DIABETICMedicine

DOI: 10.1111/dme.12806

Research: Educational and Psychological Issues

Twice- rather than once-daily basal insulin is associated with better
glycaemic control in Type 1 diabetes mellitus 12 months after
skills-based structured education in insulin self-management

1 2 3 4 5
H. E. Hopkinson , R. M. Jacques , K. J. Gardner , S. A. Amiel and P. Mansell
1 2 3 4 5
New Victoria Hospital, Glasgow, University of Sheffield, University of Dundee, King’s College London and Nottingham University Hospitals NHS Trust, UK

Accepted 13 May 2015

Abstract
Aim This study investigates the relationship between basal insulin regimen and glycaemic outcomes 12 months after skills-based
structured education in the UK Dose Adjustment for Normal Eating (DAFNE) programme for Type 1 diabetes mellitus.

Method Retrospective analysis of data from 892 DAFNE participants from 11 UK centres.
Results Mean HbA1c 12 months after DAFNE was lower in those using twice- rather than once-daily basal insulin after correcting
for differences in baseline HbA1c, age and duration of diabetes; difference –2 (95% CI –3 to –1) mmol/mol [–0.2 (–0.3 to –0.1)%],
P = 0.009. The greatest fall in HbA1c of –5 (–7 to –3) mmol/mol [–0.4 (–0.6 to –0.3)%],
P < 0.001 occurred in those with less good baseline control, HbA 1c ≥ 58 mmol/mol, who switched from once- to twice-daily basal
insulin. There was no difference in the 12-month HbA 1c between users of glargine, detemir and NPH insulin after correcting for
other variables. Relative risk of severe hypoglycaemia fell by 76% and ketoacidosis by 63%
12 months after DAFNE. The rate of severe hypoglycaemia fell from 0.82 to 0.23 events/patient year in twice-daily basal insulin
users. In the group with greatest fall in HbA 1c, the estimated relative risk for severe hypoglycaemia in twice-daily basal insulin
users versus once daily at 12 months was 1.72 (0.88–3.36, P = 0.110).

Conclusion After structured education in adults with Type 1 diabetes mellitus, use of basal insulin twice rather than once daily was
associated with lower HbA1c, independent of insulin type, with significant reductions in severe hypoglycaemia and ketoacidosis in
all groups.

Diabet. Med. 32, 1071–1076 (2015)

[3] and its efficacy has been demonstrated in a randomized

Introduction
controlled trial in which participants used exclusively twice-daily
The Dose Adjustment for Normal Eating (DAFNE) pro-gramme (bd) NPH as basal insulin [4]. However, long-acting insulin
provides structured education in flexible intensive insulin therapy analogues are now frequently prescribed and are often injected
for adults with Type 1 diabetes mellitus both within and beyond once (od) rather than twice daily. There is little evidence on
the UK [1]. Emphasis is placed on carbohydrate counting and whether the type or frequency of injection of basal insulin
meal-related short-acting insulin dose adjustment. Education and influences glycaemic control after structured education. This study
skills-based training on how to adjust basal insulin doses are also investigates the relationship between basal insulin regimen and
key components in the curriculum, but may be seen by users as glycaemic outcomes 12 months after DAFNE training.
having a secondary role [2]. DAFNE is based on the original
German ITT course

Methods
Correspondence to: Helen Hopkinson. Email: [email protected]
This is an open access article under the terms of the Creative Commons We collected baseline and 12-month follow-up data for patients
Attribution-NonCommercial License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited who had completed DAFNE training from the DAFNE research
and is not used for commercial purposes. database from its inception in 2009 to

ª 2015 The Authors.

Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK. 1071
DIABETICMedicine The effect of basal insulin injection frequency in Type 1 diabetes H. E. Hopkinson et al.

