Insulin Pump—Long-Term Effects on Glycemic Control: An Observational Study at 10 Diabetes Clinics in Sweden

Abstract

Aim:

This study examined long-term effects of continuous subcutaneous insulin infusion (CSII) in clinical practice on glycemic control in patients with type 1 diabetes.

Subjects and Methods:

We evaluated all type 1 diabetes patients at 10 diabetes outpatient clinics in Sweden who had been treated with CSII for at least 5.5 years and had valid glycated hemoglobin (HbA1c) data before starting pump use and at 5 years±6 months. Controls treated with multiple daily insulin injections (MDI) over a time-matched period were also evaluated.

Results:

There were 331 patients treated with CSII at least 5.5 years at the 10 clinics. Of these, 272 (82%) fulfilled the inclusion criteria. Patients treated with CSII were younger than those treated with MDI (mean age, 38.6 vs. 45.6 years; P<0.001), more were women (56% vs. 43%; P<0.001), and diabetes duration was shorter (mean, 15.1 years vs. 20.1 years; P<0.001). After adjusting for variables differing at baseline and influencing the change in HbA1c over the study period, the reduction in HbA1c remained statistically significant at 5 years and was estimated to be 0.20% (95% confidence interval [CI] 0.07–0.32) (2.17 mmol/mol [95% CI 0.81–3.53]) (P=0.002). The corresponding adjusted reduction at years 1 and 2 was 0.42% (95% CI 0.31–0.53) (4.59 mmol/mol [95% CI 3.41–5.77]) (P<0.001) and 0.43% (95% CI 0.31–0.55) (4.71 mmol/mol [95% CI 3.38–6.04]) (P<0.001), respectively. The effect of insulin pump use versus controls on HbA1c decreased significantly with time (P<0.001).

Conclusions:

Use of CSII in clinical practice in Sweden is associated with an approximately 0.2% (2 mmol/mol) reduction in HbA1c after 5 years.

Background

P oor glycemic control among individuals with type 1 diabetes is associated with increased risk for diabetes complications.^1
–3 At present, insulin treatment to optimize glycemic control comes in the form of either multiple daily insulin injections (MDI) or an insulin pump (i.e., continuous subcutaneous insulin infusion (CSII).^4,5 Meta-analyses of multiple clinical trial results indicate that the use of CSII therapy improves glycated hemoglobin (HbA1c) by approximately 0.3 percentage units (3 mmol/mol).^6,7 Data from clinical practice have indicated an even greater effect of CSII therapy on HbA1c level, with improvements of 0.4–0.6% (4–6 mmol/mol) observed over the first 1–2 years of therapy.⁸ Despite CSII having an effect on improving glycemic control, we recently found that the availability of the therapy greatly varies between care units and patient groups.⁹

Although the availability of CSII therapy in Sweden greatly varies by patient groups and care units, the reason for the difference is unclear. Although the availability of CSII continues to improve, it is important to confirm that beneficial effects found in previous studies of CSII over shorter time periods, generally 1–2 years, are sustained over longer treatment periods and do not decline. This may be of special concern because randomized clinical trials of CSII have generally not been blinded, and long-term studies of CSII are generally lacking.

In this study we address this gap in knowledge by evaluating HbA1c levels both before and after 5 years of CSII treatment in type 1 diabetes patients at 10 outpatient diabetes clinics in Sweden, along with controls treated with MDI over the corresponding time period.

Subjects and Methods

Data source

Data were obtained from a medical patient record system, Diab-Base (Journalia AB, Kungälv, Sweden), which is used at 10 hospital-based diabetes clinics that treat adult outpatients (18 years or older) in Sweden.¹⁰ Most clinics have used Diab-Base since approximately the year 2000. The system has previously been described in detail and has been used in several previous studies of diabetes treatments among patients with both types 1 and 2 diabetes.^8,11
–13 In brief, Diab-Base includes information on risk factors, treatments, and complications that are recorded during clinical visits. The system is constructed so that all measurements on risk factors such as HbA1c, blood pressure, blood lipids, body mass index, type of diabetes, and insulin dose can be tracked electronically and also includes information on the date when CSII treatment began. In the current study data were collected until September 2009.

