Thiazolidinediones and risk of cancer in type 2 diabetes: A systematic review and meta-analysis Isabelle N. Colmers BScH, MSc Candidate
TZDs and Cancer Risk in Type 2 Diabetes Thank you to Collaborators: Dr. Jeffrey Johnson, Dr. Me2 (Sumit) Majumdar, Dr. Samantha Bowker Funding: Alberta Diabetes Institute ACHORD Trainee Program No known conflicts of interest
Type 2 Diabetes Adult onset Over 90% of Diabetes Obesity & Insulin resistance Hyperglycemia Hyperinsulinemia R x : Lifestyle, glucose-lowering medications
Type 2 Diabetes: Comorbid Conditions unsourced image, nursenacole.com
Type 2 Diabetes: Association with Cancer Hyperinsulinemia may promote cancer growth Insulin promotes cellular growth and division Cancer cells express insulin receptor
The role of Glucose-lowering agents Glucose-lowering medications may modify association with cancer Increased risk Insulin secretagogues (sulfonylureas), exogenous insulin Decreased risk Insulin-sensitizing agents (metformin, TZDs?)
Thiazolidinediones (TZDs) Thiazolidinediones (TZDs): pioglitazone, rosiglitazone Insulin-sensitizing agents PPARγ agonists Activate tumor suppression pathways Pioglitazone source: science photo library Increased risk of bladder cancer? Animal experiments, PROactive trial Large cohort studies Warnings on Rx information: Canada, USA, Europe
Objective No systematic summary of evidence on TZDs and cancer exists. OBJECTIVE: Assess the risk of overall and site-specific cancers in individuals with type 2 diabetes using TZDs compared to those not using TZDs
Data Sources 1. Key electronic databases (12) up to June 2011 Medline, Embase, EBM reviews, Scopus, Web of Science, etc Databases searched from inception, no language restrictions 2. Clinical trials registries (2) up to June 2011 Clinicaltrials.gov, International Clinical Trials Registry Platform (ICTRP) 3. Conference proceedings (5) 2008 onward Key international diabetes meetings (CDA, EASD, ADA, CAPT, ISPE) 4. Additional Grey Literature Reference lists of relevant studies, hand search, contacting authors
Selection Criteria Study designs: RCT, Cohort or Case-Control studies Population: Individuals with type 2 diabetes Intervention/Comparison: TZD use (mono/combo) vs. no TZD use Outcomes: Incident cancer (overall and/or site-specific)
Analysis Descriptive Summary and Review 2 trained, independent reviewers Meta Analysis: Categorize by cancer site and study design RCT Observational : Cohort and Nested case-control studies Pooling: If 3 studies in a category and I 2 75% Subgroup analysis: Pioglitazone vs no pioglitazone
Study Selection Records screened: 1338 Databases (n=1138) Grey literature (n=200) Full-text articles assessed: 49 Studies included in qualitative synthesis: 23 published (n=18) unpublished (n=5) 4 RCT 8 Cohort 11 Case-Control Control Records excluded: 1289 Full-text articles excluded: 26 No report of incident cancer (13) Duplicate reports (5) No T2DM population using TZD (2) No appropriate comparison (2) Wrong study design (2)
Systematic Review Different cancers sites reported (n=21): Bladder, Prostate, Colon/Rectum, Breast, Overall etc Total participants N= 2,831,539 RCT (4) Cohort (8) Case-Control (11) Sample size 14,422 2,474,214 342,903 Total cancers 691 NE NE Incidence: (TZD users) (non-tzd users) 11.1/1000PY 11.6/1000PY NE NE - - Studies at high risk of bias 3 0 1 Table 1. Study Characteristics. NE, not estimable
Cancer site Overall RCT (n=3, I 2 =0%) Observational (n=5, I 2 =70%) Bladder RCT (n=4, I 2 =0%) Observational (n=5, I 2 =0%) Breast RCT (n=4, I 2 =11%) Observational (n=6, I 2 =44%) Colorectal Observational (n=10, I 2 =30%) Lung RCT (n=3, I 2 =0%) Observational (n=5, I 2 =35%) Pancreas Observational (n=4, I 2 =36%) Prostate RCT (n=4, I 2 =0%) Observational (n=6, I 2 =0%) Renal RCT (n=3, I 2 =0%) Decreased cancer risk TZD ever vs. never use in type 2 diabetes Meta-Analysis Pooled Meta-Analysis Risk Estimates 0.95 0.68 0.89* 0.93* 0.91* 0.81 0.92 1.14 0.99 1.04 0.98 1.45 1.15** *p<0.05 **p<0.01 0.5 1.0 2.0 Increased cancer risk
Cancer Site Bladder Observational (n=3, I 2 =0%) Breast Observational (n=2, I 2 =0%) Colorectal Observational (n=3, I 2 =0%) Lung Observational (n=2, I 2 =0%) Prostate Observational (n=2, I 2 =0%) Renal Observational (n=2, I 2 =4%) Total pooled estimates Observational (n=4, I 2 =0%) Pioglitazone ever vs. never use Subgroup Analysis Pooled Meta-Analysis Risk Estimates 0.93 0.97 0.95 0.89 1.00 1.22** *p<0.05 **p<0.01 0.1 Decreased cancer risk risk 0.5 1.0 2.0 Increased cancer risk 0.97
Key Findings 1. TZD use associated with decreased risk of: overall, lung, colorectal and breast cancer 1. TZD use associated with increased risk of bladder cancer 3. Pioglitazone associated with increased risk of bladder cancer Image source: 123rf.com
Strengths Separate analysis for each cancer site and study design, with consistent results Real world exposure and comparison definitions for TZDs (i.e. in combination with other therapies) Pioglitazone subgroup analysis
Limitations Statistical limitations by paucity of research and by wide confidence intervals of some individual risk estimates. Inability to account for possible effects of other glucose-lowering agents and exposure duration
Implications