Acta Diabetol (2014) 51:955–962 DOI 10.1007/s00592-014-0619-6
ORIGINAL ARTICLE
Treatment with continuous subcutaneous insulin infusion is associated with lower arterial stiffness Signe Rosenlund • Simone Theilade • Tine Willum Hansen • Steen Andersen Peter Rossing
•
Received: 5 May 2014 / Accepted: 16 June 2014 / Published online: 2 October 2014 Ó Springer-Verlag Italia 2014
Abstract Aims To investigate the relationship between arterial stiffness and insulin treatment mode [continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI)] in type 1 diabetes patients. Methods Cross-sectional study, from 2009 to 2011, including 601 Caucasian type 1 diabetes patients, 58 and 543 treated with CSII and MDI, respectively. Arterial stiffness was measured as pulse wave velocity (PWV) (SphygmoCor, AtCor Medical). Adjustment included gender, age, diabetes duration, HbA1c, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate (UAER), smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease (CVD), total cholesterol and statin treatment. Albuminuria was UAER C30 mg/24-h, and CVD included myocardial infarction, revascularization, peripheral arterial disease and stroke. Results CSII- versus MDI-treated patients were 48 versus 57 % men, 51 ± 11 versus 54 ± 13 years old
Managed by Antonio Secchi. S. Rosenlund (&) S. Theilade T. W. Hansen P. Rossing Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark e-mail: [email protected] S. Rosenlund S. Andersen Nordsjaellands Hospital, Dyrehavevej 29, 3400 Hilleroed, Denmark P. Rossing Aarhus University, Aarhus, Denmark P. Rossing University of Copenhagen, Copenhagen, Denmark
(mean ± SD), had 33 ± 12 versus 32 ± 16 years diabetes duration and HbA1c 7.8 ± 0.9 % (62 ± 10 mmol/mol) versus 8.0 ± 1.2 % (64 ± 13 mmol/mol) (P C 0.08 for all). PWV was lower in CSII- versus MDI-treated patients (9.3 ± 2.8 vs. 10.4 ± 3.4 m/s; P = 0.016). In fully adjusted analysis, CSII treatment was significantly (P = 0.038) associated with lower PWV, whereas HbA1clevel was not (P = 0.93). Conclusions In type 1 diabetes patients, CSII treatment was associated with lower arterial stiffness independent of other risk factors, while HbA1c was not. Although glucose variability was not assessed, our results suggest that glucose variability and not HbA1c-level affect arterial stiffness. This needs confirmation in randomised prospective studies. Keywords Type 1 diabetes Insulin pump Arterial stiffness Cardiovascular risk
Introduction In type 1 diabetes, continuous insulin infusion (CII) aims at mimicking pancreatic function using basal-bolus regime customised to each patients and thereby delivering insulin in a more physiological way. The primary method of CII is continuous subcutaneous insulin infusion (CSII); however, a very limited number of patients receive intraperitoneal insulin infusion [1]. CSII treatment is mostly used in type 1 diabetes, but has been implemented on an experimentally basis in patients with type 2 diabetes [2, 3]. CSII treatment is used for both children and adults and has become more advanced leading to better glycaemic control [4], sometimes combined with nutritional education [5]. CSII treatment reduces glucose excursions in children [6] and adults [6, 7] and lowers HbA1c-levels significantly compared with
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multiple daily injections (MDI) without increasing episodes of hypoglycaemia or ketoacidosis [8, 9]. A previous study has suggested that failure of improvement of glycaemic control may be explained by discontinuation of CSII treatment [10]. Furthermore, CSII treatment may reduce progression of albuminuria as seen in a small study of type 1 diabetes patients with microalbuminuria [11]. Moreover, CSII treatment has been related with less progression of urinary albumin excretion in patients with normoalbuminuria when compared to a control group of patients treated with MDI [12]. However, whether treatment with CSII is superior to MDI in preventing diabetes complications remains to be determined in larger randomised trials. Furthermore, the effect on macrovascular complications is unknown. Aortic pulse wave velocity (PWV) is the most validated non-invasive method to quantify arterial stiffness and is considered the gold standard [13]. PWV is an independent predictor of adverse outcomes in hypertension [14], type 2 diabetes [15], end-stage renal disease (ESRD) [16], and in the general population [17] and is recommended in current guidelines for risk assessment in hypertension [18]. Moreover, PWV increases with degree of albuminuria, retinopathy and autonomic dysfunction in both type 1 and type 2 diabetes [19–21] and with higher HbA1c in patients with type 2 diabetes and hypertension [22]. Tight glycaemic control can reduce the risk of microvascular complications and cardiovascular disease (CVD) in type 1 diabetes [23]. However, whether the beneficial effect on glycaemic load and glucose excursions from CSII treatment has impact on level of arterial stiffness has never been investigated. We examine the association between PWV and CSII versus MDI treatment in a large unselected cohort of type 1 diabetes patients.
Research design and methods Patients From September 2009 to June 2011, a cross-sectional study on Caucasian type 1 diabetes patients without ESRD (dialysis, renal transplantation or GFR/eGFR \15 ml/min/ 1.73 m2) was carried out at Steno Diabetes Center. Of 1,285 patients invited, 676 (52 %) agreed to participate. Patients declining participation were younger, but with similar gender distribution compared with contributing patients [49 ± 16 years and 57 % males vs. 54 ± 13 years and 56 % males (P \ 0.001 and 0.62)]. Valid PWV measurements were taken in 635 (93 %) patients. Those with PWV measurements were younger, with shorter diabetes duration, better kidney function, less previous CVD and antihypertensive treatment (P B 0.002).
