Copyright ©The Author(s) 2022.
World J Gastroenterol. Feb 28, 2022; 28(8): 775-793
Published online Feb 28, 2022. doi: 10.3748/wjg.v28.i8.775
Table 1 Clinical differences between hepatogenous diabetes and type 2 diabetes mellitus
Hepatogenous diabetes
Type 2 diabetes mellitus
OnsetAfter cirrhosis onsetBefore cirrhosis onset
Clinical presentationNormal FPG and HbA1c; Abnormal OGTTIncreased FPG and HbA1c
Metabolic risk FactorsLess frequentMore frequent
Vascular complicationsLess frequentMore frequent
Liver complicationMore frequentLess frequent
Effect of OLTReversal or improvementNon modification
MortalityMore than non-diabeticsMore than non-diabetics
Table 2 Studies depicting implications of diabetes on complications of patients with liver cirrhosis
Population, n
Sigal et al[59], United States, 2006Cross-sectional65 HCV-LC; 31% diabeticsHE and severe HE was higher in diabetics. DM was independent risk factor for HESmall sample size. HE was not standardized
Tietge et al[81], Germany, 2004 Case-control, prospective100 LC, 35% diabetics, 62 post-LTPre-LT IGT or DM was the major risk factor for post-LT DMOnly 31 patients were prospectively evaluated
Takahashi et al[77], Japan, 2011 Prospective203 CHCTwo hours post-challenge hyperglycaemia associated with HCCPatients received IFN
Jeon et al[64], Republic of Korea, 2013Prospective195 LC, 55.4% with HDHD correlated with HVPG, VH and large varices. Most patients with VH within 6 mo, had post-prandial hyperglycaemiaRisk stratification of varices and prophylaxis for VH were not taken into account
Zheng et al[75], China, 2013 Retrospective case-control1568 CLD, 852 with HCCDM associated with increased risk of HCC regardless of cirrhosis. Synergistic interaction between DM and HBV for HCCHospital based study. Temporal relationship between DM and HCC could not be established
Yang et al[63], Taiwan, 2014Prospective146 LC, 25% diabeticsDM was predictor of VH. Patients with VH had worse glycaemic control (HBA1c ≥ 7%)DM associated with decompensated cirrhosis, renal disease and VH
Jepsen et al[60], Denmark, 2015Database from randomized trials863 LC, 22% diabeticsDiabetics had more episodes of first-time overt HE in one year. First-time HE progression beyond grade 2 higher in diabeticsDiagnosis of DM was not standardized. Vaptan could be a confounder
Yang et al[73], United States, 2016Retrospective739 LC, 34% diabeticsDM increased the risk of HCC in patients with non-HCV cirrhosisSingle-centre probably with referral bias
Tergast et al[69], Germany, 2018Prospective case-control475 decompensated LC, 118 diabeticsDM increased risk for SBP and was higher with HbA1c values ≥ 6.4%Criteria for diagnosis of DM not clearly defined
Wang et al[65], China, 2020Retrospective207 LC, 137 diabetics; 68 had HDRebleeding rate following EST or EVL higher in diabetics, including HD at 1, 3, and 6 moRelatively small number of patients with shorter follow-up
Labenz et al[61], Germany, 2020Prospective240 LC, 27% diabeticsDM associated with covert HE at inclusion and follow-up. The risk of covert HE and overt HE was more pronounced when HbA1c ≥ 6.5%Spontaneous porto-systemic shunts, GIB, drugs were not taken into account
Table 3 Prospective and retrospective studies depicting implications of diabetes on mortality of patients with liver cirrhosis
Bianchi et al[3], Italy, 1994Retro-prospective354 LC, 98 with DM5-yr survival rate: DM: 41%, non-DM 56%Diagnosis of DM not standardized
Holstein et al[4], Germany, 2002Prospective52 LC, 71% with DM5.6-yr survival rate after diagnosis of LC: 51% of HD patients. 80% of deaths were cirrhosis-related causesSmall sample size. Comparative outcome data of non-DM patients not available
Moreau et al[79], France, 2004Prospective75 LC and refractory ascitesDM, older age, and HCC were predictors of poor survival. The survival rate of patients without DM was higherOGTT was not used to diagnose DM
Nishida et al[48], Japan, 2006Prospective56 LC, 38% diabeticsThe 5-yr survival rate was 94%, 68% and 56%, with NGT, IGT and DM, respectivelySmall sample size