Exclusion criteria were pregnancy or continuous subcuta-neous

What’s new?
insulin infusion use at baseline or 12 months; missing HbA 1c,
• In people with Type 1 diabetes mellitus a once-daily basal basal insulin type or frequency at baseline or 12 months; and use
insulin regimen is sometimes used instead of the evidence- of basal insulin other than once or twice daily. Analyses were
based twice-daily regimen during structured education. performed for the whole cohort, and on a reduced cohort
comprising patients with baseline HbA 1c ≥ 58 mmol/mol (≥ 7.5%,
an inclusion criterion in the DAFNE RCT) [4]. HbA 1c ≥ 58
• This retrospective study demonstrates lower HbA 1c in twice-
mmol/mol (≥ 7.5%) identifies participants in whom improving
daily basal insulin users after Dose Adjustment for Normal
Eating (DAFNE) education. glycaemic control is likely to be a prime objective of structured
education additional to improving quality of life with diabetes.
• Benefit in reduced severe hypoglycaemia and ketoaci-dosis Data for severe hypoglycaemia were also analysed separately for
is not influenced by basal insulin frequency or type. those with HbA1c < 58 mmol/mol (< 7.5%) at baseline, as those
with lower values already may have more incentive to use
structured education to reduce their future risk of hypoglycaemia
• Consistency of mealtime insulin replacement and basal
[6]. Glycaemic outcomes were assessed in relation to frequency of
insulin dose-adjustment training may allow differences
basal insulin injection and type using a linear multiple regression
to be detected in this study in contrast to recent reports
model for HbA1c. Negative binomial models and logistic
showing no effect of basal insulin frequency on HbA1c.
regression modelling were used to analyse patterns in severe
hypoglycaemia and ketoacidosis data. All models used population-
2012, and also information for 2007 to 2012 from the Glasgow averaged exchangeable correlation and robust standard errors to
DAFNE service, which does not participate in the research allow for clustering by centre. Analyses were performed using
database. All patients undertook DAFNE training as part of their IBM SPSS Statistics for Windows, v. 21.0 (Armonk USA) and
routine clinical care. Course participants are initially encouraged figures were drawn using R [7].
to adopt a basal regimen of 12 units twice daily unless clinical
features suggest otherwise. They are taught how to self-adjust
basal insulin by making 1–2 unit changes in dose every 2–3 days
Results
to achieve fasting glucose targets, with specific rules for overnight
hypoglycaemia. Occasional glucose testing at 3 a.m. and after Of 1238 patients with 12-month data, 99 were excluded because of
carbohydrate-free meals is promoted to check the basal insulin pregnancy or continuous subcutaneous insulin infusion use. There
dose(s), and patients are given additional algorithms for self- were 892 (78.3%) eligible patients with complete data. Mean ( SD)
adjustment in relation to exercise and illness. They also evaluate age was 41.1 (13.6) years, duration of diabetes 18.9 (13.4) years;
their own insulin sensitivity to facilitate calculation of 47% were men. Baseline HbA1c was ≥ 58 mmol/mol (≥ 7.5%) in
carbohydrate-related prandial insulin and correction doses. 739 (82.8%) patients.
Regular capil-lary glucose measurements are recommended before At baseline, 3.8% of patients were using pre-mixed insulin,
meals and before bed with additional tests for management of 31.6% basal insulin detemir (od 13.8%, bd 17.8%), 48% basal
exercise, hypoglycaemia and driving. The course lasts 5 days. insulin glargine (od 42.4%, bd 5.6%) and 16.6% NPH (od 6.7%,
There is a robust quality assurance process to ensure consistency bd 9.9%). At 12 months, basal insulin usage was detemir 40.2%
in course delivery between centres [5]. Severe hypoglycaemia is (od 8.6%, bd 31.6%), glargine 42.0% (od 30.3%, bd 11.7%) and
routinely documented at baseline and 12 months by interview and NPH 17.8% (od 1.6%, bd 16.2%). The pattern of basal insulin use
questionnaire, based on patient recall. for the reduced cohort both at baseline and at 12 months varied by
< 1% from the above. Excluding those using mixed insulin, before
Ten UK centres contribute to the research database, which holds DAFNE 65.4% (561/858) were using once-daily basal insulin.
demographic data (gender, age and duration of diabetes), Diabetes This decreased to 40.8% (350/858) after DAFNE (difference –
Control and Complications Trial (DCCT)-aligned HbA 1c, type and 24.6%, 95% CI: –27.7% to –21.5%, P < 0.001).
frequency of basal insulin injection and patient-reported numbers
of episodes of severe hypoglycaemia (defined as requiring third
party assistance) and ketoacidosis in the 12 months before
HbA1c
DAFNE and in the
12 months thereafter. Matching data for the Glasgow service were There was a fall in HbA1c for the whole cohort of –2 (95% CI –3
gathered from the DAFNE clinical audit database; and the Scottish to –1) mmol/mol [–0.2 (–0.3 to –0.1)%], P < 0.001. Those using
Care Information–Diabetes Care system (SCI-DC, now SCI- twice-daily basal insulin at 12 months had a greater fall in HbA 1c
Diabetes) for type and frequency of basal insulin injection. Paper of –3 (–4 to –2) mmol/mol [–0.3 (–0.4 to –0.2)%], P < 0.001,
clinical records were used where data could not otherwise be whereas those using once-daily basal insulin showed no
obtained. significant fall; difference –1 (–2 to –1)

