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Insulin usage in type 2 diabetes mellitus patients in UK clinical practice: a retrospective cohort-based analysis using the THIN database
Marc L Evans, Peter Sharplin, David R Owens, George H Chamberlain, Andrea J Longman and Philip McEwan British Journal of Diabetes & Vascular Disease 2010 10: 178 DOI: 10.1177/1474651410370659 The online version of this article can be found at: http://dvd.sagepub.com/content/10/4/178

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Insulin usage in type 2 diabetes mellitus patients in UK clinical practice: a retrospective cohort-based analysis using the THIN database
Marc L Evans,1 Peter Sharplin,2 David R Owens,3 George H Chamberlain,2 Andrea J Longman,2 Philip McEwan2
Abstract
his retrospective cohort-based study assessed the change in glycated haemoglobin A1C (HbA1C) in patients with type 2 diabetes, with existing prescriptions for oral antidiabetic drugs (OADs), prescribed insulin versus those prescribed subsequent OADs. A cohort of patient records drawn from the The Health Improvement Network (THIN) database was stratified by maximum concurrent number of OADs. Of 128,568 unique patient records identified, 67.7% (n=87,057) had received at least one OAD, 17.4% (n=15,138) of these patients progressed to insulin therapy. Mean HbA1C at insulin initiation was 9.5% (one OAD), 9.6% (two), 9.7% (three) and 10.1% (four), with an average HbA1C increase of 0.7% prior to insulin initiation. The greatest improvement in HbA1C was achieved with insulin therapy. A threshold HbA1C value of 8.5% above which OAD escalation is unlikely to achieve a target HbA1C 7.0% is seen. In patients not achieving HbA1C targets with OADs only, insulin-based regimens should be considered in preference to adding more or multiple OADs. Br J Diabetes Vasc Dis 2010;10:178182. Key words: glycaemic control, HbA1C, insulin initiation, oral hypoglycaemic agents, type 2 diabetes mellitus

Abbreviations and acronyms ADA American Diabetes Association Diabetes Control and Complications Trial DCCT European Association for the Study of Diabetes EASD glycated haemoglobin A1C HbA1C NICE National Institute for Health and Clinical Excellence NPH neutral protamine Hagedorn OAD oral antidiabetic agent QOF Quality Outcomes Framework THIN The Health Improvement Network UKPDS United Kingdom Prospective Diabetes Study

Introduction
Maintaining glycaemic levels as close to the non-diabetic range as possible has been demonstrated to have a beneficial effect on macro-vascular and micro-vascular complications in patients with both type 1 and type 2 diabetes.1,2 Randomised controlled

1 2

University Hospital Llandough, Cardiff, UK. CRC Limited, Cardiff, UK. 3 School of Medicine, Cardiff University, Cardiff, UK. Correspondence to: Dr Philip McEwan CRC Limited, Eastgate House, 35-43 Newport Rd, Cardiff, CF24 0AB UK. Tel +44(0) 29 2033 3805, Fax +44(0) 29 2033 3778 E-mail: pmcewan@chks.co.uk

trials, such as the DCCT in patients with type 1 diabetes3 and UKPDS, in patients with type 2 diabetes,1 combined with epidemiological data4 have helped to establish the glycaemic goals of therapy defined by a HbA1C target of 7.0%.5 Despite recent large-scale clinical trials targeting a HbA1C of 6.5% or below,6-8 the goal for the majority of patients remains 7%. In UK routine clinical practice, the QOF advocated a target HbA1C of < 7.5% for 4050% of patients, although this has recently been revised to a target of 7%, with up to 70% having an HbA1C of < 8% and 90% with an HbA1C of < 10%.9 Achieving and maintaining such glycaemic targets, however, represents a major challenge for the majority of patients with type 2 diabetes. Despite improvements in HbA1C concentrations, with lifestyle modification, secondary failure (HbA1C > 7.0%) of OADs occurs in 4060% of patients after only three years.10 Furthermore, the successive failure of non-pharmacological and pharmacological therapies results in long-term excess glycaemic burden.11 The reasons for excess glycaemic exposure are related to the pathophysiology/natural history of type 2 diabetes combined with physician response to failure of OAD therapy resulting in a delay of treatment escalation and eventual initiation of insulin. This delay in insulin initiation may contribute to the often lower than expected efficacy of insulin therapy in clinical practice.12 OADs, on average, produce reductions in HbA1C of 1%, when used at maximum dosage in a non-time dependent manner8,13 and the sequential addition of OADs does not necessarily produce additive reductions in HbA1C.13
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A retrospective cohort-based study was conducted to define relationships between glycaemic control, OAD escalation and insulin initiation. Furthermore, the analysis sought to quantify excess glycaemic exposure related to therapy failure and delay in insulin initiation, while attempting to corroborate the ADA/EASD guideline statement,5 with respect to an HbA1C threshold defining OAD failure as an indication for insulin initiation, where OAD failure is defined as failure of the treatment to decrease HbA1C to 7%, or where HbA1C has risen while OAD treatment is prescribed.

