metricas
covid
Buscar en
Annals of Hepatology
Toda la web
Inicio Annals of Hepatology The treatment of diabetes in advanced liver disease: change of a paradigm
Información de la revista
Vol. 28. Núm. 1.
(enero - febrero 2023)
Compartir
Compartir
Descargar PDF
Más opciones de artículo
Vol. 28. Núm. 1.
(enero - febrero 2023)
Opinions
Open Access
The treatment of diabetes in advanced liver disease: change of a paradigm
Visitas
2296
Maria Letizia Petronib, Lucia Brodosib, Giulio Marchesinia,b,
Autor para correspondencia
giulio.marchesini@unibo.it

Corresponding author.
a Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
b IRCCS Azienda Ospedaliera di Bologna Sant'Orsola-Malpighi, Bologna, Italy
Este artículo ha recibido

Under a Creative Commons license
Información del artículo
Texto completo
Bibliografía
Descargar PDF
Estadísticas
Texto completo

The treatment of type 2 diabetes (T2DM) has entered a new era in the past 15 years. After decades of stagnation, novel drugs, adding beneficial pleiotropic effects to their glucose lowering activity (Table 1), entered the market and totally replaced the old drugs in treatment diagrams proposed by international societies [1]. Also, the use of metformin as an initial treatment of hyperglycemia has been challenged following the evidence that gliflozins (sodium-glucose cotransporter-2 inhibitors – SGLT-2Is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of heart and kidney disease progression, the most common outcomes in patients with long-standing diabetes. A large network meta-analysis comparing the effects of 5-year T2DM treatment with these new classes versus any other intervention in randomized controlled trials (764 RCT, a total of 421,364 patients) confirmed the superiority of these drugs [2]. The risks of all-cause mortality, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, kidney failure and hospital admission for heart failure were all reduced [2], with differences between GLP-1RAs and SGLT-2Is and in relation to a priori severity of cardiovascular risk. Changes in drug use are slowly being accepted in the community, despite clinical inertia and budget restriction [3].

Table 1.

Agents for diabetes treatment and their clinical effects. The last three classes have been added to the spectrum of available treatment in the past 15 years.

Agents  Favorable effects  Adverse effects 
Metformin 
  • Modest control of glucose levels

  • Modest weight loss

  • Very low risk of hypoglycemia

  • Reduced risk of primary liver cancer

 
  • Rare abdominal discomfort

  • Dose tapering and suspension in the presence of CKD grade 4-5

  • Risk of lactic acidosis

 
Sulphonylureas and glinides 
  • Potent control of glucose levels

  • Intra-class difference in terms of renal or hepatic metabolism

 
  • Risk of hypoglycemia

  • Increased CV risk

  • Weight gain

  • Low durability

 
Pioglitazone 
  • Moderate control of glucose levels

  • CV and cerebrovascular protection

  • Very low risk of hypoglycemia

  • Reduced progression of NASH fibrosis

 
  • Weight gain

  • Heart failure risk

 
AGIs 
  • Modest post-prandial glucose control

 
  • Abdominal discomfort

  • Low compliance

 
Insulin 
  • Maximum control of glucose levels

 
  • Weight gain

  • High risk of hypoglycemia

  • Low compliance and high burden with intensive treatment

 
DPP-4Is 
  • Moderate control of glucose levels

 
  • Negligible adverse events

 
GLP-1RAs 
  • Potent control of glucose levels (valid alternative to insulin treatment)

  • Reduced CV and renal disease progression

  • Important weight loss

  • Very low risk of hypoglycemia

 
  • Nausea and abdominal discomfort (relatively high discontinuation rate)

  • Possible risk of weight loss-induced sarcopenia

  • Limited use in advanced CKD

 
SGLT-2Is 
  • Moderate control of glucose levels

  • Reduced risk of CV and renal disease progression

  • Prevention of heart failure

  • Modest weight loss

  • Very low risk of hypoglycemia

  • Long-term durability

 
  • Polyuria causing low compliance

  • Risk of genital and urinary infections

  • Low effectiveness in advanced CKD

 

AGIs, alfa-glucosidase inhibitors; DPP-4Is, dipeptidyl-peptidase-4 inhibitors; GLP-1RAs, glucagon-like peptide-1 receptor agonists; SGLT-2Is, sodium-glucose cotransporter-2 inhibitors; CKD, chronic kidney disease, CV, cardiovascular; NASH, non-alcoholic steatohepatitis.

