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Journal of Human Hypertension (2005) 19, 111–117 & 2005 Nature Publishing Group All rights reserved 0950-9240/05 $30.00 www.nature.com/jhh

ORIGINAL ARTICLE

Trends in antihypertensive and lipidlowering therapy in subjects with type II diabetes: clinical effectiveness or clinical discretion? MC Gulliford, J Charlton and R Latinovic Department of Public Health Sciences, King’s College London, London, UK

Hypertension and lipid disorders in type II diabetes contribute to increased coronary risk, but optimal drug therapy has not been defined. We investigated primary care physicians choices of antihypertensive and lipidlowering therapy for subjects with type II diabetes diagnosed with hypertension. Subjects were registered with 105 UK general practices in the General Practice Research Database and prescribed oral hypoglycaemic drugs for the first time between January 1993 and December 2001. We evaluated prescriptions for antihypertensive drugs in subjects with secondary diagnoses of hypertension in the first year following initiation of oral hypoglycaemic therapy. Data were analysed for 4519 diabetic subjects with diagnosed hypertension. Between 1993 and 2001, the proportion prescribed thiazide diuretics increased from 20 to 30%; angiotensin-converting enzyme (ACE) inhibitors from 35 to 45% and angiotensin receptor blockers from 0 to 8%.

The proportion of subjects prescribed lipid-lowering therapy increased from 8% in 1993 to 33% in 2001, with the proportion prescribed statins increasing from 1 to 30%. At different general practices, the proportion prescribed thiazide diuretics ranged from 0 to 52%, betablockers from 5 to 60%, ACE inhibitors from 15 to 81%, and statins from 0 to 50%. Variation between practices was not explained by adjusting for age, sex, prevalent coronary heart disease or study year. Trends in drug utilisation were consistent with the evolving evidence base but there were wide variations in drug utilisation between practices. A more consistent approach to drug selection might be associated with improved patient outcomes. Journal of Human Hypertension (2005) 19, 111–117. doi:10.1038/sj.jhh.1001787 Published online 9 September 2004

Keywords: type II diabetes mellitus; primary medical care; drug therapy; antihypertensive agents; lipids and

antilipidaemic agents; statins

Introduction Subjects with type II diabetes have a greatly increased risk of coronary heart disease. In a metaanalysis, Kanaya et al1 found that the relative odds of coronary heart disease in type II diabetic subjects were 2.3 times higher in men and 2.9 times higher in women when compared with nondiabetic subjects. Type II diabetes mellitus is commonly associated with elevated blood pressure2 and with atherogenic lipid abnormalities3 and this combination represents a potent cause of elevated coronary risk. This has been explicitly recognised in clinical guidelines

Correspondence: Dr M Gulliford, Department of Public Health Sciences, King’s College London, Capital House, 42 Weston St., London SE1 3QD, UK. E-mail: [email protected] Received 15 April 2004; revised and accepted 16 June 2004; published online 9 September 2004

for the management of hypertension or hypercholesterolaemia.4,5 Over the last ten years, there have been important developments in understanding of the natural history and treatment of type II diabetes mellitus. The results of the United Kingdom Prospective Diabetes Study published in 1998 demonstrated the importance of good control of blood pressure in reducing the onset and progression of microvascular and macrovascular complications of the condition.6 In a group of subjects randomised to tight control of blood pressure, there was a 24% (95% confidence interval 8–38%) reduction in diabetes related end points and a 32% (6–51%) reduction in diabetesrelated deaths.6 Evidence for the overall effectiveness of antihypertensive treatment was supplemented by accumulating evidence concerning the appropriate choice of antihypertensive drug in diabetic patients treated for hypertension.7 Results from the ALLHAT study8 suggested that long-term

