Insulin therapy in type 2 diabetes patients

Insulin therapy in type 2 diabetes patients – balancing between evidence and experience

Mariëlle van Avendonk

Utrecht: Universiteit Utrecht, Faculteit Geneeskunde Thesis Utrecht University. - with a summary in Dutch. Proefschrift Universiteit Utrecht - met een samenvatting in het Nederlands ISBN Author: Illustrations: Lay-out: Printed by:

978-90-393-54087 M.J.P. van Avendonk Esly van den Elsen (www.eslyvandenelsen.nl) Monique den Hartog Ridderprint Offsetdrukkerij BV, Ridderkerk

© M.J.P. van Avendonk

Niets uit deze uitgave mag worden vermenigvuldigd en/of openbaar gemaakt worden door middel van druk, fotokopie, microfilm, of op welke wijze dan ook, zonder voorafgaande toestemming van de auteur. No part of this book may be reproduced in any form, by print, photoprint, microfilm, or any other means, without prior permission of the author.

Insulin therapy in type 2 diabetes patients – balancing between evidence and experience

Insuline therapie in diabetes type 2 patiënten – balanceren tussen bewijs en ervaring (met een samenvatting in het Nederlands)

Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. J.C. Stoof, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 26 oktober 2010 des middags te 12.45 uur

door Mariëlle José Petra van Avendonk geboren op 19 april 1970 te Bladel

Promotor:

Prof.dr. G.E.H.M. Rutten

Co-promotores: Dr. K.J. Gorter Dr. M. van den Donk

The studies presented in this thesis were supported with an unrestricted grant by sanofi-aventis The Netherlands B.V. The author gratefully acknowledges financial support for printing this thesis by sanofi-aventis The Netherlands B.V. and the Dutch Diabetes Research Foundation.

“De ervaring doet onze wijsheid toenemen, maar niet onze dwaasheden afnemen” J. Billings (1815 – 1885)

Beoordelingscommissie Prof.dr.ir. Y.T. van der Schouw Prof.dr. Th.J.M. Verheij Prof.dr. J.B.L. Hoekstra Prof.dr. H.G.M. Leufkens Dr. T.W. van Haeften

CONTENTS Chapter 1

General Introduction

9

Chapter 2

Organisation of diabetes care in general practice in the Netherlands

19

Chapter 3

Insulin therapy in type 2 diabetes is no longer a secondary care activity in the Netherlands

33

Chapter 4

Insulin therapy in type 2 diabetes is associated with barriers to activity and psychological distress: crosssectional study in primary care

47

Chapter 5

Insulin therapy in type 2 diabetes: what is the evidence?

59

Chapter 6

Continuation of sulphonylurea does not lead to relevant effects on β-cell function after one year of insulin therapy. A randomised controlled trial

97

Chapter 7

Combinations of insulin and oral glucose lowering agents for people with type 2 diabetes mellitus on insulin treatment. Results from a Cochrane systematic review and meta-analysis

113

Chapter 8

General Discussion

165

Summary

181

Samenvatting

189

Dankwoord

197

About the author

203

General introduction

General introduction

Type 2 diabetes mellitus is a global epidemic. The number of people affected is rising due to several reasons. At first, since type 2 diabetes is more prevalent in older age, the ageing of the world population leads to an absolute increase of the number of type 2 diabetes patients. Moreover, especially in the Western world but increasingly outside, people more and more have a sedentary lifestyle and an unhealthy diet. This behaviour leads to overweight and obesity and, together with a genetic predisposition, may eventually cause type 2 diabetes even at younger ages. Worldwide the total number of type 1 and type 2 diabetes patients is expected to rise from 171 million in 2000 to 366 million in 2030.1 In 2007 740,000 patients were diagnosed with diabetes in the Netherlands.2 The majority of them (90%) suffer from type 2 diabetes.