ª 2015 The Authors.

1072 Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.
 Research article DIABETICMedicine

mmol/mol [–0.1 (–0.2 to –0.1)%], P = 0.222. For the reduced levemir and glargine, in the whole (P = 0.281) or reduced (P =
cohort with less good control at baseline, there was a fall in HbA 1c 0.337) cohorts. However, the group using twice-daily basal insulin
at 12 months of –4 (–4 to –3) mmol/mol [–0.3 (–0.4 to –0.2)%], P had a lower HbA1c at 12 months than those using once daily both
< 0.001; a fall of –5 (–7 to – in the whole cohort; 69 vs. 71 mmol/ mol (8.4% vs. 8.6%),
3) mmol/mol [–0.4 (–0.5 to –0.3)%] in the subgroup using basal difference –2 mmol/mol, 95% CI: –3 to –1 [–0.2 (–0.3 to –
insulin twice daily, P < 0.001; and a fall of –2 (–3 to 0.1)%], P = 0.009 and in the reduced cohort; 71 vs. 74 mmol/mol
0) mmol/mol [–0.2 (–0.3 to –0.1)%], P = 0.011 in the group using (8.7% vs. 8.9%); difference –
basal insulin once daily (Fig. 1). 3 (–4 to –1) mmol/mol [–0.2(–0.4 to –0.1)%], P = 0.006.
Table 1 shows data from patients grouped according to their Excluding those using mixed insulin at baseline, linear
pattern of basal insulin injection at baseline and 12 months. modelling using the grouping according to pattern of basal insulin
Excluding baseline mixed insulin users, in the whole cohort, use showed an overall difference between groups at 12 months (P
those that switched from once- to twice-daily basal insulin (od– = 0.001). Post-hoc comparisons in the full cohort showed lower
bd) had a change in HbA1c of –3 (–5 to –2) mmol/mol [–0.3 (– 12-month HbA1c in the od–bd group than the od–od group;
0.4 to –0.2)%], P < 0.001, and in the group using twice-daily difference –2 (95% CI –4 to –
basal insulin both at baseline and 12 months (bd–bd) of –3 (–4 1) mmol/mol [–0.2 (–0.3 to –0.1)%], P < 0.001, and in the bd–bd
to –1) mmol/mol [–0.3 (–0.4 to –0.1)%], P < 0.001; there was no group compared with the od–od group; difference – 2 (–4 to –1)
significant change in the HbA1c in the group who continued to use mmol/mol [–0.2 (–0.4 to –0.1)%], P = 0.005. The same analyses
once-daily basal insulin (od–od), or in the small number of performed in the reduced cohort showed difference: –3 (–6 to –1)
patients who changed from twice-daily to once-daily basal mmol/mol [–0.3(–0.5 to –0.1)%], P = 0.001 and difference: –3 (–
insulin (bd–od) (Table 1). The same pattern was found in the data 5 to –1) mmol/mol [–0.3 (–0.5 to –0.1)%], P = 0.001,
for the reduced cohort with the greatest fall in HbA 1c of – 5 (–7 to respectively.
–3) mmol/mol; [–0.4 (–0.6 to –0.3)%], P < 0.001 in the od-bd
group.
Severe hypoglycaemia

Data on severe hypoglycaemia in the 12 months before and after

Change in HbA1c correcting for age, duration of diabetes and
DAFNE were available for 730 patients (81.8%) in the full cohort
baseline HbA1c
(Table 2) and 596 (80.1%) in the reduced cohort. Rate of severe
The linear modelling analysis showed no difference in 12-month hypoglycaemia fell from 0.85 to 0.20 episodes per patient per year
HbA1c between the three types of basal insulin, NPH, in the full cohort, estimated relative risk

FIGURE 1 Mean HbA1c at baseline and 12 months after structured education in DAFNE shown for the reduced cohort (baseline HbA 1c ≥ 58 mmol/ mol, ≥
7.5%) and subgroups of participants analysed according to basal insulin regimen at 12 months, with 95% confidence intervals and P values derived from
paired t-tests. The 12-month HbA1c is significantly lower than baseline in all subgroups.