Antihypertensive and lipid-lowering therapy in type II diabetes MC Gulliford et al 112

outcomes from treatment with a diuretic, calcium channel antagonist or angiotensin-converting enzyme (ACE) inhibitor were similar. Thiazide diuretics gave a reduced occurrence of the secondary outcome cardiac failure. In the UKPDS,9 the ACE inhibitor, captopril, and the beta-blocker, atenolol, appeared to be of equal efficacy in the management of hypertension in diabetes, but other evidence suggests that ACE inhibitors or angiotensin receptor antagonists,7,10–12 might reduce proteinuria or delay the onset of nephropathy in subjects with type II diabetes mellitus. The results of the HOPE study13 suggested that the prescription of an ACE inhibitor (ramipril) to patients with diabetes mellitus had wider benefits in reducing the incidence of myocardial infarction, stroke, overt nephropathy as well as cardiovascular and all-cause mortality. There is also increasing evidence of the benefits from cholesterol-lowering therapy using statin drugs in the primary14 and secondary prevention15 of coronary heart disease in subjects with diabetes mellitus. In the Heart Protection Study,16 treatment of diabetic subjects with simvastatin led to a reduction of about a quarter in new coronary events, revascularisations and strokes even in subjects who did not have elevated baseline cholesterol concentrations. The evolving evidence base has been recognised by professional groups who prepared guidelines and other advice on the management of hypertension and raised cholesterol in the management of patients with type II diabetes mellitus.2,3 Recent clinical guidelines2,4,7 emphasise the importance of detection and treatment of high blood pressure and suggest that the choice of antihypertensive drug should be influenced by clinical considerations including the presence or absence of nephropathy, angina, myocardial infarction or left ventricular dysfunction, which might provide specific indications for particular classes of drugs. Guidelines on the management of lipid disorders set as an objective a total cholesterol of 5 mmol/l or lower, but the priority given to treatment varies according to risk of coronary heart disease.4,17 Clinical practice may depart from recommended standards based on the results of clinical trials. Surveillance of variations in clinical practice may raise questions concerning current patterns of practice and thus help to refine policies or inform interventions to promote change. The present study therefore investigated the diffusion of evidence concerning the management of hypertensive type II diabetic subjects into clinical practice in primary care in the United Kingdom between 1993 and 2001. We evaluated subjects with type II diabetes who were prescribed oral hypoglycaemic drugs. We specifically aimed to describe variations in the prescription of different drug classes over time, between patients with different characteristics, and between different general practices. Journal of Human Hypertension

Methods This paper reports an analysis of data from the General Practice Research Database (GPRD).18 The GPRD holds data from voluntarily participating general practices in the United Kingdom including details of drug prescriptions, general practice consultations and mortality. Data provided by GPRD practices are checked for quality and consistency, and data are eligible for analysis when it is shown that data recording at the practice is of a high enough standard for the data to be used in research. The data are then said to be up-to-standard (‘UTS’). The quality of these data has been shown to be good.19,20 The study period was chosen so as to optimise the number of practices and duration of follow-up while including the same practices in each of the years of study. We selected practices that were providing UTS data during a defined study period from 1 January 1992 to 31 December 2001. We were then able to analyse UTS data for 105 practices over 10 years. Eligible subjects were all patients registered with practices before 1 January 1992. These numbered approximately 650 000 subjects. No new subjects entered the eligible pool of patients after 1 January 1992, so the cohort increased in age during the study period. We selected a cohort of subjects who were prescribed oral hypoglycaemic drugs for the first time between 1 January 1993 and 31 December 2001. We used the definition of ‘non-insulin-treated diabetes’ used by the UK Office for National Statistics (ONS) in the publication ‘Key Health Statistics from General Practice 1998’.21 Subjects were selected who were prescribed drugs in sections 6.1.2.1 (sulphonylurea drugs), 6.1.2.2 (metformin) and 6.1.2.3 (other oral hypoglycaemic drugs) in the BNF22 between 1 January 1993 and 31 December 2001 but not before 1 January 1993. Thus, we only included incident cases who were prescribed oral hypoglycaemic drugs for the first time after the end of 1992. We also excluded subjects aged less than 30 years at diagnosis. Subjects entered the study at the first prescription for oral hypoglycaemic drugs and we then evaluated the first 12 months after the first prescription of oral hypoglycaemic drugs. Followup was censored if the subject died or was transferred to insulin during this time. We identified subjects with a diagnosis of hypertension21 recorded at any date up to the end of 12 months from the initiation of hypoglycaemic therapy. We evaluated whether subjects received at least one prescription during this study period for any of the following drugs classes from the BNF: thiazides and related diuretics (2.2.1), loop diuretics (2.2.2), potassium sparing diuretics (2.2.3), potassium sparing diuretics with other diuretics (2.2.4), beta-adrenoceptor blocking drugs (2.4), vasodilator antihypertensive drugs (2.5.1), centrally acting antihypertensive drugs (2.5.2), adrenergic neuron-inhibiting drugs (2.5.3), alpha-adrenoceptor-blocking


