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SGLT-2 Inhibitor and GLP-1 Receptor Agonist Treatment for Patients with Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Is Their Combination the Optimal Treatment Option?

  • Dimitrios Patoulias1,*  and
  • Theodoros Michailidis2
 Author information
Journal of Clinical and Translational Hepatology 2022;10(4):574-576

DOI: 10.14218/JCTH.2022.00278

Abstract

Keywords

Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic, representing the most common chronic liver disease worldwide.1 NAFLD is highly associated with type 2 diabetes mellitus (T2DM) and obesity, conditions that increase morbidity and mortality.2 A background of T2DM has also been shown to be predictive of cirrhosis and hepatocellular carcinoma occurrence in patients with T2DM, and cirrhotic patients with diabetes seem to have a higher risk of hepatic decompensation with manifestations of hepatic encephalopathy.3 In addition, it should not be underestimated the significantly increased risk for cardiovascular disease (CVD) and chronic kidney disease (CKD) in subjects with NAFLD, regardless of T2DM presence.4,5

Newer antidiabetic drugs, like sodium-glucose co-transporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RAs) have attracted scientific interest in the last decade, because of their multiple pleiotropic effects, with emphasis on cardio- and reno-protection with both drug classes.6 Their potential role in the treatment of NAFLD has been widely discussed recently.7

A previous meta-analysis demonstrated that both drug classes provided a significant improvement in liver enzymes and steatosis in patients with NAFLD.8 Two recent meta-analyses confirmed the beneficial effects of these drug classes on liver enzymes and liver fibrosis, along with significant improvements in the overall metabolic profile and glycemic control.9,10 What is more, a recently published retrospective study documented that 5-year treatment with SGLT-2 inhibitors in patients with T2DM and NAFLD resulted in a significant improvement in liver steatosis and fibrosis, and that addition of a GLP-1RA was safe.11 It has also been speculated that their diuretic effects might be of great value for cirrhotic patients with refractory ascites.12 Some anecdotal data retrieved from small case series support this hypothesis.13

Regarding GLP-1RAs, a previous population-based retrospective cohort study found that treatment with this antidiabetic drug class resulted in a significant decrease in the risk of individual decompensation events, including ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, esophageal variceal hemorrhage, and hepatic encephalopathy.14 However, when SGLT-2 inhibitors and GLP-1RAs were directly compared, no significant difference in decompensation rates was observed.14 Combining SGLT-2 inhibitors and GLP-1RA has been shown to be safe and highly efficacious in patients with T2DM, providing a greater reduction in glycated hemoglobin levels, body weight, and systolic blood pressure, compared with each drug class alone.15 In addition, the cardiovascular benefit obtained by combining a SGLT-2 inhibitor and GLP-1RA seems to be greater than that obtained with a SGLT-2 inhibitor or GLP-1RA alone.16

Unfortunately, except for the observations made by Akuta and colleagues11 in a small cohort of patients with NAFLD,11 there is no evidence of a synergistic effect of a SGLT-2 inhibitor plus GLP-1RA on liver steatosis and/or fibrosis in patients with NAFLD. The greater reductions of glycated hemoglobin level and body weight shown in previous randomized controlled trials and meta-analyses, should be considered a major step in achieving increased benefits with treatment of liver steatosis by combining a SGLT-2 inhibitor and GLP-1RA.15 In addition, greater reductions in subcutaneous fat and the visceral fat mass, should be expected with such a combination, along with a greater reduction in intrahepatic fat content, although that has to be confirmed in future trials.17,18 Remarkably, only an observational study in a total of 24 patients with NAFLD and T2DM showed that addition of a SGLT-2 inhibitor to an incretin-based regimen with GLP-1RA or a DPP-4 inhibitor resulted in a significant decrease in alanine aminotransferase levels that led to normalization and in a significant improvement in the FIB-4 index.19

