Clinical implications of diabetes in chronic liver disease: Diagnosis, outcomes and management, current and future perspectives

Table 1 Clinical differences between hepatogenous diabetes and type 2 diabetes mellitus

Variables	Hepatogenous diabetes	Type 2 diabetes mellitus
Onset	After cirrhosis onset	Before cirrhosis onset
Clinical presentation	Normal FPG and HbA1c; Abnormal OGTT	Increased FPG and HbA1c
Metabolic risk Factors	Less frequent	More frequent
Vascular complications	Less frequent	More frequent
Liver complication	More frequent	Less frequent
Effect of OLT	Reversal or improvement	Non modification
Mortality	More than non-diabetics	More than non-diabetics

FPG: Fasting plasma glucose; OGTT: Oral glucose tolerance test; OLT: Orthotopic liver transplantation; HbA1c: Glycated hemoglobin.

Table 2 Studies depicting implications of diabetes on complications of patients with liver cirrhosis

Ref.	Design	Population, n	Outcomes	Limitations
Sigal et al[59], United States, 2006	Cross-sectional	65 HCV-LC; 31% diabetics	HE and severe HE was higher in diabetics. DM was independent risk factor for HE	Small sample size. HE was not standardized
Tietge et al[81], Germany, 2004	Case-control, prospective	100 LC, 35% diabetics, 62 post-LT	Pre-LT IGT or DM was the major risk factor for post-LT DM	Only 31 patients were prospectively evaluated
Takahashi et al[77], Japan, 2011	Prospective	203 CHC	Two hours post-challenge hyperglycaemia associated with HCC	Patients received IFN
Jeon et al[64], Republic of Korea, 2013	Prospective	195 LC, 55.4% with HD	HD correlated with HVPG, VH and large varices. Most patients with VH within 6 mo, had post-prandial hyperglycaemia	Risk stratification of varices and prophylaxis for VH were not taken into account
Zheng et al[75], China, 2013	Retrospective case-control	1568 CLD, 852 with HCC	DM associated with increased risk of HCC regardless of cirrhosis. Synergistic interaction between DM and HBV for HCC	Hospital based study. Temporal relationship between DM and HCC could not be established
Yang et al[63], Taiwan, 2014	Prospective	146 LC, 25% diabetics	DM 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, 2015	Database from randomized trials	863 LC, 22% diabetics	Diabetics had more episodes of first-time overt HE in one year. First-time HE progression beyond grade 2 higher in diabetics	Diagnosis of DM was not standardized. Vaptan could be a confounder
Yang et al[73], United States, 2016	Retrospective	739 LC, 34% diabetics	DM increased the risk of HCC in patients with non-HCV cirrhosis	Single-centre probably with referral bias
Tergast et al[69], Germany, 2018	Prospective case-control	475 decompensated LC, 118 diabetics	DM 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, 2020	Retrospective	207 LC, 137 diabetics; 68 had HD	Rebleeding rate following EST or EVL higher in diabetics, including HD at 1, 3, and 6 mo	Relatively small number of patients with shorter follow-up
Labenz et al[61], Germany, 2020	Prospective	240 LC, 27% diabetics	DM 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

DM: Diabetes mellitus; EST: Endoscopic sclerotherapy; EVL: Endoscopic variceal ligation; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HD: Hepatogenous diabetes; HE: Hepatic encephalopathy; IGT: Impaired glucose tolerance; OGTT: Oral glucose tolerance test; VH: Variceal hemorrhage; LT: Liver transplantation; HVPG: Hepatic venous pressure gradient; HBV: Hepatitis B virus; IFN: Interferon; GIB: Gastrointestinal bleeding; SBP: Spontaneous bacterial peritonitis; LC: Liver cirrhosis; HbA1c: Glycated hemoglobin.

