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p r i m a r y c a r e d i a b e t e s 4 ( 2 0 1 0 ) 209–214

Contents lists available at ScienceDirect

Primary Care Diabetes

j o u r n a l h o m e p a g e : h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / p c d

riginal research

mproved A1C by switching to continuous subcutaneousnsulin infusion from injection insulin therapy in type 2iabetes: A retrospective claims analysis

eter Lyncha,∗, Aylin Altan Riedelb, Navendu Samantb, Ying Fanb, Tim Peoplesa,enifer Levinsona, Scott W. Leea

Medtronic, Inc., Northridge, CA, USAi3 Innovus, Inc., Eden Prairie, MN, USA

r t i c l e i n f o

rticle history:

eceived 25 February 2010

eceived in revised form

7 July 2010

ccepted 20 July 2010

vailable online 15 September 2010

eywords:

ype 2 diabetes

laims analysis

a b s t r a c t

Aims: This study was a real-world, retrospective evaluation of the clinical effectiveness of

switching to continuous subcutaneous insulin infusion (CSII) among managed care enrollees

with type 2 diabetes for whom multiple daily injections (MDI) had presumably failed.

Methods: Administrative claims with integrated A1C values from a large and geographically

diverse health plan were analyzed.

Results: Statistically significant A1C reductions (from the baseline period to follow-up period,

mean follow-up 17 months) were achieved with CSII. Among subjects using a long-acting

and rapid-acting insulin regimen at baseline, A1C decreased to mean follow-up A1C by

0.8% and to minimum follow-up A1C by 1.2% (p < 0.001). The proportion of subjects at target

(A1C < 7%) increased significantly from baseline to follow-up (8.4–22.9% [using mean A1C]

ontinuous subcutaneous insulin

nfusion

ultiple daily injections

1C

and 32.8% [using minimum A1C]; both p < 0.001). The rate of severe hypoglycemic events

was similar from baseline to follow-up.

Conclusions: CSII was associated with significant reductions in A1C without an increase

in hypoglycemic events in insulin-taking people with type 2 diabetes, including subjects

previously using a long-acting and rapid-acting insulin regimen.

ry Ca

although CSII reduced A1C significantly from baseline in all

© 2010 Prima

. Introduction

onventional, basal, and intensive injection-based insulinelivery is widely used to treat type 2 diabetes after

ther glucose-lowering agents have failed. Few insulin-takingeople with type 2 diabetes, however, use continuous subcuta-eous insulin infusion (CSII), which offers more physiological

∗ Corresponding author. Medtronic, Inc., Diabetes, 18000 Devonshire Stax: +1 818 576 6216.

E-mail address: peter.m.lynch@medtronic.com (P. Lynch).751-9918/$ – see front matter © 2010 Primary Care Diabetes Europe. Puoi:10.1016/j.pcd.2010.07.004

re Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

delivery of insulin, better tolerability, and reduction inglycemic excursions than multiple daily injections (MDI) [1].Three recent systematic reviews [2–4] examined a total of fourrandomized controlled trials (RCTs [5–8]) and concluded that

reet, Northridge, CA 91325, USA. Tel.: +1 41 21 803 8256;

RCTs, the available evidence indicates no glycemic advantagefor CSII over MDI. Of the RCTs used to arrive at these results,three did not demonstrate a statistically significant difference

blished by Elsevier Ltd. All rights reserved.