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There was no difference in gender distribution, HbA1c, urinary albumin excretion rate (UAER), office mean arterial pressure (MAP) or numbers on CSII treatment (P C 0.19). Data on PWV in the entire cohort have been published previously without information on insulin delivery method [24]. A total of 73 patients were on CSII treatment. Of these, 15 were excluded due to short CSII treatment (\1 year) prior to participation. Remaining patients (n = 562) were treated with MDI. Of these, 19 were excluded because of blindness, as eyesight is required for CSII treatment. Thus, the total number of patients included in the present analysis was 601. Treatment with CSII had been initiated according to the Danish Health Authority guidelines [25], predominantly due to dysregulation [HbA1c [7.5 % (58 mmol/mol)]. The study was conducted in accordance with the Declaration of Helsinki and approved by the local ethical committee (2009-056; NCT01171248). All patients gave written informed consent. Clinical and laboratory methods Office blood pressure was recorded after 15 min of rest in supine position as the average of three measurements with a validated devise (A&D Medical, UA787) and an appropriate cuff size. Subsequently, measurement of aortic PWV was taken by trained laboratory technicians with the SphygmoCor device (AtCor Medical, Sydney, Australia). Three measurements were taken, and the two closest to each other was averaged and used. All participants had blood samples, and phenotypic characteristics collected. HbA1c was measured by highperformance liquid chromatography and plasma creatinine by an enzymatic method (Hitachi 912, Roche Diagnostics, Germany). UAER was measured in 24-h sterile urine collections by enzyme immunoassay. Patients were stratified as normoalbuminuric if UAER was \30 mg/24 h, and albuminuric if UAER was or in the past had been C30 mg/24 h, in two out of three consecutive measurements. Estimated GFR (eGFR) was calculated by the four variables Modification of Diet in Renal Disease (MDRD) formula [26]. Body mass index was weight in kilograms divided by height in metres squared. Based on standardised questionnaires, smoking was current use of C1 cigarettes/cigars/pipes per day. A history of CVD was myocardial infarction, revascularization, peripheral arterial disease or stroke based on questionnaires, and patient records at Steno Diabetes Center. Statistical analysis Normally distributed variables are given as mean ± SD and non-normally distributed variables as median
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Table 1 General characteristics
Data represent percentage (%), mean ± SD or median (IQR) CSII continuous subcutaneous insulin infusion, MDI multiple daily injections, eGFR estimated glomerular filtration rate and CVD cardiovascular disease (previous myocardial infarction, revascularization, peripheral arterial disease or stroke). P values are for unadjusted comparisons (t test or chi-square test) between patients treated with CSII versus MDI
All patients n = 601
CSII treatment n = 58
MDI treatment n = 543
P
Men, %
56
48
57
0.19
Age, years
54 ± 13
51 ± 11
54 ± 13
0.08
Diabetes duration, years
32 ± 16
33 ± 12
32 ± 16
0.42
HbA1c, %
8.0 ± 1.2
7.8 ± 0.9
8.0 ± 1.2
0.20
HbA1c, mmol/mol
64 ± 13
62 ± 10
64 ± 13
0.20
Total cholesterol, mmol/L
4.7 ± 0.9
4.8 ± 0.9
4.7 ± 0.9
0.36
HDL cholesterol, mmol/L Triglycerides, mmol/L
1.7 ± 0.5 1.11 ± 0.6
1.7 ± 0.5 0.98 ± 0.6
1.7 ± 0.5 1.13 ± 0.6
0.60 0.10
Body mass index, kg/m2
25.4 ± 5.9
25.6 ± 4.2
25.4 ± 6.1
0.82
P-creatinine, lmol/L
76 (66–95)
77 (68–91)
76 (66–95)
0.91
eGFR, mL/min/1,73 m2
84 ± 28
81 ± 25
84 ± 28
0.31
Urinary albumin excretion rate, mg/24 h
17 (8–61)
15 (8–62)
17 (8–61)
0.90
Previous CVD, %
19
17
20
0.67
Smokers, %
21
19
21
0.69
Insulin daily dose, IE/24 h
48.5 ± 34.4
43.2 ± 23.0
49.0 ± 35.4
0.22
Antihypertensive treatment, %
71
76
70
0.63
Statin treatment, %
59
50
60
0.13
Systolic blood pressure, mmHg
136 ± 14
136 ± 12
136 ± 15
0.83 0.06
Diastolic blood pressure, mmHg
75 ± 10
78 ± 7
75 ± 7
Mean arterial pressure, mmHg
93 ± 11
92 ± 10
93 ± 10
0.49
Heart rate, beats per minute
71 ± 9
69 ± 12
72 ± 12
0.10
Albuminuria, % Pulse wave velocity, m/s
48 10.4 ± 3.3
40 9.3 ± 2.8
50 10.4 ± 3.4
0.16 0.02
Adjusted linear regression analysis was performed to assess whether level of PWV was independently associated with CSII treatment. Adjustment included gender, age, diabetes duration, HbA1c, heart rate, MAP, P-creatinine, UAER, smoking, daily insulin dose, antihypertensive treatment, previous CVD, total cholesterol and statin treatment. A two-tailed P \ 0.05 was considered significant. All statistics were performed with SPSS for windows version 20.0 (SPSS, Chicago, IL).
Results Fig. 1 Pulse wave velocity in patients treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) shown as mean and SD. P value is for unadjusted comparisons (t test)
[interquartile range] and log10 transformed before analysis with the exception of CSII duration which is squared. Comparisons between groups were assessed by t test for continuous variables and the chi-square test for categorical variables.
General characteristics General characteristics of the study population are shown in Table 1. In short, patients were (mean ± SD) 54 ± 13 years, 56 % male, had 32 ± 16 years of diabetes duration, PWV of 10.3 ± 3.3 m/s and HbA1c of 8.0 ± 1.2 % (64 ± 13 mmol/mol). The median (IQR) duration of CSII treatment was 5.1 (2.7–20.4) years. Age, gender distribution, diabetes duration, HbA1c, blood pressure, total cholesterol, heart rate, body mass
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Table 2 Adjusted linear regression coefficients for pulse wave velocity Variable (SD)
Regression coefficient
SE
P
Age (13 years)a
0.47
0.009
\0.001
Diabetes duration (16 years)a
0.27
0.007
\0.001
Heart rate (9 beats per minute)a
0.11
0.008
\0.001 \0.001
Mean arterial pressure (9 mmHg)
a
0.21
0.01
P-creatinine
0.09
0.71
0.007
Urinary albumin excretion rate
0.07
0.16
0.036
CSII versus MDI treatment
0.06
0.33
0.038
The adjusted linear regression models included age, gender, diabetes duration, HbA1c, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate, smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease, total cholesterol, statin treatment and CSII versus MDI treatment. Only variables with significant association are shown CSII continuous subcutaneous insulin infusion and MDI multiple daily injections a