Research design and methods

The data utilised for this study were drawn from a large national computerised medical record database known as THIN, which contains longitudinal data from original patient records collected from urban and rural UK primary care practices.14 At the time of the data request, the THIN database included data from 211 practices over a 15-year period with 2.34 million active registered patients who can be prospectively followed. THIN data on patient demographics, medical history, test results and drug treatments were collected. The data were anonymised at the collection stage using encrypted identifiers for the physician and patient. Ethical approval for this study was obtained from the London Multiple Research Ethics Committee (Number 06/MRE02/32).

handled using non-interpolated data in a linear mixed model allowing for repeated measures and clinical practice identification as a random effect.16 Analysis was conducted using SPSS 8 for Windows (SPSS Inc, Chicago, Illinois, USA). Analysis was conducted on all patients and stratified by therapy group (no OADS prescribed, 1, 2, 3 OADs and those prescribed any insulin-based regimen plus OADs). Patients were categorised on the basis of the maximum number of OADs that were simultaneously prescribed during each quarter. Analysis was conducted using the mean HbA1C over quarterly periods with linearly interpolated HbA1C values used for periods where no actual HbA1C readings were recorded.

Results
Data were analysed from the records of 128,568 patients identified with a diagnosis of type 2 diabetes mellitus over the 5-year study period (January 2001 to December 2006); of these 87,057 (67.7%) had at least one HbA1C measurement recorded before the beginning of the 5-year study period and had been prescribed at least one OAD. Data were excluded for 7,998 (6.2%) potential type 1 patients who received no OADs prior to insulin initiation. Summary statistics for the study cohort are presented in table 1. An overall improvement (reduction) in mean levels of HbA1C was observed over the 5-year study period. Across the entire cohort (n=128,568), in the 12-month period of 2001, HbA1C was measured in 26.4% (n=33,942) of all type 2 diabetes patients, yielding an overall mean HbA1C of 7.6%; comprising 48.9%, 40.7% and 10.4% of patients with mean HbA1C levels in the < 7.0%; 7.0% to < 10.0%, or 10.0% ranges, respectively. In 2006, the proportion of patients with type 2 diabetes who had at least one HbA1C measurement had increased to 50.0% (n=64,284); overall mean HbA1C had reduced to 7.4% with 62.0%, 31.6% and 6.4% of patients achieving mean HbA1C levels in the < 7.0%; 7.0% to < 10%, or 10% ranges, respectively. During the 5-year study period 82.6% (71,919) of the identified cohort (n=87,057) continued to be prescribed at least one OAD; in these patients there was an increase in mean HbA1C and an increase in the number of prescribed OADs (table 1). For the 17.4% (15,138) of the identified cohort who had insulin added to their OAD-based regimen in the 5-year study period, there was a substantial increase in mean HbA1C in the quarter prior to insulin initiation (HbA1C 9.7%) compared to the cohort of patients continuing on OADs only (HbA1C 7.2%). Categorising mean HbA1C levels by the maximum number of prescribed OADs prior to insulin initiation showed a linear relationship with number of OADs prescribed and HbA1C levels: 1 OAD, HbA1C 9.5%; 2 OADs, HbA1C 9.6%; 3 OADs, HbA1C 9.7%; and 4 OADs, HbA1C 10.1%. Patients who were initiated onto insulin may have been receiving one, two or three OADs, but the observed deterioration in HbA1C prior to initiation occurred irrespective of the number of OADs prescribed. Figure 1 displays the HbA1C profile in the 5 years before and after insulin initiation. A key feature of this profile is the large