e t e s

210 p r i m a r y c a r e d i a b

between the CSII and MDI groups in A1C reduction [5,6,8]. Thepopulations for these included people with newly diagnosedtype 2 diabetes [8], adults ≥60 years of age [5], or otherwisehealthy people with type 2 diabetes [6]. The time on therapyin these studies was treatment to 2 weeks of euglycemia with1-year follow-up [8], 6 months [6], and 1 year [5]. Also, the studyreported by Weng et al. was designed to evaluate the effective-ness of intensive insulin therapy—not to compare CSII andMDI—and the primary endpoint was not A1C reduction [8].Finally, only 1 RCT used in the systematic reviews demon-strated a statistically significant difference between CSII andMDI in A1C reduction. Wainstein et al. reported results from acrossover study of 2 periods of 18 weeks each (i.e., all subjectsreceived both CSII and MDI). A total of 40 obese subjects wererandomized into 2 crossover groups, and the authors reporteda statistically significant difference in mean reduction in A1Cbetween CSII and MDI favoring CSII [7]. Finally, one additionalRCT has been conducted that showed a statistically significantadvantage in A1C for CSII over MDI, but it was not included inany of the recent systematic reviews [9].

Interpretation of these results is further confounded bythe insulin regimens used in the MDI groups, which mostlyinclude intermediate-acting and short-acting insulin for-mulations rather than long-acting and rapid-acting insulinregimens. Clinical evidence indicates that regimens using onlythese insulin formulations may offer clinical and tolerabil-ity advantages to regimens using intermediate-acting andshort-acting insulin formulations [10–12]. Among the afore-mentioned RCTs of CSII in type 2 diabetes, however, fourcompared CSII to MDI using either premixed NPH insulin andinsulin lispro [9], NPH insulin and insulin aspart [6], and NPHinsulin and insulin regular [7,8]. The only RCT of CSII vs. MDIin type 2 diabetes to use long-acting and rapid-acting insulin(glargine and aspart) formulations in MDI resulted in no differ-ence in A1C reduction between CSII and MDI [5]. This study,however, only included subjects who were ≥60 years of age,thus limiting the generalizability of the study’s results.

Despite the inconclusive results to date, CSII remains apromising therapy for insulin-taking people with type 2 dia-betes, especially those for whom MDI has failed. A consistentresult in RCTs of CSII in type 2 diabetes is that both MDIand CSII—i.e., intensive insulin therapy—reduced A1C frombaseline. Moreover, studies of CSII in type 2 diabetes have con-sistently found that the reduction of A1C is not accompaniedby an increase in the incidence of severe hypoglycemic events[5,6,8,13].

The present study was conducted to investigate whethera real-world population of people with type 2 diabetes wouldachieve clinical benefit after switching from injection insulintherapy to CSII. The purpose of the study was to examine A1Creduction and the incidence of severe hypoglycemia followingthe adoption of CSII among managed care enrollees with type2 diabetes for whom MDI had presumably failed.

2. Methods

This study was a retrospective claims analysis using medical,pharmacy, enrollment, and laboratory data to assess bene-fits of CSII. Subjects were enrollees in a large, geographically

4 ( 2 0 1 0 ) 209–214

diverse, U.S. managed care health plan with documentationof type 2 diabetes. Data were accessed in a manner compliantwith the Health Insurance Portability and Accountability Act.

Medical claims or encounter data were collected fromall available points of service—such as inpatient and outpa-tient hospital, emergency room, physician’s office, surgerycenter—and included specialty, preventive, and office-basedtreatments. Medical claims and coding conformed to insur-ance industry standards. Included in the database were A1Ctests that were sent for processing to two of the largestlaboratory facilities in the country and pharmacy claims rep-resenting all prescriptions filled at outpatient pharmacies andsubmitted to the insurance plan for reimbursement.

A 12-month period was used to examine baseline demo-graphic and clinical characteristics. The potential follow-upperiod was a minimum of 6 months and a maximum of 40months. Baseline and follow-up periods were measured fromthe date of CSII initiation.

Potential subjects were included if they initiated CSII dur-ing the subject identification period (January 1, 2005–October31, 2007) and had evidence of type 2 diabetes. Evidence oftype 2 diabetes was determined by any prescription for aglucose-lowering agent or International Classification of Diseases,9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes fortype 2 diabetes. Exclusion criteria included missing informa-tion on gender, age < 18 years, evidence of CSII use duringthe baseline period, lack of continuous enrollment in theirhealth plan for a 12-month baseline period, follow-up period <6 months, any evidence in the claims history of type 1 diabetes(by ICD-9-CM codes), and no evidence of previous insulin use(for the A1C analysis only).