Table 3 Prospective and retrospective studies depicting implications of diabetes on mortality of patients with liver cirrhosis

Ref.	Design	Population	Outcomes	Limitations
Bianchi et al[3], Italy, 1994	Retro-prospective	354 LC, 98 with DM	5-yr survival rate: DM: 41%, non-DM 56%	Diagnosis of DM not standardized
Holstein et al[4], Germany, 2002	Prospective	52 LC, 71% with DM	5.6-yr survival rate after diagnosis of LC: 51% of HD patients. 80% of deaths were cirrhosis-related causes	Small sample size. Comparative outcome data of non-DM patients not available
Moreau et al[79], France, 2004	Prospective	75 LC and refractory ascites	DM, older age, and HCC were predictors of poor survival. The survival rate of patients without DM was higher	OGTT was not used to diagnose DM
Nishida et al[48], Japan, 2006	Prospective	56 LC, 38% diabetics	The 5-yr survival rate was 94%, 68% and 56%, with NGT, IGT and DM, respectively	Small sample size
Quintana et al[80], México, 2011	Prospective	110 compensated LC, 45% diabetics	2.5 yr cumulated survival years: DM: 48 vs non-DM: 69% (P < 0.05). DM was not predictor of death	Maybe DM death- prediction capability was masked by Child-Pugh C score
García-Compeán et al[78], México, 2014	Prospective	100 compensated LC and normal FPG	Patients with IGT + DM had lower 5-yr cumulated survival rate. Death causes in 90 % were cirrhosis related	Small sample size
Elkrief et al[40], Canada, 2014	Retrospective	348 HCV-LC, 40% diabetics	DM significantly associated with ascites, renal dysfunction, infections, HCC and mortality during the follow-up period	Retrospective. Potential errors in the diagnosis of DM
Khafaga et al[67], Egypt, 2015	Case-control	60 LC, 50% diabetics	Diabetics had higher incidence of VH, hospitalizations, HE and mortality rate	Small sample size
Qi et al[66], China, 2015	Retrospective	145 LC, 29 diabetics	In-hospital mortality was higher in diabetics	Small number of patients
Hoehn RS et al[82], United States, 2015	Retrospective	12442 pos- LT, 24% with DM	Diabetic recipients had longer hospitalization, higher peri-transplant mortality and 30-d readmission rates	More diabetic patients were on haemodialysis and received allografts from older donors
Rosenblatt et al[70], United States, 2021	Retrospective	906559 LC with DM, and 109694 uncontrolled DM	Uncontrolled DM associated with increased risk of bacterial infection and increased risk of death in elderly patients	Subject to administrative error. Criteria for DM was not standardized

DM: Diabetes mellitus; FPG: Fasting plasma glucose; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HD: Hepatogenous diabetes; HE: Hepatic encephalopathy; IGT: Impaired glucose tolerance; NGT: Normal glucose tolerance; OGTT: Oral glucose tolerance test; VH: Variceal hemorrhage; LT: Liver transplantation; LC: Liver cirrhosis.

Table 4 Kinetics, metabolism and excretion of the currently available anti-hyperglycaemic drugs[102]

Drug	Half life	Metabolism	Excretion
Short-acting insulins
Human	140 min	Proteolytic degradation
Lyspro	80 min	Proteolytic degradation
Aspart	80 min	Proteolytic degradation
Glulisine	80 min	Proteolytic degradation
Long-acting insulins
Human-NPH	6.6 h	Proteolytic degradation
Glargine	12.1 h	Proteolytic degradation
Levemir	5-7 h	Proteolytic degradation
Degludec	25 h	Proteolytic degradation
Glargine-300	19 h	Proteolytic degradation
Sulfonylureas
Glibenclamide	10 h	Liver 100%	Urines 50%; feces 50%1
Glimepiride	9 h	Liver 100%	Urines 60%; feces 40%1
Gliclazide	10-11 h	Liver 100%	Urines 80%; feces 20%
Glipizide	2-5 h	Liver 90%	Urines mainly
Meglitinides
Repaglinide	1 h	Liver 100%	Bile 92%; urines 8%
Biguanides
Metformin	1.5-3 h	Not metabolised	Urines 100%
Thiazolidinediones
Pioglitazone	3.7 h	Liver 100%	Feces 55%; urines 45%
DPP-4 inhibitors
Sitagliptin	8–24 h	Limited	Urines
Vildagliptin	1.5–4.5 h	Limited	Urines
Saxagliptin	2–4 h	Moderate	Urines
Linagliptin	10–40 h	Extensive	Feces
Alogliptin	12–21 h	Limited	Urines
GLP-1RAs
Exenatide	2.4 h	Proteolytic degradation	Renal
Liraglutide	13 h	Proteolytic degradation	No specific organ
Lixisenatide	3 h	Proteolytic degradation	Renal
Exenatide LAR	5-6 d	Proteolytic degradation	Renal
Dulaglutide	5 d	Proteolytic degradation	No specific organ
Semaglutide	7 d	Proteolytic degradation	No specific organ
α-glicosidase inhibitors
Acarbose	4 h	Intestine	Urines 35%; feces 65%
SGLT2 inhibitors
Dapaglifozin	10-13 h	Glucuronidation	Urines 33%; feces 42%
Canaglifozin	12.9 h	Glucuronidation	Urines 75%; feces 21%
Empaglifozin	12.4 h	Glucuronidation	Urines 54%; feces 41%
Ertugliflozin	17 h	Glucuronidation	Urines 50%; feces 41%