drugs (2.5.4), drugs affecting the renin–angiotensin system (2.5.5), including ACE inhibitors (2.5.5.1) and angiotensin-II receptor antagonists (2.5.5.2) or calcium channel blockers (2.6.2). We also analysed lipid regulating drugs (BNF section 2.12) with statins and fibrates analysed as separate classes. In the data presented, results for vasodilator antihypertensive drugs, centrally acting antihypertensive drugs, adrenergic neuron-inhibiting drugs and fibrates were omitted because they were each prescribed to less than 2% of patients. We estimated the proportions of subjects who were prescribed different major drug classes during the study period. The major classes were labelled following Brown et al:23 A, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers; B, beta-blockers; C, calcium antagonists; D, thiazide diuretics including potassium-sparing diuretics and potassium-sparing diuretic combinations. Data for subjects who were not treated with antihypertensive drugs are tabulated separately. We estimated the proportion of subjects with diabetes and hypertension who were treated with different classes of antihypertensive or lipid-regulating drugs. Risk ratios were estimated from regression models for binomial data using the ‘binreg’ command in Stata version 7.24 Robust standard errors were estimated to allow for clustering by practice. Explanatory variables were age at start of hypoglycaemic treatment, sex, coronary heart disease at any time up to the start of treatment

with oral hypoglycaemic drugs and year of entry to the study. The medical codes used for coronary heart disease and hypertension were those used by the UK ONS.21

Results There were 9365 patients aged 30 years or older who were prescribed oral hypoglycaemic drugs for the first time between 1 January 1993 and 31 December 2001. Of these, 4519 (48%) had a diagnosis of hypertension recorded at some time up to the end of the first 12 months of oral hypoglycaemic therapy. The proportion of subjects who were diagnosed with hypertension increased from 34% in 1993 to 58% in 2001. There was a linear trend by study year after adjusting for age group, sex and prevalent coronary heart disease (Table 1). Further analysis was confined to the 4519 subjects with diagnosed hypertension. Table 1 shows the proportion of subjects entering the study each year who were prescribed each class of antihypertensive or lipid-lowering drug. Throughout the study period ACE inhibitors, betablockers, calcium channel antagonists and thiazide diuretics represented the most frequently prescribed classes of antihypertensive drugs. However, there were important changes in the relative frequency with which different drug classes were prescribed. Use of thiazide diuretics, alpha-blockers, ACE

Table 1 Subjects with diagnosed type II diabetes and hypertension who were prescribed different classes of antihypertensive or lipidlowering drugs by year of entry to study 1993 Diabetes Diagnosed with hypertension

1994

1995

1996

1997

1999

2000

2001

RR (95% CI)a

P-valueb

879 931 857 919 925 1028 1170 1355 1301 298 (34) 403 (43) 370 (43) 398 (43) 404 (44) 535 (52) 600 (51) 762 (56) 749 (58) 1.06 (1.05–1.07) o0.001