A1C data from the follow-up period was analyzed using theminimum A1C result and the mean of all A1C results. BaselineA1C was the test closest to, preceeding, or on the first datethat an insulin pump or a related supply item was ordered.No follow-up A1C tests within 60 days of ordering an insulinpump or related supplies were included in the analysis.

Subjects with insulin use in the baseline period werecategorized into three groups: long-acting insulin only, anycombination of insulin use, and long-acting plus rapid-actinginsulin (a subset of combination insulin use).

Hypoglycemic events leading to office, ER or hospital visitswere identified and analyzed as severe hypoglycemic events.The number of severe hypoglycemic events was calculatedduring baseline and follow-up periods. Because the baselineperiod was fixed at 365 days for all subjects and the follow-upperiod varied, the number of hypoglycemic events is presentedas events per subject per month (PSPM).

2.1. Statistical analysis

All study variables were analyzed descriptively. Numbers andpercentages were provided for dichotomous and polychoto-mous variables. Means, medians, standard deviations, andpercentiles were provided for continuous variables. Univari-

ate analysis was performed on the change in A1C using pairedt-tests. Univariate analysis was performed to compare the pro-portion of subjects with A1C <7% during the baseline andfollow-up periods using the �2 test.

e s 4 ( 2 0 1 0 ) 209–214 211

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Table 1 – Baseline subject demographics.

Characteristic Value (n = 943)

Mean follow-up, months ± SD 17.10 (8.39)Age, years ± SD 47.99 ± 11.39Baseline mean Charlson-Deyo

Comorbidity score ± SD2.03 ± 1.52

Age group, n (%)18–24 34 (3.6)25–44 293 (31.1)45–64 578 (61.3)65 and older 38 (4.0)Sex, n (%)Male 444 (47.1)Female 499 (52.9)U.S. region, n (%)Northeasta 68 (7.2)Midwestb 269 (28.5)Southc 506 (53.7)Westd 100 (10.6)Year of CSII initiation, n (%)2005 242 (25.7)2006 374 (39.7)2007 327 (34.7)

a CT, MA, ME, NH, NJ, NY, PA, RI, VT.b IA, IL, IN, KS, MI, MN, MO, OH, ND, NE, SD, WI.c

p r i m a r y c a r e d i a b e t

Change in A1C after CSII using mean (−0.9 ± 1.9%), mini-um (−1.2 ± 2.0%), and maximum (−0.5 ± 2.0%) values during

he follow-up period were calculated and were similar to onenother. This article presents mean and minimum follow-up1C values. The Pearson correlation was used to determine

he relationship between A1C values during the baseline andollow-up periods.

Severe hypoglycemic events were calculated as PSPM.ecause the design of the study led to the same subject beingbserved and analyzed before and after switching to CSII, itas necessary to adjust for intra-subject correlation. A neg-

tive binomial model was used to calculate the rate ratio ofypoglycemic events (baseline:follow-up) in order to adjust fororrelation and calculate robust standard errors. An adjusted-value for the difference between severe hypoglycemic eventst baseline and after switching to CSII was used.

Outcomes were considered to be statistically significant ifhey were p < 0.05.

. Results

.1. Subject population

here were 943 subjects identified for the study. Mean agemong these subjects was 48 years, and mean follow-up was7 months (6–39 months; Table 1). Of these subjects, 282ubjects had a recorded baseline A1C, 145 subjects had suf-cient laboratory data for a comparison of change in A1Cfter switching to CSII (i.e., a baseline value and at leastfollow-up value), and 131 subjects had evidence of pre-

ious insulin use. Commonly reported comorbid conditionsncluded lipid metabolism disorders; hypertension; and dis-ases of the heart, thyroid, and eye. During the baseline period,1% (14/131) of the subjects in this study were using long-cting insulin only, 85% (111/131) were using any combinationf insulin, and 58% (76/131) were using long-acting and rapid-cting insulin.

