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Risk of cardiovascular disease and all cause mortality amongpatients with type 2 diabetes prescribed oral antidiabetesdrugs: retrospective cohort study using UK general practiceresearch database Ioanna Tzoulaki, lecturer,1 Mariam Molokhia, senior lecturer,2 Vasa Curcin, research associate,3 Mark P Little,reader,1 Christopher J Millett, senior lecturer in public health,4 Anthea Ng, research associate,4 Robert IHughes, research associate,5 Kamlesh Khunti, professor,6 Martin R Wilkins, professor,5 Azeem Majeed,professor,4 Paul Elliott, professor1,7 although this requires replication in other studies, it may Objective To investigate the risk of incident myocardial have implications for prescribing within this class of infarction, congestive heart failure, and all cause mortality associated with prescription of oral antidiabetes More than 180 million people worldwide have type 2 Setting UK general practice research database, diabetes, a disease associated with at least double the risk of death, mainly from cardiovascular disease.1 Participants 91 521 people with diabetes.
Oral antidiabetes drugs are commonly used to improve Main outcome measures Incident myocardial infarction, glycaemic control, but there are concerns that some congestive heart failure, and all cause mortality. Person may increase the risk of cardiovascular events.2-11 Thia- time intervals for drug treatment were categorised by drug zolidinediones, for example, were initially approved as class, excluding non-drug intervals and intervals for glucose lowering agents with a beneficial effect on insu- lin sensitivity and a potential beneficial effect on risk of Results 3588 incident cases of myocardial infarction, cardiovascular disease. The initial enthusiasm for this 6900 of congestive heart failure, and 18 548 deaths class of drugs was, however, soon tempered by the occurred. Compared with metformin, monotherapy with observation in several clinical trials that rosiglitazone first or second generation sulphonylureas was associated and pioglitazone were associated with an increased inci- with a significant 24% to 61% excess risk for all cause dence of congestive heart failure, resulting in a black Cite this as: BMJ 2009;339:b4731doi:10.1136/bmj.b4731 mortality (P<0.001) and second generation box warning against the use of these drugs in patients sulphonylureas with an 18% to 30% excess risk for with pre-existing congestive heart failure.2 A meta-ana- congestive heart failure (P=0.01 and P<0.001). The lysis of data from clinical trials then found an increased thiazolidinediones were not associated with risk of risk of myocardial infarction and death from cardio- myocardial infarction; pioglitazone was associated with a vascular causes in relation to use of rosiglitazone, significant 31% to 39% lower risk of all cause mortality although a further meta-analysis and other studies failed (P=0.02 to P<0.001) compared with metformin. Among the to replicate this result.3-5 The mortality associated with thiazolidinediones, rosiglitazone was associated with a these drugs and their net benefit on cardiovascular 34% to 41% higher risk of all cause mortality (P=0.14 to events is still highly debated. This debate is set against P=0.01) compared with pioglitazone. A large number of a background of uncertainty about the cardiovascular potential confounders were accounted for in the study; safety of another class of oral antidiabetes drugs-sul- however, the possibility of residual confounding or phonylureas-with some studies suggesting an adverse confounding by indication (differences in prognostic factors between drug groups) cannot be excluded.
Given the common and increasing use of anti- Conclusions Our findings suggest a relatively diabetes drugs, it is essential to determine their relative unfavourable risk profile of sulphonylureas compared benefits and disadvantages to cardiovascular health.
with metformin for all outcomes examined. Pioglitazone Analyses of observational data examining risks asso- was associated with reduced all cause mortality ciated with use of antidiabetes drugs among patients compared with metformin. Pioglitazone also had a attending general practice are limited,13-16 but such favourable risk profile compared with rosiglitazone; "phase IV" studies are an important additional step in drug surveillance.17 Phase III randomised controlled untreated patients, without prescriptions for anti- trials are often too small and of too short a duration to diabetes treatment, from further analyses.
detect small or cumulative adverse effects and arenecessarily prescriptive in their choice of patients for entry into trials. In contrast, surveillance data through We used an interval of drug treatment as the unit of general practice are able to capture information on observation, defined as the period from onset of a drugs and events routinely on a wide range of patients drug treatment to onset of the next drug treatment, or as they present for clinical care. This is an important until censored or until occurrence of the event of inter- strength that cannot be captured in other ways.
