Chinese herbal medicine decreases incidence of hepatocellular carcinoma in diabetes mellitus patients with regular insulin management

Table 1 Baseline characteristics and comorbidities for herb nonusers and herb users in diabetes mellitus patients with regular insulin management in Taiwan between 2000 and 2017

Variables	DM patients with regular insulin use				SMD
	Herb non-users, n = 140547		Herb users, n = 46849
	n	%	n	%
Sex					0.014
Female	71872	51.14	24288	51.84
Male	68675	48.86	22561	48.16
Age, yr
20-40	11623	8.27	4160	8.88	0.022
40-60	55239	39.30	18684	39.88	0.012
> 60	73685	52.43	24005	51.24	0.024
Mean (SD)	59.47 (13.25)		59.11 (13.38)		0.027
Comorbidities
Hypertension	107255	76.31	35223	75.18	0.026
Coronary heart disease	60016	42.70	19862	42.40	0.006
Ischemic stroke	32117	22.85	10366	22.13	0.017
Hemorrhagic stroke	3418	2.43	1146	2.45	0.001
Hyperlipidemia	114028	81.13	37707	80.49	0.016
Renal insufficiency	24394	17.36	7823	16.70	0.018
Cirrhosis	4952	3.52	1847	3.94	0.022
Alcoholic liver damage	10313	7.34	3386	7.23	0.004
Nonalcoholic fatty liver disease	12398	8.82	4178	8.92	0.003
HBV infection	9560	6.80	3472	7.41	0.024
HCV infection	5770	4.11	2107	4.50	0.019
Medication
Lipid-lowering drug
Statin	8217	5.85	2766	5.90	0.003
Non-statin	13990	9.95	4299	9.18	0.026
Aspirin	4890	3.48	1559	3.33	0.008
HBV treatment	1947	1.39	696	1.49	0.008
HCV treatment	451	0.32	192	0.41	0.015
OAD
Biguanides	9142	6.50	3054	6.52	0.001
Sulfonamide	8855	6.30	2914	6.22	0.003
AGI	22759	16.19	7829	16.71	0.014
Thiazolidinediones	20022	14.25	7325	15.64	0.039
DPP4 inhibitors	14313	10.18	5648	12.06	0.060
GLP-1 receptor agonist	2982	2.12	1359	2.90	0.050
SGLT2 inhibitors	8376	5.96	3639	7.77	0.072
Glinide	25298	18.00	8886	18.97	0.025
Insulin dose (mg), mean (SD)	9449.92 (135.59)		8248.88 (115.34)		0.071

AGI: -Glucosidase inhibitors; DPP4: Dipeptidyl peptidase 4; GLP-1: Glucagon-like peptide-1; HBV: Hepatitis B virus; HCV: Hepatitis B virus; OAD: Oral antidiabetic agents; DM: Diabetes mellitus; SGLT2: Sodium-glucose co-transporter 2; SMD: Standard mean difference.

Table 2 Incidence rates of liver cancer, stratified by sex, age, comorbidities and medications, and comparing herb nonusers with herb users in diabetes mellitus patients with insulin management