The study was approved by the ethical committee of the University of Gothenburg, Gothenburg, Sweden.

Inclusion criteria for CSII patients

The following inclusion criteria were used for the CSII group: type 1 diabetes; diabetes duration for at least 1 year prior to starting CSII; beginning CSII 6 or more months after inclusion in Diab-Base; and CSII treatment for at least 5.5 years.

Exclusion criteria for CSII patients

All patients without information regarding the date of diagnosis of diabetes were excluded. Patients with missing HbA1c measurements within 6 months before initiating CSII and close to 5 years of treatment with CSII, either 6 months before or 6 months after, were also excluded. Those with a missing or 0 value of insulin dose at CSII start were excluded as well.

Control group

The control group consisted of patients treated with MDI over a time period corresponding to that during which patients were treated with CSII. The control group was selected by matching the highest possible number of unique control patients to each patient from the CSII group with respect to CSII start date. Similar to the CSII treatment group, the control group included only patients with a diabetes duration of >1 year. Only those with HbA1c values available at 5 years (±6 months) were included in the control group. Patients with intermittent use of CSII were excluded.

Data cohort

There were 331 type 1 diabetes patients treated with CSII for more than 5.5 years who had initiated the therapy at least 6 months after registration in Diab-Base and with diabetes duration of >1 year. In total, 272 patients (272/331 [82%]) were included in the analyses. Two patients were excluded because of missing diabetes diagnosis date, 44 because of missing HbA1c at CSII start, 12 because of missing HbA1c at 5 years, and one because of insulin dose 0 at CSII start.

Among MDI patients there were 3,039 who had had type 1 diabetes for at least 1 year and available HbA1c data at 5 years. Of those, 2,448 (i.e., nine controls per each CSII patient) were selected in the matching process, and 11 of these were excluded from the final analytical cohort for having an insulin dose equal to 0 at baseline, resulting in 2,437 control patients included in the analyses.

Data analysis

To estimate whether various effects on HbA1c occurred with respect to time, we analyzed the change in HbA1c level from baseline (i.e., prior to initiating CSII) to the HbA1c value at 1 year, 2 years, and 5 years of treatment and performed corresponding analyses for controls. Specifically, we assessed whether any variables had a significant effect on the change in HbA1c at any point during follow-up. First, unadjusted analyses for tests between groups were performed, followed by adjusted tests after accounting for differences in baseline characteristics, The primary end point was adjusted HbA1c level at 5 years. Variables considered to be potential confounders at baseline were age, sex, HbA1c, body mass index, insulin dose, and diabetes duration.

Because diabetes clinics in Sweden used HbA1c methods calibrated to the high-performance liquid chromatography Mono S method until September 2010, all HbA1c values were converted to the National Glycohemoglobin Standardization Program and International Federation for Clinical Chemistry standards.¹⁴

Statistics

To obtain the highest possible number of controls during a follow-up period corresponding to the follow-up period for those treated with CSII, t statistics and the P value from the t test were used to test the differences between the CSII group and controls with respect to the start date. The time interval allowed around the calendar date was±182 days. The average number of controls for each CSII patient was nine.

Age, sex, HbA1c, body mass index, diabetes duration, and insulin dose at baseline were compared between groups using a t test for continuous variables and Fisher's exact test for dichotomous variables. The Pearson correlation coefficient between baseline characteristics and the change in HbA1c level from baseline to the first HbA1c value after 1, 2, and 5 years was calculated. Unadjusted analyses of the change in HbA1c from baseline to the first HbA1c value after 1, 2, and 5 years in the two groups were analyzed using a paired t test. HbA1c was the only variable that differed significantly at baseline between the groups and demonstrated a significant relationship with the change in HbA1c level at any point during follow-up. Analyses of the change in HbA1c after adjusting for variables other than treatment group were performed using analysis of covariance. As a sensitivity analysis, the corresponding analyses at 1, 2, and 5 years were performed adjusting for all baseline variables, as well as those not differing between the groups at baseline or affecting the studied variable significantly. All tests were two-tailed and conducted at the 5% significance level. All analyses were conducted using SAS version 9.2 (SAS Institute Inc., Cary, NC).