est. For example, a patient prescribed monotherapy We investigated the risk of myocardial infarction, with sulphonylureas at entry to the cohort then pre- congestive heart failure, and all cause mortality asso- scribed a combination of sulphonylurea and metfor- ciated with prescription of different classes of oral anti- min and remaining on that combination therapy until diabetes drugs among men and women with diabetes a myocardial infarction occurred, or until censored, included in the general practice research database in was considered to have contributed a total of two inter- the United Kingdom. A previous analysis of the data- vals. Similarly, if a patient was prescribed monother- base based on a much smaller patient population apy with sulphonylureas at entry to the cohort and then focused on risk of congestive heart failure among continued taking sulphonylurea but was also pre- users of older oral antidiabetes drugs and insulin.16 scribed aspirin, a new drug interval was calculated. In We aimed to expand these data by studying a much total there were 2 843 007 intervals of oral antidiabetes larger patient population (n=91 521) and a range of treatments among 91 521 patients with diabetes. We cardiovascular and other outcomes, and to examine excluded periods when patients received insulin ther- the risks associated with the thiazolidinediones rosigli- apy, and events throughout these periods.
We used Cox regression stratified by age at diagno- sis (quartiles) and calendar year of prescription to account for secular trends in events under study. Alter-native models stratifying by either age at diagnosis The general practice research database comprises clin- (continuous) or duration of diabetes or adjusting for ical and prescribing data from anonymised patient age at diagnosis (continuous) resulted in similar risk based clinical records of about five million people.17 18 estimates. Censoring was at the end of each period of We obtained data on patients aged 35-90 years with an constant prescription (or the end of the study). As met- episode of care between 1 January 1990 and 31 Decem- formin is advocated as first line pharmacotherapy for ber 2005 and a diagnostic (Read) code associated with type 2 diabetes we compared the risk associated with a clinical or referral event for diabetes. We excluded each drug or drug class with that of metformin those records with multiple or missing date of death monotherapy.21 22 We also compared risks among the thiazolidinediones. Analyses were further adjusted,sequentially, for sex and duration of diabetes (model 1); plus previous complications from diabetes, pre- Primary events were first occurrence of incident myo- vious peripheral artery disease, previous cardio- cardial infarction, congestive heart failure, and all cause vascular disease, and coprescribed drugs (model 2); mortality. Events were identified by Read codes (see plus body mass index, cholesterol concentration, sys- web extra appendix tables 1-3). Validation studies tolic blood pressure, HbA1c level, creatinine concen- within the general practice research database have con- tration, albumin concentration, and smoking status firmed about 83-90% of diagnoses for myocardial (model 3). Covariates were reascertained at the onset infarction and congestive heart failure.1619 We included of each interval except for sex and smoking, which fractures (non-hip) as a positive control because of the were ascertained only at baseline. Data on model 2 known association between thiazolidinedione use and were missing for 503 to 169 103 intervals. For model risk of fractures.20 We identified oral antidiabetes treat- 3 we included the first non-missing measurement dur- ments of individual patients from prescription records: ing the prescription interval. If this was not available, rosiglitazone monotherapy, rosiglitazone combination we used the most recent preceding measurement if therapy (with other antidiabetes drugs), pioglitazone available, dating back to baseline (909 367 to 948 800 monotherapy, pioglitazone combination therapy, met- intervals). Overall, 28 812 patients had missing values formin monotherapy, monotherapy with first genera- of at least one covariate used in model 3 and therefore tion sulphonylureas (acetohexamide, chlorpropamide, tolbutamide, or tolazamide), monotherapy with second Sensitivity analyses included an analysis of prescrip- generation sulphonylureas (glipizide, gliquidone, gli- tions for second generation sulphonylureas only (a simi- mepiride, glibenclamide, or gliclazide), other oral anti- lar analysis was not feasible for first generation diabetes drugs (for example, acarbose, nateglinide, sulphonylureas owing to small numbers), adjustment repaglinide), and combination therapies excluding thia- for cumulative past prescriptions of antidiabetes drugs zolidinediones and insulin. As the pioglitazone mono- prescribed from the start of the study period until the therapy group was small, we analysed it jointly with the beginning of each drug interval, only drug prescriptions after introduction of thiazolidinediones (≥2000) into the market, patients aged more than 65 or 65 or less at pre- table 1). Table 1 shows the patients' characteristics scription for oral antidiabetes drug, sex specific ana- lyses, and subgroup analyses by thirds of duration ofdiabetes before drug treatment. To explore possible interactions we fitted interaction terms (model 2) sepa- First and second generation sulphonylureas were asso- rately for each drug or drug class by age (>65 or ≤65), ciated with a significant excess risk of a first episode of sex, aspirin use, and statin or fibrate use.