These beneficial effects prompt to reconsider the treatment of T2DM also in patients with liver disease, a specific area of research where the risk of hepatotoxicity, drug-drug interaction, comorbidity and frailty commonly indicate the use of insulin as a preferred drug. The questions now are: 1) May we confidently use these drugs in the presence of advanced liver disease? 2) Do these beneficial effects also occur in patients with T2DM and cirrhosis? 3) Is there any evidence that these drugs may also improve – or reduce the progression of – the underlying liver disease?

As to the first question, all SGLT-2Is share similar pharmacokinetic characteristics. Following oral administration and rapid absorption, they undergo extensive hepatic metabolism via glucuronidation to inactive metabolites, which are finally excreted by the kidney. Their systemic exposure (Cmax and AUC) increases with the severity of hepatic disease, classified according to Child-Pugh score [4], but no signs of hepatotoxicity have ever been reported. Nonetheless, very few data are available, and review articles suggest caution for use in patients with advanced liver disease [5] and even more in the presence of combined liver and renal failure. No dose adjustment is suggested for patients up to Child-Pugh B class [6].

Incretin-based therapies include GLP-1RAs and the dipeptidyl-peptidase-4 inhibitors (DPP-4Is). Both classes are scarcely metabolized by the liver and are mostly excreted unchanged by the kidney [7], which regulates systemic exposure (with the notable exception of linagliptin). DPP-4Is are safe and do not induce hypoglycemia, but do not share the beneficial effects of GLP-1RAs on the cardiovascular and renal systems. Therefore, they are considered the second choice in the treatment algorithm. On the contrary, liraglutide and the long-acting weekly GLP-1RAs (exenatide LAR, dulaglutide and semaglutide) qualify as potential treatment also in the presence of liver disease [8], considering their safety and efficacy [9]. The only possible risk comes from the reported interaction of GLP-1RAs with beta-blocking agents for the prevention of recurrent bleeding [10], requiring further investigation.

As to the second question, there are no systematic data on cardiovascular and renal disease progression in specific cohorts with T2DM and liver disease, a group of patients largely identifiable as NASH-cirrhosis. The beneficial effects of GLP-1RAs and SGLT-2Is have been extensively reproduced in large cohorts of patients with T2DM, and most of them were expected to have non-alcoholic steatohepatitis (NASH) superimposed to T2DM. Old studies identified liver failure or bleeding, not cardiovascular events, as most common cause of death in cirrhosis with T2DM [11], but the present epidemics of metabolic liver disease significantly increased the cardiovascular risk in the general population with advanced liver disease [1213]. Although liver disease was not systematically considered an exclusion criterion in cardiovascular and renal outcome trials [14–23], probably very few enrolled patients might be classified as NASH-cirrhosis. This is a very novel area of research that should be extensively investigated in the future.

The third question is far more intriguing. GLP-1RAs have been extensively investigated as treatment for NASH, but the results are inconclusive. Liraglutide and semaglutide reduced steatosis and NASH [24], but failed to improve fibrosis [2526]. Similar effects on steatosis and liver biomarkers were observed with dulaglutide [27] and tirzepatide, the dual GIP (glucose-dependent insulinotropic peptide)/GLP-1RA [28], and data on fibrosis are being investigated. SGLT-2Is similarly reduced steatosis [24], with no definite effect on fibrosis. For both classes, changes in steatosis and fibrosis biomarkers might stem from weight loss [29], favored by behavioral treatment [30]. Beneficial effects might also be achieved by high dose semaglutide and tirzepatide, causing 15% mean weight reduction [3132], provided that the negative effects of weight loss-associated sarcopenia are adequately corrected [33]. A recent report compared the effectiveness of antidiabetic agents at reducing the risk of hepatic decompensation (hospitalization for ascites, bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy, bleeding varices) in T2DM with cirrhosis (60% NASH-cirrhosis), based on a large US commercial claims dataset [9]. After accurate propensity-score matching, patients receiving GLP-1RAs experienced lower rates of decompensation compared with DPP-4Is or sulphonylureas (HR 0.68, 95%CI 0.53-0.88; and HR 0.64, 95%CI 0.48-0.84), respectively), whereas no differences were observed between the cohorts treated with GLP-1RAs and SGLT-2Is. A role of SGLT-2Is in decompensated cirrhosis is also being explored in adequately powered trials, following anecdotal reports of control of refractory ascites, hydrothorax and peripheral edema [34,35]. With the limits of possible bias inherent to observational studies, these drugs appear to be safe and effective for T2DM treatment in cirrhosis.