Variables	HCC			cHR	95%CI	P value	aHR1	95%CI	P value
	n	PY	IR
Herb non-users	1487	771295	1.93	1.00	(Ref.)		1.00	(Ref.)
Herb users	639	309158	2.07	1.04	(0.94, 1.14)	0.461	0.88	(0.80, 0.97)b	0.001
Sex
Female	799	573926	1.39	1.00	(Ref.)		1.00	(Ref.)
Male	1327	506527	2.62	1.93	(1.77, 2.10)c	< 0.001	1.77	(1.62, 1.94)c	< 0.001
Age, yr
20-40	24	100697	0.24	1.00	(Ref.)		1.00	(Ref.)
40-60	777	469199	1.66	7.01	(4.67, 10.52)c	< 0.001	5.59	(3.71, 8.40)c	< 0.001
> 60	1325	510557	2.60	11.80	(7.90, 17.73)c	< 0.001	11.19	(7.43, 16.86)c	< 0.001
Comorbidities
Hypertension	1653	798612	2.07	1.29	(1.16, 1.43)c	< 0.001	1.10	(0.98, 1.23)	0.046
Coronary heart disease	954	443562	2.15	1.19	(1.09, 1.29)c	< 0.001	1.07	(0.97, 1.17)	0.052
Ischemic stroke	457	217351	2.10	1.14	(1.02, 1.26)a	0.016	0.98	(0.88, 1.09)	0.948
Hemorrhagic stroke	45	20459	2.20	1.21	(0.90, 1.62)	0.210	1.09	(0.81, 1.48)	0.400
Hyperlipidemia	1502	875554	1.72	0.57	(0.52, 0.62)c	< 0.001	0.67	(0.61, 0.74)c	< 0.001
Renal insufficiency	300	146465	2.05	1.15	(1.01, 1.30)a	0.030	0.92	(0.81, 1.04)	0.326
Cirrhosis	574	29944	19.17	14.20	(12.91, 15.65)c	< 0.001	4.28	(3.80, 4.82)c	< 0.001
Alcoholic liver damage	264	67522	3.91	2.24	(1.97, 2.55)c	< 0.001	1.08	(0.94, 1.25)	0.165
Nonalcoholic fatty liver disease	244	90700	2.69	1.42	(1.25, 1.63)c	< 0.001	1.24	(1.09, 1.42)b	< 0.001
HBV infection	647	68514	9.44	6.61	(6.03, 7.25)c	< 0.001	2.59	(2.32, 2.90)c	< 0.001
HCV infection	592	39215	15.10	10.60	(9.68, 11.71)c	< 0.001	4.56	(4.09, 5.08)c	< 0.001
Medication
Lipid-lowering drug
Statin	108	63427	1.70	0.85	(0.70, 1.04)	0.112	0.88	(0.70, 1.11)	0.313
Non-statin	169	106674	1.58	0.78	(0.67, 0.92)b	0.002	0.86	(0.73, 1.01)	0.124
Aspirin	64	35231	1.82	0.93	(0.73, 1.20)	0.590	0.75	(0.56, 1.01)	0.050
HBV treatment	324	13557	23.90	14.70	(13.05, 16.54)c	< 0.001	3.69	(3.21, 4.25)c	< 0.001
HCV treatment	71	3899	18.21	9.20	(7.26, 11.66)c	< 0.001	1.47	(1.14, 1.88)b	0.012
OAD
Biguanides	168	68930	2.44	1.27	(1.08, 1.48)b	0.003	1.16	(0.84, 1.61)	0.368
Sulfonamide	166	66481	2.50	1.30	(1.11, 1.52)b	0.001	1.08	(0.78, 1.50)	0.676
AGI	379	175908	2.15	1.12	(1.00, 1.25)	0.052	0.93	(0.83, 1.06)	0.475
Thiazolidinediones	344	161421	2.13	1.09	(0.97, 1.23)	0.134	1.07	(0.95, 1.21)	0.197
DPP4 inhibitors	289	119437	2.42	1.26	(1.11, 1.42)c	< 0.001	1.15	(0.99, 1.32)	0.085
GLP-1 receptor agonist	14	27416	0.51	0.25	(0.15, 0.42)c	< 0.001	0.40	(0.24, 0.68)c	< 0.001
SGLT2 inhibitors	88	76062	1.16	0.56	(0.45, 0.69)c	< 0.001	0.79	(0.64, 0.98)a	0.010
Glinide	418	195582	2.14	1.11	(1.00, 1.24)	0.051	0.93	(0.82, 1.04)	0.222

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

¹adjusted by variables in Table 1.

AGI: -Glucosidase inhibitors; aHR: Adjusted hazard ratio; cHR: Crude hazard ratio; DPP4: Dipeptidyl peptidase 4; GLP-1: Glucagon-like peptide-1; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis B virus; IR: Incidence rate per 1000 person-years; N: Number of events; OAD: Oral antidiabetic agents; PY: Person-years; SGLT2: Sodium-glucose co-transporter 2.

Table 3 Risk of hepatocellular carcinoma stratified by the duration of herb use compared with nonherb use

Variables	HCC			cHR	95%CI	P value	aHR1	95%CI	P value
	n	PY	IR
Herb non-users	1487	771295	1.93	1.00	(Ref.)		1.00	(Ref.)
Herb users
< 1 yr	181	89349	2.03	1.04	(0.89, 1.22)	0.610	0.88	(0.76, 1.03)	0.074
1-2.9 yr	171	81924	2.09	1.05	(0.9, 1.24)	0.514	0.92	(0.78, 1.08)	0.169
3-4.9 yr	87	39932	2.18	1.09	(0.88, 1.35)	0.450	0.94	(0.76, 1.17)	0.436
≥ 5 yr	200	97953	2.04	0.99	(0.86, 1.15)	0.943	0.82	(0.71, 0.95)a	0.003

^aP < 0.05.