myocardial infarction compared with metformin Statistical analysis was done by IT and MPL using monotherapy in models 1 and 2: the adjusted hazard SAS v9.0 and SPSS v15.0. A two sided P value of ratio ranged from 1.37 (95% confidence interval 1.15 0.05 was used to denote significance. We found no evi- to 1.62) to 1.27 (1.07 to 1.50) for first generation sul- dence for violation of the proportional hazard assump- phonylureas and from 1.31 (1.21 to 1.43) to 1.25 (1.15 tion, assessed by testing for a non-zero slope of the to 1.36) for second generation sulphonylureas (table 2, scaled Schoenfeld residuals on functions of time.
figure). The excess risk associated with sulphonylureaswas observed for all subclasses of second generation drugs (see web extra appendix table 4). In the fully The mean (SD) age of the 91 521 people receiving oral adjusted model (model 3), based on 30% of intervals, antidiabetes agents was 65.0 (11.9) years. The median point estimates for risk of myocardial infarction for follow-up period was 24 days (interquartile range both first and second generation drug groups were 13-42 days) per interval and the mean follow-up per still above 1, although these hazard ratios were no individual was 7.1 years. During the study period longer statistically significant. (In evaluating the effects there were 3588 first events of myocardial infarction, of additional adjustment for confounders in model 3 6900 first events of congestive heart failure, 18 548 compared with models 1 and 2, the much reduced sam- deaths, and 2123 fractures. Among all drug treatments, ple size consequent on use of model 3 should be con- metformin monotherapy was most commonly pre- sidered in interpreting these non-significant results).
scribed (74.5% of patients), followed by monotherapy Rosiglitazone, either alone or in combination, with second generation sulphonylureas (63.5%; showed no significant association with incidence of Table 1 | Characteristics of drug treatment intervals at onset of each interval. Values are means (standard deviations) unless stated otherwise Duration of diabetes at prescription (years) ACE inhibitors or angiotensin II receptor ACE=angiotensin converting enzyme; NSAIDS=non-steroidal anti-inflammatory drugs.
adjusted model 3 (table 2 and figure). When compared with pioglitazone (either monotherapy or in combina- tion with other oral antidiabetes drugs) rosiglitazone was associated with 34% (model 1) to 14% (model 3)non-significant higher risks of myocardial infarction (figure, and see web extra appendix figures 1a and2a). Other drugs and combination therapies excluding thiazolidinediones were associated with an excess risk of myocardial infarction compared with metformin, although this was not the case in the fully adjustedmodel 3 (table 2 and figure, and see web extra appen- Congestive heart failureCompared with metformin monotherapy, first genera-tion sulphonylureas were associated with a significant excess risk of a first episode of congestive heart failure in models 1 and 2; hazard ratios ranged from 1.29 (1.17 to 1.44) to 1.46 (1.32 to 1.63; table 3 and figure). In the fully adjusted model 3, however, associations becamenon-significant, possibly reflecting the reduced sample size and small numbers of events in this analysis. Sec- ond generation sulphonylureas were associated with a significant excess risk of congestive heart failure in all models, with hazard ratios ranging from 1.18 (1.04 to1.34) in model 3 to 1.30 (1.22 to 1.38) in model 1. The subclasses of second generation sulphonylureas wereassociated with an excess risk of congestive heart fail- ure in most analyses (see web extra appendix tables 4- 6). Individuals prescribed rosiglitazone combination therapy had a significant excess risk of developing con- gestive heart failure compared with those prescribed metformin monotherapy in models 1 and 2; hazard ratios ranged from 1.27 (1.06 to 1.53) in model 2 to 1.31 (1.09 to 1.58) in model 1 (table 3 and figure).
The association, however, lost statistical significance in the fully adjusted model 3. Pioglitazone monother- apy or combination therapy was associated with a non- Risk of myocardial infarction, congestive heart failure, and all significant excess risk of heart failure, ranging from cause mortality for different comparisons of drug groups.