Results

Baseline characteristics of the 272 individuals treated with CSII and the 2,437 controls are presented in Table 1. Patients in the CSII group were younger than those treated with MDI (mean age, 38.6 years vs. 45.6 years; P<0.001). There were fewer men treated with CSII than with MDI (44% vs. 57%; P<0.001). The HbA1c level was greater in CSII patients (8.39% [68.1 mmol/mol] vs. 8.07% [64.7 mmol/mol]; P<0.001), their insulin doses were lower (0.63 units/kg vs. 0.67 units/kg; P=0.09), and they had shorter diabetes duration (15.1 years vs. 20.1 years; P<0.001).

Table 1.

Patient Characteristics

Variable	CSII (n=272)	MDI (n=2,437)	P value ^a
Gender
Male	119 (43.8%)	1,391 (57.1%)
Female	153 (56.3%)	1,046 (42.9%)	<0.001
Age (years)	38.6 (11.3) (n=267)	45.6 (14.4) (n=2,437)	<0.001
HbA1c (%)^b	n=272	n=2,437
NGSP	8.39 (1.30)	8.07 (1.27)	<0.001
IFCC	68.1 (14.2)	64.7 (13.9)
BMI (kg/m²)	24.8 (3.4) (n=266)	25.0 (3.8) (n=2,392)	0.38
Insulin dose (U/kg)	0.632 (0.372) (n=271)	0.671 (0.226) (n=2,427)	0.090
Diabetes duration (years)	15.1 (11.2) (n=272)	20.1 (13.2) (n=2,437)	<0.001

For categorical variables, n (%) is presented. For continuous variables, mean (SD) (n) values are presented.

For comparison between groups, Fisher's exact test was used for dichotomous variables, and t test was used for continuous variables.

The unit for National Glycohemoglobin Standardization Program (NGSP) is %, and for that International Federation for Clinical Chemistry (IFCC) is mmol/mol.

BMI, body mass index; CSII, continuous subcutaneous insulin infusion; HbA1c, glycated hemoglobin; MDI, multiple daily insulin injections.

In unadjusted analyses there was a statistically significant decrease in HbA1c from baseline to 1, 2, and 5 years in patients treated with CSII (Table 2). The HbA1c value closest to 5 years was 0.44% [4.83 mmol/mol]; P<0.001) lower compared with baseline HbA1c. Among control patients, there was a smaller yet significant decrease in HbA1c level at 5 years (0.11% [1.20 mmol/mol]; P<0.001). Consequently, the unadjusted relative reduction in HbA1c level in patients treated with CSII versus MDI at 5 years was 0.33% (3.63 mmol/mol) (P<0.001).

Table 2.

Unadjusted and Adjusted Changes in Glycated Hemoglobin from Baseline to 1, 2, and 5 Years for Patients Treated with Continuous Subcutaneous Insulin Infusion Compared with Patients Treated with Multiple Daily Insulin Injections

Variable	CSII (n=272)	MDI (n=2,437)
HbA1c
At baseline	n=272	n=2,437
NGSP	8.39 (1.30)	8.07 (1.27)
IFCC	68.1 (14.2)	64.7 (13.9)
At 1 year	n=260	n=2,213
NGSP	7.88 (1.24)	8.03 (1.27)
IFCC	62.6 (13.6)	64.3 (13.9)
Change in HbA1c from baseline to 1 year	n=260	n=2,213
NGSP	−0.540 (1.111)	−0.033 (0.860)
IFCC	−5.90 (12.14)	−0.359 (9.404)
P	<0.001	0.07
Unadjusted difference between groups for change in HbA1c from baseline to 1 year
NGSP	−0.507 (−0.647; −0.367)
IFCC	−5.54 (−7.07; −4.01)
P	<0.001
Adjusted difference between groups for change in HbA1c from baseline to 1 year^a
NGSP	−0.420 (−0.528; −0.312)
IFCC	−4.59 (−5.77; −3.41)
P	<0.001
HbA1c at 2 years	n=256	n=2,204
NGSP	7.80 (1.18)	8.01 (1.27)
IFCC	61.7 (12.8)	64.1 (13.9)
Change from baseline in HbA1c at 2 years	n=256	n=2,204
NGSP	−0.592 (1.070)	−0.050 (1.028)
IFCC	−6.47 (11.70)	−0.548 (11.238)
P	<0.001	0.022
Unadjusted difference between groups for change in HbA1c from baseline to 2 years
NGSP	−0.542 (−0.675; −0.408)
IFCC	−5.92 (−7.38; −4.46)
P	<0.001
Adjusted difference between groups for change in HbA1c from baseline to 2 years^a
NGSP	−0.431 (−0.553; −0.309)
IFCC	−4.71 (−6.04; −3.38)
P	<0.001
HbA1c at 5 years	n=272	n=2,437
NGSP	7.94 (1.20)	7.96 (1.23)
IFCC	63.3 (13.1)	63.5 (13.5)
Change in HbA1c from baseline at 5 years	n=272	n=2,437
NGSP	−0.442 (1.228)	−0.110 (1.116)
IFCC	−4.83 (13.42)	−1.20 (12.20)
P	<0.001	<0.001
Unadjusted difference between groups for change in HbA1c from baseline to 5 years
NGSP	−0.332 (−0.485; −0.179)
IFCC	−3.63 (−5.30; −1.96)
P	<0.001
Adjusted difference between groups for change in HbA1c from baseline to 5 years^a
NGSP	−0.198 (−0.323; −0.074)
IFCC	−2.17 (−3.53; −0.81)
P	0.002