Diabetes population
From data collected between January 2001 and December 2006 (5-year period), patients were identified as diabetic based on a relevant medical diagnosis via the Read code system,14 or prescriptions for any OAD. Diagnosis of diabetes was attributed on a stepwise principal. For those patients who did not have a specific diagnosis of diabetes, a diagnosis of type 2 diabetes mellitus was attributed if the subject had received any non-insulin diabetes-related medication (an OAD). Patients initiated onto an insulin-based regimen, but with no prior OAD were excluded from the analysis as potential type 1 diabetes mellitus patients.

Patients initiated onto insulin

Patients were identified to have been initiated onto insulin if there was a first report of a prescription for an insulin-based regimen documented in the 5-year period between January 2001 and December 2006, and had at least one HbA1C reading recorded between the 24 years prior to the date of insulin initiation. Following insulin initiation, patients were categorised by their prescribed OAD status. The principle outcome investigated in this analysis was glycaemic control, based on HbA1C measured locally in each general practice.

Statistical analysis
The principle outcome measure of interest was change in HbA1C over time. This was structured into quarterly data, with linear interpolation used for quarters with missing values. Secondary analyses of improvements in HbA1C between therapies was

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Table 1. Oral antidiabetic drug and insulin usage in a type 2 diabetes population in 2006 (non-insulinised) and in the quarter prior to insulin initiation (insulinised)

Number of oral antidiabetic agents

Non-insulinised Patients (n) Percentage male aAge (years) at 2006 aWeight (kg) aBMI aHbA1C (%)* None (SD) 41,511 51.8 70.3 (16.6) 83.7 (18.9) 29.8 (5.9) 6.4 (0.7) One (SD) 37,935 49.7 65.8 (17.4) 85.6 (19.8) 30.4 (6.5) 7.1 (1.2) 6,619 49.7 63.3 (15.6) 89.1 (20.0) 29.9 (6.3) 9.5 (2.1) Two (SD) 26,075 54.9 68.2 (13.2) 86.6 (20.2) 30.7 (6.3) 7.6 (1.3) 5,821 53.4 65.8 (13.4) 88.7 (20.0) 30.1 (6.2) 9.6 (1.7) Three (SD) 7,045 57.9 64.4 (12.2) 90.5 (21.1) 31.9 (6.7) 7.9 (1.4) 2,559 55.5 64.8 (12.5) 90.5 (20.2) 30.6 (6.6) 9.7 (1.6) Four (SD) 864 64.1 63.8 (11.4) 89.7 (20.2) 31.4 (6.2) 8.3 (1.4) Total (SD) 113,430 52.1 65.9 (15.9) 85.8 (19.9) 30.5 (6.3) 7.2 (1.3)

Insulinised Patients (n) Percentage male aAge at 2006 (years) aWeight (kg) aBMI a HbA1C (%)
a

139 15,138 64.5 55.8 62.2 64.0 (12.1) (15.6) 90.0 89.6 (19.2) (19.9) 30.7 30.3 (6.4) (6.3) 10.1 9.7 (2.0) (1.9)

Values are mean with SD in parentheses

*HbA1C, weight and BMI recorded in second quarter of 2006 HbA1C, weight and BMI in quarter prior to insulin initiation. Key: BMI = body mass index; HbA1C = glycated haemoglobin A1C; SD = standard deviation

increase in HbA1C observed in the year prior to insulin initiation in which the average rate of increase in HbA1C over this period was 0.7%; this pattern was consistent across levels of prior oral usage. In the years immediately prior to the rapid increase in HbA1C, the mean annual increase in HbA1C was 0.2%. An increase in the number of OAD prescriptions was associated with greater exposure to hyperglycaemia. Figure 2 illustrates the relationship between prescription escalation of OADs and increased exposure to hyperglycaemia: 0.73 years of a HbA1C > 7%, between one and two OADs, and 0.27 years between two and three OADs (a 1-year increase between one and three OADs) in the 5 years prior to insulin initiation in a subset of people for whom HbA1C was recorded. Similar results are seen for HbA1C levels of > 8% (0.91 years between one and three OADs) and > 9% (0.6 years between one and three OADs). Overall improvements in glycaemic control coincided with changes to prescribed interventions. In multivariate analysis, adjusting for age, sex and baseline HbA1C, patients initiated to insulin were observed to have a 0.25% greater reduction in HbA1C, than those receiving additional OADs. In patients for whom HbA1C measurements were available, a similar analysis
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showed that in patients with a baseline HbA1C of 8.5% switching from two OADs to an insulin-based regimen achieved a 0.28% greater reduction in HbA1C than increasing from two to three OADs (table 1).

