Effects of metformin and donepezil on the prevention of doxorubicin-induced cardiotoxicity in breast cancer: a randomized controlled trial

Abstract

Doxorubicin (DOX) causes deleterious cardiotoxicity. We aimed to investigate the protective roles of metformin and donepezil against DOX-induced cardiotoxicity. In this randomized-controlled trial, 143 female breast cancer patients were enrolled. Metformin (n = 43), donepezil (n = 52), or placebo (n = 48) were prescribed during DOX treatment. The primary endpoint was a proportion of patients with high sensitivity troponin-I (hsTnI) more than the 99th percentile value (> 15.6 ng/L) after DOX treatment. The secondary outcomes were the changes in the hsTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), global longitudinal strain (GLS) and peripheral blood mononuclear cells analysis for mitochondrial respiration. Baseline characteristics were similar between the groups. The primary endpoint occurred in 58.54% of metformin group, 76.92% in donepezil group, and 69.77% in placebo group (p = 0.215). The level of hsTnI increased after receiving DOX with subsequent decline in LVEF and GLS. Metformin and donepezil did not attenuate hsTnI elevation, LVEF or GLS reduction. There was no significant change in NT-proBNP level. Mitochondrial respiratory dysfunction was observed in the placebo and donepezil groups. However, metformin preserved mitochondrial respiration during DOX therapy. In conclusion, co-treatment with metformin or donepezil did not prevent myocardial injury. Metformin had a favorable mitochondrial outcome and warranted future studies.

Figure 1

Trial protocol. Baseline evaluation included clinical data collection, echocardiogram, and blood test for biomarkers and PBMCs analysis. Blood samples were obtained at baseline, at 2nd cycle, 4th cycle, 2-week post-DOX and every 3-month until 12-month post-DOX. Echocardiogram was repeated at 2-week post-DOX and every 3-month until 12-month post-DOX. PBMCs peripheral blood mononuclear cells, DOX doxorubicin, C cycle.

Figure 2

Consort diagram. Patients were screened for eligibility then were randomized to metformin, donepezil, or placebo group. Patients who had primary outcome data were included in the modified intention-to-treat analysis. mITT modified intention-to-treat.

Figure 3

Bar graph of primary outcome. Proportion of patients with hsTnI more than the 99th percentile cut-off value (> 15.6 ng/L) was presented. There was no significant different in the proportion of patients with hsTnI more than the cut-off value between placebo, metformin, and donepezil. hsTnI high sensitivity troponin-I.

Figure 4

Predictive margins of hsTnI, NT-proBNP, LVEF, and GLS during the follow-up period between metformin, donepezil, and placebo. (A) hsTnI; Treatment with doxorubicin led to an increase in hsTnI level at 2-week with a gradual reduction at 3-month (p-value for quadratic time interaction effects < 0.001 in placebo arm). The rate of hsTnI changes were not different in patients taking metformin (p = 0.919) and donepezil (p = 0.351) when compared to placebo. (B) NT-proBNP; There was no significant change in the level of NT-proBNP during treatment with doxorubicin (p-value for quadratic time interaction effects = 0.340 in placebo arm). When compared to placebo, taking metformin and donepezil had similar changes in NT-proBNP level (metformin; p = 0.919 and donepezil; p = 0.302). (C) LVEF; There was a gradual reduction in LVEF overtime (p-value for linear time interaction effects < 0.001 in placebo arm). The rate of LVEF reduction was not statistically difference in patients taking metformin (p = 0.523) and donepezil (p = 0.199) when compared to placebo. (D) GLS; The level of GLS decreased after doxorubicin (p-value for linear time interaction effects < 0.001 in placebo arm). When compared to placebo, there was no significant difference in the rate of GLS reduction in patients taking metformin (p = 0.961) and donepezil (p = 0.176). hsTnI high sensitivity troponin-I, NT-proBNP N-terminal pro B-type natriuretic peptide, LVEF left ventricular ejection fraction, GLS global longitudinal strain, DOX doxorubicin.

Figure 5

PBMCs analysis of apoptotic cells, live cells and mitochondrial respiration at 2nd cycle and 4th cycle of doxorubicin between metformin, donepezil, and placebo. (A) Number of apoptotic cells. (B) Number of live cells. (C) Level of ATP. (D) Level of maximal mitochondrial respiration. (E) Level of spare respiratory capacity. After DOX treatment, the number of apoptotic cells and live cells were comparable across all groups. ATP levels were not different across all groups. There was a significant reduction in maximal mitochondrial respiration and the spare respiratory capacity level during doxorubicin treatment in placebo and donepezil groups. Metformin preserved maximal mitochondrial respiration and the spare respiratory during doxorubicin treatment. PBMCs peripheral blood mononuclear cells, DOX doxorubicin, ATP adenosine triphosphate.