Type 2 diabetes in primary care In order to cope with capacity problems and costs diabetes care has shifted from secondary to primary care, especially in Europe.3-5 In the Netherlands, as well as in many other European countries, over 75% of type 2 diabetes patients are treated in primary care.6 The rapidly rising number of patients with type 2 diabetes force general practitioners (GPs) to engage in aspects of diabetes management traditionally provided by specialists. Not all GPs are likely to have the time, confidence or experience to do so. Nevertheless, primary care is characterised by continuous and integral care, so this setting might facilitate individual treatment decisions based on contextual factors for patients. The treatment of type 2 diabetes patients comprises a broad approach. Several studies showed that intensive glucose control results in a significant reduction of microvascular endpoints.7-9 There is some inconsistency in the evidence of the effects of intensive glucose lowering treatment on macrovascular outcomes and mortality. Recently, three large long-term clinical trials comparing standard with intensive therapy did not show a significant reduction of cardiovascular outcomes as a result of a lower HbA1c.9-11 The same applied to mortality, while even one study was terminated early since mortality increased in the intensively treated group.10 These trials showed that the risk of cardiovascular disease and mortality also depends on other factors, including long disease duration, severe hypoglycaemic episodes and the presence of cardiovascular comorbidity.12 The general target of HbA1c 8.5%

40 % GPs

30 20 10 0 40-65

65-80

> 80

Age (years)

Figure 1 The HbA1c level at which general practitioners report to start insulin therapy when oral medication fails. Multivariate logistic regression analysis on significant univariate variables showed that male GPs, GPs above the age of 40, and GPs working in a health centre are more inclined to start insulin treatment themselves. On the contrary, GPs working in urban regions less often start insulin than GPs in rural areas. The presence of a practice nurse and diabetes clinics is positively associated with providing insulin therapy in general practice (table 3).

Discussion Seven out of ten GPs in our study start insulin therapy in patients with type 2 diabetes. Male GPs and those above the age of 40 tend to start insulin therapy themselves more often, as well as GPs working in a health centre and those working together with a practice nurse. GPs working in urban regions less often start insulin. The most often mentioned barriers for starting and/or monitoring insulin therapy in general practice are lack of knowledge of insulin therapy, lack of time and insufficient financial incentives.

40

Insulin therapy in type 2 diabetes is no longer a secondary care activity

Table 3

Associations between general practitioner and practice characteristics with active and less active management of insulin therapy. Univariate odds ratios and adjusted* odds ratios with 95% confidence intervals (significant in bold)

GP male GP age ≤ 40 years 41-50 years > 50 years Diabetes postgraduate education GP past 3 years GP-trainer

Active versus less active (univariate)

Active versus less active (multivariate)

1.66 (1.30 – 2.11) 1 (ref.) 1.52 (1.13 – 2.05) 1.67 (1.24 – 2.25) 1.84 (1.10 – 3.07)

1.80 (1.25 – 2.59) 1 (ref.) 1.66 (1.11 - 2.46) 1.88 (1.25 – 2.82)

1.66 (1.31 – 2.09)

Practice type: single-handed dual partnership group health centre Practice location: rural urbanised rural urban Practice in lower socioeconomic district Number of patients per GP/fte < 2350 2350 – 3500 > 3500 Number of DM2 patients per GP/fte: < 50 51-125 > 125 Practice nurse Diabetes clinics Shared care protocol

1 (ref.) 1.08 (0.84 – 1.38) 1.87 (1.36 – 2.56) 2.55 (1.69 – 3.84) 1 (ref.) 1.14 (0.79 – 1.64) 0.64 (0.45 – 0.91) 0.64 (0.49 – 0.83)

Cooperation with diabetes services

0.70 (0.56 – 0.88)

1 (ref.) 1.25 (0.88 – 1.76) 1.35 (0.89 - 2.04) 2.58 (1.50 – 4.44) 1 (ref.) 1.12 (0.75 – 1.67) 0.57 (0.39 - 0.85)

1 (ref.) 1.16 (0.89 – 1.50) 0.99 (0.60 – 1.63) 1 (ref.) 1.46 (1.05 – 2.03) 2.01 (1.32 – 3.05) 2.85 (2.28 – 3.55) 2.37 (1.89 – 2.97) 1.61 (1.22 – 2.13)

