 (1.38) 0.01 (0.09) 0.01 (0.09)
Nocturnal rate (events/person/6 months) 0.05 (0.34) 0.00 (0.05) 0.00 (0.00)
Body weight, kg
Start 83.2 (15.4) 90.7 (19.4) 79.1 (16.5)
4 year 86.1 (14.4) 92.7 (20.8) 82.2 (17.2)
Change +3.0 (7.8) +1.9 (8.3) +3.2 (7.0)
Data are mean (SD) or n (%).

[12] mmol/mol) and highest in N Europe (7.9 [1.4]%; 63 [15] lower in N Europe (10.6 [3.4] mmol/l) (Fig. 2). FPG at 4 years
mmol/mol). Accordingly, the change in HbA1 c at 4 years declined to 7.2 [1.8], 8.2 [3.7] and 7.9 [2.6] mmol/l, respectively.
was 2.4 (2.0)% (23 [22] mmol/mol) in E Europe but 1.2 Thus, change in FPG at 4 years was greatest in E Europe
(2.1)% ( 13 [23] mmol/mol) in N Europe (Table 2). HbA1c ( 4.5 [3.2] mmol/l) and least in N Europe ( 2.5 [3.8] mmol/l)
<7.0% was achieved at 4 years by 40% of participants in E (Table 2). Mean (SD) PPPG was initially 13.7 [3.6], 14.3 [5.3]
Europe, 30% in N Europe and 32% in S Europe. and 13.7 [4.4] mmol/l in E, N and S Europe and declined at
Mean (SD) FPG when starting insulin was similar in E Eur- 4 years to 8.7 [2.2], 10.5 [4.1] and 9.6 [3.3] mmol/l (Fig. 2).
ope (11.7 [3.1] mmol/L) and S Europe (11.9 [3.9] mmol/L), but The change in PPPG at 4 years was 4.9 [3.7], 3.3 [5.4] and
diabetes research and clinical practice 1 3 3 ( 2 0 1 7 ) 1 5 0 1 5 8 155

Fig. 2 Evolution of HbA1c (A), FPG (B), PPPG (C), insulin dose (D) and change in body weight (E) over 4 years, with proportion of
people having at least one documented hypoglycemia episode in the 6 months before each year interval (F) by region in
Europe. Data (A-E) are mean (SD).

4.7 [5.0] mmol/l (Table 2). Most of the decline in HbA1c, FPG documented symptomatic hypoglycemia in E Europe in years
and PPPG occurred in the first year (Fig. 2). 14 was 0.82 [2.28], 0.93 [2.89], 1.10 [3.38] and 1.34 [4.37]
events/person-6-months. In N Europe this was 0.51 [2.25],
3.5. Hypoglycemia 0.46 [2.02], 0.30 [1.32] and 0.35 [1.26] events/person-6-
months, and in S Europe 1.01 [4.19], 1.07 [5.00], 0.76 [2.73]
Reported hypoglycemia by any measure tended to be highest and 0.92 [3.37] events/person-6-months. The rate of docu-
in E Europe and lowest in N Europe. Thus, the percentage of mented nocturnal symptomatic hypoglycemia episodes in
participants who reported at least one hypoglycemia episode years 14 was 0.18 [0.69], 0.19 [0.82], 0.26 [0.99] and 0.33
in the last 6 months of each year ranged from a high of 22.6% [1.16] events/person-6-months in E Europe; 0.13 [0.75], 0.09
at year 2 to a low of 20.7% at year 4 in E Europe, from 12.3% at [0.76], 0.07 [0.54] and 0.07 [0.56] events/person-6-months in
year 1 to 8.3% at year 4 in N Europe and from 16.6% at year 1 to N Europe; and 0.11 [0.70], 0.10 [0.61], 0.07 [0.42] and 0.17
14.2% at year 4 in S Europe (Fig. 2). The rate (SD) of [0.94] events/person-6-months in S Europe. The proportion
156 diabetes research and clinical practice 1 3 3 ( 2 0 1 7 ) 1 5 0 1 5 8