1.17 (0.77 to 1.77) in model 3 to 1.18 (0.88 to 1.57) in Analysis is stratified by year of prescription and quartiles of age at treatment, and adjusted for sex, duration of diabetes,previous peripheral arterial disease, previous cardiovascular disease, aspirin, statin or fibrate, diuretics, calcium channel Sulphonylureas, either first or second generation, were blockers, spironolactone, β adrenergic antagonists,angiotensin converting enzyme inhibitors or angiotensin II associated with an increased risk of mortality compared receptor blockers, nitrates, steroids, non-steroidal anti- with metformin alone in all models examined. Hazard inflammatory drugs, digoxin, and any previous complications ratios for first generation sulphonylureas were higher from diabetes (model 2). *Any therapy (monotherapy and than for second generation sulphonylureas and ranged combinations). †Other drugs and combinations of any oral from 1.37 (1.11 to 1.71) for the fully adjusted model 3 to antidiabetes drugs excluding rosiglitazone and pioglitazone 1.61 (1.49 to 1.74) adjusted for age, sex, year, and dura-tion of diabetes in model 1 (table 4, figure). Risks werehigher at younger compared with older ages (see web myocardial infarction when compared with metformin extra appendix tables 7 and 8). Rosiglitazone combina- monotherapy in all models; hazard ratios ranged from tion therapy was associated with a reduced risk of all 0.79 (0.41 to 1.53) in the fully adjusted model 3 to 0.94 cause mortality compared with metformin, as was pio- (0.62 to 1.43) in the minimally adjusted model 1 for glitazone alone and combined. Hazard ratios for piogli- monotherapy and 0.82 (0.56 to 1.20) to 1.08 (0.86 to tazone attained statistical significance in all models and 1.36) for combination therapy, respectively. Pioglita- ranged from 0.69 (0.49 to 0.98, P=0.024) in model 3 to zone was associated with a non-significant reduced 0.61 (0.47 to 0.80, P=0.0003) in model 1. Among the risk of myocardial infarction, which ranged from 22% thiazolidinediones, rosiglitazone was associated with a in both model 1 and model 2 to 29% in the fully higher risk of all cause mortality than pioglitazone; hazard ratios ranged from 1.41 (1.09 to 1.83) in model 1 report important differences in risk associated with dif- to 1.34 (0.90 to 1.97) in model 3 (figure and see web ferent classes of oral antidiabetes drugs. Compared with metformin, monotherapy with either first or sec- Findings were similar when analyses were limited to ond generation sulphonylureas was associated with a drug prescriptions from 2000 onwards after introduc- significant excess risk of all cause mortality, and second tion of thiazolidinediones and when analyses were generation sulphonylureas with an excess risk of con- adjusted for the cumulative dose of all other previous gestive heart failure. The thiazolidinediones were not prescriptions of oral antidiabetes drugs (see web extra associated with risk of myocardial infarction; there was appendix tables 9 and 10). Sensitivity analyses for men a significantly lower risk of all cause mortality asso- and women, for different duration of disease before ciated with pioglitazone use compared with metfor- treatment, and for inclusion of recurrent events are min. Among the thiazolidinediones, a higher risk of presented in web extra appendix tables 11-16, and all cause mortality was observed for rosiglitazone com- tests of interaction in web extra appendix table 17.
pared with pioglitazone; however, risk was not signifi-cant in the fully adjusted model.
FracturesThiazolidinediones were associated with an excess risk of non-hip fractures compared with metformin alone.
Our study of observational data in general practice After adjustment for confounders, there was a 53% allows assessment of the relative benefits and hazards excess risk for rosiglitazone combination therapy com- of use of oral antidiabetes drugs in a "real world" clin- pared with metformin alone (hazard ratio 1.53, 1.25 to 1.88, P<0.001; see web extra appendix table 18). Pio- A diagnosis of cardiovascular disease in the general glitazone was associated with a non-significant excess practice research database has been shown to have risk (hazard ratio 1.28, 0.93 to 1.77; P=0.127).