2.18 (1.60 – 2.98) 1.39 (1.01 – 1.90)

* adjusted for: sex, age, practice type, practice location, practice nurse, diabetes clinics. Fte=full-time equivalent

A strength of this study is that it gives a nation-wide overview of insulin therapy in primary health care. Its results may be helpful for a wide range of organisations related to the primary health care setting. A limitation of this study is the low 41

Chapter 3

response rate of 42%. A non-responder analysis was not possible, because GP’s identification data were anonymised. It could be argued that only motivated GPs who are more likely to start insulin therapy themselves may have participated. On the other hand, the characteristics of the participating GPs and practices are representative for the Dutch GPs and their practices. The questionnaire has been face validated only. As a consequence the results have to be interpreted with care. Finally, we only assessed the relation between GPs and insulin treatment. Patientrelated factors also contribute to the provision of insulin treatment in primary care, but they were not the object of our study. The need for an enlargement of the practice staff with practice nurses when starting with insulin therapy in primary care was described earlier.8,11,15,16 The same studies identified a perceived complexity and therefore a sense of inability of GPs to manage insulin therapy.8,11,15,16 The most recent and strongly evidence based recommendation to start insulin therapy by adding a once-daily injection to oral blood glucose lowering treatment17,18 is likely to make the start of insulin therapy less complex. We found that older GPs more often start insulin, possibly as a consequence of being more experienced and hence being more selfconfident. Whereas in previous studies GP’s fear of hypoglycaemia and weight gain served as barriers8,16,19, in our study only a few GPs (~ 10%) mentioned these as important inhibiting factors. After the decision to start insulin therapy, 75% of the GPs refer the patient to a diabetes nurse for additional education as a first step before actually starting therapy. Studies in primary care showed that education was effective in improving glycaemic control and postponing the need for insulin therapy in about 25% in patients treated with maximal oral therapy.20,21 The HbA1c level at which GPs initiate insulin therapy is depending on the age of the patient. A study in primary care has reported that patients switched to insulin were younger, had a shorter duration of diabetes and a higher HbA1c (8.5% versus 7.9% in non-switchers) compared to non-switchers.22 These results are inconsistent with other studies, in which older patients with a long duration of diabetes were more likely to be prescribed insulin.23-25 Female gender and the presence of diabetes complications were also factors associated with the use of insulin.23,24 Most GPs start insulin therapy with once daily long-acting insulin in combination with oral medication. The advantages of this simple regimen have been demonstrated: a relative reduction of the daily required insulin, less weight gain and less hypoglycaemic events.17,18

42


We may assume that at least more than half of the Dutch GPs start insulin therapy themselves in type 2 diabetes patients. Insulin therapy started in general practice in type 2 diabetes patients effectively improves glycaemic control and has no adverse influence on well-being and treatment satisfaction.26,27 The regimen of once-daily long-acting insulin while continuing the oral medication will undoubtedly enhance the provision of insulin therapy in a primary care setting. On top of this, insulin therapy in primary care might be less expensive as compared to insulin therapy in secondary care. So, insulin therapy in the primary care setting across European countries may be possible if a number of conditions have been set. First, there is still need to reduce the experienced lack of time by e.g. enlarging the practice staff. Other barriers that can be influenced are the often perceived skills deficit and lack of financial incentives. In the UK the introduction of a pay-for-performance system has been associated with an improvement in diabetes care.28,29 Since 2006, in the Netherlands, organisational and clinical care improvements also have been encouraged by incentive payments by the health insurance companies. If ‘providing insulin therapy in general practice’ will be added to the set of quality indicators for diabetes care, subsequently more GPs may provide insulin therapy themselves. In conclusion, in practical sense insulin therapy is feasible in a primary care setting. If a shared care model has to be established, one can take the findings of our study into account. Other countries can also build on the results of the Dutch experience, as elucidated by this study.

43

Chapter 3

References 1.

2.

3. 4. 5.

6. 7. 8. 9.

10.

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12. 13.

14.