Discussion
This study demonstrates that in UK clinical practice therapy escalation occurs following a significant deterioration in glycaemic control. Overall, in general practice HbA1C levels have decreased suggesting that diabetes care, as indicated by glycaemic control, has improved since publication of 2002 NICE guidelines for diabetes17 and will hopefully continue to improve with support from the updated NICE guidelines18 and the 2009/2010 QOF targets.19 However, in this analysis the greatest incremental reduction in HbA1C (figure 1) occurred in 2002 in association with the introduction of initial NICE guidance. Initial introduction of the QOF target, HbA1C < 7.5%, in 2004 coincided with a less pronounced observed reduction. In this analysis, despite the delay in initiation, insulin therapy resulted in a 1.7% mean reduction in HbA1C from baseline compared with an HbA1C reduction of 1.2% produced by oral therapy escalation.
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Figure 1. Mean glycated haemoglobin A1C (HbA1C; %) in the 5 years before and after insulin initiation (year zero) by number of oral antidiabetic agents prescribed in the quarter before insulin initiation (n=4,431 with HbA1C observations over 10-year horizon)

9.5

One oral agent Two oral agents Three oral agents

Mean HbA1c (%)

9.0

8.5

8.0

7.5

Pre-insulin initiation (years)

Post-insulin initiation (years)

The observed delay in insulin initiation in this study may reflect either healthcare professionals, or patients concerns about insulin therapy or dose escalation of existing therapies, a general lack of structured programmes for insulin initiation in

primary care, along with a lack of clear consensus on the optimal initial insulin regimen of choice.12, 20, 21 The delay in treatment intensification resulted in excess and prolonged patient exposure to hyperglycaemia, which may contribute to a subsequent increased risk of diabetes, related micro-vascular and macro-vascular complications.22 In these results, oral therapy escalation was incrementally less effective, such that a maximal reduction of only 0.7% in HbA1C arose due to progression from two to three OADs. This might be due to reduced therapy adherence as a function of polypharmacy,11 and also illustrates the lack of additive effect of multiple oral combination therapies when endogenous insulin secretion is severely compromised.13 The analysis suggests that in routine clinical practice, as in clinical trials, at HbA1C levels > 8.5%, further oral therapy escalation is unlikely to achieve the desired goal of 7.0%. Such an observation is consistent with the ADA/EASD consensus,5 which recommends that insulin should be introduced to the medication regimen when HbA1C levels exceed 7%. Considerable debate persists regarding the optimal initial insulin regimen in patients with type 2 diabetes. Confounding factors include incidence of hypoglycaemia, weight gain, and frequency of blood glucose monitoring and insulin injections.12,13,20 Simple but effective insulin regimens are essential when initiating insulin in patients with type 2 diabetes. The UKPD 49 results support the use of a once daily long or intermediate acting insulin

Figure 2. Mean number of years of excess glycaemic exposure per patient per number of oral antidiabetics prescribed <AQ4>

2.5 1 OAD (n=667) 2 1.78 1.63 Patient years 1.5 1.36 2 OAD (n=2,590) 3 OAD (n=1,174)

