Study of oral drugs for type 2 diabetes and all cause mortality

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Transcript Study of oral drugs for type 2 diabetes and all cause mortality

Cardio Diabetes Master Class May 21-23, 2010, Amsterdam

Presentation topic Oral drugs for type 2 diabetes and all cause mortality in General Practice Slide lecture prepared and held by:

Ioanna Tzoulaki

Epidemiology and Biostatistics School of Public Health Imperial College London

H Y S I C I A N S ’

C A D E M Y F O R

A R D I O V A S C U L A R

D U C A T I O N

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

Thiazolidinediones and IHD

• 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 risk based on RCTs (closed and open squares) and their meta-analyses (closed and open diamonds)

Kaul, S. et al. Circulation 2010;121:1868-1877

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

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?

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

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

too rare to be detected in randomized trials of drugs are often • 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

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

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

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

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 P value Model 2 (N=2,761,889 intervals) 1 st generation sulphonylurea monotherapy N events 170 2 nd generation sulphonylurea monotherapy 1575 Rosiglitazone monotherapy 23 Rosiglitazone combination HR 1.27

1.25

0.97

83 1.06

Pioglitazone monotherapy and combination 24 0.78

Lower 95% CI 1.07

1.15

0.64

0.84

0.52

Upper 95% CI 1.50

1.36

1.48

1.33

1.17

0.007

<0.000

1 0.902

0.610

0.224

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

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) 1 st generation sulphonylurea monotherapy N events 520 2 nd generation sulphonylurea monotherapy 3276 Rosiglitazone monotherapy 38 Rosiglitazone combination 125 Pioglitazone monotherapy and combination 48 HR 1.29

1.19

1.07

1.27

1.10

Lower 95% CI 1.17

1.12

0.77

1.06

0.83

Upper 95% CI 1.44

1.27

1.48

1.53

1.47

P value <0.000

1 <0.000

1 0.688

0.011

0.512

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

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