of participants in E Europe who reported at least one severe In the current study, weight gain was similar in the three
hypoglycemia episode was 3.6%, 4.1%, 5.2% and 4.7% in the regions, albeit in the context of the less improvement in glu-
last 6 months of years 14. In N Europe, these proportions cose control in N Europe. Baseline body weight appeared to
appear lower at 0.5%, 0.8%, 1.4% and 0.9%, as also in S Europe differ, but is broadly consistent with WHO population data
at 1.0%, 0.8%, 0.5% and 0.9%. suggesting obesity is a particular problem in two of our north-
In S Europe the incidence of documented symptomatic ern European countries, intermediate in eastern Europe and
hypoglycemia tended to be higher in participants taking insu- less of a problem in Italy [15], perhaps reflecting known cul-
lin alone, compared with the groups using oral agents (includ- tural differences in eating. Reported hypoglycemia was also
ing/not including a sulfonylurea) in addition to insulin lower in this region. Possible explanations are differences in
(Supplemental Table 3). Within the other regions incidence attitudes to recording hypoglycemic symptoms, or because
was similar between the three groups. The event rates, and expectations of people with diabetes and/or their clinicians
incidence of severe hypoglycemia, had too high variance to over hypoglycemia and weight gain differed.
allow valid judgement between regions. In all regions, basal insulin was most commonly used to
initiate insulin therapy. However, patterns of insulin use did
3.6. Body weight change differ over time. A prandial + basal regimen was already more
common in E Europe when starting insulin, perhaps reflecting
Body weight differed at starting insulin between the three the poorer initial glucose control, and became dominant with
regions (Table 1). Mean (SD) body weight at 4 years increased time. This was not true of N Europe, where premix use,
most in S Europe (3.2 [7.0] kg) and in E Europe (3.0 [7.8] kg), but already high as a starting regimen, was used by one-third of
by 1.9 [8.3] kg in N Europe (Table 2); most of the gain occurred participants by 4 years, compared with around a quarter still
in the first year (Fig. 2). on basal and a quarter on a basal bolus regimen. Premix use
could be related to patient preferences for a lower number
of injections.
4. Discussion Stopping insulin, presumably switching to oral therapies
in those in whom glucose control had improved, was rare in
The CREDIT study assessed the relationship between blood E Europe but occurred in a significant percentage of people
glucose control and cardiovascular events in people with type in N Europe. Whether this relates to differences in physician
2 diabetes beginning any insulin regimen in real-world med- practice, such as a higher preference for non-insulin thera-
ical practice. Overall results have been published elsewhere pies or better adherence to lifestyle changes, is unclear. In
[7]. From this study, we report the evolution of different insu- the overall population, people stopping insulin had the best
lin regimens and blood glucose control change over 4 years in final glucose control [7]. An alternative explanation, in a
E, N and S Europe, concentrating on the differences between non-interventional study like CREDIT, is the presence of
regions and identifying clinically relevant differences. Indeed, unknown differences in the patient populations in different
it seems that the populations with type 2 diabetes starting regions; for example, people starting insulin at the time of
insulin in the three defined regions differed, with the E Euro- an acute metabolic crisis or hospital admission for another
pean group starting in poorer glucose control but achieving a reason might be more likely to be able to stop it again
greater reduction in HbA1c even in the first year. The figures subsequently.
for this group are not dissimilar from the overall data in the The difference in metformin and sulfonylurea use is not
A1chieve study, performed in non-Western countries [4]. In unexpected; sulfonylureas were always the mainstay of oral
that study, the authors attributed the large improvements in agent therapy in Europe until after the UKPDS study reports
glucose control as much to changes in patient education [16,17], and the metformin evidence base seems to have had
and behavior as to the insulins themselves, largely because a lower/slower impact in E Europe than in W Europe, where
in that study body weight did not increase and hypoglycemia IDF and EASD guidelines have had significant impact. How-
was minimal, independent of the insulin used. By contrast, ever, even in the 4 years of study, some evolution is seen in
HbA1c in N Europe was lower when insulin was started that regard, though the impact of weight gain and hypo-
(though still poor) and decreased the smallest amount despite glycemia may also have been significant in driving the change
reasonable insulin dosage, perhaps suggesting the gain in in balance of oral agents.
control here was to a greater extent due to the insulin rather The study has a number of limitations. Compared with the
than improved patient education and motivation. other regions, a greater percentage of participants from E Eur-
Although there were marked differences in type of physi- ope were women, though this does not seem to impact dura-
cian involved in starting insulin between the regions (Table 1), tion of diabetes, body mass index and macrovascular
these reflect some known factors such as the high number of complications in ways that might be expected. This bias
diabetologist specialists in Italy, the long-standing predomi- may be related to evidence from other studies suggesting that
nance of women as specialists in ex-Soviet countries and dif- men in this region may have less awareness of health issues,
ferences in structure of care in individual countries in Europe, be more reluctant to visit doctors and have a lower level of
with no regional pattern [13,14]. Therefore it does not seem self-care health [8], but might also be related to recruitment
possible to attribute differences in baseline characteristics bias related to time off from employment or willingness to
or care provided when starting insulin to physician share data. It is not, however, possible to know whether a
characteristics. more typical proportion of men, as in the other regions,
diabetes research and clinical practice 1 3 3 ( 2 0 1 7 ) 1 5 0 1 5 8 157