In conclusion, a large body of evidence is accumulating for a systematic use of novel antidiabetic drugs, namely GLP-1RAs and SGLT-2Is, also in subjects with cirrhosis, as well as in candidates for liver transplantation [36], a population at very high risk of cardiovascular and renal disease. These novel drugs might be effectively associated with metformin and/or pioglitazone. Metformin continuation in cirrhosis with T2DM, in the safe renal function area, improved survival [37] and also reduced the risk of primary liver cancer [38], whereas pioglitazone remains the only drug associated with reduced risk of NASH fibrosis [39].

References
[1]
B Draznin, VR Aroda, G Bakris, G Benson, FM Brown, American Diabetes Association Professional Practice Committee, et al.
9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022.
Diabetes Care, 45 (2022), pp. S125-SS43
[2]
SC Palmer, B Tendal, RA Mustafa, et al.
Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.
BMJ, 372 (2021), pp. m4573
[3]
E Bonora, S Cataudella, G Marchesini, et al.
A view on the quality of diabetes care in Italy and the role of Diabetes Clinics from the 2018 ARNO Diabetes Observatory.
Nutr Metab Cardiovasc Dis, 30 (2020), pp. 1945-1953
[4]
AJ. Scheen.
Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease.
Expert Opin Drug Metab Toxicol, 10 (2014), pp. 839-857
[5]
D Garcia-Compean, JA Gonzalez-Gonzalez, FJ Lavalle-Gonzalez, EI Gonzalez-Moreno, HJ Maldonado-Garza, JZ. Villarreal-Perez.
The treatment of diabetes mellitus of patients with chronic liver disease.
Ann Hepatol, 14 (2015), pp. 780-788
[6]
H Yamada, H Ohira, F Ikegami, et al.
Effects of Child-Pugh B cirrhosis on pharmacokinetics of tofogliflozin, a new sodium-glucose co-transporter (SGLT2) inhibitor.
Drug Res (Stuttg), 70 (2020), pp. 401-409
[7]
AJ. Scheen.
Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes.
Clin Pharmacokinet, 54 (2015), pp. 1-21
[8]
SM Morris, MJ Armstrong, PN. Newsome.
Safety and efficacy of glucagon-like peptide 1 receptor agonists in patients with cirrhosis.
Clin Gastroenterol Hepatol, 20 (2022), pp. 1220-1222
[9]
TG Simon, E Patorno, S. Schneeweiss.
Glucagon-like peptide-1 receptor agonists and hepatic decompensation events in patients with cirrhosis and diabetes.
Clin Gastroenterol Hepatol, 20 (2022),
[10]
R Vukotic, F Raimondi, L Brodosi, et al.
The effect of liraglutide on beta-blockade for preventing variceal bleeding: a case series.
Ann Intern Med, 173 (2020), pp. 404-405
[11]
G Bianchi, G Marchesini, M Zoli, E Bugianesi, A Fabbri, E. Pisi.
Prognostic significance of diabetes in patients with cirrhosis.
Hepatology, 20 (1994), pp. 119-125
[12]
J An, JH Shim, SO Kim, et al.
Prevalence and prediction of coronary artery disease in patients with liver cirrhosis: a registry-based matched case-control study.
Circulation, 130 (2014), pp. 1353-1362
[13]
ML Petroni, L Brodosi, E Bugianesi, G. Marchesini.
Management of non-alcoholic fatty liver disease.
BMJ, 372 (2021), pp. m4747
[14]
SP Marso, SC Bain, A Consoli, et al.
Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
N Engl J Med, 375 (2016), pp. 1834-1844
[15]
M Husain, AL Birkenfeld, M Donsmark, et al.
Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.
N Engl J Med, 381 (2019), pp. 841-851
[16]
SP Marso, GH Daniels, K Brown-Frandsen, et al.
Liraglutide and cardiovascular outcomes in type 2 diabetes.
N Engl J Med, 375 (2016), pp. 311-322
[17]
HC Gerstein, HM Colhoun, GR Dagenais, et al.
Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.
[18]
HC Gerstein, HM Colhoun, GR Dagenais, et al.
Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
[19]
JFE Mann, DD Orsted, K Brown-Frandsen, et al.
Liraglutide and renal outcomes in type 2 diabetes.