¹Excreted as weakly active metabolite.

DPP-4: Dipeptidyl peptidase 4; GLP-1RAs: Glucagon-like peptide 1 receptor agonists; SGLT2: Sodium-glucose cotransporter 2; LAR: Long-acting release; NPH: Neutral protamine Hagedorn.

Table 5 Use of anti-hyperglycaemic agents in cirrhotic individuals according to Child-Pugh class[102]

Drug	Child-Pugh class A	Child-Pugh class B	Child-Pugh class C
Short-acting insulins
Human	Allowed	Allowed	Allowed (dose reduction)
Lyspro	Allowed	Allowed	Allowed
Aspart	Allowed	Allowed	Allowed
Glulisine	Allowed	Allowed	Allowed
Long-acting insulins
Human-NPH	Allowed	Allowed	Allowed (dose reduction)
Glargine	Allowed	Allowed	Allowed
Levemir	Allowed	Allowed	Allowed
Degludec	Allowed	Allowed	Allowed
Glargine-300	Allowed	Allowed	Allowed
Sulfonylureas
Glibenclamide	Not recommended	Contraindicated	Contraindicated
Glimepiride	Allowed (caution)	Not recommended	Contraindicated
Gliclazide	Allowed (caution)	Not recommended	Contraindicated
Glipizide	Allowed (caution)	Not recommended	Contraindicated
Meglitinides
Repaglinide	Allowed (caution)	Not recommended	Contraindicated
Biguanides
Metformin	Allowed	Allowed (dose reduction)	Contraindicated
Thiazolidinediones
Pioglitazone	Allowed	Contraindicated	Contraindicated
DPP-4 inhibitors
Sitagliptin	Allowed	Allowed	Contraindicated
Vildagliptin	Contraindicated	Contraindicated	Contraindicated
Saxagliptin	Allowed	Allowed	Contraindicated
Linagliptin	Allowed	Allowed	Contraindicated
Alogliptin	Allowed	Allowed	Contraindicated
GLP-1RAs
Exenatide	Allowed	Contraindicated	Contraindicated
Liraglutide	Allowed	Contraindicated	Contraindicated
Lixisenatide	Allowed	Allowed	Contraindicated
Exenatide LAR	Allowed	Allowed	Contraindicated
Dulaglutide	Allowed	Allowed	Contraindicated
Semaglutide	Allowed	Allowed	Contraindicated
α-glicosidase inhibitors
Acarbose	Allowed	Allowed (caution)	Contraindicated
SGLT2 inhibitors
Dapaglifozin	Allowed	Allowed	Contraindicated
Canaglifozin	Allowed	Allowed	Contraindicated
Empaglifozin	Allowed	Allowed	Contraindicated
Ertugliflozin	Allowed	Allowed	Contraindicated

DPP-4: Dipeptidyl peptidase 4; GLP-1 RAs: Glucagon-like peptide 1 receptor agonists; SGLT2: Sodium-glucose cotransporter 2; NPH: Neutral protamine Hagedorn; LAR: Long-acting release.