Regression coefficient given as standardised coefficient
index, number of smokers, eGFR and UAER did not differ between patients receiving CSII versus MDI treatment (P C 0.08, Table 1). Arterial stiffness and CSII versus MDI treatment Although clinical characteristics were similar, PWV was significantly lower in patients receiving CSII compared with MDI treatment: 9.3 ± 2.8 versus 10.4 ± 3.4 m/s (P = 0.016; Fig. 1). In adjusted linear regression, CSII treatment was significantly associated with lower PWV (P = 0.038). Younger age, shorter diabetes duration, lower P-creatinine, UAER, heart rate and MAP were also associated with lower PWV (P B 0.04; Table 2), whereas HbA1c was not (P = 0.93). Also gender, smoking, total daily insulin dose, antihypertensive treatment, previous CVD, total cholesterol and statin treatment were not related to PWV (P C 0.66). Additional inclusion of triglyceride or triglyceride/HDLcholesterol ratio in the adjusted linear regression model did not change the significant association between CSII treatment and lower PWV (P = 0.038). Arterial stiffness in subgroups, CSII versus MDI treatment Of the 601 patients, 311 (52 %) had albuminuria. Of the patients with albuminuria, 35 (11 %) were treated with CSII and 276 (89 %) with MDI. Among the normoalbuminuric patients, this distribution was 23 (8 %) and 267 (92 %), respectively. In patients with normoalbuminuria, PWV was low both for patients treated with CSII and MDI (9.4 ± 3.2 vs. 9.5 ± 3.1 m/s) without significant difference (P = 0.88). Furthermore, there was no adjusted association between CSII treatment and PWV (P = 0.97). There was no difference in general characteristics between CSII- versus
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MDI-treated normoalbuminuric patients (P C 0.06), except for lower eGFR in CSII-treated patients (P = 0.03). In patients with albuminuria, PWV was significantly lower in those receiving CSII versus MDI treatment (P \ 0.001, Table 3). CSII-treated patients were slightly younger, but CSII treatment remained significantly (P = 0.029) associated with lower PWV even after fully adjustment including age. General characteristics for the albuminuric patients are shown in Table 3. Of the 601 patients, 117 (19 %) had previous CVD. Of 484 patients without previous CVD, 48 (10 %) were treated with CSII and 436 (90 %) with MDI. In patients with previous CVD, this distribution was 10 (9 %) and 106 (91 %), respectively. Patients treated with CSII without previous CVD had the lowest PWV of 8.8 ± 2.3 m/s, which was significantly lower than in MDI-treated patients (P = 0.01). Furthermore, CSII treatment was associated with lower PWV in fully adjusted analyses (P = 0.005). General characteristics for the patients without previous CVD are shown in Table 3. In patients with previous CVD, both CSII- and MDItreated patients had increased PWV, and PWV did not differ between the groups (11.7 ± 4.0 vs. 12.1 ± 3.5; P = 0.78), although numbers were small. Among patients with previous CVD, none of the general characteristics were different between CSII- and MDI-treated patients (P C 0.05). In neither of the subgroups, the level of HbA1c was associated with PWV in adjusted linear regression analyses (P C 0.88). Arterial stiffness and duration of CSII treatment To investigate the association between levels of PWV and duration of CSII treatment, we performed additional linear regression analyses only including the 58 patients treated
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Table 3 General characteristics for patients with albuminuria and for patients without cardiovascular disease Albuminuria (n = 311) CSII treatment n = 35
Without previous cardiovascular disease (n = 484)
MDI treatment n = 276
P
CSII treatment n = 48
MDI treatment n = 436
P
Men, %
46
60
0.54
44
57
0.09
Age, years
50 ± 12
56 ± 11
0.006
50 ± 11
53 ± 13
0.15
Diabetes duration, years
36 ± 10
36 ± 13
0.74
32 ± 11
30 ± 16
0.39
HbA1c, %
8.1 ± 1.0
8.3 ± 1.2
0.45
7.8 ± 1.0
8.0 ± 1.5
0.31
HbA1c, mmol/mol
65 ± 11
67 ± 14
0.45
61 ± 11
64 ± 13
0.31
Total cholesterol, mmol/L
4.8 ± 0.8
4.6 ± 1.0
0.35
4.8 ± 0.8
4.7 ± 0.8
0.39
HDL cholesterol, mmol/L
1.6 ± 0.4
1.7 ± 0.5
0.55
1.8 ± 0.5
1.7 ± 0.5
0.24
Triglycerides, mmol/L
1.08 ± 0.6
1.20 ± 0.7
0.37
0.93 ± 0.6
1.09 ± 0.6
0.07
Body mass index, kg/m2
26.0 ± 4.4
26.0 ± 7.7
0.99
25.2 ± 4.1
25.5 ± 6.5
0.75
P-creatinine, lmol/L
81 (70–105)
88 (70–122)
0.39
73 (66–86)
75 (65–89)
0.72
eGFR, mL/min/1,73 m2
78 ± 30
74 ± 30
0.48
83 ± 26
87 ± 27
0.23
Urinary albumin excretion rate, mg/24 h
41 (15–132)
55 (23–195)
0.57
15 (7–72)
15 (8–47)
0.55
Previous CVD, %
26
29
0.71
–
–
–
Smokers, % Insulin daily dose, IE/24 h
26 47.7 ± 26.9
22 49.6 ± 25.3
0.64 0.65
19 39.5 ± 20.1
22 49.4 ± 37.6
0.65 0.08
Antihypertensive treatment, %
91
95
0.46
71
65
0.40
Statin treatment, %
66
78
0.13
44
54
0.17
Systolic blood pressure, mmHg
136 ± 11
138 ± 15
0.37
135 ± 12
135 ± 14
0.70
Diastolic blood pressure, mmHg
77 ± 6
75 ± 8
0.20
79 ± 6
77 ± 8
0.05
Mean arterial pressure, mmHg
92 ± 9
94 ± 10
0.31
93 ± 10
93 ± 10
0.87
Heart rate, beats per minute
71 ± 12
74 ± 12
Pulse wave velocity, m/s
9.3 ± 2.5
11.3 ± 3.4
0.24
69 ± 12
72 ± 12
0.04
\0.001
8.8 ± 2.3
10.0 ± 3.2
0.001
Data represent percentage (%), mean ± SD or median (IQR) Albuminuria: urinary albumin excretion rate C30 mg/24 h CSII continuous subcutaneous insulin infusion, MDI multiple daily injections, eGFR estimated glomerular filtration rate and CVD cardiovascular disease (previous myocardial infarction, revascularization, peripheral arterial disease or stroke). P values are for unadjusted comparisons (t test or chi-square test) between patients with albuminuria or without previous CVD treated with CSII versus MDI
with CSII. In unadjusted regression, lower PWV was associated with younger age, shorter diabetes duration, no antihypertensive treatment, lower daily insulin dose and no previous CVD (P B 0.02), whereas PWV not was associated with gender, HbA1c, heart rate, MAP, P-creatinine, UAER, smoking, total cholesterol, statin treatment or duration of CSII treatment (P C 0.068). In adjusted regression, only younger age and lower insulin dose remained associated with lower PWV (P \ 0.001).