44

Rutten GEHM, De Grauw WJC, Nijpels G, Goudswaard AN, Uitewaal PJM, Van der Does FEE, et al. Guideline on diabetes care of the Dutch college of GPs (NHG Standaard Diabetes Mellitus type 2). Huisarts Wet 2006;49:137-52. Goyder EC, McNally PG, Drucquer M, Spiers N, Botha JL. Shifting of care for diabetes from secondary to primary care, 1990-5: review of general practices. BMJ 1998; 316(7143):1505-6. Khunti K, Ganguli S. Who looks after people with diabetes: primary or secondary care? J R Soc Med 2000;93:183-6. Brunton S, Carmichael B, Funnel M, Lorber D, Rakel R, Rubin R. The role of Insulin. Type 2 diabetes. Fam Pract 2005;supplement:445-52. Van Avendonk M, Gorter K, Van den Donk M, Rutten GE. Niet alle huisartsen hebben de praktijkorganisatie om optimale diabeteszorg te leveren. Een vragenlijstonderzoek.(Not all general practitioners have the practice organisation to provide optimal diabetes care. A questionnaire survey). Huisarts Wet 2007;50(11):529-34. Hunt LM, Valenzuela MA, Pugh JA. NIDDM patients' fears and hopes about insulin therapy - The basis of patient reluctance. Diabetes Care 1997;20:292-8. Snoek F. Breaking the barriers to optimal glycaemic control-what physicians need to know from patients'perspectives. Int J Clin Pract Suppl 2002;129:80-4. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obes 2002;26, suppl 3:s18-s24. Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews DR, et al. Resistance to Insulin Therapy Among Patients and Providers: Results of the crossnational Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28(11):2673-9. Mollema ED, Snoek FJ, Pouwer F, Heine RJ, van der Ploeg HM. Diabetes Fear of Injecting and Self-Testing Questionnaire: a psychometric evaluation. Diabetes Care 2000;23(6):765-9. Veltmaat LJ, Miedema K, Reenders K. Overschakeling op insuline bij NIADMpatiënten. (Conversion to insulin in not insulin dependent diabetes mellitus patients), in Dutch with English abstract. Huisarts Wet 1995;38:608-13. Riddle MC. The underuse of insulin therapy in North America. Diabetes Metab Res Rev 2002;18:S42-S49. Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews DR, et al. Resistance to Insulin Therapy Among Patients and Providers: Results of the crossnational Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005;28 (11):2673-9. Kenens R, Hingstman L. Cijfers uit de registratie van huisartsen. Peiling 2004 (General Practitioners registration. Survey 2004). The Netherlands Institute for Health Services Research (NIVEL) 2004.