.2. A1C

ean reductions in A1C (Table 2) and the increase in the pro-

ortion of subjects with A1C < 7% (Table 3) during the follow-uperiod were statistically significant for all subjects and amongll previous insulin regimen subgroups whether using meanr minimum follow-up A1C. Higher A1C at baseline was cor-

Table 2 – Change in A1C (%) from baseline to follow-up after sw

All subjects(n = 131)

Long-acting inonly (n = 14)

Mean baseline A1C 8.9 8.7Mean follow-up A1C 8.0 7.7� from baseline to mean A1C −0.9 −1.0p-Value for � from baseline to

mean A1C<0.001 0.01

Minimum follow-up A1C 7.7 7.7� from baseline to minimum A1C −1.2 −1p-Value for � from baseline to

minimum A1C<0.001 0.004

AL, AR, DC, DE, FL, GA, KY, MD, NC, OK, MS, TN, LA, SC, VA, TX,WV.

d AK, AZ, CA, CO, HI, ID, MT, NM, NV, OR, UT, WA, WY.

related with more substantial decrements in follow-up A1C(correlation: −0.7%; follow-up mean A1C change with baselineA1C < 7%: 0.4 ± 2.1%, baseline A1C ≥ 7%: −1.0 ± 1.9%, baselineA1C ≥ 8%: −1.4 ± 2.1%).

Mean A1C at baseline was 8.9% for all subjects (n = 131).The mean A1C reduction was 0.9% (8.9–8.0%, p < 0.001) tomean follow-up A1C and 1.2% (8.9–7.7%, p < 0.001) to min-imum follow-up A1C. For the long-acting and rapid-actinginsulin regimen subgroup, the mean A1C reduction was 0.8%(9.0–8.2%, p < 0.001) to mean follow-up A1C and 1.2% (9.0–7.8%,p < 0.001) to minimum follow-up A1C. Table 2 displays A1C dur-ing the baseline and follow-up periods for all subjects and forall subgroups by previous insulin regimen.

Overall, the proportion of subjects at target (A1C < 7%,

using American Diabetes Association criteria [14], based onmean A1C) increased significantly from the baseline periodto the follow-up period (8–23%, p < 0.001). Furthermore, theproportion of subjects at target increased significantly in the

itching to CSII.

sulin Any combination of≥2 insulin types(n = 111)

Long- and rapid-actinginsulin regimen (n = 76)

8.9 9.08.1 8.2

−0.8 −0.8<0.001 <0.001

7.7 7.8−1.2 −1.2<0.001 <0.001

212 p r i m a r y c a r e d i a b e t e s 4 ( 2 0 1 0 ) 209–214

Table 3 – Subjects (n, %) reaching ranges of A1C (%) from baseline to follow-up switching to CSII.

All subjects(n = 131)

Any combination of ≥2insulin types (n = 111)

Long- and rapid-actinginsulin regimen (n = 76)

Baseline A1C<7 11 (8.4) 8 (7.2) 3 (4.0)7 to <8 36 (27.5) 29 (26.1) 20 (26.3)8 to <9 32 (24.4) 29 (26.1) 22 (29.0)9 to <10 17 (13.0) 16 (14.4) 10 (13.2)≥10 35 (26.7) 29 (26.1) 21 (27.6)Mean follow-up A1C<7 30 (22.9) 23 (20.7) 12 (15.8)7 to <8 45 (34.4) 38 (34.2) 27 (35.5)8 to <9 29 (22.1) 26 (23.4) 20 (26.3)9 to <10 16 (12.2) 15 (13.5) 12 (15.8)≥10 11 (8.4) 9 (8.1) 5 (6.6)p-Value for � from baseline to mean A1C <0.001 <0.001 <0.001Minimum follow-up A1C<7 43 (32.8) 36 (32.4) 21 (27.6)7 to <8 45 (34.4) 38 (34.2) 29 (38.2)8 to <9 20 (15.3) 16 (14.4) 12 (15.8)9 to <10 14 (10.7) 14 (12.6) 9 (11.8)

≥10 9 (6.9)p-Value for � from baseline to minimum A1C <0.001

combination insulin subgroup (7–21%, p < 0.001) and the long-and rapid-acting subgroup (4–16%, p < 0.001). Table 3 displaysthe proportion of subjects reaching several A1C values duringthe baseline and follow-up periods.