Discussion To our knowledge, this is the first study to investigate the association between arterial stiffness and CSII versus MDI treatment in type 1 diabetes patients. In the whole study population, PWV was lower in patients receiving CSII treatment. Adjusted linear regression revealed a significant
relation between CSII treatment and lower PWV. Moreover, among patients with albuminuria, those on MDI treatment had high levels of PWV, whereas CSII-treated patients had PWV levels similar to normoalbuminuric patients. In patients without previous CVD, the level of PWV was significantly lower in CSII-treated patients compared with MDI, whereas PWV levels were equally high in CSII- and MDI-treated patients with previous CVD. It is not evident why there was a significant difference in PWV between CSII- and MDI-treated patients with albuminuria and thus a higher risk for CVD, but not in patients with previous CVD, except that the number of CSII-treated patients with previous CVD was very small. The level of PWV was 2.0 m/s higher in MDI-treated patients with albuminuria and 1.2 m/s higher in MDItreated patients without previous CVD. In a meta-analysis, Vlachopoulos et al. [27] found, over a mean of 7.7 years of follow-up, an adjusted relative risk of 1.14
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for cardiovascular events and of 1.15 for cardiovascular as well as all-cause mortality per 1 m/s increase in PWV. Thus, the observed differences in PWV are clinically relevant. In patients with type 2 diabetes, Cruickshank et al. [15] showed an adjusted relative risk of 1.08 for cardiovascular as well as all-cause mortality with 1 m/s increase in PWV over 10.7 years of follow-up. Based on these results, CSII-treated patients with albuminuria in our study could have around 30 % reduced risk of cardiovascular events and 16–30 % reduced risk of cardiovascular and all-cause mortality over 7–10 years. For patients without previous CVD, the reduced risk of cardiovascular event and all-cause mortality could be around 8–15 %. However, whether treatment with CSII can reduce arterial stiffness or slow development of arterial stiffness and whether this can be translated into a reduction in cardiovascular events needs to be demonstrated in large prospective intervention trials. Arterial stiffness has been linked to micro- and macrovascular complications in type 1 diabetes [28]. Our data suggest that CSII treatment either protects the arterial wall or even modifies arterial stiffness. Since patients receiving CSII often have preceding poor glycaemic control, as they had to fulfil the criteria of glycaemic dysregulation to qualify for CSII treatment [25], it is even more interesting that they had lower arterial stiffness. Patients treated with MDI or CSII were alike on other parameters, with few exceptions: (1) in patients with albuminuria, where the CSII-treated patients were younger, (2) in patients with normoalbuminuria, where eGFR was higher in the MDItreated group, and (3) in patients without previous CVD, where CSII-treated patients had a lower heart rate. There was no association between PWV and duration of CSII treatment which could suggest lack of causality although the time–effect relationship is unknown. Within the group of CSII-treated patients, we only found an association between younger age and lower daily insulin dose to lower PWV in adjusted analyses which most likely reflect lack of power. However, when including patients with CSII treatment\1 year (n = 15) in the adjusted analysis of CSII durations and level of PWV, longer duration of CSII treatment was borderline (P = 0.07) associated with lower PWV (data not shown). This could indicate that CSII treatment should be continued for more than a year to have an effect on PWV. Treatment with CSII delivers insulin in a more physiological manner than MDI and likely ensures less glucose variability. The STAR 3 study showed sensor-augmented CSII therapy to lower glucose variability, but did not assess the effect on complications [29]. Chimenti et al. [7] showed a significant reduction in glucose variability in patients changing from MDI to CSII treatment, but they also did not assess the effect on complications.
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Maybe, lower glucose variability rather than or in addition to HbA1c-level is of significance in this setting. This is supported by the facts that HbA1c was not associated with PWV neither in the whole cohort nor in the subgroups examined. The FinnDiane study also observed that arterial stiffness was not associated with HbA1c except in macroalbuminuric patients [28]. Variability of HbA1c reflecting glucose variability over longer periods of time has been associated with diabetic micro- and macrovascular complications [30]. However, a recent study by Cesana et al. [31] using continuous glucose monitoring for 24 h did not find an association between arterial distensibility and glucose variability. In addition, the Epidemiology of Diabetes Intervention and Complications study (DCCT/EDIC) was unable to link higher glucose variability to diabetes complications [32, 33]. However, the variability was accessed from seven point glucose profiles which may not be adequate to investigate glucose excursions and may explain the lack of association. Thus, it remains unclear whether reduced HbA1c or glucose variability related to CSII treatment may contribute to the lower arterial stiffness. Unfortunately, data on glycaemic variability are not available in our cohort. Management of glycaemic control in diabetes largely rely on measurements of HbA1c. However, this measure is inadequate to register acute changes and fluctuation of glucose level. Studies have shown that extreme glucose levels affect arterial morphology through oxidative stress, advanced glycation end product formation and endothelial dysfunction [34, 35]. Thus, stabilisation of glucose levels could expectedly protect arterial health and delay or prevent arterial pathology. However, randomised, controlled intervention studies comparing CSII and MDI treatment are required to investigate whether CSII treatment can revert or inhibit progression of arterial stiffness. We intend to follow-up the current cohort to investigate changes in arterial stiffness over time in patients receiving CSII versus MDI treatment. The limitation of this study is primarily the cross-sectional design, excluding conclusions on causality. It cannot be excluded that there is a selection of healthy patients for CSII treatment as self-care skills are required to receive CSII treatment. On the other hand, most often CSII treatment is initiated in patients with poorer glycaemic control, although clinical characteristics between groups were almost similar in our study. Moreover, the subgroup analyses are based on limited number of patients and thus reduced power. The strengths are the overall large number of patients and the broad recruitment from the clinic. Also, most patients have been followed at Steno Diabetes Center for many years which make recording of albuminuria and CVD fairly reliable although under-reporting of CVD may be suspected.
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Conclusion In summary, CSII treatment and not HbA1c were associated with lower arterial stiffness independently of other risk factors in a cross-sectional study of comparable groups of patients with type 1 diabetes. The same association was seen in patients with albuminuria or without previous CVD. Although glucose variability was not assessed, our results support the hypothesis that glucose variability and not mean glucose level as reflected by HbA1c-level affects arterial stiffness. This needs confirmation in randomised prospective studies assessing the development of vascular complications as well as glucose variability. Acknowledgments S.R. collected and analysed data and wrote the manuscript, S.T. collected and analysed data and wrote the manuscript, T.H. reviewed/edited the manuscript and contributed to the introduction and the discussion, S.A. and P.R. reviewed/edited the manuscript. S.R. is the guarantor of this work and has had full access to the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. The authors acknowledge the excellent technical assistance from the laboratory at Steno Diabetes Center, Gentofte, Denmark. Conflict of interest SR., S.T., T.H. and P.R. have no conflict of interest. S.A. has received an unrestricted research grant from Medtronic A/S, Denmark. Human and animal rights All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki of 1975, as revised in 2008. Informed consent Informed consent was obtained from all patients for being included in the study.