ª 2015 The Authors.

Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK. 1073
DIABETICMedicine The effect of basal insulin injection frequency in Type 1 diabetes H. E. Hopkinson et al.

Table 1 Whole-cohort HbA1c data: participants grouped by frequency of basal insulin injection at baseline and 12 months. There was a significant fall in
HbA1c for twice-daily basal insulin users who continue to use twice daily, and in once-daily basal insulin users who switch to twice daily after structured
education in DAFNE

Baseline HbA1c 12-month HbA1c Difference

Baseline mmol/mol (%) mmol/mol (%) between
basal 12-month baseline and
insulin basal insulin 12-month HbA1c
Group regimen regimen N Mean SD Mean SD mmol/mol (%) 95% CI P
1 Once daily Once daily 341 72 (8.8) 17 (1.5) 71 (8.8) 17 (1.5) –1 (–0.1) –2 to 1 (–0.2 to 0.1) 0.281
2 Once daily Twice daily 220 71 (8.8) 14 (1.3) 68 (8.5) 14 (1.3) –3 (–0.3) –5 to –2 (–0.4 to –0.2) < 0.001
3 Twice daily Once daily 9 81 (9.7) 23 (2.1) 77 (9.3) 17 (1.5) –4 (–0.4) –17 to 8 (–1.5 to 0.7) 0.449
4 Twice daily Twice daily 288 71 (8.8) 15 (1.4) 69 (8.5) 15 (1.4) –3 (–0.3) –4 to –1 (–0.4 to –0.1) < 0.001

Table 2 Event data for the full cohort for severe hypoglycaemia (n = 730) and diabetic ketoacidosis (n = 689) at baseline and 12 months after skills-based
training in DAFNE

Before DAFNE training (baseline) 12 months after DAFNE training

Patients Events Range Rate* %† Patients Events Range Rate* %†

Severe hypoglycaemia
Injections
Once daily 455 375 0–40 0.82 20.9 284 42 0–12 0.15 6.7
Twice daily 275 244 0–50 0.89 23.3 446 102 0–12 0.23 9.2
Insulin type
NPH 138 72 0–8 0.52 21.0 142 22 0–6 0.15 5.6
Glargine 342 375 0–50 1.10 21.3 300 75 0–12 0.25 9.3
Detemir 227 154 0–20 0.68 22.5 288 47 0–12 0.16 8.3
Mixed 23 18 0–8 0.78 26.1 – – – – –
Total 730 619 0–50 0.85 21.8 730 144 0–12 0.20 8.2
Ketoacidosis
Injections
Once daily 434 31 0–3 0.07 4.8 272 8 0–1 0.03 2.9
Twice daily 255 13 0–3 0.05 4.3 417 8 0–2 0.02 1.7
Insulin type
NPH 116 9 0–2 0.08 6.9 121 2 0–1 0.02 1.7
Glargine 337 25 0–3 0.07 5.0 295 9 0–1 0.03 3.1
Detemir 214 8 0–3 0.04 2.3 273 5 0–2 0.02 1.5
Mixed 22 2 0–1 0.09 9.1 – – – – –
Total 689 44 0–3 0.06 4.6 689 16 0–2 0.02 2.2

*Number of events per patient per year.

†Per cent of patients with at least one event.