¹adjusted by variables in Table 1.

AHR: Adjusted hazard ratio; cHR: Crude hazard ratio; HCC: Hepatocellular carcinoma; IR: Incidence rate pre 1000 person-years; n: Number of events; PY: Person-years.

Table 4 Possible pharmacological effects of the ingredients in the top 10 herbs and formulas

	Possible pharmacological effects of the ingredients	Average daily dose (g)	No. of persons-dosage	Frequency (%)	aHR1	95%CI	P value
Single Herbs: Pin-yin name/Latin name					1.00	(Ref.)
Da Huang/Rheum palmatum L	Reduces oxidative stress, inhibits β-cell apoptosis and improves β-cell function[28]; Activates AMP-Activated Protein Kinase and improves glucose tolerance[37]; Ameliorates insulin resistance via reducing FATP1-mediated skeletal muscle lipid accumulation[38]; Inhibits HCC via inhibiting STAT 3 signaling pathway[39]	1	1060286	109102 (15.25)	0.83	(0.7, 0.98)a	0.013
Dan Shen/Salvia miltiorrhiza Bunge	Reduces oxidative stress and inhibits apoptosis and inflammation via the regulation of Wnt/β-catenin, TSP-1/TGF-β1/STAT3, JNK/PI3K/Akt, TGF-β1/NF-κB, AMPK/ACC, signaling pathways in DM model[40]. Inhibits IGF-1[31,32]. Inhibits HCC via modulating PI3K/Akt, MAPK and JAK/STAT3 signaling pathways[41]	1.9	2162061	107301 (15.00)	0.87	(0.76, 1.00)a	0.0123
Huang Qi/Astragalus propinquus	Protects pancreatic β cells from apoptotic death[29]. Regulates resistin (an insulin-resistance protein)[29]. Ameliorates insulin resistance[42]. Induces apoptosis in HCC via decreasing the expression of Notch 1[43]. Inhibits HCC via repression of M2 polarization of tumor-associated macrophages[44]	2.2	2188885	94799 (13.25)	0.87	(0.75, 1.01)	0.0183
Tian Hua Fen/Trichosanthes kirilowii Maxim	Ameliorates insulin resistance via decreasing the expression of PTGS2, NF-κB, JNK, and AKT[45]. Stimulates insulin receptor kinase activity and enhances glucose clearance[46]. Inhibits HCC cell proliferation via blocking PKM2-dependent glycolysis[47]	2.2	1787396	77376 (10.81)	0.83	(0.71, 0.97)a	0.0027
Yan Hu Suo/Corydalis yanhusuo	Induces autophagy in HCC via activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascade and impairing the ERK/AKT signaling pathway[26]	1.8	925275	62808 (8.78)	0.89	(0.77, 1.03)	0.0496
Ge Gen/Pueraria montana var. lobata	Elevates insulin expression and enhances insulin sensitivity index[48]. Ameliorates insulin resistance[49]. Inhibits HCC invasion and metastasis via miR-21-mediated PTEN/AKT signaling pathway[50]	1.8	1032475	62061 (8.67)	0.86	(0.73, 1.00)	0.0128
Xuan Shen/Scrophularia ningpoensis Hemsl	Improves insulin sensitivity via AMPK-mediated NLRP3 inflammasome inhibition[51,52]	2.2	1099700	52418 (7.33)	0.79	(0.67, 0.94)b	0.002
Huang Chin/Scutellaria baicalensis Georgi	Regulates IGF-1R/AKT signaling pathway[53]. Ameliorates insulin resistance via inhibiting macrophage-mediated inflammation[54]. Elevates AMPK expression[34]. Modulates gut microbiota[34]. Inhibits HCC via affecting p53 signal pathway, MAPK signal pathway, apoptosis pathway, T cell receptor pathway, and macrophage-mediated tumor immunity[55]	1.9	852156	50546 (7.06)	0.93	(0.80, 1.09)	0.2098
Mai Men Dong/Ophiopogon japonicus (Thunb.) Ker Gawl	Ameliorates insulin resistance via InsR/IRS-1/PI3K/Akt/GSK-3/Glut-4 signalling pathway[56]. Modulates gut microbiota[35]. Inhibits HCC via downregulating PTP1B expression, thereby inactivating the PI3K/AKT pathway and activating the AMPK pathway[57]	2.3	1064080	49974 (6.98)	0.88	(0.75, 1.04)	0.0429
Hou Po/Magnolia officinalis	Decreases IGF-1 and IGFBP-5[33]. Protects pancreatic β-cells[30]. Inhibits HCC via AKT inhibition[58]	2.1	946453	49148 (6.87)	0.84	(0.70, 1.01)	0.0232
Herbal Formula: Pin-yin name/Latin name
Ji Sheng Shen Qi Wan	Ameliorates insulin resistance[59]. Inhibits HCC development[60]	6.9	6239325	87687 (15.62)	0.82	(0.71, 0.96)a	0.0026
Liu Wei Di Huang Wan	Ameliorates insulin resistance via antioxidative effect and supressing inflammation[61]. Induces apoptosis in HCC[62]	8.6	6803688	78029 (13.90)	0.83	(0.72, 0.96)a	0.0022
Shu Jing Huo Xie Tang	Ameliorates insulin resistance[63]. Inhibits HCC via regulating iron metabolism[64]	7.8	3550686	56106 (10.00)	0.86	(0.74, 1.00)a	0.0152
Xue Fu Zhu Yu Tang	Ameliorates insulin resistance, inflammation and oxidative stress[65]. Inhibits angiogenesis in HCC via blocking ERK/MAPK and NF-κB signalling pathway[66]	6.4	3466030	55091 (9.81)	0.80	(0.68, 0.94)b	0.0025
Jia Wei Xiao Yao San	Ameliorates insulin resistance[67]. Induces apoptosis in HCC[68]. Inhibits invasion and metastasis in HCC[69]	7.7	3823372	51350 (9.15)	0.92	(0.78, 1.08)	0.1529
Qi Ju Di Huang Wan	Ameliorates insulin resistance[70]. Modulates gut microbiota[71]. Inhibits HCC via inducing p53-mediated apoptosis and inhibiting proliferation[62]	7.7	4309801	50271 (8.96)	0.83	(0.68, 1.00)a	0.0219
Ma Zi Ren Wan	Reduces oxidative stress, inhibits β-cell apoptosis and improves β-cell function[28]. Inhibits HCC via AKT inhibition[58]	5	2609093	50100 (8.93)	0.87	(0.70, 1.08)	0.1288
Zhi Bai Di Huang Wan	Ameliorates insulin resistance via IRS-1/PI3K/AKT pathway[72]. Modulates gut microbiota[36]. Induces autophagy and apoptosis in HCC[27]	7.1	3557458	46284 (8.25)	1.05	(0.89, 1.23)	0.9271
Bai Hu Jia Ren Shen Tang	Inhibits IGF-1R/Akt pathway[73]. Ameliorates insulin resistance[74,75]. Induces apoptosis in HCC[76]	8.4	4051247	43451 (7.74)	0.79	(0.65, 0.96)a	0.0043
Zhi Gan Cao Tang	Decreases blood glucose[77]; Ameliorates insulin resistance[77]; Induces apoptosis and inhibits proliferation in HCC via blocking PI3K/AKT signal pathway[78]	5.9	2423303	42951 (7.65)	0.77	(0.63, 0.93)b	0.0042