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ORIGINAL ARTICLE
Treatment with continuous subcutaneous insulin infusion is associated with lower arterial stiffness Signe Rosenlund • Simone Theilade • Tine Willum Hansen • Steen Andersen Peter Rossing
•
Received: 5 May 2014 / Accepted: 16 June 2014 / Published online: 2 October 2014 Ó Springer-Verlag Italia 2014
Abstract Aims To investigate the relationship between arterial stiffness and insulin treatment mode [continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI)] in type 1 diabetes patients. Methods Cross-sectional study, from 2009 to 2011, including 601 Caucasian type 1 diabetes patients, 58 and 543 treated with CSII and MDI, respectively. Arterial stiffness was measured as pulse wave velocity (PWV) (SphygmoCor, AtCor Medical). Adjustment included gender, age, diabetes duration, HbA1c, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate (UAER), smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease (CVD), total cholesterol and statin treatment. Albuminuria was UAER C30 mg/24-h, and CVD included myocardial infarction, revascularization, peripheral arterial disease and stroke. Results CSII- versus MDI-treated patients were 48 versus 57 % men, 51 ± 11 versus 54 ± 13 years old
Managed by Antonio Secchi. S. Rosenlund (&) S. Theilade T. W. Hansen P. Rossing Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark e-mail: [email protected] S. Rosenlund S. Andersen Nordsjaellands Hospital, Dyrehavevej 29, 3400 Hilleroed, Denmark P. Rossing Aarhus University, Aarhus, Denmark P. Rossing University of Copenhagen, Copenhagen, Denmark
(mean ± SD), had 33 ± 12 versus 32 ± 16 years diabetes duration and HbA1c 7.8 ± 0.9 % (62 ± 10 mmol/mol) versus 8.0 ± 1.2 % (64 ± 13 mmol/mol) (P C 0.08 for all). PWV was lower in CSII- versus MDI-treated patients (9.3 ± 2.8 vs. 10.4 ± 3.4 m/s; P = 0.016). In fully adjusted analysis, CSII treatment was significantly (P = 0.038) associated with lower PWV, whereas HbA1clevel was not (P = 0.93). Conclusions In type 1 diabetes patients, CSII treatment was associated with lower arterial stiffness independent of other risk factors, while HbA1c was not. Although glucose variability was not assessed, our results suggest that glucose variability and not HbA1c-level affect arterial stiffness. This needs confirmation in randomised prospective studies. Keywords Type 1 diabetes Insulin pump Arterial stiffness Cardiovascular risk
Introduction In type 1 diabetes, continuous insulin infusion (CII) aims at mimicking pancreatic function using basal-bolus regime customised to each patients and thereby delivering insulin in a more physiological way. The primary method of CII is continuous subcutaneous insulin infusion (CSII); however, a very limited number of patients receive intraperitoneal insulin infusion [1]. CSII treatment is mostly used in type 1 diabetes, but has been implemented on an experimentally basis in patients with type 2 diabetes [2, 3]. CSII treatment is used for both children and adults and has become more advanced leading to better glycaemic control [4], sometimes combined with nutritional education [5]. CSII treatment reduces glucose excursions in children [6] and adults [6, 7] and lowers HbA1c-levels significantly compared with
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multiple daily injections (MDI) without increasing episodes of hypoglycaemia or ketoacidosis [8, 9]. A previous study has suggested that failure of improvement of glycaemic control may be explained by discontinuation of CSII treatment [10]. Furthermore, CSII treatment may reduce progression of albuminuria as seen in a small study of type 1 diabetes patients with microalbuminuria [11]. Moreover, CSII treatment has been related with less progression of urinary albumin excretion in patients with normoalbuminuria when compared to a control group of patients treated with MDI [12]. However, whether treatment with CSII is superior to MDI in preventing diabetes complications remains to be determined in larger randomised trials. Furthermore, the effect on macrovascular complications is unknown. Aortic pulse wave velocity (PWV) is the most validated non-invasive method to quantify arterial stiffness and is considered the gold standard [13]. PWV is an independent predictor of adverse outcomes in hypertension [14], type 2 diabetes [15], end-stage renal disease (ESRD) [16], and in the general population [17] and is recommended in current guidelines for risk assessment in hypertension [18]. Moreover, PWV increases with degree of albuminuria, retinopathy and autonomic dysfunction in both type 1 and type 2 diabetes [19–21] and with higher HbA1c in patients with type 2 diabetes and hypertension [22]. Tight glycaemic control can reduce the risk of microvascular complications and cardiovascular disease (CVD) in type 1 diabetes [23]. However, whether the beneficial effect on glycaemic load and glucose excursions from CSII treatment has impact on level of arterial stiffness has never been investigated. We examine the association between PWV and CSII versus MDI treatment in a large unselected cohort of type 1 diabetes patients.
Research design and methods Patients From September 2009 to June 2011, a cross-sectional study on Caucasian type 1 diabetes patients without ESRD (dialysis, renal transplantation or GFR/eGFR \15 ml/min/ 1.73 m2) was carried out at Steno Diabetes Center. Of 1,285 patients invited, 676 (52 %) agreed to participate. Patients declining participation were younger, but with similar gender distribution compared with contributing patients [49 ± 16 years and 57 % males vs. 54 ± 13 years and 56 % males (P \ 0.001 and 0.62)]. Valid PWV measurements were taken in 635 (93 %) patients. Those with PWV measurements were younger, with shorter diabetes duration, better kidney function, less previous CVD and antihypertensive treatment (P B 0.002).