0.24 (95% CI: 0.16–0.36, P < 0.001); from 0.83 to 0.20 episodes injection, adjusted for the number of severe hypoglycaemia events
per patient per year in the reduced cohort, with relative risk 0.26 at baseline, HbA1c at 12 months, age and diabetes duration. This
(95% CI: 0.16–0.40, P < 0.001). In the full cohort, the rate of found no overall difference between 12-month severe
severe hypoglycaemia in twice-daily basal insulin users fell from hypoglycaemia rates for the three types of insulin (full cohort P =
0.89 to 0.23, and from 0.82 to 0.15 in once-daily users. The 0.389; reduced cohort P = 0.298). The estimated relative risk of
estimated odds ratio (OR) of severe hypoglycaemia after DAFNE severe hypoglycaemia for those using twice-daily compared with
compared to before DAFNE was 0.32 (95% CI: 0.27–0.38, P < once-daily basal insulin was 1.85 (95% CI: 1.01–3.42, P = 0.049);
0.001) in the full cohort and in the reduced cohort with poorer baseline control 1.72 (95% CI:
0.33 (95% CI: 0.26–0.42, P < 0.001) in the reduced cohort. For 0.88–3.36, P = 0.110); and in the small group with good baseline
patients who entered DAFNE with good glycaemic control control 3.86 (95% CI: 0.55–24.88, P = 0.181).
[baseline HbA1c < 58 mmol/mol (7.5%), n = 134] there was no
significant difference in severe hypoglycaemia at 12 months A logistic regression model was used to test if there was a
between once and twice-daily basal insulin users. A negative difference in the number of people having at least one severe
binomial model was used to test for a difference in the rate of hypoglycaemia event at 12 months between the different types of
severe hypoglycaemia at 12 months between different types of insulin and the number of injections. This model was adjusted for
basal insulin and frequency of basal insulin HbA1c at 12 months, age, duration and if the

ª 2015 The Authors.

1074 Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.
 Research article DIABETICMedicine

individual had severe hypoglycaemia at baseline or not. The Modelling analyses using the grouping according to pattern of
estimated OR for severe hypoglycaemia of those using twice-daily basal insulin use (Table 1) showed no difference in estimated
basal insulin compared with those using once-daily basal insulin in relative risk or in OR for ketoacidosis between groups 1 to 4.
the full cohort was 2.68 (95% CI: 1.29–3.52, P = 0.003) and in the
reduced cohort 1.80 (1.02–3.16, P = 0.041).