2.05

1.05 1 0.72 0.44 0.84

1.04

0.5

0 >7 >8 >9 >7 >8 HbAlc distribution >9 >7 >8 >9

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regimen.10 NPH is sometimes recommended as first line insulin in various guidelines,5 but basal insulin analogues with longer nonpeaking profiles are associated with reduced risk of hypoglycaemia and are thus widely used as the initial insulin of choice in routine practice. The purpose of this analysis was to evaluate the relative effectiveness of insulin initiation per se rather than to assess the relative effectiveness of individual insulin regimens. There are several limitations to this study. The study did not include an analysis of the effects of the newer incretin-based therapies as these therapies had not been licensed for use in the UK in the time period to the end of 2006. The analysis was based on a general categorisation of progression of one, to two to three agents or insulin usage and not individual therapy classes or their relative effectiveness within the treatment paradigm of type 2 diabetes. Furthermore, the study uses the number of prescribed medications and includes no evaluations of specific dose or medication compliance. However, other studies have shown that oral therapy escalations may also be delayed in a similar fashion to the delay in insulin initiations observed in this study.11,13 Importantly, this analysis has been conducted using routine data from UK clinical practice, which allows an insight into how patients are managed in current UK practice. In summary, this study demonstrates a persisting delay both in oral therapy escalation and insulin initiations in patients with type 2 diabetes, with a relative reduction in the effectiveness of oral therapy escalation. There is an apparent threshold HbA1C of > 8.5% beyond which additional oral therapy in routine practice appears unlikely to achieve an HbA1C target 7.0%. This study thus highlights the need for more timely escalation of glucose-lowering therapy, including insulin initiation, in order to limit unnecessary patient exposure to hyperglycaemia and associated serious consequences, such as macro-vascular and micro-vascular complications.

Acknowledgements
This work was supported by sanofi-aventis, Guildford, UK.

References
1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53. 2. Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care 1999;22:99-111. 3. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the development and progression of long term complications in insulin dependent diabetes. N Engl J Med 1993;329:978-86.

4. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643-53. 5. Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: A consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2009;32: 193-203. 6. The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59. 7. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72. 8. Duckworth W, Abraira C, Moritz T et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129-39. 9. Department of Health. Quality and Outcomes Framework (QOF), 2009. http://www.dh.gov.uk/en/Healthcare/Primarycare/Primarycarecontracting/ QOF/index.htm (Accessed 11 November 2009) 10. Turner RC, Cull CA, Holman RR. Glycemic control with diet, sulfonylurea, metformin and insulin in patients with type 2 diabetes. Progressive requirement for multiple therapies. UKPDS 49. JAMA 1999;281:2005-12. 11. Brown, JA, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care 2004;27:1535-40. 12. Rubino A, McQuay LJ, Gough SC et al. Delayed initiation of subcutaneous insulin therapy after failure of oral glucose-lowering agents in patients with type 2 diabetes: a population-based analysis in the UK. Diabet Med 2007;24:1412-18. 13. Krentz AJ, Bailey CJ. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 2005;65:385-411. 14. Poole CD, Tetlow T, McEwan P et al. The prescription cost of managing people with type 1 and type 2 diabetes following initiation of treatment with either insulin glargine or insulin detemir in routine general practice in the UK: A retrospective database analysis. Curr Med Res Opin 2007;23(suppl 1):S41-8. 15. Currie CJ, Poole CD, Tetlow T et al. The outcome of care in people with type 1 and type 2 diabetes following switching to treatment with either insulin glargine or insulin detemir in routine general practice in the UK: A retrospective database analysis. Curr Med Res Opin 2007;23(suppl 1):S33-9. <AQ3> 16. Pinheiro J, Bates DM. Mixed Effects Models in S and S-PLUS. New York: Springer Verlag, 2000. 17. National Institute of Health and Clinial Excelence. Diabetes, Type 2 diabetes: blood glucose. London: NICE, 2002. http://www.nice.org.uk/ Guidance/G (Accessed 3 September 2009) 18. National Institute of Health and Clinial Excelence. Diabetes, Type 2 (update). London: NICE, 2008. http://www.nice.org.uk/Guidance/ CG66 (Accessed: 3 September 2009) 19. BMA. QOF Changes and new indicators for 2009/10. London: BMA, 2008. http://www.bma.org.uk/employmentandcontracts/independent_contractors/quality_outcomes_framework/QoFchangesOct08.jsp (Accessed 3 September 2009) 20. Peyrot M, Rubin RR, Lauritzen T et al. Resistance to insulin therapy among patients and providers. Diabetes Care 2005;28:2673-9. 21. Surwit RS, van Tilburg MAL, Parekh PI et al. Treatment regimen determines the relationship between depression and glycemic control. Diabetes Res Clin Practice 2005;69:78-80. 22. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-65.

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