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There was no difference in gender distribution, HbA1c, urinary albumin excretion rate (UAER), office mean arterial pressure (MAP) or numbers on CSII treatment (P C 0.19). Data on PWV in the entire cohort have been published previously without information on insulin delivery method [24]. A total of 73 patients were on CSII treatment. Of these, 15 were excluded due to short CSII treatment (\1 year) prior to participation. Remaining patients (n = 562) were treated with MDI. Of these, 19 were excluded because of blindness, as eyesight is required for CSII treatment. Thus, the total number of patients included in the present analysis was 601. Treatment with CSII had been initiated according to the Danish Health Authority guidelines [25], predominantly due to dysregulation [HbA1c [7.5 % (58 mmol/mol)]. The study was conducted in accordance with the Declaration of Helsinki and approved by the local ethical committee (2009-056; NCT01171248). All patients gave written informed consent. Clinical and laboratory methods Office blood pressure was recorded after 15 min of rest in supine position as the average of three measurements with a validated devise (A&D Medical, UA787) and an appropriate cuff size. Subsequently, measurement of aortic PWV was taken by trained laboratory technicians with the SphygmoCor device (AtCor Medical, Sydney, Australia). Three measurements were taken, and the two closest to each other was averaged and used. All participants had blood samples, and phenotypic characteristics collected. HbA1c was measured by highperformance liquid chromatography and plasma creatinine by an enzymatic method (Hitachi 912, Roche Diagnostics, Germany). UAER was measured in 24-h sterile urine collections by enzyme immunoassay. Patients were stratified as normoalbuminuric if UAER was \30 mg/24 h, and albuminuric if UAER was or in the past had been C30 mg/24 h, in two out of three consecutive measurements. Estimated GFR (eGFR) was calculated by the four variables Modification of Diet in Renal Disease (MDRD) formula [26]. Body mass index was weight in kilograms divided by height in metres squared. Based on standardised questionnaires, smoking was current use of C1 cigarettes/cigars/pipes per day. A history of CVD was myocardial infarction, revascularization, peripheral arterial disease or stroke based on questionnaires, and patient records at Steno Diabetes Center. Statistical analysis Normally distributed variables are given as mean ± SD and non-normally distributed variables as median
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Table 1 General characteristics
Data represent percentage (%), mean ± SD or median (IQR) CSII continuous subcutaneous insulin infusion, MDI multiple daily injections, eGFR estimated glomerular filtration rate and CVD cardiovascular disease (previous myocardial infarction, revascularization, peripheral arterial disease or stroke). P values are for unadjusted comparisons (t test or chi-square test) between patients treated with CSII versus MDI
All patients n = 601
CSII treatment n = 58
MDI treatment n = 543
P
Men, %
56
48
57
0.19
Age, years
54 ± 13
51 ± 11
54 ± 13
0.08
Diabetes duration, years
32 ± 16
33 ± 12
32 ± 16
0.42
HbA1c, %
8.0 ± 1.2
7.8 ± 0.9
8.0 ± 1.2
0.20
HbA1c, mmol/mol
64 ± 13
62 ± 10
64 ± 13
0.20
Total cholesterol, mmol/L
4.7 ± 0.9
4.8 ± 0.9
4.7 ± 0.9
0.36
HDL cholesterol, mmol/L Triglycerides, mmol/L
1.7 ± 0.5 1.11 ± 0.6
1.7 ± 0.5 0.98 ± 0.6
1.7 ± 0.5 1.13 ± 0.6
0.60 0.10
Body mass index, kg/m2
25.4 ± 5.9
25.6 ± 4.2
25.4 ± 6.1
0.82
P-creatinine, lmol/L
76 (66–95)
77 (68–91)
76 (66–95)
0.91
eGFR, mL/min/1,73 m2
84 ± 28
81 ± 25
84 ± 28
0.31
Urinary albumin excretion rate, mg/24 h
17 (8–61)
15 (8–62)
17 (8–61)
0.90
Previous CVD, %
19
17
20
0.67
Smokers, %
21
19
21
0.69
Insulin daily dose, IE/24 h
48.5 ± 34.4
43.2 ± 23.0
49.0 ± 35.4
0.22
Antihypertensive treatment, %
71
76
70
0.63
Statin treatment, %
59
50
60
0.13
Systolic blood pressure, mmHg
136 ± 14
136 ± 12
136 ± 15
0.83 0.06
Diastolic blood pressure, mmHg
75 ± 10
78 ± 7
75 ± 7
Mean arterial pressure, mmHg
93 ± 11
92 ± 10
93 ± 10
0.49
Heart rate, beats per minute
71 ± 9
69 ± 12
72 ± 12
0.10
Albuminuria, % Pulse wave velocity, m/s
48 10.4 ± 3.3
40 9.3 ± 2.8
50 10.4 ± 3.4
0.16 0.02
Adjusted linear regression analysis was performed to assess whether level of PWV was independently associated with CSII treatment. Adjustment included gender, age, diabetes duration, HbA1c, heart rate, MAP, P-creatinine, UAER, smoking, daily insulin dose, antihypertensive treatment, previous CVD, total cholesterol and statin treatment. A two-tailed P \ 0.05 was considered significant. All statistics were performed with SPSS for windows version 20.0 (SPSS, Chicago, IL).
Results Fig. 1 Pulse wave velocity in patients treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI) shown as mean and SD. P value is for unadjusted comparisons (t test)
[interquartile range] and log10 transformed before analysis with the exception of CSII duration which is squared. Comparisons between groups were assessed by t test for continuous variables and the chi-square test for categorical variables.
General characteristics General characteristics of the study population are shown in Table 1. In short, patients were (mean ± SD) 54 ± 13 years, 56 % male, had 32 ± 16 years of diabetes duration, PWV of 10.3 ± 3.3 m/s and HbA1c of 8.0 ± 1.2 % (64 ± 13 mmol/mol). The median (IQR) duration of CSII treatment was 5.1 (2.7–20.4) years. Age, gender distribution, diabetes duration, HbA1c, blood pressure, total cholesterol, heart rate, body mass
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Table 2 Adjusted linear regression coefficients for pulse wave velocity Variable (SD)
Regression coefficient
SE
P
Age (13 years)a
0.47
0.009
\0.001
Diabetes duration (16 years)a
0.27
0.007
\0.001
Heart rate (9 beats per minute)a
0.11
0.008
\0.001 \0.001
Mean arterial pressure (9 mmHg)
a
0.21
0.01
P-creatinine
0.09
0.71
0.007
Urinary albumin excretion rate
0.07
0.16
0.036
CSII versus MDI treatment
0.06
0.33
0.038
The adjusted linear regression models included age, gender, diabetes duration, HbA1c, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate, smoking, total daily insulin dose, antihypertensive treatment, previous cardiovascular disease, total cholesterol, statin treatment and CSII versus MDI treatment. Only variables with significant association are shown CSII continuous subcutaneous insulin infusion and MDI multiple daily injections a
