Prognostic roles of diabetes mellitus and hypertension in advanced hepatocellular carcinoma treated with sorafenib

Abstract

Background & aims: It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib.

Methods: From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups.

Results: DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026).

Conclusions: Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib.

Fig 1. Overall survival (OS) and progression-free survival (PFS) curves of control, DM-only, HTN-only and DM+HTN groups.

(A) The median OS was 7.70±0.58, 11.83±1.38, 8.80±0.85 and 11.43±2.24 months in control, DM-only, HTN-only and DM+HTN groups respectively. In comparison with control group, both DM-only and DM+HTN groups had better OS (p = 0.003 and p = 0.008 respectively) while HTN-only group showed an insignificant OS difference (p = 0.111). (B) The median PFS was 3.70±0.37, 6.83±1.70, 4.43±0.80 and 6.33±1.78 months in control, DM-only, HTN-only and DM+HTN groups respectively. In comparison with control group, both DM-only and DM+HTN groups had better PFS (p = 0.008 and p = 0.004 respectively) while HTN-only group showed an insignificant PFS difference (p = 0.094). *Log-rank test: A p-value below 0.05 was considered statistically significant.

Fig 2. Overall survival (OS) and progression-free survival (PFS) curves of control, metformin, non-metformin OHA and RI/NPH groups.

(A) The median OS was 7.70±0.58, 12.60±2.17, 10.80±1.20 and 15.20±4.45 months in control, metformin, non-metformin OHA and RI/NPH groups respectively. In comparison with control group, metformin, non-metformin OHA and RI/NPH groups significantly presented better OS (p = 0.011, p = 0.016 and p = 0.026 respectively). (B) The median PFS was 3.70±0.37, 8.17±1.53, 5.67±1.57 and 7.17±2.04 months in control, metformin, non-metformin OHA and RI/NPH groups respectively. Compared with control group, metformin, non-metformin OHA and RI/NPH groups significantly presented better PFS (p = 0.009, p = 0.017 and p = 0.039 respectively). *Log-rank test: A p-value below 0.05 was considered statistically significant.

Fig 3. Anti-tumor mechanisms of sorafenib, metformin and protamine: A review of previous studies [, , , –, –66].

Abbreviation: VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PKC, protein kinase C; IGF-1, insulin-like growth factor 1; IGF-1R, IGF-1 receptor; PI3K, phosphoinositide 3-kinase; LKB1, liver kinase B1; AMPK, adenosine 5’-monophosphate-activated protein kinase; TSC1/2, tuberous sclerosis proteins 1 and 2 complex; mTOR, mammalian Target of Rapamycin.