1. P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N Oral drugs for type 2 diabetes and all cause mortality in General Practice Ioanna Tzoulaki Epidemiology and Biostatistics School of Public Health Imperial College London Cardio Diabetes Master Class May 21-23, 2010, Amsterdam Slide lecture prepared and held by: Presentation topic

2. Oral antidiabetes drugs Diabetes is considered a coronary heart disease equivalent in adults older than 40 years Oral antidiabetes drugs for glycemic control –recommendations based principally on evidence for reduced microvascular risk –concerns that some may increase the risk of cardiovascular events

3. Initially approved as glucose lowering agents with a beneficial effect on insulin sensitivity and a potential beneficial effect on risk of CVD –Meta-analysis (Nissen et al 2007) of clinical trials showed increased risk of ischemic heart disease –Alternative meta-analysis techniques, new meta-analysis, new results from RCTs, observational studies provided variable evidence –RECORD and PROactive only RCTs to assess effect of rosiglitazone on CVD outcomes Thiazolidinediones and IHD

4. Kaul, S. et al. Circulation 2010;121:1868-1877 Thiazolidinediones and IHD risk based on RCTs (closed and open squares) and their meta-analyses (closed and open diamonds)‏

5. Pioglitazone PROactive and meta-analysis no increased risk on IHD –Significant reduction in composite endpoints Observational studies mixed results Pio vs. rosiglitazone limited evidence for reduced IHD events for pioglitazone from observational data –No head to head comparisons in RCTs

6. Thiazolidinediones and HF Evidence for increased risk of HF for rosi and pioglitazone –Meta-anaysis (Lago et al 2007), RECORD and PROActive No increased risk of CVD mortality –Volume retention/ weight gain associated with thiazolidinedione harmful?

7. Sulphonylureas University Group Diabetes Study: increased numbers of deaths from cardiovascular disease among users of tolbutamide United Kingdom Prospective Diabetes Study: no increase in CVD or death with sulphonylurea use compared with conventional diet group ADOPT: no difference in cardiovascular event rates between groups treated with glibenclamide or metformin ADVANCE: intensive therapy based on gliclazide reduced the risk of combined macrovascular/microvascular endpoint (driven mostly by reduced nephropathy) vs. less intensive therapy –but had no significant effect on macrovascular events alone

8. The observational design Limitations –Bias/ Confounding by indication –Differences in prognostic factors between different drug groups e.g. patients who had a greater risk of myocardial infarction were preferentially given specific treatment Advantages –Clinically important but unexpected adverse effects of drugs are often too rare to be detected in randomized trials Meta-analysis of RCT included trials with very few events –Surveillance data through general practice are able to capture information on drugs and events routinely on a wide range of patients as they present for clinical care

9. Aims of this study To examine relative risk of MI, heart failure and all cause mortality among different oral anti-diabetes drugs in a population study

10. Methods- GPRD The general practice research database (GPRD) comprises clinical and prescribing data from anonymised patient based clinical records of about five million people Obtained data on patients 35-90 between 1990 and 2005 and a diagnostic code of diabetes Extracted data on prescriptions, MI, heart failure and all cause mortality, cardiovascular risk factors

11. Methods- data analysis Interval of drug treatment as the unit of observation, defined as the period from onset of a drug treatment to onset of the next drug treatment, or until censored/ event 2,843,007 intervals of oral antidiabetes treatments among 91,521 patients with diabetes Periods when patients received insulin therapy, and events throughout these periods were excluded Cox regression stratified by age at diagnosis and calendar year of prescription Covariates were re-ascertained at each interval onset

13. Hazard ratios (HR) (95% CI) for first episode of myocardial infarction among patients receiving rosiglitazone, pioglitazone, sulphonylureas and other drugs and combinations compared with patients receiving metformin monotherapy Model 2 (N=2,761,889 intervals) N events HRLower 95% CI Upper 95% CI P value 1 st generation sulphonylurea monotherapy 1701.271.071.500.007 2 nd generation sulphonylurea monotherapy 15751.251.151.36 <0.000 1 Rosiglitazone monotherapy 230.970.641.480.902 Rosiglitazone combination 831.060.841.330.610 Pioglitazone monotherapy and combination 240.780.521.170.224 Adjusted for age at prescription, year of prescription, sex, previous peripheral arterial disease, previous CVD or HF, co-prescriptions of CVD drugs and any previous diabetes complications Tzoulaki, I. et al. BMJ 2009;339:b4731

14. Hazard ratios (HR) (95% CI) for first episode of heart failure among patients receiving rosiglitazone, pioglitazone, sulphonylureas and other drugs and combinations compared with patients receiving metformin monotherapy Model 2 (N=2,673,904 intervals) N events HRLower 95% CI Upper 95% CI P value 1 st generation sulphonylurea monotherapy 5201.291.171.44 <0.000 1 2 nd generation sulphonylurea monotherapy 32761.191.121.27 <0.000 1 Rosiglitazone monotherapy 381.070.771.480.688 Rosiglitazone combination 1251.271.061.530.011 Pioglitazone monotherapy and combination 481.100.831.470.512 Adjusted for age at prescription, year of prescription, sex, previous peripheral arterial disease, previous CVD or HF, co-prescriptions of CVD drugs and any previous diabetes complications Tzoulaki, I. et al. BMJ 2009;339:b4731

15. Sensitivity analyses SUs subclasses: no differences Analysis truncated at 2000: no differences Analysis stratified for older than/ less than 65years: no differences No interactions between age, sex, aspirin or statin use and duration of diabetes Model 3: adjustment for CVD risk factors, 60% reduction in sample size, results need to be interpreted with caution Associations between thiazolodinediones and fracture risk significant

16. Summary & Conclusions Differences in risk associated with different classes of oral antidiabetes drugs –Thiazolidinediones were not associated with risk of MI compared to metformin –Thiazolidinediones were associated with higher HF risk compared to metformin –Pioglitazone was associated with reduced all cause mortality compared with metformin –Pioglitazone had a favourable risk profile compared with rosiglitazone requires replication in other studies may have implications for prescribing within this class of drugs. –First and second generation SUs were associated with higher risk of MI and HF Findings favour metformin as the initial treatment for type 2 diabetes –Thiazolidinediones increase the risk of heart failure and should not be initiated in patients with class III/IV CHF –Evidence for thiazolidinediones and CVD insufficient –Insufficient data exist to support the choice of pioglitazone over rosiglitazone –Further evidence for sulphonylureas and CVD is required