Regression coefficient given as standardised coefficient
index, number of smokers, eGFR and UAER did not differ between patients receiving CSII versus MDI treatment (P C 0.08, Table 1). Arterial stiffness and CSII versus MDI treatment Although clinical characteristics were similar, PWV was significantly lower in patients receiving CSII compared with MDI treatment: 9.3 ± 2.8 versus 10.4 ± 3.4 m/s (P = 0.016; Fig. 1). In adjusted linear regression, CSII treatment was significantly associated with lower PWV (P = 0.038). Younger age, shorter diabetes duration, lower P-creatinine, UAER, heart rate and MAP were also associated with lower PWV (P B 0.04; Table 2), whereas HbA1c was not (P = 0.93). Also gender, smoking, total daily insulin dose, antihypertensive treatment, previous CVD, total cholesterol and statin treatment were not related to PWV (P C 0.66). Additional inclusion of triglyceride or triglyceride/HDLcholesterol ratio in the adjusted linear regression model did not change the significant association between CSII treatment and lower PWV (P = 0.038). Arterial stiffness in subgroups, CSII versus MDI treatment Of the 601 patients, 311 (52 %) had albuminuria. Of the patients with albuminuria, 35 (11 %) were treated with CSII and 276 (89 %) with MDI. Among the normoalbuminuric patients, this distribution was 23 (8 %) and 267 (92 %), respectively. In patients with normoalbuminuria, PWV was low both for patients treated with CSII and MDI (9.4 ± 3.2 vs. 9.5 ± 3.1 m/s) without significant difference (P = 0.88). Furthermore, there was no adjusted association between CSII treatment and PWV (P = 0.97). There was no difference in general characteristics between CSII- versus
123
MDI-treated normoalbuminuric patients (P C 0.06), except for lower eGFR in CSII-treated patients (P = 0.03). In patients with albuminuria, PWV was significantly lower in those receiving CSII versus MDI treatment (P \ 0.001, Table 3). CSII-treated patients were slightly younger, but CSII treatment remained significantly (P = 0.029) associated with lower PWV even after fully adjustment including age. General characteristics for the albuminuric patients are shown in Table 3. Of the 601 patients, 117 (19 %) had previous CVD. Of 484 patients without previous CVD, 48 (10 %) were treated with CSII and 436 (90 %) with MDI. In patients with previous CVD, this distribution was 10 (9 %) and 106 (91 %), respectively. Patients treated with CSII without previous CVD had the lowest PWV of 8.8 ± 2.3 m/s, which was significantly lower than in MDI-treated patients (P = 0.01). Furthermore, CSII treatment was associated with lower PWV in fully adjusted analyses (P = 0.005). General characteristics for the patients without previous CVD are shown in Table 3. In patients with previous CVD, both CSII- and MDItreated patients had increased PWV, and PWV did not differ between the groups (11.7 ± 4.0 vs. 12.1 ± 3.5; P = 0.78), although numbers were small. Among patients with previous CVD, none of the general characteristics were different between CSII- and MDI-treated patients (P C 0.05). In neither of the subgroups, the level of HbA1c was associated with PWV in adjusted linear regression analyses (P C 0.88). Arterial stiffness and duration of CSII treatment To investigate the association between levels of PWV and duration of CSII treatment, we performed additional linear regression analyses only including the 58 patients treated
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Table 3 General characteristics for patients with albuminuria and for patients without cardiovascular disease Albuminuria (n = 311) CSII treatment n = 35
Without previous cardiovascular disease (n = 484)
MDI treatment n = 276
P
CSII treatment n = 48
MDI treatment n = 436
P
Men, %
46
60
0.54
44
57
0.09
Age, years
50 ± 12
56 ± 11
0.006
50 ± 11
53 ± 13
0.15
Diabetes duration, years
36 ± 10
36 ± 13
0.74
32 ± 11
30 ± 16
0.39
HbA1c, %
8.1 ± 1.0
8.3 ± 1.2
0.45
7.8 ± 1.0
8.0 ± 1.5
0.31
HbA1c, mmol/mol
65 ± 11
67 ± 14
0.45
61 ± 11
64 ± 13
0.31
Total cholesterol, mmol/L
4.8 ± 0.8
4.6 ± 1.0
0.35
4.8 ± 0.8
4.7 ± 0.8
0.39
HDL cholesterol, mmol/L
1.6 ± 0.4
1.7 ± 0.5
0.55
1.8 ± 0.5
1.7 ± 0.5
0.24
Triglycerides, mmol/L
1.08 ± 0.6
1.20 ± 0.7
0.37
0.93 ± 0.6
1.09 ± 0.6
0.07
Body mass index, kg/m2
26.0 ± 4.4
26.0 ± 7.7
0.99
25.2 ± 4.1
25.5 ± 6.5
0.75
P-creatinine, lmol/L
81 (70–105)
88 (70–122)
0.39
73 (66–86)
75 (65–89)
0.72
eGFR, mL/min/1,73 m2
78 ± 30
74 ± 30
0.48
83 ± 26
87 ± 27
0.23
Urinary albumin excretion rate, mg/24 h
41 (15–132)
55 (23–195)
0.57
15 (7–72)
15 (8–47)
0.55
Previous CVD, %
26
29
0.71
–
–
–
Smokers, % Insulin daily dose, IE/24 h
26 47.7 ± 26.9
22 49.6 ± 25.3
0.64 0.65
19 39.5 ± 20.1
22 49.4 ± 37.6
0.65 0.08
Antihypertensive treatment, %
91
95
0.46
71
65
0.40
Statin treatment, %
66
78
0.13
44
54
0.17
Systolic blood pressure, mmHg
136 ± 11
138 ± 15
0.37
135 ± 12
135 ± 14
0.70
Diastolic blood pressure, mmHg
77 ± 6
75 ± 8
0.20
79 ± 6
77 ± 8
0.05
Mean arterial pressure, mmHg
92 ± 9
94 ± 10
0.31
93 ± 10
93 ± 10
0.87
Heart rate, beats per minute
71 ± 12
74 ± 12
Pulse wave velocity, m/s
9.3 ± 2.5
11.3 ± 3.4
0.24
69 ± 12
72 ± 12
0.04
\0.001
8.8 ± 2.3
10.0 ± 3.2
0.001
Data represent percentage (%), mean ± SD or median (IQR) Albuminuria: urinary albumin excretion rate C30 mg/24 h CSII continuous subcutaneous insulin infusion, MDI multiple daily injections, eGFR estimated glomerular filtration rate and CVD cardiovascular disease (previous myocardial infarction, revascularization, peripheral arterial disease or stroke). P values are for unadjusted comparisons (t test or chi-square test) between patients with albuminuria or without previous CVD treated with CSII versus MDI
with CSII. In unadjusted regression, lower PWV was associated with younger age, shorter diabetes duration, no antihypertensive treatment, lower daily insulin dose and no previous CVD (P B 0.02), whereas PWV not was associated with gender, HbA1c, heart rate, MAP, P-creatinine, UAER, smoking, total cholesterol, statin treatment or duration of CSII treatment (P C 0.068). In adjusted regression, only younger age and lower insulin dose remained associated with lower PWV (P \ 0.001).