high validity.16 19 Our analyses of the database involvedabout three million intervals of drug treatments, with ascertainment of drug co-prescriptions and covariates Our study presents observational data from large num- at the beginning of each interval. This enabled us to bers of patients with type 2 diabetes attending for rou- account for switching of drugs and timing of treat- tine clinical care in general practice in the UK. We ments, make extensive adjustments for covariates,and provide prognostic information associated withdifferent drug therapies. We used metformin mono- Table 2 | Risk of a first episode of myocardial infarction among patients receiving therapy as a common reference group, in contrast rosiglitazone, pioglitazone, sulphonylureas, and other drugs and combinations compared with the meta-analyses of data from clinical trials that pooled results across studies with varying drug and non-drug reference groups, introducing possible het- We assumed that a drug prescription interval equates to the patient taking the drug, whereas it is well known that there is variable adherence with pre- scribed treatments.23 Also, we assumed that patients were prescribed more than one oral antidiabetes treat- ment if more than one drug was prescribed on the samedate. In a few cases the second drug might have been prescribed some days later. On the basis that these assumptions lead to non-systematic misclassification errors, they may result in underestimation of true effects, although overestimation is also possible since, for example, specific groups of patients (with varying morbidities) may be more or less likely to comply with As with any observational study, the possibility of residual confounding or confounding by indication (dif- ferences in prognostic factors between different drug groups) cannot be excluded. This may result in spurious associations of drug with events. We guarded against this possibility by careful sequential building of models, including a large number of potential confounders in Model 1: adjusted for sex and duration of diabetes, stratified by year and quartiles of age at treatment. Model our analyses, and we included fractures as a positive 2: model 1 plus previous peripheral arterial disease, previous cardiovascular disease, previous heart failure,aspirin, statin or fibrate, diuretics, calcium channel blockers, spironolactone, β adrenergic antagonists, control because of the well known association with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, nitrates, steroids, non-steroidal thiazolidinediones. We presented models both adjusted anti-inflammatory drugs, digoxin, and any previous complications from diabetes. Model 3: model 2 plus and unadjusted for potential confounders as some fac- cholesterol concentration, body mass index, HbA1c level, creatinine concentration, albumin concentration,systolic blood pressure, and smoking.
tors, such as body mass index, may be considered mortality. Concerns about the safety of sulphonylureas Table 3 | Risk of a first episode of congestive heart failure among patients receivingrosiglitazone, pioglitazone, sulphonylureas, and other drugs and combinations compared were first raised by the University Group Diabetes Study, which showed increased numbers of deathsfrom tolbutamide.25 More recently, increased risk of all cause mortality by 43% and cardiovascular disease mortality by 70% have been reported among users of sulphonylureas compared with metformin,8 consistent with other observational studies.26 27 These findings contrast with results of the United Kingdom Prospec- tive Diabetes Study, where there was no increase in cardiovascular events or death with sulphonylurea use compared with a conventional diet group among non-obese people (despite greater weight gain and higher insulin plasma concentrations with sulpho- nylurea therapy).28 However, among a subgroup of obese participants randomised to metformin, sulpho- nylureas, insulin, or conventional therapy in the Uni- ted Kingdom Prospective Diabetes Study, metformin was associated with a significantly lower all cause mor- tality than in the groups assigned intensive therapy with sulphonylureas (P=0.021).29 Although A Diabetes Outcome Progression Trial (ADOPT) did not find a difference in cardiovascular event rates between groups treated with glibenclamide or metformin, the comparison had low power as it was not part of the Model 1: adjusted for sex and duration of diabetes, stratified by year and quartiles of age at treatment. Model study design.30 Our study extends the evidence, sug- 2: model 1 plus previous peripheral arterial disease, previous cardiovascular disease, previous heart failure, gesting higher mortality with sulphonylurea use than aspirin, statin or fibrate, diuretics, calcium channel blockers, spironolactone, β adrenergic antagonists, metformin use, among unselected patients attending angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, nitrates, steroids, non-steroidalanti-inflammatory drugs, digoxin, and any previous complications from diabetes. Model 3: model 2 plus cholesterol concentration, body mass index, HbA1c level, creatinine concentration, albumin concentration, The mechanism by which commonly prescribed sul- systolic blood pressure, and smoking.
phonylureas (such as glibenclamide) may adverselyaffect cardiovascular risk and mortality is speculative, intermediate factors and not confounders. False nega- but a previously reported dose-response relation sug- tive results were also possible owing to the reduction gests a direct drug action.31 Sulphonylureas bind to a in sample size in the analyses adjusted for multiple cov- regulatory subunit of the inward rectifier potassium ariates (model 3) where large numbers with missing data (KATP) channel, leading to an increase in intracellular were excluded. Missing values in model 3 are assumed potassium ion concentrations, the opening of voltage to be missing at random, since similar patient character- gated calcium channels, and an influx of calcium ions.
istics were shown in intervals with missing and non- In pancreatic β cells this promotes insulin secretion, missing values. Intervals missing not at random might but inhibition of KATP channels in cardiac myocytes affect the validity of results presented for model 3,24 and and vascular smooth muscle cells impairs ischaemic thus these analyses need to be interpreted with caution.