For the actual values, mean (SD) (n) (P) values are presented. For the unadjusted difference between the groups, mean values (95% confidence interval) for the difference (P) are presented. For the adjusted difference between the groups, least square mean values (95% confidence interval) for the difference (P) are presented. For comparison between groups, t test was used for continuous variables. For comparison within groups, paired Student's t test was used. Calculation of confidence interval for continuous variables is based on the assumption of normality. When variances are not equal (P<0.05), the SD is based on Satterthwaite's approximation; otherwise, SD is based on the pooled SDs. The unit for National Glycohemoglobin Standardization Program (NGSP) is %, and for that International Federation for Clinical Chemistry (IFCC) is mmol/mol.

Test for adjusted difference between groups for change from baseline in glycated hemoglobin (HbA1c) have been performed by using analysis of covariance with HbA1c at baseline as covariate.

CSII, continuous subcutaneous insulin infusion; MDI, multiple daily insulin injections.

The effects of CSII versus MDI on HbA1c level estimated by analysis of covariance adjusted for differences in HbA1c at baseline are shown in Table 2. At 5 years, there was a significant reduction in HbA1c level for patients receiving CSII compared with those continuing with MDI (0.20% [95% CI 0.07–0.32]; 2.17 mmol/mol [95% CI 0.81–3.53]; P=0.002). At 1 and 2 years the corresponding adjusted reductions in HbA1c in favor of CSII treatment were 0.42% (95% CI 0.31–0.53) (4.59 mmol/mol [95% CI 3.41–5.77]) (P<0.001) and 0.43% (95% CI 0.31–0.55) (4.71 mmol/mol [95% CI 3.38–6.04]) (P<0.001), respectively.

When analyzing patients treated with CSII separately to understand the treatment effect on HbA1c level over time, the beneficial effect on HbA1c level by CSII decreased nonsignificantly with time (P=0.10). In contrast, the effect on HbA1c level in patients with MDI increased significantly with time (P<0.001). The change in HbA1c level over time for patients with CSII compared with that of MDI on HbA1c level decreased significantly over time (adjusted P<0.001).

In a sensitivity analysis of the effect on HbA1c level by CSII when adjusting for all baseline variables (Table 1), those not differing at baseline or affecting the studied variable also showed similar results as the main analysis. At 5 years the adjusted reduction in HbA1c level in favor of CSII was 0.22% (95% CI 0.095–0.35) (2.45 mmol/mol [95% CI 1.04–3.85]) (P=0.001). At 1 and 2 years the corresponding reductions both in favor of CSII were 0.42% (95% CI 0.31–0.53) (4.62 mmol/mol [95% CI 3.40–5.84]) and 0.44% (95% CI 0.31–0.56) (4.76 mmol/mol [95% CI 3.40–6.12]), respectively.