would have brought the E European data more into line with Eli Lilly, GlaxoSmithKline, Merck, Novartis, Novo Nordisk,
those from S and N Europe, or resulted in a greater deviation. Pfizer, Sanofi, Servier and The Medicines Company. G.V. has
It is also possible that cultural and medical care considera- served on advisory panels for Eli Lilly, Novo Nordisk, Roche
tions affected reporting of rates of hypoglycemia, which are Diagnostics, GlaxoSmithKline, Meteda and Sanofi and has
known to vary widely between studies. However, our defini- received research support from Lifescan. P.H., either personally
tions depend on confirmation by self-monitoring, so if any- or through institutions with which he is associated, receives
thing, one might expect the greater access in W Europe to funding for research, advisory and educational activities from
give higher rates, the opposite of what was found. most insulin and oral agent manufacturers, including Eli Lilly,
Irrespective of the regimen, the mean starting dose of Novo Nordisk and Sanofi.
insulin was generally lower in N Europe, but the dose at The funding source (Sanofi) participated in initial discus-
4 years was generally higher than in other regions. Again, this sions about trial design, participated in the respective study
suggests greater initial therapeutic caution in these countries, steering committees and performed the data analysis and
with the poorer glucose control driving dose titration in time. preparation of study reports. Company representatives are
Examination of data pertaining to age, duration of diabetes, named as authors on the manuscript and contributed to its
body mass index or concomitant medication use does not development as described in the authors contributions. The
suggest these as explanations. authors had access to all data and participated in the analysis
This sub-analysis is encouraging in confirming the overall and interpretation of data. The authors vouch for the com-
study results, that patients in all regions had a marked and pleteness and veracity of the data and analyses.
sustained (4-year) reduction in HbA1c after beginning insulin
and that the rates of hypoglycemia including severe hypo- Contributions
glycemia and nocturnal hypoglycemia were relatively modest
and did not increase with time. L.B. contributed to the data analysis and writing of the manu-
In conclusion, in different parts of Europe, insulin in the script. M.M. contributed to the study design and writing. M.V.
CREDIT study was initiated at different levels of glucose con- contributed to the data analysis and writing. S.B. contributed
trol, with some notable differences in evolution of insulin reg- to the data analysis and critical re-reading of the manuscript.
imens and of reported hypoglycemia. The findings may relate V.P. contributed to the study design, study conduct/data col-
to differences in medical practice and resources. Neverthe- lection, data analysis and writing. N.D. contributed to the
less, the findings are generally positive in all regions, perhaps study design, study conduct/data collection, data analysis
more so where the baseline situation was poorer, and the and writing the manuscript. G.V. contributed to the study
improvements were generally sustained, independent of the design, data collection and writing. P.H. contributed to the
insulin regimen used. study design, study conduct/data collection, data analysis
and writing of the manuscript.
Acknowledgments
Appendix A. Supplementary materials
The CREDIT study was funded by Sanofi. Editorial support
was provided by Tom Claus, PhD, of PPSI (a PAREXEL com- Supplementary data associated with this article can be found,
pany), funded by Sanofi. in the online version, at http://dx.doi.org/10.1016/j.diabres.
2017.08.016.

Conflict of interest
R E F E R E N C E S
L.B. has served on advisory panels for AstraZeneca,
GlaxoSmithKline, Intarcia Therapeutics, Inc., Janssen Pharma-
ceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Quest Diagnos-
[1] International Diabetes Federation.IDF Clinical Guidelines
tics and Sanofi; has served on speaker bureaus for
Task Force. Global guideline for Type 2 diabetes. International
AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Novo Diabetes Federation Web site. https://www.aace.com/files/
Nordisk and Sanofi; either personally or through his institution dm-guidelines-ccp.pdf [accessed 03.04.13].
has received research support from AstraZeneca, Eli Lilly and [2] Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E,
Company, Janssen Pharmaceuticals, Inc., Merck & Co., Lexicon Nauck M, et al. Management of hyperglycemia in type 2
Pharmaceuticals, Inc., Novo Nordisk, Inc. and Sanofi. M.M., diabetes: a patient-centered approach: position statement of
the American Diabetes Association (ADA) and the European
either personally or through institutions with which he is asso-
Association for the Study of Diabetes (EASD). Diabetes Care
ciated, receives funding for research, advisory and educational 2012;35(6):136479.
activities from most insulin and oral agent manufacturers, [3] NICE. Blood-glucose-lowering therapy for type 2 diabetes.
including Sanofi. M.V. and V.P. are employees of Sanofi. S.B. is National Institute for Health and Care Excellence.
a consultant to Sanofi. N.D. has received research grants from <http://pathways.nice.org.uk/pathways/diabetes#path=view
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