Among hypertensive subjects No drug treatment 54 (18) 68 (17) 70 (19) 73 (18) 79 (20) Thiazide diuretic 59 (20) 97 (24) 63 (17) 86 (22) 83 (21) Potassium-sparing 13 (4) 8 (2) 9 (2) 11 (3) 9 (2) diuretics Potassium-sparing 40 (13) 48 (12) 36 (10) 47 (12) 28 (7) diuretic combinations Beta-adrenoceptor89 (30) 115 (29) 121 (33) 109 (28) 109 (27) blocking drugs Alpha adrenoceptor6 (2) 14 (3) 11 (3) 17 (4) 25 (6) blocking drugs ACE inhibitors 103 (35) 148 (37) 140 (38) 132 (33) 157 (39) Angiotensin II 0 (0) 0 (0) 1 (0) 6 (2) 14 (3) receptor antagonists Calcium channel 98 (33) 135 (34) 115 (31) 134 (34) 129 (32) blockers Lipid-lowering drugs Statins Loop diuretics

1998

24 (8) 4 (1) 34 (11)

35 (9) 10 (2) 57 (14)

43 (12) 20 (5) 59 (16)

55 (14) 24 (6) 61 (15)

83 (16) 91 (15) 77 (10) 124 (17) 0.96 (0.93–0.99) 0.010 111 (21) 150 (25) 241 (32) 223 (30) 1.07 (1.05–1.09) o0.001 9 (2) 11 (2) 16 (2) 16 (2) 0.94 (0.87–1.01) 0.107 44 (8)

32 (5)

39 (5)

27 (4)

0.86 (0.83–0.89) o0.001

150 (28) 190 (32) 274 (36) 231 (31) 1.02 (1.00–1.03) 35 (7)

57 (10)

85 (11)

66 (9)

0.071

1.19 (1.14–1.25) o0.001

233 (44) 294 (49) 366 (48) 336 (45) 1.04 (1.03–1.06) o0.001 22 (4) 34 (6) 64 (8) 58 (8) 1.44 (1.35–1.55) o0.001 183 (34) 215 (36) 271 (36) 246 (33) 1.00 (0.99–1.02)

0.769

65 (16) 112 (21) 142 (24) 286 (38) 247 (33) 1.21 (1.18–1.24) o0.001 43 (11) 78 (15) 122 (20) 254 (33) 227 (30) 1.35 (1.31–1.40) o0.001 83 (21) 100 (19) 103 (17) 129 (17) 98 (13) 1.00 (0.98–1.03) 0.863

a

Relative annual change adjusted for age group, sex, prevalent coronary heart disease and clustering by practice. Test for linear trend by year. Figures are frequencies (column percent) except where indicated. b

Journal of Human Hypertension


inhibitors and angiotensin receptor antagonists increased, while use of fixed dose combinations that included potassium sparing diuretics declined. The proportion prescribed beta-blockers or calcium channel antagonists remained constant. The proportion of subjects who were prescribed lipid-lowering therapy also increased and this was mostly explained by a rapid increase in the prescription of statin drugs. The prescription of loop diuretics showed no linear trend. There were substantial variations in the prescription of drugs by age (Table 2). While prescription of all diuretic classes increased with age, the prescription of ACE inhibitors declined. Other antihypertensive drug classes showed a more complex association with age first increasing and then declining in the oldest age group. The prescription

of statin drugs also showed this pattern. Subjects with coronary heart disease (Table 3) were less often prescribed thiazide diuretics but were more often prescribed potassium-sparing diuretic combinations, beta-blockers, calcium channel blockers and lipid-lowering drugs including statins. There were wide variations among practices in the prescription of all drug classes (Table 4). Particularly wide variations were observed for the proportions of subjects treated with thiazide diuretics that ranged from 0 to 52% at different practices, the proportion treated with beta-blockers that ranged from 5 to 60%, ACE inhibitors from 15 to 81% and statins from 0 to 50%. Table 5 shows the frequency with which different classes of drugs in combination were prescribed. Approximately 37% of subjects were prescribed

