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Methodological challenges to control for immortal time bias in addressing drug effects in type 2 diabetes
Xi-Lin Yang1, Xiao-Xu Huo1, Juliana Cn Chan1
1Xi-Lin Yang, Xiao-Xu Huo, Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
Abstract:
There are multiple biases in using observational studies to examine treatment effects such as those from prevalent drug users, immortal time and drug indications. We used renin angiotensin system (RAS) inhibitors and statins as reference drugs with proven efficacies in randomized clinical trials (RCTs) and examined their effectiveness in the prospective Hong Kong Diabetes Registry using adjustment methods proposed in the literature. Using time-dependent exposures to drug treatments yielded greatly inflated hazard ratios (HR) regarding the treatment effects of these drugs for cardiovascular disease (CVD) in type 2 diabetes. These errors were probably due to changing indications to use these drugs during follow up periods, especially at the time of drug commencement making time-dependent analysis extremely problematic. Using time-fixed analysis with exclusion of immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of RAS inhibitors for CVD was comparable to that in RCT. The result supported the use of the Registry for performing pharmacoepidemiological analysis which revealed an attenuated low low-density lipoprotein cholesterol related cancer risk with RAS inhibitors. On the other hand, time-fixed analysis with including immortal time and adjustment for confounders at baseline and/or during follow-up periods, the HR of statins for CVD was similar to that in the RCT. Our results highlight the complexity and difficulty in removing these biases. We call for validations of the methods to cope with immortal time and drug use indications before applying them to particular research questions, so to avoid making erroneous conclusions.
Insights
Observational studies on drug effectiveness face biases like immortal time. Time-fixed analysis, excluding immortal time, yielded reliable results for renin-angiotensin system inhibitors and statins in type 2 diabetes patients.
Area of Science:
- Pharmacoepidemiology
- Observational Research Methods
- Cardiovascular Disease in Diabetes
Background:
- Observational studies face biases (e.g., prevalent user bias, immortal time bias, indication bias) when assessing drug treatment effects.
- Randomized clinical trials (RCTs) confirm the efficacy of renin-angiotensin system (RAS) inhibitors and statins for cardiovascular disease (CVD).
- Type 2 diabetes patients are at high risk for CVD, making accurate assessment of medication effectiveness crucial.
Purpose of the Study:
- To evaluate the effectiveness of RAS inhibitors and statins in preventing CVD in type 2 diabetes using the Hong Kong Diabetes Registry.
- To investigate the impact of different analytical methods, particularly time-dependent versus time-fixed analyses, on estimating treatment effects.
- To identify and address biases inherent in observational studies, such as immortal time and indication bias.
Main Methods:
- Utilized the prospective Hong Kong Diabetes Registry for pharmacoepidemiological analysis.
- Compared time-dependent and time-fixed exposure analyses for RAS inhibitors and statins.
- Applied adjustment methods for confounders at baseline and during follow-up.
- Specifically addressed and attempted to mitigate immortal time bias and indication bias.
Main Results:
- Time-dependent analysis produced significantly inflated hazard ratios (HR) for both drug classes, likely due to indication changes during follow-up.
- Time-fixed analysis excluding immortal time yielded HR for RAS inhibitors comparable to RCT findings.
- Time-fixed analysis including immortal time yielded HR for statins similar to RCT findings.
- RAS inhibitors showed an attenuated low-density lipoprotein cholesterol-related cancer risk.
Conclusions:
- Time-dependent analysis is problematic for assessing drug effectiveness in observational studies due to changing indications.
- Time-fixed analysis, with careful handling of immortal time and confounders, can provide valid estimates of drug effectiveness.
- Validation of methods to address immortal time and indication bias is essential before applying them to specific research questions to prevent erroneous conclusions.
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