Discussion
In the full cohort, the estimated OR for severe hypoglyca-emia
between basal insulin pairs were glargine : NPH 2.68 (95% CI: This analysis of clinical audit data from UK DAFNE services has
1.38–5.21, P = 0.004), detemir : NPH 1.57 (95% CI: 0.64–3.81, P shown an increased HbA1c benefit from twice- rather than once-
= 0.323) and glargine : detemir 1.71 (95% CI: 0.97–3.01, P = daily usage of basal insulin 12 months after DAFNE training in
0.062); respective ratios in the reduced cohort were 2.81 (95% CI: insulin self-management skills for Type 1 diabetes mellitus. The
1.14–6.95, P = 0.025), 1.28 (95% CI: 0.46–3.53, P = 0.637) and
most clinically meaningful fall in HbA 1c of 5 mmol/mol (0.4%)
2.20 (95% CI: 1.18– 4.12, P = 0.014).
was associated with patients who embarked on DAFNE with
higher baseline HbA1c ≥ 58 mmol/mol (7.5%) and were using the
Modelling analyses using the grouping according to pattern of
recommended twice-daily basal insulin regimen after DAFNE. By
basal insulin use (Table 1) showed no difference in estimated
contrast, the North American Type 1 Diabetes Exchange Clinic
relative risk or in OR for severe hypoglycaemia between groups 1
Regis-try have published data in abstract form without finding any
to 4.
difference in outcomes between once-daily and twice-daily basal
insulin users [8]. A recent systematic review and network meta-
Diabetic ketoacidosis analysis [9] examined both randomized and non-randomized
studies comparing basal insulin regimens in people with Type 1
Ketoacidosis data were available for 689 patients (77.2%) in the diabetes mellitus. The analysis was primarily designed to consider
full cohort (Table 2) and 577 (78.1%) in the reduced cohort. differences between insulin types, but studies using one insulin
Absolute numbers of episodes were small; 44 at baseline and 16 at type at different injection frequencies were also included. This
12 months. In the full cohort, rates of ketoacidosis fell from 0.06 analysis also found no systematic differences in HbA 1c between
to 0.02 episodes per patient per year, estimated relative risk 0.37 once- and twice-daily basal insulin use for any of NPH, detemir or
(95% CI: 0.20–0.68, P = 0.001), and in the reduced cohort from glargine. The data used in these analyses are from a variety of
0.07 to 0.02 episodes per patient per year, relative risk 0.37 (95% centres with no unifying educational curriculum and so differ
CI: 0.18–0.72, P = 0.004). The estimated OR of ketoacidosis after markedly from our study population of people who have received
DAFNE compared with before DAFNE in the full cohort was 0.46 uniform guidance for dose adjustment. We may, therefore, be able
(95% CI: 0.27–0.76, P = 0.002) and in the reduced cohort was to detect differences relating to the insulin regimen because of
0.44 (95% CI: 0.25–0.76, P = 0.003). consistency both in the meal-related insulin replacement and in
basal insulin dose-adjustment behaviours; and outcomes may
In the negative binomial model comparing the rates of relate to the difference between randomized trials and partic-ipant
ketoacidosis at 12 months, adjusting for the number of ketoac- preference for once- or twice-daily basal insulin use. In clinical
practice, patients embark on DAFNE training with a variety of
idosis episodes at baseline, HbA1c at 12 months, age and duration
of diabetes, there was no difference in the estimated relative risk issues including HbA1c above target, problematic hypoglycaemia
of ketoacidosis for those using twice- compared with once-daily and a desire for dietary freedom. Our study does not allow us to
basal insulin: full cohort 1.26 (95% CI: 0.44– 3.59, P = 0.665); explain the rationale behind choices of basal insulin regimen.
reduced cohort 1.22 (95% CI: 0.39–3.78, P = 0.734). In the
logistic regression model testing for a difference in the number of
people having at least one ketoacidosis episode at 12 months
between the different types of basal insulin and the number of One possible reason for clinicians recommending analogue
injections, adjustment was made for HbA 1c at 12 months, age, basal insulin over NPH may be concern over hypoglycaemia.
These data confirm earlier reports of a major reduction in severe
duration and if the individual had a ketoacidosis episode at
hypoglycaemia 12 months after the ITTP and DAFNE [6,10,11],
baseline or not. There was no difference in the estimated OR ratio
for diabetic ketoacidosis in twice-daily basal insulin users which is largely independent of HbA 1c (above or below 58
compared to once daily: full cohort 1.20 (95% CI: 0.41 to 3.56, P mmol/mol, 7.5%), insulin type or injection fre-quency. We
= 0.739; reduced cohort P = 0.808). There is an overall difference propose the 76% reduced risk of severe hypoglycaemia arises
in number of people having at least one ketoacidosis episode at 12 from the total DAFNE education package, not just the basal
months between the different types of basal insulin: full cohort P insulin regimen. The statistical modelling corrects for baseline
= 0.004; reduced cohort P = 0.025. We have not investigated for hypoglycaemia events as well as HbA 1c, both of which can be
differences in ketoacidosis rates between individual basal insulins linked to future severe hypoglycaemia risk. For participants with
due to the low total number of episodes. baseline HbA1c ≥ 58 mmol/mol (7.5%) using twice-daily basal

ª 2015 The Authors.

Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK. 1075
DIABETICMedicine The effect of basal insulin injection frequency in Type 1 diabetes H. E. Hopkinson et al.

insulin at 12 months the fall in mean HbA1c of 5 mmol/mol (0.4%)

Acknowledgements
could provide a ~ 15% reduction in estimated risk of
microvascular complications. Although the estimated relative risk Dr Ian Lawrence had the original idea for this analysis in 2005.
of severe hypoglycaemia in this group compared with the once-
daily users was 1.72 (OR 1.8), given the large fall in absolute risk
of hypoglycaemia after DAFNE, this equates to a difference in
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Competing interests 13 Heise TI, Nosek L, Rønn BB, Endahl L, Heinemann L, Kapitza C et al.
Lower within-subject variability of insulin detemir in com-parison to
The DAFNE organisation has received sponsorship from Eli Lilly, NPH insulin and insulin glargine in people with type 1 diabetes.
Novo Nordisk and Sanofi-aventis in support of non-promotional Diabetes 2004; 53: 1614–1620.
educational activities.

ª 2015 The Authors.

1076 Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.