Table 2 Subjects with diagnosed type II diabetes and hypertension who were prescribed different classes of antihypertensive or lipidlowering drugs by age group Age group (years)

Diabetic subjects Diagnosed with hypertension Untreated Thiazide diuretics Potassium-sparing diuretics Potassium-sparing diuretic combinations Beta-adrenoceptor-blocking drugs Alpha-adrenoceptor-blocking drugs ACE inhibitors Angiotensin II receptor antagonists Calcium channel blockers Lipid-lowering drugs Statins Loop diuretics

o44

45–54

55–64

65–74

75–84

85+

698 175 (25) 63 (36) 26 (15) 1 (1) 1 (1) 31 (18) 10 (6) 79 (45) 4 (2) 30 (17) 27 (15) 21 (12) 10 (6)

1434 613 (43) 119 (19) 141 (23) 5 (1) 12 (2) 212 (35) 42 (7) 273 (45) 25 (4) 186 (30) 138 (23) 115 (19) 56 (9)

2402 1221 (51) 201 (16) 279 (23) 17 (1) 62 (5) 401 (33) 84 (7) 512 (42) 54 (4) 409 (34) 321 (26) 254 (21) 122 (10)

2704 1476 (56) 197 (13) 386 (26) 42 (3) 141 (10) 484 (33) 121 (8) 635 (43) 69 (5) 532 (36) 378 (26) 304 (21) 253 (17)

1698 865 (51) 115 (13) 236 (27) 29 (3) 86 (10) 231 (27) 50 (6) 362 (42) 42 (5) 322 (37) 134 (15) 86 (10) 231 (27)

429 169 (39) 24 (14) 45 (27) 8 (5) 39 (23) 29 (17) 9 (5) 48 (28) 5 (3) 47 (28) 11 (7) 2 (1) 52 (31)

P-valuea

o0.001 0.016 0.009 o0.001 o0.001 0.237 0.025 0.533 0.003 o0.001 o0.001 o0.001

a Test for difference across age groups after adjusting for year, sex, prevalent coronary heart disease and clustering by practice. Figures are frequencies (column percent) except where indicated.

Table 3 Subjects with diagnosed type II diabetes and hypertension who were prescribed different classes of antihypertensive or lipidlowering drugs according to presence of coronary heart disease No CHD Diabetic diagnosed with hypertension Untreated Thiazides Potassium-sparing diuretics Potassium-sparing diuretic combinations Beta-adrenoceptor-blocking drugs Alpha adrenoceptor-blocking drugs ACE inhibitors Angiotensin II receptor antagonists Calcium channel blockers Lipid-lowering drugs Statins Loop diuretics

3520 642 939 73 228 987 252 1460 149 1037 633 466 444

(18) (27) (2) (6) (28) (7) (41) (4) (29) (18) (13) (13)

a Adjusted for year, sex, age group and clustering by practice. Figures are frequencies (column percent) except where indicated.


CHD 999 77 174 29 113 401 64 449 50 489 376 316 280

(8) (17) (3) (11) (40) (6) (45) (5) (49) (38) (32) (28)

RR (95% CI)a 1.11 0.44 0.65 1.31 1.64 1.48 0.84 1.08 1.10 1.60 2.09 2.27 2.04

(1.06–1.16) (0.35–0.56) (0.56–0.75) (0.83–2.06) (1.30–2.07) (1.32–1.66) (0.64–1.11) (0.99–1.17) (0.85–1.45) (1.48–1.73) (1.88–2.32) (2.01–2.57) (1.76–2.36)

P-value o0.001 o0.001 o0.001 0.255 o0.001 o0.001 0.225 0.086 0.453 o0.001 o0.001 o0.001 o0.001