Discussion

In this study of 272 type 1 diabetes patients treated with CSII for more than 5.5 years at 10 different hospital-based outpatient clinics in Sweden, glycemic control improved significantly in patients receiving CSII compared with controls receiving MDI in both unadjusted and adjusted analyses. The adjusted change in HbA1c level at 5 years, which was the primary end point in the study, showed a modest but significant reduction in HbA1c (0.20% [2 mmol/mol]) in favor of CSII treatment. In contrast, the corresponding reduction in HbA1c level at 1 and 2 years was greater, at approximately 0.4% (4 mmol/mol). These results demonstrate persistent but diminishing effects of CSII on HbA1c level versus MDI over time.

To our knowledge long-term clinical trials over 5 years on the effect of CSII versus MDI on HbA1c level are absent.^5
–7 In a recent comprehensive review of the effect of CSII, the authors requested clinical trials with long duration and focused the importance of giving the corresponding education to the control group on MDI to confirm beneficial effects on HbA1c level by CSII.¹⁵ There are few previous studies from clinical practice that have examined the effects of CSII on HbA1c level over longer time periods. In a retrospective study without a control group of 138 type 1 diabetes patients receiving CSII, published in 2002,¹⁶ the HbA1c level decreased during the first year of CSII from 9.3±0.2% (87±2 mmol/mol) to 7.9±0.1% (72±1 mmol/mol) and then remained unchanged. The patients had been using CSII over 7.4 years as a mean and with a range between 0.3 to 19.9 years of use. One small study from the Czech Republic examined 35 patients treated with CSII and 35 controls treated with MDI over 7 years.¹⁷ These researchers observed reductions in HbA1c level and hypoglycemia among patients treated with CSII compared with MDI.¹⁷ In another uncontrolled study of 46 patients from a single outpatient diabetes clinic in Sweden, a reduction in HbA1c level was also observed.¹⁸ The effects of CSII on HbA1c level are difficult to conclude from these studies because of their limited sample sizes,^17,18 lack of control groups,^16,18 inclusion of patients soon after diagnosis,¹⁶ and the fact that patients were recruited from single centers¹⁸ with populations that may not have adequately represented the general population from which they were derived.

The reduction in HbA1c level observed among patients receiving CSII treatment in clinical practice is of interest from a health-economics perspective. CSII therapy is several times more expensive than MDI, and the cost-effectiveness of CSII was recently evaluated in a comprehensive review.¹⁵ We have detected a persistent reduction in HbA1c level after 5.5 years of CSII therapy. Yet, it is difficult to know what effect a reduction in HbA1c level of approximately 0.20 percentage units (2 mmol/mol) might have on the risk for diabetes complications or cumulative lifetime medical costs. Analyses from the Diabetes Control and Complications Trial have previously demonstrated that HbA1c reductions of around 0.3% (3.0 mmol/mol) probably reduce progression of diabetic retinopathy.¹⁹ However, it is difficult to predict to what extent such differences in HbA1c level affect the development of more advanced diabetes complications such as visual loss, amputations, renal failure, and cardiovascular disease. It is also noteworthy that CSII may have a beneficial effect in reducing hypoglycemia²⁰ and improve quality of life²¹ in clinical practice, which also are important factors to consider in understanding possible benefits of CSII.

Future research should examine the reasons for the significant decrease in the effect of CSII over time. Possible explanations include the fact that patients receive more intensive diabetes care at the time of initiating CSII and that patients become enthusiastic about trying novel therapies and thereby self-intensify their diabetes treatment. The current results may suggest that novel strategies regarding education and care might be crucial to prolong the period of benefit from CSII. Today, patients initiating CSII in Sweden usually receive education before starting the treatment, on the day for the start of CSII, and have regular contacts during some weeks after initiating CSII. The education can be in groups of three or four patients or individually depending on the circumstances. The length of the education and time frame for learning various applications of the pump can vary between clinics, but they also depend on the patient's own capability. Complementary educations are usually performed at regular clinical visits, but group education is sometimes also offered during the first year. Sometimes structured educations in groups are performed after longer time periods of CSII, but this is not performed consistently. Differences in the length, organization, and repetition of the education may be factors influencing how a beneficial effect by CSII can be sustained over time. It is, however, possible that patients treated with MDI may benefit from extended educations as well in improving their glycemic control.

