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. 2023 Sep 1;34(5):690-699.
doi: 10.1097/EDE.0000000000001626. Epub 2023 May 23.

Evaluating Metformin Strategies for Cancer Prevention: A Target Trial Emulation Using Electronic Health Records

Barbra A Dickerman  1   2 , Xabier García-Albéniz  1   2   3 , Roger W Logan  1   2 , Spiros Denaxas  4   5   6 , Miguel A Hernán  1   2   7
Affiliations

Evaluating Metformin Strategies for Cancer Prevention: A Target Trial Emulation Using Electronic Health Records

Barbra A Dickerman et al. Epidemiology. .

Abstract

Background: Metformin users appear to have a substantially lower risk of cancer than nonusers in many observational studies. These inverse associations may be explained by common flaws in observational analyses that can be avoided by explicitly emulating a target trial.

Methods: We emulated target trials of metformin therapy and cancer risk using population-based linked electronic health records from the UK (2009-2016). We included individuals with diabetes, no history of cancer, no recent prescription for metformin or other glucose-lowering medication, and hemoglobin A1c (HbA1c) <64 mmol/mol (<8.0%). Outcomes included total cancer and 4 site-specific cancers (breast, colorectal, lung, and prostate). We estimated risks using pooled logistic regression with adjustment for risk factors via inverse-probability weighting. We emulated a second target trial among individuals regardless of diabetes status. We compared our estimates with those obtained using previously applied analytic approaches.

Results: Among individuals with diabetes, the estimated 6-year risk differences (metformin - no metformin) were -0.2% (95% CI = -1.6%, 1.3%) in the intention-to-treat analysis and 0.0% (95% CI = -2.1%, 2.3%) in the per-protocol analysis. The corresponding estimates for all site-specific cancers were close to zero. Among individuals regardless of diabetes status, these estimates were also close to zero and more precise. By contrast, previous analytic approaches yielded estimates that appeared strongly protective.

Conclusions: Our findings are consistent with the hypothesis that metformin therapy does not meaningfully influence cancer incidence. The findings highlight the importance of explicitly emulating a target trial to reduce bias in the effect estimates derived from observational analyses.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

Figure 1.
Figure 1.
Selection and flow of eligible individuals when emulating a target trial of metformin therapy and cancer risk (a) among individuals regardless of diabetes status and (b) among individuals with diabetes, 2009–2016. Panel B shows the flow of individuals after applying the additional eligibility criterion of type 2 diabetes. Numbers in parentheses represent unique individuals in each group. Counts of initiator and non-initiator individuals do not sum to the total number of eligible individuals because some eligible individuals contributed to both groups in different nested trials.
Figure 1.
Figure 1.
Selection and flow of eligible individuals when emulating a target trial of metformin therapy and cancer risk (a) among individuals regardless of diabetes status and (b) among individuals with diabetes, 2009–2016. Panel B shows the flow of individuals after applying the additional eligibility criterion of type 2 diabetes. Numbers in parentheses represent unique individuals in each group. Counts of initiator and non-initiator individuals do not sum to the total number of eligible individuals because some eligible individuals contributed to both groups in different nested trials.
Figure 2.
Figure 2.
Estimated risk of cancer by metformin therapy among individuals with diabetes (observational analogue to an intention-to-treat [a] and per-protocol [b] analysis), and among individuals regardless of diabetes status (observational analogue to an intention-to-treat [c] and per-protocol [d] analysis), using linked electronic health records from Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics, 2009–2016. Shaded areas represent pointwise 95% confidence intervals.
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References

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