preconditioning, a mechanism for protecting the myo- A further issue is that during the period of the study noticeable falls in cardiovascular disease rates tookplace in the UK. This should not affect comparisons of sulphonylurea treatment with metformin, as both We did not find evidence of an excess risk of myo- were routinely prescribed antidiabetes treatments in cardial infarction associated with rosiglitazone com- the UK throughout the period, nor of rosiglitazone pared with metformin use. A meta-analysis of small with pioglitazone; however, it may affect comparisons clinical trials reported a significant 43% increased risk of the thiazolidinediones with metformin, since the of myocardial infarction among rosiglitazone users thiazolidinediones were not introduced into the UK compared with other drug groups,3 although reanalysis until 2000. We addressed this concern by both stratify- of these data yielded non-significant results.5 Although ing by calendar year in all our analyses and restricting another meta-analysis reported a 31% increased risk in analyses to 2000 onwards; this did not materially affect ischaemic heart disease, the risk for a cardiovascular composite end point was not significantly increased.33Both meta-analyses had limitations, including short follow-up, low event rates, no time to event data, incomplete outcome ascertainment, and heterogeneity Monotherapy with either first or second generation of effects between the combined studies, and concerns sulphonylureas was associated with an excess risk of have been raised about the ability of such meta- analyses to detect rare cardiovascular events.34 oral hypoglycaemic agent combination therapies,7 RECORD (Rosiglitazone Evaluated for Cardio- whereas two other studies in patients with diabetes vascular outcomes in Oral agent combination therapy did not show an increased risk.13 14 Overall, to date for type 2 Diabetes) is an ongoing trial among 4447 there is no clear or consistent evidence on the possible patients with type 2 diabetes, designed to compare cardiovascular benefits or harms of rosiglitazone ther- the effects of rosiglitazone in combination with metfor- apy, and results of clinical trials are awaited.
min or sulphonylurea use compared with metformin The observed excess risk of congestive heart failure and sulphonylureas in relation to cardiovascular dis- associated with rosiglitazone or pioglitazone use com- ease. In a recent analysis by these researchers, over pared with metformin alone accords with previous evi- 5.5 years of follow-up, risks between the two groups dence from clinical trials and observational studies.2 4 36 were similar for the primary end point of death from In the present study, pioglitazone was associated with cardiovascular causes or admission to hospital for a lower mortality than metformin. Our results for piogli- cardiovascular event (hazard ratio 0.99, 0.85 to tazone are in good agreement with those from the 1.16).4 In the same analysis, findings were inconclusive PROspective PioglitAzone Clinical Trial In Macro- for myocardial infarction, for which a non-significant Vascular Events Study (PROACTIVE) trial, the lar- increase for the rosiglitazone group was reported (1.14, gest randomised clinical trial of pioglitazone on 0.80 to 1.63). A further meta-analysis including the cardiovascular disease reported to date.37 Their find- results from an interim analysis by RECORD, the ings showed that pioglitazone non-significantly ADOPT and DREAM (Diabetes Reduction Assess- reduced the risk of the composite primary end point ment with Ramipril and Rosiglitazone Medication) of all macrovascular events and significantly reduced clinical trials, and all small trials included in the pre- the risk of the predefined secondary end point of all vious meta-analysis,3 again suggested rosiglitazone cause mortality, myocardial infarction, or stroke was associated with an increased risk of myocardial (hazard ratio 0.84, 95% confidence interval 0.72 to infarction (odds ratio 1.33, 95% confidence interval 0.98).37 Overall, the trial data suggest a possible cardio- 1.02 to 1.72).35 Previous observational data are also vascular protective effect of pioglitazone despite the conflicting; a significant 80% excess risk of myocardial infarction was reported among elderly patients asso- In our study, mortality associated with pioglitazone ciated with rosiglitazone use compared with other was significantly lower than with rosiglitazone.
Although both drugs are approved as "highly selec-tive" peroxisome proliferator activated receptor γ ago- Table 4 | Risk for all cause mortality among patients receiving rosiglitazone, pioglitazone, nists, recent studies suggest that pioglitazone represses sulphonylureas, and other drugs and combinations compared with patients receiving key endothelial and hepatic inflammatory responses through peroxisome proliferator activated receptor α, an effect not apparently shared by rosiglitazone.38 Furthermore, the molecular mechanisms underlying peroxisome proliferator activated receptor γ activation are complex, involving heterodimerisation, corepres- sors, and coactivators; minor differences in the ligand structure of peroxisome proliferator activated receptor γ could result in significant differences in target gene response.39 Such pharmacological differences maytranslate into a differential effect on cardiovascular protection.40-43 It is already reported that pioglitazone has a more favourable effect on triglycerides and high density lipoprotein cholesterol concentrations than rosiglitazone.44 Pioglitazone has been shown to decrease the rate of progression of carotid intima media thickness and of coronary atherosclerosis,45 46 suggesting a possible role in slowing the development The sulphonylureas, along with metformin, have long been considered the mainstay of drug treatment for type 2 diabetes. Our findings suggest a relatively unfa- vourable risk profile of sulphonylureas compared with Model 1: adjusted for sex and duration of diabetes, stratified by year and quartiles of age at treatment. Model metformin. This is consistent with the recommenda- 2: model 1 plus previous peripheral arterial disease, previous cardiovascular disease,previous heart failure,aspirin, statin or fibrate, diuretics, calcium channel blockers, spironolactone, β adrenergic antagonists, tions of the American Diabetes Association and Inter- angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, nitrates, steroids, non-steroidal national Diabetes Federation that favour metformin as anti-inflammatory drugs, digoxin, and any previous complications from diabetes. Model 3: model 2 plus the initial treatment for type 2 diabetes.21 22 Within cholesterol concentration, body mass index, HbA1c level, creatinine concentration, albumin concentration,systolic blood pressure, and smoking.