Table 4 Variation in proportions of subjects with diagnosed type II diabetes and hypertension who were prescribed different classes of antihypertensive or lipid-lowering drugs at different practices Practice-specific proportions (%)

Diabetic diagnosed with hypertension Untreated Thiazides Potassium-sparing diuretics Potassium-sparing diuretic combinations Beta-adrenoceptor-blocking drugs Alpha adrenoceptor-blocking drugs ACE inhibitors Angiotensin II receptor antagonists Calcium channel blockers Lipid-lowering drugs Statins Loop diuretics

Minimum

Lower quartile

Median

Upper quartile

Maximum

P-valuea

31 0 0 0 0 5 0 15 0 6 6 0 0

41 9 16 0 4 25 3 33 0 28 16 12 10

46 14 25 1 6 31 6 44 4 33 22 16 15

54 19 32 4 11 36 9 52 7 40 27 23 21

87 48 52 11 27 60 57 81 22 57 56 50 50

o0.001 o0.001 o0.001 0.564 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001 o0.001

a

Test for variation among practices after adjusting for age, sex, prevalent coronary heart disease and year.

Table 5 Frequency of utilisation of different drug classes by type II diabetic subjects with hypertension Label

Drug classes

Frequency (%)

None A B C D AB AC AD BC BD CD ABC BCD ABD ACD Other

ACE inhibitor or AII antagonist Beta-blocker Calcium antagonist Diuretic ACE inhibitor or AII antagonist and beta-blocker ACE inhibitor or AII antagonist and calcium antagonist ACE inhibitor or AII antagonist and diuretic Beta-blocker and calcium antagonist Beta-blocker and diuretic Calcium antagonist and diuretic ACE inhibitor or AII antagonist, beta-blocker and calcium antagonist Beta-blocker, calcium antagonist and diuretic ACE inhibitor or AII antagonist, beta-blocker and diuretic ACE inhibitor or AII antagonist, calcium antagonist and diuretic

719 707 283 347 311 177 281 205 166 238 163 126 98 110 199 389

(16) (16) (6) (8) (7) (4) (6) (5) (4) (5) (4) (3) (2) (2) (4) (9)

Figures are frequencies (column percent). AII antagonist, angiotensin II receptor antagonist.

only one of the major classes of drugs during the study year. Approximately 28% of patients were prescribed two of the major drug classes during the year, of these 8% were prescribed ‘AB’ or ‘CD’ combinations, while 20% were prescribed ‘A’ or ‘B’ and ‘C’ or ‘D’ combinations. There were approximately 11% of patients who were prescribed three of the major drug classes during the study year and ‘ACD’ combinations were the most frequent of these.

Discussion Main findings

The main changes in prescribing to diabetic subjects with hypertension during this period were consistent with the accumulating evidence for the efficacy

of ACE inhibitors, diuretics and statins in the management of subjects with type II diabetes. The prescription of these drugs increased while the prescription of beta-blockers and calcium channel antagonists remained largely unchanged. There was also evidence that some variations in prescribing were consistent with clinical need because subjects with coronary heart disease were more often prescribed statins, beta-blockers and calcium channel blockers in keeping with current evidence and clinical practice recommendations. However, the considerable diversity in prescribing and especially the wide variations in prescription between practices suggest that unexplained variations in clinical practice play an important role in determining the treatment prescribed to individual diabetic subjects with hypertension. This was also reflected in the Journal of Human Hypertension


frequency with which major drug classes were co-prescribed. There were substantial numbers of subjects prescribed only a single drug class or combinations of drugs that were subsequently classified as less preferred, such as ACE inhibitors with beta-blockers, as reported in previous studies.25,26 Implications for policy and practice