Quintana et al[80], México, 2011Prospective110 compensated LC, 45% diabetics2.5 yr cumulated survival years: DM: 48 vs non-DM: 69% (P < 0.05). DM was not predictor of deathMaybe DM death- prediction capability was masked by Child-Pugh C score
García-Compeán et al[78], México, 2014Prospective100 compensated LC and normal FPGPatients with IGT + DM had lower 5-yr cumulated survival rate. Death causes in 90 % were cirrhosis relatedSmall sample size
Elkrief et al[40], Canada, 2014 Retrospective348 HCV-LC, 40% diabeticsDM significantly associated with ascites, renal dysfunction, infections, HCC and mortality during the follow-up periodRetrospective. Potential errors in the diagnosis of DM
Khafaga et al[67], Egypt, 2015Case-control60 LC, 50% diabeticsDiabetics had higher incidence of VH, hospitalizations, HE and mortality rateSmall sample size
Qi et al[66], China, 2015Retrospective145 LC, 29 diabeticsIn-hospital mortality was higher in diabeticsSmall number of patients
Hoehn RS et al[82], United States, 2015Retrospective12442 pos- LT, 24% with DMDiabetic recipients had longer hospitalization, higher peri-transplant mortality and 30-d readmission ratesMore diabetic patients were on haemodialysis and received allografts from older donors
Rosenblatt et al[70], United States, 2021Retrospective906559 LC with DM, and 109694 uncontrolled DMUncontrolled DM associated with increased risk of bacterial infection and increased risk of death in elderly patientsSubject to administrative error. Criteria for DM was not standardized
Table 4 Kinetics, metabolism and excretion of the currently available anti-hyperglycaemic drugs[102]
Half life
Short-acting insulins
Human140 minProteolytic degradation
Lyspro80 minProteolytic degradation
Aspart80 minProteolytic degradation
Glulisine80 minProteolytic degradation
Long-acting insulins
Human-NPH6.6 hProteolytic degradation
Glargine12.1 hProteolytic degradation
Levemir5-7 hProteolytic degradation
Degludec25 hProteolytic degradation
Glargine-30019 hProteolytic degradation
Glibenclamide10 hLiver 100%Urines 50%; feces 50%1
Glimepiride9 hLiver 100%Urines 60%; feces 40%1
Gliclazide10-11 hLiver 100%Urines 80%; feces 20%
Glipizide2-5 hLiver 90%Urines mainly
Repaglinide1 hLiver 100%Bile 92%; urines 8%
Metformin1.5-3 hNot metabolisedUrines 100%
Pioglitazone3.7 hLiver 100%Feces 55%; urines 45%
DPP-4 inhibitors
Sitagliptin8–24 hLimitedUrines
Vildagliptin1.5–4.5 hLimitedUrines
Saxagliptin2–4 hModerateUrines
Linagliptin10–40 hExtensiveFeces
Alogliptin12–21 hLimitedUrines
Exenatide2.4 hProteolytic degradationRenal
Liraglutide13 hProteolytic degradationNo specific organ
Lixisenatide3 hProteolytic degradationRenal
Exenatide LAR5-6 dProteolytic degradationRenal
Dulaglutide5 dProteolytic degradationNo specific organ
Semaglutide7 dProteolytic degradationNo specific organ
α-glicosidase inhibitors
Acarbose4 hIntestineUrines 35%; feces 65%
SGLT2 inhibitors
Dapaglifozin10-13 hGlucuronidationUrines 33%; feces 42%
Canaglifozin12.9 hGlucuronidationUrines 75%; feces 21%
Empaglifozin12.4 hGlucuronidationUrines 54%; feces 41%
Ertugliflozin17 hGlucuronidationUrines 50%; feces 41%
Table 5 Use of anti-hyperglycaemic agents in cirrhotic individuals according to Child-Pugh class[102]
Child-Pugh class A
Child-Pugh class B
Child-Pugh class C
Short-acting insulins
HumanAllowedAllowedAllowed (dose reduction)
Long-acting insulins
Human-NPHAllowedAllowedAllowed (dose reduction)
GlibenclamideNot recommendedContraindicatedContraindicated
GlimepirideAllowed (caution)Not recommendedContraindicated
GliclazideAllowed (caution)Not recommendedContraindicated
GlipizideAllowed (caution)Not recommendedContraindicated
RepaglinideAllowed (caution)Not recommendedContraindicated
MetforminAllowedAllowed (dose reduction)Contraindicated
DPP-4 inhibitors
Exenatide LARAllowedAllowedContraindicated
α-glicosidase inhibitors
AcarboseAllowedAllowed (caution)Contraindicated
SGLT2 inhibitors