class differences in risk among the sulphonylureas Data sharing: The technical appendix and statistical code (through permission of the general practice research database) are available fromthe corresponding author.
Oral antidiabetes drugs are commonly used for glycaemic control; however, concerns are thatsome may increase cardiovascular risk World Health Organization. Diabetes. 2008. www.who.int/ Their relative benefits and disadvantages to cardiovascular health are not well established mediacentre/factsheets/fs312/en/index.html.
Lago RM, Singh PP, Nesto RW. Congestive heart failure and Analyses of observational data examining risks associated with antidiabetes drugs among cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomisedclinical trials. Lancet 2007;370:1129-36.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med2007;356:2457-71.
Our findings suggest a relatively unfavourable risk profile of sulphonylureas compared with Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascularoutcomes in oral agent combination therapy for type 2 diabetes The findings support recommendations of the American Diabetes Association and (RECORD): a multicentre, randomised, open-label trial. Lancet International Diabetes Federation that favour metformin as the initial treatment for type 2 Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on therisk for myocardial infarction and cardiovascular death. Ann Intern Pioglitazone was associated with reduced all cause mortality compared with metformin and it had a favourable risk profile compared with rosiglitazone Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk ofcardiovascular events in patients with type 2 diabetes mellitus: ameta-analysis of randomized trials. JAMA 2007;298:1180-8.
Lipscombe LL, Gomes T, Levesque LE, Hux JE, Juurlink DN, Alter DA.
were not observed. We do not confirm previous Thiazolidinediones and cardiovascular outcomes in older patients reports of an excess risk of myocardial infarction asso- with diabetes. JAMA 2007;298:2634-43.
ciated with rosiglitazone compared with metformin.
Evans J, Ogston S, Emslie-Smith A, Morris A. Risk of mortality andadverse cardiovascular outcomes in type 2 diabetes: a comparison Pioglitazone was associated with reduced all cause of patients treated with sulphonylureas and metformin. Diabetologia mortality compared with metformin, and it had a Action to Control Cardiovascular Risk in Diabetes Study Group.
favourable risk profile compared with rosiglitazone, Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med which requires replication in other studies. This may have implications for prescribing within this class of 10 ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 11 Turner RC, Holman RR, Stratton IM, Cull CA, Matthews DR, Manley SE, Imperial College London are supported by the National Institute for et al. Effect of intensive blood-glucose control with metformin on Health Research (NIHR) biomedical research centre programme. The complications in overweight patients with type 2 diabetes (UKPDS Department of Primary Care and Social Medicine, Imperial College, and the Department of Health Science, University of Leicester, are supported 12 Bell DSH. Do sulfonylurea drugs increase the risk of cardiac events? by the NIHR collaboration for leadership in applied health research and care programme. MM is funded by an NIHR postdoctoral award and 13 Johannes CB, Koro CE, Quinn SG, Cutone JA, Seeger JD. The risk of together with VC and AM are investigators for the EU-ADR FP7 project on coronary heart disease in type 2 diabetic patients exposed to adverse drug reactions. CM and AN are funded by the NIHR service thiazolidinediones compared to metformin and sulphonylureatherapy. Pharmacoepidemiol Drug Saf 2007;16:504-12.
delivery and organisation programme. PE is an NIHR senior investigator.
14 Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Imperial College receives a contribution for AM's salary from the UK Krumholz HM. Thiazolidinediones, metformin, and outcomes in older Diabetes Research Network. The funders had no role in study design, data patients with diabetes and heart failure: an observational study.
collection and analysis, decision to publish, or preparation of the manuscript. We thank Deborah Ashby for helpful comments.