These data raise a question concerning the appropriate management of hypertension in subjects with type II diabetes. The evidence available to clinicians has been evolving during the time of the study, and more recent evidence has been published since 2001. Much of this evidence was synthesised into clinical practice guidelines published by the UK National Institute for Clinical Excellence in 2002,17 the International Diabetes Federation (IDF)7 and other groups.2,4 These allow for considerable clinical discretion in the management of hypertension and lipid disorders in diabetes. A contrasting approach has been suggested by Law et al27,28 who proposed that all subjects aged 55 years or greater or who had known coronary heart disease should be treated with a combination of three agents including a diuretic, a beta-blocker and an angiotensin-converting enzyme inhibitor. Law et al argue that this approach is justified by the low predictive value of blood pressure measurement for the later development of coronary heart disease, the synergistic effect of these agents in lowering blood pressure and the consequent reduction in risk of cardiovascular events throughout the range of blood pressure. A parallel conclusion in the application of lipidlowering therapy might be suggested by the MRC/ BHF Heart Protection Study16 in which people with diabetes were randomised to simvastatin or placebo therapy. In this study, the reduction in risk of cardiovascular events from simvastatin therapy was achieved throughout the range of cholesterol values. These contrasting approaches suggest that policy options include a choice between the recommendation for more universal pharmacotherapy as compared to the existing situation in which considerable clinical discretion leads to wide clinical practice variations and ineffective treatment.25 Making an appropriate choice will involve trade-offs between the optimising benefits of intervention while minimising the side effects and costs of treatment.29 In the longer term, the effects of wider populationbased measures to reduce obesity, hypertension and lipid disorders through diet and other lifestyle interventions must also be considered. Limitations of study

The study had the strength of a large sample drawn from a large number of general practices. Most of the population in the UK is registered with a general Journal of Human Hypertension

practice, and the sample can therefore be considered to be population-based. However, all the practices were providing data of established quality and may have represented more highly motivated practices. We only included subjects from the time they were first treated with oral hypoglycaemic drugs and included the first 12 months of follow-up. This was done so as to avoid difficulties of interpretation that would result from comparison of groups of patients with differing durations of diabetes. However, the frequency of antihypertensive therapy might be expected to increase with increasing duration of diabetes. The case definition for diabetes relied on therapy only, while the case definition for hypertension was based on medical diagnoses. This was because oral hypoglycaemic therapy is specific for type II diabetes, while antihypertensive drugs may be prescribed for other indications. We only had access to prescriptions recorded in general practice computers and some patients may have received prescriptions from hospital clinics or prescriptions that were otherwise not recorded, but equally we did not include subjects who only received oral hypoglycaemic drugs prescribed from other sources. These forms of misclassification may have been more important for practices giving extreme values in the distribution. One of the main limitations of the study is the limited clinical information analysed concerning patient characteristics. In the GPRD, the results of clinical measurements and laboratory tests are recorded in a separate file (the ‘prevention’ file) that is not subject to the same quality checks as other data. Thus, we did not have records of patients’ blood pressure or cholesterol values available for analysis. Similarly, possible clinical indications for specific drugs were not explored in detail. In the assessment of coprescribing of drug classes, we did not fully investigate whether drugs were substituted rather than added, nor whether drug classes were intermittently rather than continuously prescribed. Estimates of the utilisation of drug combinations may therefore be slightly inflated. In spite of these limitations, it appears safe to conclude that there are substantial variations in the prescription of antihypertensive and lipid-lowering drugs over time, between patients with different characteristics and between different general practices.

Conclusion Prescribing to subjects with oral hypoglycaemic treated type II diabetes and hypertension has been characterised by increased use of ACE inhibitors, angiotensin receptor blockers and statin drugs. There are substantial variations in prescriptions that are, in part, accounted for by individual patient characteristics but variations between practices were larger than could be accounted for by measured confounders. These findings raise a question


concerning whether greater standardisation in the management of hypertension in diabetes could lead to better outcomes for subjects with diabetes and hypertension.

Acknowledgements This work was supported by the Charitable Foundation of Guy’s and St Thomas’ Hospital.

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