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Jeavons D, Hungin APS, Cornford CS. Patients with poorly controlled diabetes in primary care: healthcare clinicians' beliefs and attitudes. Postgrad Med J 2006;82(967): 347-50. Davis SN, Renda SM. Psychological Insulin Resistance: Overcoming Barriers to Starting Insulin Therapy. The Diabetes Educator 2006;32(Suppl_4):146S-152. Goudswaard AN, Stolk RP, Zuithoff P, de Valk HW, Rutten GE. Starting insulin in type 2 diabetes: continue oral hypoglycemic agents? A randomized trial in primary care. J Fam Pract 2004;53:393-9. Goudswaard AN, Furlong F.N.J, Valk G.D., Stolk RP, Rutten GE. Insulin monotherapy versus combinations of insulin with oral hypoglycaemic agents in patients with type 2 diabetes mellitus. Cochrane Collaboration, Metabolic and Endocrine Disorders Group 2004. Haque M, Hayden Emerson S, Dennison CR, Navsa M, Levitt NS. Barriers to initiating insulin therapy in patients with type 2 diabetes mellitus in public-sector primary health care centres in Cape Town. SAMJ 2005;95(10):798-802. Goudswaard AN, Stolk RP, Zuithoff NPA, de Valk HW, Rutten GEHM. Long-term effects of self-management education for patients with Type 2 diabetes taking maximal oral hypoglycaemic therapy: a randomized trial in primary care. Diabet Med 2004;21(5):491-6. Berghout L, Gorter KJ, Rutten GE. Improvement of glycemic regulation without exogenous insulin in 40% of poorly regulated patients with type 2 diabetes mellitus; a study in 18 family practices. Ned Tijdschr Geneeskd 2001;145(42):2035-9. Spoelstra JA, Stol RP, de Bruyne MC, Erkens JA, Herings RM, Leufkens HG, et al. Factors associated with switching from oral hypoglycaemic agents to insulin therapy. Neth J Med 2002;60(6):243-8. Mazzaglia G, Yurgin N, Boye KS, Trifirò G, Cottrell S, Allen E, et al. Prevalence and antihyperglycemic prescribing trends for patients with type 2 diabetes in Italy: A 4-year retrospective study from national primary care data. Pharmacological Research 2008;57(5):358-63. Yurgin N, Secnik K, Lage MJ. Antidiabetic prescriptions and glycemic control in German patients with type 2 diabetes mellitus: A retrospective database study. Clin Ther 2007;29(2):316-25. Eliasson B, Eeg-Olofsson K, Cederholm J, Nilsson P, Gudbjornsdottir S, Steering Committee of the Swedisch National Diabetes Register (NDR). Antihyperglycaemic treatment of type 2 diabetes: results from a national diabetes register. Diabetes Metab 2007;33(4):269-76. de Sonnaville JJ, Snoek FJ, Colly LP, Deville W, Wijkel D, Heine RJ. Well-being and symptoms in relation to insulin therapy in type 2 diabetes. Diabetes Care 1998;21:91924. de Grauw WJ, van de Lisdonk EH, van Gerwen WH, van den Hoogen HJ, van Weel C. Insulin therapy in poorly controlled type 2 diabetic patients: does it affect quality of life? Br J Gen Pract 2001;51:527-32.

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28. 29.

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Tahrani A, McCarthy M, Godson J, Taylor S, Slater H, Capps Neal. Diabetes care and the GMS contract: The evidence for a whole county. Br J Gen Pract 2007;57:483-5. Campbell S, Reeves D, Kontopantelis E, Middleton E, Sibbald B, Roland M. Quality of Primary Care in England with the Introduction of Pay for Performance. N Engl J Med 2007;357(2):181-90.

Insulin therapy in type 2 diabetes is associated with barriers to activity and psychological distress: crosssectional study in primary care M.J.P. van Avendonk, M. van den Donk, F.G.W. Cleveringa, K.J. Gorter, N.P.A. Zuithoff, G.E.H.M.Rutten. Submitted

Insulin therapy associated with worse patient-reported outcomes

Abstract Background Earlier studies showed inconsistent effects of insulin therapy in type 2 diabetes patients on patient-reported outcomes. Objective To compare health status, psychosocial functioning and treatment satisfaction between type 2 diabetes patients using only oral glucose lowering agents and patients on (different regimens of) insulin therapy with or without oral agents. Methods Cross-sectional study in fifty-five Dutch family practices. Baseline measurements of people participating in a randomised controlled trial were used with regard to Short Form(SF)-36, Diabetes Health Profile (DHP) and Diabetes Treatment Satisfaction Questionnaire (DTSQ). Results from people with and without insulin therapy were compared with generalised estimated equations models to control for confounding and clustering at practice level. Results 1927 participants were included in the analysis. Average response rate on the questionnaires: 65%, no difference between groups. Insulin-users had a longer duration of type 2 diabetes and more microvascular complications. Their HbA1c and BMI was higher; diastolic blood pressure and total cholesterol were lower. Insulin-users reported significantly worse outcomes on the SF-36 subdomains physical functioning and general health; and on DHP total score, DHP barriers to activity and DHP psychological distress. Insulin regimen and diabetes duration did not influence these outcomes. Conclusion Insulin therapy in type 2 diabetes patients was associated with less physical functioning, barriers to activity and psychological distress. Our findings stress the need to weigh the long term effects of insulin therapy on micro- and macrovascular outcomes against patient-reported outcomes.