15 McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM. Coronary heart Contributors: IT and MM contributed equally to the study. PE, MRW, AM, disease outcomes in patients receiving antidiabetic agents.
KK, IT, and MM conceived and designed the study. IT, MM, VC, KK, AM, Pharmacoepidemiol Drug Saf 2007;16:711-25.
MPL, MRW, and PE analysed and interpreted the data. All authors drafted 16 Maru S, Koch GG, Stender M, Clark D, Gibowski L, Petri H, et al.
the manuscript and critically revised the manuscript for important Antidiabetic drugs and heart failure risk in patients with type 2diabetes in the UK primary care setting. Diabetes Care 2005;28:20-6.
intellectual content. IT and MPL carried out the statistical analysis. VC 17 Barton S. Which clinical studies provide the best evidence? BMJ provided technical support. PE, IT, MM, and AM supervised the study. PE 18 General practice research database. 2009. www.gprd.com/home/ Funding: No funding was obtained for this study. This study is based on data from the full feature general practice research database funded 19 Meier CR, Derby LE, Jick SS, Vasilakis C, Jick H. Antibiotics and risk of through the Medical Research Council's license agreement with the UK subsequent first-time acute myocardial infarction. JAMA Medicines and Healthcare Products Regulatory Agency. The interpretation and conclusions contained in this study are those of the 20 Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med2008;168:820-5.
Competing interests: PE is a coprincipal investigator on a grant cofunded 21 Clinical Guidelines Task Force, International Diabetes Federation.
by the UK Medical Research Council and GlaxoSmithKline. MRW has Global guidelines for type 2 diabetes. Chapter 9: Glucose control: received consultancy fees from GlaxoSmithKline in the past five years.
oral therapy. 2008. www.idf.org/webdata/docs/GGT2D%2009% MM has received grants from Pfizer, AstraZeneca, and the Serious Adverse Events Consortium (collaboration between industry and 22 American Diabetes Association. Standards of medical care in academia). KK has acted in a consultant capacity or as a speaker for diabetes-2007. Diabetes Care 2007;30:S4-41.
Novo-Nordisk, Sanofi, Lilli, Merck Sharp & Dohme, Tekeda, GSK, and 23 Cramer JA. A systematic review of adherence with medications for Bayer and has received research grants from Servier, Novartis, Novo- diabetes. Diabetes Care 2004;27:1218-24.
Nordisk, Sanofi-Aventis, Merck Sharp & Dohme, Pfizer, Bayer, Unilever, 24 Little RJA, Rubin DB. Statistical analysis with missing data, 2nd edn.
25 Meinert CL, Knatterud GL, Prout TE, Klimt CR. A study of the effects of Ethical approval: The GPRD Group has obtained ethical approval from a hypoglycemic agents on vascular complications in patients with multicentre research ethics committee for all purely observational adult-onset diabetes. II. Mortality results. Diabetes research using anonymised records from the general practice research database. This study was approved by the general practice research 26 Simpson SH, Majumdar SR, Tsuyuki RT, Eurich DT, Johnson JA. Dose- database Independent Scientific Advisory Committee.
response relation between sulphonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study. CMAJ peroxisome proliferator-activated receptor-[alpha]-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol 27 Johnsen SP, Monster TB, Olsen ML, Thisted H, McLaughlin JK, Sørensen HT, et al. Risk and short-term prognosis of myocardial 39 Kintscher U. Pharmacological differences of glitazones: does infarction among users of antidiabetic drugs. Am J Ther peroxisome proliferator-activated receptor-[alpha] activation make the difference? J Am Coll Cardiol 2008;52:882-4.
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30 Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, James NP, et al. Glycaemic durability of rosiglitazone, metformin or glyburidemonotherapy. N Engl J Med 2006;355:2427-43.
42 Donnelly R. Effect of pioglitazone on the drivers of cardiovascular risk in type 2 diabetes. Int J Clin Pract 2007;61:1160-9.
31 Boyd AE III, Aguilar-Bryan L, Nelson DA. Molecular mechanisms of action of glyburide on the beta cell. Am J Med 1990;89:S3-10.
43 Gerber P, Lubben G, Heusler S, Dodo A. Effects of pioglitazone on 32 Engler RL, Yellon DM. Sulphonylurea KATP blockade in type II metabolic control and blood pressure: a randomised study in diabetes and preconditioning in cardiovascular disease: time for patients with type 2 diabetes mellitus. Curr Med Res Opin reconsideration. Circulation 1996;94:2297-301.
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