3.3. Severe hypoglycemic events

The rate of severe hypoglycemic events PSPM was similar frombaseline period to the follow-up period (n = 943; 0.024 ± 0.104to 0.024 ± 0.095, p = 0.91). Results were similar after adjust-ment for covariates in a multivariate negative binomial model.Severe hypoglycemic event rate comparisons were similarfrom the baseline period to the follow-up period among sub-jects using long-acting insulin only (n = 14, 0.006 ± 0.023 to0.051 ± 0.105, p = 0.17), any combination of ≥2 types (n = 111,0.023 ± 0.065 to 0.031 ± 0.099, p = 0.45), and long- and rapid-acting insulin (n = 76, 0.026 ± 0.067 to 0.026 ± 0.076, p = 0.95) atbaseline.

4. Discussion

To our knowledge, this study is the first published databaseanalysis of CSII in people with type 2 diabetes. The healthclaims database allowed for the examination of health careoutcomes in a real-world setting, away from the highly con-trolled environment of clinical trials. The plan database usedin our study includes a large number of subjects with diversemedical histories living throughout the United States. Webelieve these results are generalizable to other populations ofpeople with type 2 diabetes enrolled in a managed care planwith similar benefit and exception criteria.

Our results provide robust evidence that CSII is a viable

replacement for MDI to reduce A1C in people with poorly con-trolled type 2 diabetes. The mean baseline A1C in our studywas 8.9%, well above the American Diabetes Association (ADA)recommendation of 7% [14]. Baseline values in RCTs of CSII in

7 (6.3) 5 (6.6)<0.001 <0.001

type 2 diabetes have ranged from 8.1 to 10.1% [3,5–9]. Afterswitching from combination insulin therapy, subjects in ourstudy experienced a mean reduction in A1C of 0.9% to meanfollow-up A1C or 1.2% to minimum follow-up A1C.

It is probable that many of the subjects categorized asusing combination insulin therapy were using MDI, whichtypically includes 1 basal and 2 or more bolus insulin injec-tions per day. To provide a greater degree of specificity, weanalyzed combination insulin therapy users who were usingboth long-acting and rapid-acting insulin—i.e., newer insulinformulations—at baseline. We found that most of the sub-jects in our study (n = 76/131) were using both long-acting andrapid-acting insulin at baseline. Subjects using long-actingand rapid-acting insulin at baseline experienced a statisticallysignificant reduction in A1C of 0.8% to mean follow-up A1Cand 1.2% to minimum follow-up A1C. The proportion of sub-jects at target significantly increased from 4% at baseline to16% at follow-up using mean A1C and 28% at follow-up usingminimum A1C. These results suggest that CSII has clinicaladvantages over an MDI regimen that uses newer long-actingand rapid-acting insulin formulations in type 2 diabetes.

An important safety concern for intensive insulin therapy(e.g., CSII or MDI) is a higher incidence of severe hypo-glycemia. The Diabetes Control and Complication Trial (DCCT)demonstrated the clinical effectiveness of intensive insulintherapy by both MDI and CSII but also found that these ther-apies increased the likelihood of severe hypoglycemia [15,16].Though DCCT did not report more severe hypoglycemic eventsamong CSII users relative to MDI [15,16], studies of CSII havepaid special attention to whether incremental benefits inA1C come at the expense of increased severe hypoglycemicevents. Consistent with previous studies [5,6,8,13], subjects

in our study experienced clinical benefits from CSII withoutan increased incidence of severe hypoglycemia. It is likely,however, that severe hypoglycemia was underreported in ourstudy because the database did not capture events that did

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ot result in medical intervention. Also, severe hypoglycemiaates during the follow-up period were lower among subjectssing long- and rapid-acting insulin formulations at base-

ine than other baseline insulin regimens, but the numbers inhese subgroups were too small to draw clinical conclusions.