N Engl J Med, 377 (2017), pp. 839-848
[20]
M Packer, SD Anker, J Butler, et al.
Cardiovascular and renal outcomes with empagliflozin in heart failure.
N Engl J Med, 383 (2020), pp. 1413-1424
[21]
B Zinman, C Wanner, JM Lachin, et al.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
N Engl J Med, 373 (2015), pp. 2117-2128
[22]
SD Wiviott, I Raz, MP Bonaca, et al.
Dapagliflozin and cardiovascular outcomes in type 2 diabetes.
N Engl J Med, 380 (2019), pp. 347-357
[23]
B Neal, V Perkovic, KW Mahaffey, et al.
Canagliflozin and cardiovascular and renal events in type 2 diabetes.
N Engl J Med, 377 (2017), pp. 644-657
[24]
A Mantovani, CD Byrne, G. Targher.
Efficacy of peroxisome proliferator-activated receptor agonists, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors for treatment of non-alcoholic fatty liver disease: a systematic review.
Lancet Gastroenterol Hepatol, 7 (2022), pp. 367-378
[25]
PN Newsome, K Buchholtz, K Cusi, et al.
A placebo-controlled trial of subcutaneous semaglutide in non-alcoholic steatohepatitis.
N Engl J Med, 384 (2020), pp. 1113-1124
[26]
MJ Armstrong, P Gaunt, GP Aithal, et al.
Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.
[27]
MS Kuchay, S Krishan, SK Mishra, et al.
Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial).
Diabetologia, 63 (2020), pp. 2434-2445
[28]
ML Hartman, AJ Sanyal, R Loomba, et al.
Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of non-alcoholic steatohepatitis in patients with type 2 diabetes.
Diabetes Care, 43 (2020), pp. 1352-1355
[29]
S Colosimo, F Ravaioli, ML Petroni, et al.
Effects of antidiabetic agents on steatosis and fibrosis biomarkers in type 2 diabetes: A real-world data analysis.
Liver Int, 41 (2021), pp. 731-742
[30]
ML Petroni, L Montesi, S Colosimo, MT Caletti, A Mazzotti, G. Marchesini.
Combination of GLP-1 receptor agonists and behavioural treatment in type 2 diabetes elicits synergistic effects on body weight: a retrospective cohort study.
Endocrinol Diab Metab, 2 (2019), pp. e00082
[31]
JPH Wilding, RL Batterham, S Calanna, et al.
Once-weekly semaglutide in adults with overweight or obesity.
N Engl J Med, 384 (2021), pp. 989-1002
[32]
AM Jastreboff, LJ Aronne, NN Ahmad, et al.
Tirzepatide once weekly for the treatment of obesity.
N Engl J Med, 387 (2022), pp. 205-216
[33]
D McCarthy, A. Berg.
Weight loss strategies and the risk of skeletal muscle mass loss.
[34]
Y Gao, L Wei, DD Zhang, Y Chen, B. Hou.
SGLT2 inhibitors: a new dawn for recurrent/refractory cirrhotic ascites.
J Clin Transl Hepatol, 9 (2021), pp. 795-797
[35]
D Patoulias, A Katsimardou, C Papadopoulos, M. Doumas.
Letter to the Editor: Sodium-glucose cotransporter 2 inhibitors ameliorate ascites and peripheral edema in patients with cirrhosis and diabetes.
Hepatology, 73 (2021), pp. 866
[36]
L Brodosi, S Petta, ML Petroni, G Marchesini, MC. Morelli.
Management of diabetes in candidates for liver transplantation and in transplant recipients.
Transplantation, 106 (2021), pp. 462-478
[37]
X Zhang, WS Harmsen, TA Mettler, et al.
Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes.
Hepatology, 60 (2014), pp. 2008-2016
[38]
ZJ Zhang, ZJ Zheng, R Shi, Q Su, Q Jiang, KE. Kip.
Metformin for liver cancer prevention in patients with type 2 diabetes: a systematic review and meta-analysis.
J Clin Endocrinol Metab, 97 (2012), pp. 2347-2353
[39]
G Musso, M Cassader, E Paschetta, R. Gambino.
Pioglitazone for advanced fibrosis in non-alcoholic steatohepatitis: new evidence, new challenges.
Hepatology, 65 (2017), pp. 1058-1061
Copyright © 2022. Fundación Clínica Médica Sur, A.C.
Descargar PDF
Opciones de artículo
es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos