Trends in antihypertensive and lipidlowering therapy in subjects with type II diabetes: clinical effectiveness or clinical discretion?

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1 ORIGINAL ARTICLE Trends in ntihypertensive nd lipidlowering therpy in subjects with type II dibetes: clinicl effectiveness or clinicl discretion? MC Gulliford, J Chrlton nd R Ltinovic Deprtment of Public Helth Sciences, King s College London, London, UK (2005) 19, & 2005 Nture Publishing Group All rights reserved /05 $ Hypertension nd lipid disorders in type II dibetes contribute to incresed coronry risk, but optiml drug therpy hs not been defined. We investigted primry cre physicins choices of ntihypertensive nd lipidlowering therpy for subjects with type II dibetes dignosed with hypertension. Subjects were registered with 105 UK generl prctices in the Generl Prctice Reserch Dtbse nd prescribed orl hypoglycemic drugs for the first time between Jnury 1993 nd December We evluted prescriptions for ntihypertensive drugs in subjects with secondry dignoses of hypertension in the first yer following initition of orl hypoglycemic therpy. Dt were nlysed for 4519 dibetic subjects with dignosed hypertension. Between 1993 nd 2001, the proportion prescribed thizide diuretics incresed from 20 to 30%; ngiotensin-converting enzyme (ACE) inhibitors from 35 to 45% nd ngiotensin receptor blockers from 0 to 8%. The proportion of subjects prescribed lipid-lowering therpy incresed from 8% in 1993 to 33% in 2001, with the proportion prescribed sttins incresing from 1 to 30%. At different generl prctices, the proportion prescribed thizide diuretics rnged from 0 to 52%, betblockers from 5 to 60%, ACE inhibitors from 15 to 81%, nd sttins from 0 to 50%. Vrition between prctices ws not explined by djusting for ge, sex, prevlent coronry hert disese or study yer. Trends in drug utilistion were consistent with the evolving evidence bse but there were wide vritions in drug utilistion between prctices. A more consistent pproch to drug selection might be ssocited with improved ptient outcomes. (2005) 19, doi: /sj.jhh Published online 9 September 2004 Keywords: type II dibetes mellitus; primry medicl cre; drug therpy; ntihypertensive gents; lipids nd ntilipidemic gents; sttins Introduction Subjects with type II dibetes hve gretly incresed risk of coronry hert disese. In metnlysis, Kny et l 1 found tht the reltive odds of coronry hert disese in type II dibetic subjects were 2.3 times higher in men nd 2.9 times higher in women when compred with nondibetic subjects. Type II dibetes mellitus is commonly ssocited with elevted blood pressure 2 nd with therogenic lipid bnormlities 3 nd this combintion represents potent cuse of elevted coronry risk. This hs been explicitly recognised in clinicl guidelines Correspondence: Dr M Gulliford, Deprtment of Public Helth Sciences, King s College London, Cpitl House, 42 Weston St., London SE1 3QD, UK. E-mil: mrtin.gulliford@kcl.c.uk Received 15 April 2004; revised nd ccepted 16 June 2004; published online 9 September 2004 for the mngement of hypertension or hypercholesterolemi. 4,5 Over the lst ten yers, there hve been importnt developments in understnding of the nturl history nd tretment of type II dibetes mellitus. The results of the United Kingdom Prospective Dibetes Study published in 1998 demonstrted the importnce of good control of blood pressure in reducing the onset nd progression of microvsculr nd mcrovsculr complictions of the condition. 6 In group of subjects rndomised to tight control of blood pressure, there ws 24% (95% confidence intervl 8 38%) reduction in dibetes relted end points nd 32% (6 51%) reduction in dibetesrelted deths. 6 Evidence for the overll effectiveness of ntihypertensive tretment ws supplemented by ccumulting evidence concerning the pproprite choice of ntihypertensive drug in dibetic ptients treted for hypertension. 7 Results from the ALLHAT study 8 suggested tht long-term

2 112 outcomes from tretment with diuretic, clcium chnnel ntgonist or ngiotensin-converting enzyme (ACE) inhibitor were similr. Thizide diuretics gve reduced occurrence of the secondry outcome crdic filure. In the UKPDS, 9 the ACE inhibitor, cptopril, nd the bet-blocker, tenolol, ppered to be of equl efficcy in the mngement of hypertension in dibetes, but other evidence suggests tht ACE inhibitors or ngiotensin receptor ntgonists, 7,10 12 might reduce proteinuri or dely the onset of nephropthy in subjects with type II dibetes mellitus. The results of the HOPE study 13 suggested tht the prescription of n ACE inhibitor (rmipril) to ptients with dibetes mellitus hd wider benefits in reducing the incidence of myocrdil infrction, stroke, overt nephropthy s well s crdiovsculr nd ll-cuse mortlity. There is lso incresing evidence of the benefits from cholesterol-lowering therpy using sttin drugs in the primry 14 nd secondry prevention 15 of coronry hert disese in subjects with dibetes mellitus. In the Hert Protection Study, 16 tretment of dibetic subjects with simvsttin led to reduction of bout qurter in new coronry events, revsculristions nd strokes even in subjects who did not hve elevted bseline cholesterol concentrtions. The evolving evidence bse hs been recognised by professionl groups who prepred guidelines nd other dvice on the mngement of hypertension nd rised cholesterol in the mngement of ptients with type II dibetes mellitus. 2,3 Recent clinicl guidelines 2,4,7 emphsise the importnce of detection nd tretment of high blood pressure nd suggest tht the choice of ntihypertensive drug should be influenced by clinicl considertions including the presence or bsence of nephropthy, ngin, myocrdil infrction or left ventriculr dysfunction, which might provide specific indictions for prticulr clsses of drugs. Guidelines on the mngement of lipid disorders set s n objective totl cholesterol of 5 mmol/l or lower, but the priority given to tretment vries ccording to risk of coronry hert disese. 4,17 Clinicl prctice my deprt from recommended stndrds bsed on the results of clinicl trils. Surveillnce of vritions in clinicl prctice my rise questions concerning current ptterns of prctice nd thus help to refine policies or inform interventions to promote chnge. The present study therefore investigted the diffusion of evidence concerning the mngement of hypertensive type II dibetic subjects into clinicl prctice in primry cre in the United Kingdom between 1993 nd We evluted subjects with type II dibetes who were prescribed orl hypoglycemic drugs. We specificlly imed to describe vritions in the prescription of different drug clsses over time, between ptients with different chrcteristics, nd between different generl prctices. Methods This pper reports n nlysis of dt from the Generl Prctice Reserch Dtbse (GPRD). 18 The GPRD holds dt from voluntrily prticipting generl prctices in the United Kingdom including detils of drug prescriptions, generl prctice consulttions nd mortlity. Dt provided by GPRD prctices re checked for qulity nd consistency, nd dt re eligible for nlysis when it is shown tht dt recording t the prctice is of high enough stndrd for the dt to be used in reserch. The dt re then sid to be up-to-stndrd ( UTS ). The qulity of these dt hs been shown to be good. 19,20 The study period ws chosen so s to optimise the number of prctices nd durtion of follow-up while including the sme prctices in ech of the yers of study. We selected prctices tht were providing UTS dt during defined study period from 1 Jnury 1992 to 31 December We were then ble to nlyse UTS dt for 105 prctices over 10 yers. Eligible subjects were ll ptients registered with prctices before 1 Jnury These numbered pproximtely subjects. No new subjects entered the eligible pool of ptients fter 1 Jnury 1992, so the cohort incresed in ge during the study period. We selected cohort of subjects who were prescribed orl hypoglycemic drugs for the first time between 1 Jnury 1993 nd 31 December We used the definition of non-insulin-treted dibetes used by the UK Office for Ntionl Sttistics (ONS) in the publiction Key Helth Sttistics from Generl Prctice Subjects were selected who were prescribed drugs in sections (sulphonylure drugs), (metformin) nd (other orl hypoglycemic drugs) in the BNF 22 between 1 Jnury 1993 nd 31 December 2001 but not before 1 Jnury Thus, we only included incident cses who were prescribed orl hypoglycemic drugs for the first time fter the end of We lso excluded subjects ged less thn 30 yers t dignosis. Subjects entered the study t the first prescription for orl hypoglycemic drugs nd we then evluted the first 12 months fter the first prescription of orl hypoglycemic drugs. Followup ws censored if the subject died or ws trnsferred to insulin during this time. We identified subjects with dignosis of hypertension 21 recorded t ny dte up to the end of 12 months from the initition of hypoglycemic therpy. We evluted whether subjects received t lest one prescription during this study period for ny of the following drugs clsses from the BNF: thizides nd relted diuretics (2.2.1), loop diuretics (2.2.2), potssium spring diuretics (2.2.3), potssium spring diuretics with other diuretics (2.2.4), bet-drenoceptor blocking drugs (2.4), vsodiltor ntihypertensive drugs (2.5.1), centrlly cting ntihypertensive drugs (2.5.2), drenergic neuron-inhibiting drugs (2.5.3), lph-drenoceptor-blocking

3 drugs (2.5.4), drugs ffecting the renin ngiotensin system (2.5.5), including ACE inhibitors ( ) nd ngiotensin-ii receptor ntgonists ( ) or clcium chnnel blockers (2.6.2). We lso nlysed lipid regulting drugs (BNF section 2.12) with sttins nd fibrtes nlysed s seprte clsses. In the dt presented, results for vsodiltor ntihypertensive drugs, centrlly cting ntihypertensive drugs, drenergic neuron-inhibiting drugs nd fibrtes were omitted becuse they were ech prescribed to less thn 2% of ptients. We estimted the proportions of subjects who were prescribed different mjor drug clsses during the study period. The mjor clsses were lbelled following Brown et l: 23 A, ngiotensin-converting enzyme inhibitors nd ngiotensin receptor blockers; B, bet-blockers; C, clcium ntgonists; D, thizide diuretics including potssium-spring diuretics nd potssium-spring diuretic combintions. Dt for subjects who were not treted with ntihypertensive drugs re tbulted seprtely. We estimted the proportion of subjects with dibetes nd hypertension who were treted with different clsses of ntihypertensive or lipid-regulting drugs. Risk rtios were estimted from regression models for binomil dt using the binreg commnd in Stt version Robust stndrd errors were estimted to llow for clustering by prctice. Explntory vribles were ge t strt of hypoglycemic tretment, sex, coronry hert disese t ny time up to the strt of tretment with orl hypoglycemic drugs nd yer of entry to the study. The medicl codes used for coronry hert disese nd hypertension were those used by the UK ONS. 21 Results There were 9365 ptients ged 30 yers or older who were prescribed orl hypoglycemic drugs for the first time between 1 Jnury 1993 nd 31 December Of these, 4519 (48%) hd dignosis of hypertension recorded t some time up to the end of the first 12 months of orl hypoglycemic therpy. The proportion of subjects who were dignosed with hypertension incresed from 34% in 1993 to 58% in There ws liner trend by study yer fter djusting for ge group, sex nd prevlent coronry hert disese (Tble 1). Further nlysis ws confined to the 4519 subjects with dignosed hypertension. Tble 1 shows the proportion of subjects entering the study ech yer who were prescribed ech clss of ntihypertensive or lipid-lowering drug. Throughout the study period ACE inhibitors, betblockers, clcium chnnel ntgonists nd thizide diuretics represented the most frequently prescribed clsses of ntihypertensive drugs. However, there were importnt chnges in the reltive frequency with which different drug clsses were prescribed. Use of thizide diuretics, lph-blockers, ACE 113 Tble 1 Subjects with dignosed type II dibetes nd hypertension who were prescribed different clsses of ntihypertensive or lipidlowering drugs by yer of entry to study RR (95% CI) P-vlue b Dibetes Dignosed with 298 (34) 403 (43) 370 (43) 398 (43) 404 (44) 535 (52) 600 (51) 762 (56) 749 (58) 1.06 ( ) o0.001 hypertension Among hypertensive subjects No drug tretment 54 (18) 68 (17) 70 (19) 73 (18) 79 (20) 83 (16) 91 (15) 77 (10) 124 (17) 0.96 ( ) Thizide diuretic 59 (20) 97 (24) 63 (17) 86 (22) 83 (21) 111 (21) 150 (25) 241 (32) 223 (30) 1.07 ( ) o0.001 Potssium-spring diuretics 13 (4) 8 (2) 9 (2) 11 (3) 9 (2) 9 (2) 11 (2) 16 (2) 16 (2) 0.94 ( ) Potssium-spring diuretic combintions 40 (13) 48 (12) 36 (10) 47 (12) 28 (7) 44 (8) 32 (5) 39 (5) 27 (4) 0.86 ( ) o0.001 Bet-drenoceptorblocking drugs 89 (30) 115 (29) 121 (33) 109 (28) 109 (27) 150 (28) 190 (32) 274 (36) 231 (31) 1.02 ( ) Alph drenoceptorblocking drugs 6 (2) 14 (3) 11 (3) 17 (4) 25 (6) 35 (7) 57 (10) 85 (11) 66 (9) 1.19 ( ) o0.001 ACE inhibitors 103 (35) 148 (37) 140 (38) 132 (33) 157 (39) 233 (44) 294 (49) 366 (48) 336 (45) 1.04 ( ) o0.001 Angiotensin II receptor ntgonists 0 (0) 0 (0) 1 (0) 6 (2) 14 (3) 22 (4) 34 (6) 64 (8) 58 (8) 1.44 ( ) o0.001 Clcium chnnel blockers 98 (33) 135 (34) 115 (31) 134 (34) 129 (32) 183 (34) 215 (36) 271 (36) 246 (33) 1.00 ( ) Lipid-lowering drugs 24 (8) 35 (9) 43 (12) 55 (14) 65 (16) 112 (21) 142 (24) 286 (38) 247 (33) 1.21 ( ) o0.001 Sttins 4 (1) 10 (2) 20 (5) 24 (6) 43 (11) 78 (15) 122 (20) 254 (33) 227 (30) 1.35 ( ) o0.001 Loop diuretics 34 (11) 57 (14) 59 (16) 61 (15) 83 (21) 100 (19) 103 (17) 129 (17) 98 (13) 1.00 ( ) Reltive nnul chnge djusted for ge group, sex, prevlent coronry hert disese nd clustering by prctice. b Test for liner trend by yer. Figures re frequencies (column percent) except where indicted.

4 114 inhibitors nd ngiotensin receptor ntgonists incresed, while use of fixed dose combintions tht included potssium spring diuretics declined. The proportion prescribed bet-blockers or clcium chnnel ntgonists remined constnt. The proportion of subjects who were prescribed lipid-lowering therpy lso incresed nd this ws mostly explined by rpid increse in the prescription of sttin drugs. The prescription of loop diuretics showed no liner trend. There were substntil vritions in the prescription of drugs by ge (Tble 2). While prescription of ll diuretic clsses incresed with ge, the prescription of ACE inhibitors declined. Other ntihypertensive drug clsses showed more complex ssocition with ge first incresing nd then declining in the oldest ge group. The prescription of sttin drugs lso showed this pttern. Subjects with coronry hert disese (Tble 3) were less often prescribed thizide diuretics but were more often prescribed potssium-spring diuretic combintions, bet-blockers, clcium chnnel blockers nd lipid-lowering drugs including sttins. There were wide vritions mong prctices in the prescription of ll drug clsses (Tble 4). Prticulrly wide vritions were observed for the proportions of subjects treted with thizide diuretics tht rnged from 0 to 52% t different prctices, the proportion treted with bet-blockers tht rnged from 5 to 60%, ACE inhibitors from 15 to 81% nd sttins from 0 to 50%. Tble 5 shows the frequency with which different clsses of drugs in combintion were prescribed. Approximtely 37% of subjects were prescribed Tble 2 Subjects with dignosed type II dibetes nd hypertension who were prescribed different clsses of ntihypertensive or lipidlowering drugs by ge group Age group (yers) o P-vlue Dibetic subjects Dignosed with hypertension 175 (25) 613 (43) 1221 (51) 1476 (56) 865 (51) 169 (39) o0.001 Untreted 63 (36) 119 (19) 201 (16) 197 (13) 115 (13) 24 (14) Thizide diuretics 26 (15) 141 (23) 279 (23) 386 (26) 236 (27) 45 (27) Potssium-spring diuretics 1 (1) 5 (1) 17 (1) 42 (3) 29 (3) 8 (5) Potssium-spring diuretic combintions 1 (1) 12 (2) 62 (5) 141 (10) 86 (10) 39 (23) o0.001 Bet-drenoceptor-blocking drugs 31 (18) 212 (35) 401 (33) 484 (33) 231 (27) 29 (17) o0.001 Alph-drenoceptor-blocking drugs 10 (6) 42 (7) 84 (7) 121 (8) 50 (6) 9 (5) ACE inhibitors 79 (45) 273 (45) 512 (42) 635 (43) 362 (42) 48 (28) Angiotensin II receptor ntgonists 4 (2) 25 (4) 54 (4) 69 (5) 42 (5) 5 (3) Clcium chnnel blockers 30 (17) 186 (30) 409 (34) 532 (36) 322 (37) 47 (28) Lipid-lowering drugs 27 (15) 138 (23) 321 (26) 378 (26) 134 (15) 11 (7) o0.001 Sttins 21 (12) 115 (19) 254 (21) 304 (21) 86 (10) 2 (1) o0.001 Loop diuretics 10 (6) 56 (9) 122 (10) 253 (17) 231 (27) 52 (31) o0.001 Test for difference cross ge groups fter djusting for yer, sex, prevlent coronry hert disese nd clustering by prctice. Figures re frequencies (column percent) except where indicted. Tble 3 Subjects with dignosed type II dibetes nd hypertension who were prescribed different clsses of ntihypertensive or lipidlowering drugs ccording to presence of coronry hert disese No CHD CHD RR (95% CI) P-vlue Dibetic dignosed with hypertension ( ) o0.001 Untreted 642 (18) 77 (8) 0.44 ( ) o0.001 Thizides 939 (27) 174 (17) 0.65 ( ) o0.001 Potssium-spring diuretics 73 (2) 29 (3) 1.31 ( ) Potssium-spring diuretic combintions 228 (6) 113 (11) 1.64 ( ) o0.001 Bet-drenoceptor-blocking drugs 987 (28) 401 (40) 1.48 ( ) o0.001 Alph drenoceptor-blocking drugs 252 (7) 64 (6) 0.84 ( ) ACE inhibitors 1460 (41) 449 (45) 1.08 ( ) Angiotensin II receptor ntgonists 149 (4) 50 (5) 1.10 ( ) Clcium chnnel blockers 1037 (29) 489 (49) 1.60 ( ) o0.001 Lipid-lowering drugs 633 (18) 376 (38) 2.09 ( ) o0.001 Sttins 466 (13) 316 (32) 2.27 ( ) o0.001 Loop diuretics 444 (13) 280 (28) 2.04 ( ) o0.001 Adjusted for yer, sex, ge group nd clustering by prctice. Figures re frequencies (column percent) except where indicted.

5 Tble 4 Vrition in proportions of subjects with dignosed type II dibetes nd hypertension who were prescribed different clsses of ntihypertensive or lipid-lowering drugs t different prctices 115 Prctice-specific proportions (%) Minimum Lower qurtile Medin Upper qurtile Mximum P-vlue Dibetic dignosed with hypertension o0.001 Untreted o0.001 Thizides o0.001 Potssium-spring diuretics Potssium-spring diuretic combintions o0.001 Bet-drenoceptor-blocking drugs o0.001 Alph drenoceptor-blocking drugs o0.001 ACE inhibitors o0.001 Angiotensin II receptor ntgonists o0.001 Clcium chnnel blockers o0.001 Lipid-lowering drugs o0.001 Sttins o0.001 Loop diuretics o0.001 Test for vrition mong prctices fter djusting for ge, sex, prevlent coronry hert disese nd yer. Tble 5 Frequency of utilistion of different drug clsses by type II dibetic subjects with hypertension Lbel Drug clsses Frequency (%) None 719 (16) A ACE inhibitor or AII ntgonist 707 (16) B Bet-blocker 283 (6) C Clcium ntgonist 347 (8) D Diuretic 311 (7) AB ACE inhibitor or AII ntgonist nd bet-blocker 177 (4) AC ACE inhibitor or AII ntgonist nd clcium ntgonist 281 (6) AD ACE inhibitor or AII ntgonist nd diuretic 205 (5) BC Bet-blocker nd clcium ntgonist 166 (4) BD Bet-blocker nd diuretic 238 (5) CD Clcium ntgonist nd diuretic 163 (4) ABC ACE inhibitor or AII ntgonist, bet-blocker nd clcium ntgonist 126 (3) BCD Bet-blocker, clcium ntgonist nd diuretic 98 (2) ABD ACE inhibitor or AII ntgonist, bet-blocker nd diuretic 110 (2) ACD ACE inhibitor or AII ntgonist, clcium ntgonist nd diuretic 199 (4) Other 389 (9) Figures re frequencies (column percent). AII ntgonist, ngiotensin II receptor ntgonist. only one of the mjor clsses of drugs during the study yer. Approximtely 28% of ptients were prescribed two of the mjor drug clsses during the yer, of these 8% were prescribed AB or CD combintions, while 20% were prescribed A or B nd C or D combintions. There were pproximtely 11% of ptients who were prescribed three of the mjor drug clsses during the study yer nd ACD combintions were the most frequent of these. Discussion Min findings The min chnges in prescribing to dibetic subjects with hypertension during this period were consistent with the ccumulting evidence for the efficcy of ACE inhibitors, diuretics nd sttins in the mngement of subjects with type II dibetes. The prescription of these drugs incresed while the prescription of bet-blockers nd clcium chnnel ntgonists remined lrgely unchnged. There ws lso evidence tht some vritions in prescribing were consistent with clinicl need becuse subjects with coronry hert disese were more often prescribed sttins, bet-blockers nd clcium chnnel blockers in keeping with current evidence nd clinicl prctice recommendtions. However, the considerble diversity in prescribing nd especilly the wide vritions in prescription between prctices suggest tht unexplined vritions in clinicl prctice ply n importnt role in determining the tretment prescribed to individul dibetic subjects with hypertension. This ws lso reflected in the

6 116 frequency with which mjor drug clsses were co-prescribed. There were substntil numbers of subjects prescribed only single drug clss or combintions of drugs tht were subsequently clssified s less preferred, such s ACE inhibitors with bet-blockers, s reported in previous studies. 25,26 Implictions for policy nd prctice These dt rise question concerning the pproprite mngement of hypertension in subjects with type II dibetes. The evidence vilble to clinicins hs been evolving during the time of the study, nd more recent evidence hs been published since Much of this evidence ws synthesised into clinicl prctice guidelines published by the UK Ntionl Institute for Clinicl Excellence in 2002, 17 the Interntionl Dibetes Federtion (IDF) 7 nd other groups. 2,4 These llow for considerble clinicl discretion in the mngement of hypertension nd lipid disorders in dibetes. A contrsting pproch hs been suggested by Lw et l 27,28 who proposed tht ll subjects ged 55 yers or greter or who hd known coronry hert disese should be treted with combintion of three gents including diuretic, bet-blocker nd n ngiotensin-converting enzyme inhibitor. Lw et l rgue tht this pproch is justified by the low predictive vlue of blood pressure mesurement for the lter development of coronry hert disese, the synergistic effect of these gents in lowering blood pressure nd the consequent reduction in risk of crdiovsculr events throughout the rnge of blood pressure. A prllel conclusion in the ppliction of lipidlowering therpy might be suggested by the MRC/ BHF Hert Protection Study 16 in which people with dibetes were rndomised to simvsttin or plcebo therpy. In this study, the reduction in risk of crdiovsculr events from simvsttin therpy ws chieved throughout the rnge of cholesterol vlues. These contrsting pproches suggest tht policy options include choice between the recommendtion for more universl phrmcotherpy s compred to the existing sitution in which considerble clinicl discretion leds to wide clinicl prctice vritions nd ineffective tretment. 25 Mking n pproprite choice will involve trde-offs between the optimising benefits of intervention while minimising the side effects nd costs of tretment. 29 In the longer term, the effects of wider popultionbsed mesures to reduce obesity, hypertension nd lipid disorders through diet nd other lifestyle interventions must lso be considered. Limittions of study The study hd the strength of lrge smple drwn from lrge number of generl prctices. Most of the popultion in the UK is registered with generl prctice, nd the smple cn therefore be considered to be popultion-bsed. However, ll the prctices were providing dt of estblished qulity nd my hve represented more highly motivted prctices. We only included subjects from the time they were first treted with orl hypoglycemic drugs nd included the first 12 months of follow-up. This ws done so s to void difficulties of interprettion tht would result from comprison of groups of ptients with differing durtions of dibetes. However, the frequency of ntihypertensive therpy might be expected to increse with incresing durtion of dibetes. The cse definition for dibetes relied on therpy only, while the cse definition for hypertension ws bsed on medicl dignoses. This ws becuse orl hypoglycemic therpy is specific for type II dibetes, while ntihypertensive drugs my be prescribed for other indictions. We only hd ccess to prescriptions recorded in generl prctice computers nd some ptients my hve received prescriptions from hospitl clinics or prescriptions tht were otherwise not recorded, but eqully we did not include subjects who only received orl hypoglycemic drugs prescribed from other sources. These forms of misclssifiction my hve been more importnt for prctices giving extreme vlues in the distribution. One of the min limittions of the study is the limited clinicl informtion nlysed concerning ptient chrcteristics. In the GPRD, the results of clinicl mesurements nd lbortory tests re recorded in seprte file (the prevention file) tht is not subject to the sme qulity checks s other dt. Thus, we did not hve records of ptients blood pressure or cholesterol vlues vilble for nlysis. Similrly, possible clinicl indictions for specific drugs were not explored in detil. In the ssessment of coprescribing of drug clsses, we did not fully investigte whether drugs were substituted rther thn dded, nor whether drug clsses were intermittently rther thn continuously prescribed. Estimtes of the utilistion of drug combintions my therefore be slightly inflted. In spite of these limittions, it ppers sfe to conclude tht there re substntil vritions in the prescription of ntihypertensive nd lipid-lowering drugs over time, between ptients with different chrcteristics nd between different generl prctices. Conclusion Prescribing to subjects with orl hypoglycemic treted type II dibetes nd hypertension hs been chrcterised by incresed use of ACE inhibitors, ngiotensin receptor blockers nd sttin drugs. There re substntil vritions in prescriptions tht re, in prt, ccounted for by individul ptient chrcteristics but vritions between prctices were lrger thn could be ccounted for by mesured confounders. These findings rise question

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