Strengths of the present study are the long follow-up of over 5 years, multicenter design, use of a randomly selected time-matched control group, and relatively high proportion of patients (82%) from the studied background participating in the study.

It is noteworthy that most prior studies that have evaluated the effect of novel therapies (e.g., insulin analogs) in clinical practice among type 1 diabetes patients have not had a control group or been studied over longer time periods and have not been performed across multiple clinical units, but rather only in single research centers.²² A limitation is that although adjustments were made for potential confounding selection, bias cannot be ruled out because of the nonrandomized design. Moreover, it must be noted that education associated with initiation of insulin pump therapy may have contributed to the reductions in HbA1c level among the CSII-treated group. One could speculate that if patients with MDI would have received the same extended education and follow-up, an improvement in HbA1c level may have been observed for patients with MDI as well. Furthermore, we did not have complete data of hypoglycemia or the indication for initiating an insulin pump. It is hence possible that certain patient groups may rather have benefited with respect to reducing hypoglycemia when initiating use of insulin pumps. It is, however, noteworthy that lack of proper recordings of hypoglycemia is generally a limitation in studies from real-life data. One reason is that hypoglycemia episodes are often not completely recorded in patient records, but another problem, compared with clinical trials, is that patients do often not measure glucose levels at symptoms of hypoglycemia before taking carbohydrates, and the definition of hypoglycemia is a reduced glucose level.²³ In clinical practice CSII is initiated in some patients because of hypoglycemia, fluctuating blood glucose levels, or a quality of life perspective, but our experience is that in most patients there is at least partially an aim of improving the HbA1c level when initiating CSII. This is also supported by the fact that CSII is recommended at impaired glycemic control in national guidelines on the premise of reducing the HbA1c level. Our group has previously also shown that CSII is significantly more often initiated the higher the HbA1c level, over the 6.0–9.8% (42–83 mmol/mol)⁹ range of HbA1c levels, where hypoglycemia episodes generally are more rare.¹ Little is known regarding risks of diabetic ketoacidosis in studies of CSII from population-based studies compared with risks in those with MDI,²¹ which would also be of interest for understanding possible benefits and risks of CSII in clinical practice. This was not evaluated in the current study but may be possible in the future, by linking data to national registers of discharge codes.

In conclusion, this is the first study comparing effects of CSII with MDI on HbA1c levels over a 5-year period in adult type 1 diabetes patients in clinical practice. It shows that there are beneficial effects on HbA1c (approximately 0.20% [2 mmol/mol]) of introducing CSII into clinical practice in Sweden after 5 years of treatment. The effects of CSII on HbA1c level declined with time and were smaller than we expected from previous studies treating patients with CSII during shorter time periods. The current findings indicate that strategies are needed to prolong the greater initial effects seen by CSII on HbA1c level, and there is a need for other strategies in patients with type 1 diabetes to target goals of HbA1c level in reducing future diabetes complications. It is noteworthy that other beneficial effects by CSII may exist for certain patient groups, such as effects on hypoglycemia and quality of life, which were not evaluated in this study. Further studies are needed to determine if the effects of CSII on HbA1c level differ by geographic region and whether beneficial effects persist for even longer follow-up periods than 5 years.

Footnotes

Acknowledgments

This study was supported by a grant from the Region of Västra Götaland, Sweden. We want to thank all staff working with Diab-Base for being central in the collecting of data.

Author Disclosure Statement

B.-M.C. has presented lectures at education workshops in the diabetes field that have been supported by Eli Lilly, Novo Nordisk, and Sanofi. S.A. has presented lectures at education workshops in the diabetes field that have been supported by Eli Lilly, Novo Nordisk, Sanofi, and Medtronic. M.L. has received honoraria or served as a consultant for Astra Zeneca, Bayer, Eli Lilly, Novartis, Novo Nordisk, Medtronic, Pfizer, and Sanofi-aventis. He has been a member of the advisory board of Novo Nordisk. M.L.'s department has received grants from Astra Zeneca, Novo Nordisk Scandinavia, and Abbott Scandinavia. M.C. has received honoraria from Medtronic. S.G., A.P., and L.S. have no competing financial interests.

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