Introduction During the course of type 2 diabetes, insulin therapy may be essential for many patients. However, still about one third of the patients are reluctant to switch from oral medication to insulin therapy. This so-called ‘psychological insulin resistance’ includes fear of hypoglycemia and weight gain, fear for injections, reluctance to restrictions in lifestyle and feelings of guilt and failure.1-4 Consequently, it could be expected that insulin therapy may have negative effects on psychological outcomes, well-being and treatment satisfaction for a lot of patients. Nevertheless, several studies, that investigated patients who shortly 49

Chapter 4

started insulin therapy, showed positive effects on quality of life5,6, well-being7-9 or treatment satisfaction.7,8,10 Others found no effects.11,12 In two studies, in which the duration of insulin use was unknown, negative effects were shown on one or more of these outcomes.13,14 Psychosocial functioning and treatment satisfaction were sparsely described in the large number of studies comparing different insulin regimens, and with conflicting results. Once daily long acting insulin with or without oral glucose lowering agents in comparison to twice daily mix insulin showed either positive effects7,15, no differences16,17 or negative effects18 on treatment satisfaction or quality of life. The aim of this study was to compare the health status, psychosocial functioning and treatment satisfaction between type 2 diabetes patients using only oral glucose lowering agents and patients using (different regimens of) insulin therapy with or without oral agents.

Methods Population In this cross-sectional study a database of type 2 diabetes patients in 55 primary care practices in the Netherlands was used. The database was constructed for a cluster randomised trial, which has been described elsewhere, to investigate the effects of a diabetes care protocol.19 From 171,821 registered patients all type 2 diabetes patients were identified. Patients who had a short life expectancy, those who were unable to visit the primary care practice, or were receiving diabetes treatment from a medical specialist were excluded. Initially, 3,979 patients were eligible, but 548 subjects refused to participate and 40 failed to participate for unknown reasons. The final study population consisted of 3,391 patients. For the present study their baseline data were used.

Measurements Patients’ characteristics as age, sex, duration of diabetes, presence of retinopathy (assessed by fundus screening), neuropathy (assessed by feet examination), amputation or ulcer and history of cardiovascular disease were registered. Medication use was recorded by ATC-codes. Blood pressure, length and weight were assessed by the practice nurse. HbA1C, fasting glucose, total and HDLcholesterol and triglycerides were measured in local laboratories. Glomerular 50

Insulin therapy associated with worse patient-reported outcomes

filtration rate was estimated with the Modification by Diet in Renal Disease (MDRD)-formula. A MDRD-score of less than 60 ml/min/1.73m2 was considered as nephropathy. Practice nurses handed out questionnaires to the participating patients, who completed these at home and returned them in a postage paid envelope. Patients were asked to send the questionnaires to the research centre. When the original questionnaires were not returned within three months, patients received a reminder letter and a copy of the questionnaires.

Questionnaires Health status. The Short Form-36 (SF-36) is a 36-item questionnaire which measures perceived health, encompassing eight dimensions: general health, vitality, mental health, physical functioning, limitations due to physical difficulties (role physical), bodily pain, social functioning, and limitations due to emotional difficulties (role emotional). For each of these dimensions, scores are transformed to a scale ranging from 0 to 100, with higher scores indicating better health.20 Psychosocial dysfunctioning. The Diabetes Health Profile (DHP-1) identifies psychosocial dysfunctioning of diabetes patients. It comprises three dimensions: psychological distress (14 items), barriers to activity (13 items) and disinhibited eating (five items) (range 0-100; 100 indicates no dysfunction).21 Treatment satisfaction. The Diabetes Treatment Satisfaction Questionnaire (DTSQ) contains a six-item scale assessing treatment satisfaction. The total score ranges between 0 and 36, with higher scores indicating greater satisfaction with treatment.22

Analysis Data were analysed using SPSS 15.0.1. The differences between the group using only oral agents and the group using insulin with or without oral agents and the differences between the insulin regimens were analysed with t-test for continuous variables and Chi-square test for categorical variables. P