Discussion To our knowledge, this is the first study to investigate the association between arterial stiffness and CSII versus MDI treatment in type 1 diabetes patients. In the whole study population, PWV was lower in patients receiving CSII treatment. Adjusted linear regression revealed a significant
relation between CSII treatment and lower PWV. Moreover, among patients with albuminuria, those on MDI treatment had high levels of PWV, whereas CSII-treated patients had PWV levels similar to normoalbuminuric patients. In patients without previous CVD, the level of PWV was significantly lower in CSII-treated patients compared with MDI, whereas PWV levels were equally high in CSII- and MDI-treated patients with previous CVD. It is not evident why there was a significant difference in PWV between CSII- and MDI-treated patients with albuminuria and thus a higher risk for CVD, but not in patients with previous CVD, except that the number of CSII-treated patients with previous CVD was very small. The level of PWV was 2.0 m/s higher in MDI-treated patients with albuminuria and 1.2 m/s higher in MDItreated patients without previous CVD. In a meta-analysis, Vlachopoulos et al. [27] found, over a mean of 7.7 years of follow-up, an adjusted relative risk of 1.14
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for cardiovascular events and of 1.15 for cardiovascular as well as all-cause mortality per 1 m/s increase in PWV. Thus, the observed differences in PWV are clinically relevant. In patients with type 2 diabetes, Cruickshank et al. [15] showed an adjusted relative risk of 1.08 for cardiovascular as well as all-cause mortality with 1 m/s increase in PWV over 10.7 years of follow-up. Based on these results, CSII-treated patients with albuminuria in our study could have around 30 % reduced risk of cardiovascular events and 16–30 % reduced risk of cardiovascular and all-cause mortality over 7–10 years. For patients without previous CVD, the reduced risk of cardiovascular event and all-cause mortality could be around 8–15 %. However, whether treatment with CSII can reduce arterial stiffness or slow development of arterial stiffness and whether this can be translated into a reduction in cardiovascular events needs to be demonstrated in large prospective intervention trials. Arterial stiffness has been linked to micro- and macrovascular complications in type 1 diabetes [28]. Our data suggest that CSII treatment either protects the arterial wall or even modifies arterial stiffness. Since patients receiving CSII often have preceding poor glycaemic control, as they had to fulfil the criteria of glycaemic dysregulation to qualify for CSII treatment [25], it is even more interesting that they had lower arterial stiffness. Patients treated with MDI or CSII were alike on other parameters, with few exceptions: (1) in patients with albuminuria, where the CSII-treated patients were younger, (2) in patients with normoalbuminuria, where eGFR was higher in the MDItreated group, and (3) in patients without previous CVD, where CSII-treated patients had a lower heart rate. There was no association between PWV and duration of CSII treatment which could suggest lack of causality although the time–effect relationship is unknown. Within the group of CSII-treated patients, we only found an association between younger age and lower daily insulin dose to lower PWV in adjusted analyses which most likely reflect lack of power. However, when including patients with CSII treatment\1 year (n = 15) in the adjusted analysis of CSII durations and level of PWV, longer duration of CSII treatment was borderline (P = 0.07) associated with lower PWV (data not shown). This could indicate that CSII treatment should be continued for more than a year to have an effect on PWV. Treatment with CSII delivers insulin in a more physiological manner than MDI and likely ensures less glucose variability. The STAR 3 study showed sensor-augmented CSII therapy to lower glucose variability, but did not assess the effect on complications [29]. Chimenti et al. [7] showed a significant reduction in glucose variability in patients changing from MDI to CSII treatment, but they also did not assess the effect on complications.
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Maybe, lower glucose variability rather than or in addition to HbA1c-level is of significance in this setting. This is supported by the facts that HbA1c was not associated with PWV neither in the whole cohort nor in the subgroups examined. The FinnDiane study also observed that arterial stiffness was not associated with HbA1c except in macroalbuminuric patients [28]. Variability of HbA1c reflecting glucose variability over longer periods of time has been associated with diabetic micro- and macrovascular complications [30]. However, a recent study by Cesana et al. [31] using continuous glucose monitoring for 24 h did not find an association between arterial distensibility and glucose variability. In addition, the Epidemiology of Diabetes Intervention and Complications study (DCCT/EDIC) was unable to link higher glucose variability to diabetes complications [32, 33]. However, the variability was accessed from seven point glucose profiles which may not be adequate to investigate glucose excursions and may explain the lack of association. Thus, it remains unclear whether reduced HbA1c or glucose variability related to CSII treatment may contribute to the lower arterial stiffness. Unfortunately, data on glycaemic variability are not available in our cohort. Management of glycaemic control in diabetes largely rely on measurements of HbA1c. However, this measure is inadequate to register acute changes and fluctuation of glucose level. Studies have shown that extreme glucose levels affect arterial morphology through oxidative stress, advanced glycation end product formation and endothelial dysfunction [34, 35]. Thus, stabilisation of glucose levels could expectedly protect arterial health and delay or prevent arterial pathology. However, randomised, controlled intervention studies comparing CSII and MDI treatment are required to investigate whether CSII treatment can revert or inhibit progression of arterial stiffness. We intend to follow-up the current cohort to investigate changes in arterial stiffness over time in patients receiving CSII versus MDI treatment. The limitation of this study is primarily the cross-sectional design, excluding conclusions on causality. It cannot be excluded that there is a selection of healthy patients for CSII treatment as self-care skills are required to receive CSII treatment. On the other hand, most often CSII treatment is initiated in patients with poorer glycaemic control, although clinical characteristics between groups were almost similar in our study. Moreover, the subgroup analyses are based on limited number of patients and thus reduced power. The strengths are the overall large number of patients and the broad recruitment from the clinic. Also, most patients have been followed at Steno Diabetes Center for many years which make recording of albuminuria and CVD fairly reliable although under-reporting of CVD may be suspected.
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Conclusion In summary, CSII treatment and not HbA1c were associated with lower arterial stiffness independently of other risk factors in a cross-sectional study of comparable groups of patients with type 1 diabetes. The same association was seen in patients with albuminuria or without previous CVD. Although glucose variability was not assessed, our results support the hypothesis that glucose variability and not mean glucose level as reflected by HbA1c-level affects arterial stiffness. This needs confirmation in randomised prospective studies assessing the development of vascular complications as well as glucose variability. Acknowledgments S.R. collected and analysed data and wrote the manuscript, S.T. collected and analysed data and wrote the manuscript, T.H. reviewed/edited the manuscript and contributed to the introduction and the discussion, S.A. and P.R. reviewed/edited the manuscript. S.R. is the guarantor of this work and has had full access to the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. The authors acknowledge the excellent technical assistance from the laboratory at Steno Diabetes Center, Gentofte, Denmark. Conflict of interest SR., S.T., T.H. and P.R. have no conflict of interest. S.A. has received an unrestricted research grant from Medtronic A/S, Denmark. Human and animal rights All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki of 1975, as revised in 2008. Informed consent Informed consent was obtained from all patients for being included in the study.
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