^aP < 0.05.

^bP < 0.01.

¹adjusted by variables in Table 1.

ACC: Acetyl-CoA carboxylase; aHR: Adjusted hazard ratio; AMP: Adenosine monophosphate; AMPK: Adenosine monophosphate-activated protein kinase; ERK: Extracellular signal-regulated kinase; FATP1: Fatty acid transport protein 1; GLUT-4: Glucose transporter type 4; IGF-1: Insulin-like growth factor 1; IGFBP-5: Insulin-like growth factor binding protein-5; IRS-1: Insulin receptor substrate 1; JAK: Janus-activated kinase; JNK: C-Jun N-terminal kinases; MAPK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; Notch 1: Neurogenic locus notch homolog protein 1; PI3K: Phosphatidylinositol-3-kinase; PKM2: Pyruvate kinase M2; PTEN: Phosphatase and tensin homolog; PTGS2: Prostaglandin-endoperoxide synthase 2; PTP1B: Protein-tyrosine phosphatase 1B; ROS: Reactive oxygen species; STAT3: Signal transducer and activator of transcription 3 ; TGF-β1: Transforming growth factor beta-1; TSP1: Thrombospondin-1; ULK1: Unc-51-like kinase 1; HCC: Hepatocellular carcinoma; DM: Diabetes mellitus.