Subjects in our study received training and treatment in theeal-world and not in the context of a rigorous clinical trial.SII requires a great deal of training and dose adjustment,nd the training received by clinical trial subjects increaseshe likelihood of positive results. Under real-world conditions,

ethods of teaching people to properly use CSII differ widelyepending on the supervising clinician’s expertise, training,nd clinical setting, so it is notable that such a heteroge-eous sample was able to decrease their A1C while avoidingn increase in severe hypoglycemia.

Administrative claims have some limitations which areommon to all analyses conducted with this data source.here are limits to the degree to which claims data can accu-ately capture an individual’s medical history. Claims data areollected for the purpose of payment and not research. Whilehese data are excellent for understanding patterns of healthutcomes, they are susceptible to coding errors, coding forhe purpose of ruling something out rather than the actualisease, and undercoding.

We studied data retrospectively and therefore had no con-rol over treatment decisions. Also, there was no true controlroup in this study, because inclusion in the analysis wasetermined by switching to CSII. Given the large sample sizend heterogeneity of data, it would not be clear if differencesetween the study group and a possible control group resultedrom treatment or some other factor. This aspect of the study,owever, also indicates the usefulness of the data—the largeample size and heterogeneity of data result from real-worldonditions. Indeed, the plans used for analysis include a wideeographic distribution across the United States, and there-ore provide the capability for generalizability to managed careopulations on a national level.

Finally, our results are limited by the fact that A1C val-es were not available for all subjects. The database used toollect A1C values for this study was not the same databasesed by the health plan for diabetes disease management. Thetudy database captured A1C values for people whose labora-ory samples were assessed by two of the largest vendors inhe United States. The company that conducted the study (i3nnovus) does not have access to laboratory data collected byhe health plan for diabetes disease management. Therefore,he study database did not capture all laboratory result valuesrom the subjects who comprised the study sample. There waso evidence, however, that A1C data are systematically miss-

ng from the study database, and the missing data should notnvalidate the results.

The potential for decreased A1C values to return to base-ine levels is a concern worth further investigation and futurextensions of this study could employ longitudinal designso investigate this possibility. However, in the sample avail-ble at the time of this study, only a subset of subjects had

1 A1C value available during the follow-up period. Resultsere similar, however, between mean, minimum, and max-

mum A1C values. Limiting the sample size to subjects withultiple results in the baseline and follow-up periods would

( 2 0 1 0 ) 209–214 213

raise methodological concerns. First, substantial reductionson sample size would reduce the statistical power, and second,the sample could biased to subjects with better diabetes man-agement (as indicated by frequent A1C testing). Though careguidelines suggest that people with diabetes should obtaintwo A1C values over the time period described in this study,many do not have the test performed with the frequency dic-tated by care guidelines. The low proportion of subjects withA1C values during the baseline and follow-up periods may bean illustration of this latter point, though the incompletenessof the database may also be a factor.

The results of this study augment the small body of evi-dence suggesting that CSII is more effective in the treatmentof type 2 diabetes than MDI, especially after the latter regi-men has failed. Specifically, this study shows that people withinsulin-requiring type 2 diabetes may experience significantclinical benefit from switching to CSII. CSII should be consid-ered as an alternative to MDI for people with insulin-requiringtype 2 diabetes, especially for those who have not achieveddiabetes management goals with MDI.

Conflict of interest

Peter Lynch, Tim Peoples, Jenifer Levinson, and Scott W. Leewere employees and stockholders of Medtronic at the timethe article was drafted and submitted.

Acknowledgements

This claims analysis was supported by Medtronic. Thisresearch was partially presented as a poster to the DiabetesTechnology Meeting in San Francisco, CA, USA in November2009.

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