To our knowledge, this is the first study investigating the role of metformin in Nordic lung cancer patient population treated with EGFR TKIs. Concurrent metformin use with EGFR TKIs showed a non-significant trend for inferior survival in the EGFR mutant type cohort. In addition, metformin use associated significantly with a shorter EGFR TKI treatment duration. The use of other diabetes medication than metformin did not associate with survival of the patients or EGFR TKI treatment duration.
Preclinical studies have suggested that many of the anti-tumoral effects of metformin may require high doses but especially in combination with other cancer treatments metformin could provide efficacy and tolerability in conventional doses (Pollak 2014; Levy and Doyen 2018). Diarrhea is a common side effect of both metformin and EGFR TKIs, and it is possible that especially high doses of metformin may increase the side effects leading to dose reductions or interruptions of EGFR TKI treatment and subsequently impairing the efficacy of the treatment. In our study, metformin use associated with a shorter EGFR TKI treatment duration which likely reflects shorter PFS but may also indicate higher incidence of side effects leading to treatment discontinuation. Nevertheless, no significant correlations between metformin use and EGFR TKI dose reductions or treatment breaks were found but it should be noted that the number of patients in these subgroup analyses were small. In the randomized study showing survival benefit with combination of metformin and EGFR TKI (Arrieta et al. 2019), the daily dose of metformin was 1000 mg, and the combination did not result in increased toxicity. On the contrary, in the trial showing no survival benefit (Li et al. 2019), metformin dose was gradually increased up to 2000 mg daily and both diarrhea and grade 3–4 side effects occurred more commonly in the metformin group. Also, early safety results of METAL trial investigating the combination of metformin and erlotinib in the second line treatment of EGFR wt NSCLC, showed grade 3 gastrointestinal toxicity in 2/3 patients treated with 2000 mg metformin per day, whereas daily dose 1500 mg of metformin combined with erlotinib was quite well tolerated (Morgillo et al. 2017). In the present study, information of metformin dose was unavailable but based on the previous data, metformin dose may be important in the treatment combination with EGFR TKIs.
The effects of metformin in NSCLC may also be influenced by ethnicity of the patients. In a recent meta-analysis (Xiao et al. 2020), lung cancer incidence was reduced in T2D patients treated with metformin compared to those without only in studies including Asian patients, but not among European patients. Also, survival of lung cancer patients with T2D and metformin medication was better compared to those without metformin, and even though this association was found in both Asian and non-Asian populations, the possible protective effect of metformin seemed to be greater among the Asian patients (HR 0.57 and HR 0.79, respectively) (Xiao et al. 2020). The previous retrospective studies showing improved survival among NSCLC patients with metformin and EGFR TKIs are East Asian and most of these studies included only patients with EGFR mutant NSCLC (Chen et al. 2015; Han et al. 2021). On the contrary, in the present study with Nordic patients, metformin use did not statistically significantly correlate with OS and there was even a trend for shorter survival with metformin. In our study, EGFR mutation status was not known but we created an EGFR mutant type cohort based on the reimbursement criteria and erlotinib treatment duration and found that the results were similar in the whole patient cohort and in the EGFR mutant type cohort. It is well known that the incidence of activating EGFR mutations in NSCLC is much higher in East Asian patient population than in Caucasian (Zhang, Y. L. et al. 2016). In addition, the effects of metformin may vary between different ethnicities due to variation in genes involved in metformin’s mechanisms of action (Zhou et al. 2015). For example, LKB1/STK11 gene, which is important in the activation of AMPK pathway and for the functions of metformin, is mutated more frequently in NSCLC among Caucasian than Asian patients (Koivunen et al. 2008). LKB1 deficiency may alter the anti-tumoral functions of metformin although preclinical studies suggest also mechanisms independent of LKB1 (Choi and Park 2013; Fatehi Hassanabad and MacQueen 2021). In a post hoc analysis by Arrieta et al, combining metformin with EGFR TKIs seemed to improve OS only among patients expressing LKB1 (Arrieta et al. 2019).
Other factors that could explain the varying results in different populations include comorbidities and smoking status of the patients. Smoking increases the risk for developing both T2D and its complications (Zhu et al. 2017), and NSCLC with smoking associates with worse survival (Tammemagi et al. 2004). Comorbidities associated with T2D include cardiovascular diseases and diabetic nephropathy and neuropathy (Zheng et al. 2018). Comorbidities influence on all-cause mortality and therefore lung cancer specific survival endpoints might provide different results than OS. Comorbidities may also impair administration of subsequent cancer treatments, in EGFR mutant NSCLC especially platinum-based chemotherapy due to its nephrotoxicity and neurotoxicity. Nevertheless, in the present study, among patients with other diabetes medication than metformin, survival and duration of EGFR TKI treatment were similar compared to those without any diabetes medications. It is possible that T2D medication used reflects some characteristics of the patient populations, e.g., it has been suggested that metabolic dysfunction may be more difficult among T2D patients whose medication includes metformin whereas metformin monotherapy may associate with a better general health status (Fatehi Hassanabad and MacQueen 2021). It is also important to notice that the metabolic state is different among T2D patients and patients without T2D, and also the effects of metformin in cancer treatment may be different in these patient populations.
The strengths of our study include a large nationwide patient material which was collected using reliable nationwide registries and combining the data with personal identity codes. The study has also some limitations. Several possible confounding factors for which the data was unavailable, e.g., comorbidities, smoking status, and metformin doses used, may have influenced on the associations found in this study. In addition, we had no information on possible hospital treatment periods of the patients and medication received during hospitalization. Also, even though the patient material is quite large, the number of patients in some of the subgroup analyses remained rather small. Furthermore, the results cannot be extrapolated to non-diabetic patients as the effects of metformin may be different in patients without diabetes.
To conclude, in this material of Finnish NSCLC patients treated with EGFR TKIs, metformin use associated with a shorter EGFR TKI treatment duration and also a non-significant trend for inferior survival was found. Differences in the patient materials, e.g., ethnicity, differences in mutation profiles, comorbidities, smoking status and metformin doses used, may explain the variance in the results of retrospective studies investigating the role of metformin in EGFR TKI treatment responses.