Of course, it has to be admitted that the safety and efficacy of a great number of drug classes and investigational agents for the treatment of NAFLD with or without comorbidities testing are currently under investigation in clinical trials.20 Peroxisome proliferator-activated receptor agonists, pyruvate carrier (MPC) inhibitors, farnesoid X receptor agonists, liver X receptor alpha inhibitors, fibroblast growth factor analogs/activators, dual GLP-1 and glucose-dependent insulinotropic peptide receptor analogs or agonists, thyroid hormone receptor (THR-β)-selective agonists, antioxidants, fibrosis-targeted treatment options, and their combinations, are being assessed for their potential incorporation into the armamentarium of NAFLD treatments.20 Of note, some are also being tested in combination with either SGLT-2 inhibitors or GLP-1RAs.20

Therefore, it appears that such a combination would be of great value for patients with NAFLD and comorbidities, such as obesity, CVD, or even CKD (a simplified treatment approach is shown in Fig. 1). However, no studies have yet assessed the impact of such a combination on histological outcomes in patients with NAFLD and T2DM to confirm whether an SGLT-2 inhibitor/GLP-1RA combination might have beneficial synergistic effects on liver steatosis and fibrosis. Well-designed, prospective studies are required to answer this sound, scientific question. In addition, cost-effectiveness analyses are needed.

A simplified treatment approach for patients with NAFLD and type 2 diabetes mellitus.
Fig. 1  A simplified treatment approach for patients with NAFLD and type 2 diabetes mellitus.

NAFLD, nonalcoholic fatty liver disease.

Abbreviations

CKD: 

chronic kidney disease

CVD: 

cardiovascular disease

GLP-1RA: 

glucagon-like peptide-1 receptor agonists

NAFLD: 

nonalcoholic fatty liver disease

SGLT-2: 

sodium-glucose co-transporter-2

T2DM: 

type 2 diabetes mellitus

Declarations

Funding

None to declare.

Conflict of interest

The authors have no conflict of interests related to this publication.

Authors’ contributions

DP and TM wrote the draft, DP critically revised the manuscript before submission.

References

  1. Pappachan JM, Babu S, Krishnan B, Ravindran NC. Non-alcoholic Fatty Liver Disease: A Clinical Update. J Clin Transl Hepatol 2017;5(4):384-393 View Article PubMed/NCBI
  2. Kumar R, Priyadarshi RN, Anand U. Non-alcoholic Fatty Liver Disease: Growing Burden, Adverse Outcomes and Associations. J Clin Transl Hepatol 2020;8(1):76-86 View Article PubMed/NCBI
  3. Raff EJ, Kakati D, Bloomer JR, Shoreibah M, Rasheed K, Singal AK. Diabetes Mellitus Predicts Occurrence of Cirrhosis and Hepatocellular Cancer in Alcoholic Liver and Non-alcoholic Fatty Liver Diseases. J Clin Transl Hepatol 2015;3(1):9-16 View Article PubMed/NCBI
  4. Mantovani A, Csermely A, Petracca G, Beatrice G, Corey KE, Simon TG, et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2021;6(11):903-913 View Article PubMed/NCBI
  5. Mantovani A, Zaza G, Byrne CD, Lonardo A, Zoppini G, Bonora E, et al. Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: A systematic review and meta-analysis. Metabolism 2018;79:64-76 View Article PubMed/NCBI
  6. Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet 2021;398(10296):262-276 View Article PubMed/NCBI
  7. Snyder HS, Sakaan SA, March KL, Siddique O, Cholankeril R, Cummings CD, et al. Non-alcoholic Fatty Liver Disease: A Review of Anti-diabetic Pharmacologic Therapies. J Clin Transl Hepatol 2018;6(2):168-174 View Article PubMed/NCBI
  8. Kumar J, Memon RS, Shahid I, Rizwan T, Zaman M, Menezes RG, et al. Antidiabetic drugs and non-alcoholic fatty liver disease: A systematic review, meta-analysis and evidence map. Dig Liver Dis 2021;53(1):44-51 View Article PubMed/NCBI
  9. Ding C, Tang Y, Zhu W, Huang P, Lian P, Ran J, et al. Sodium-glucose cotransporter protein-2 inhibitors and glucagon-like peptide-1 receptor agonists versus thiazolidinediones for non-alcoholic fatty liver disease: A network meta-analysis. Acta Diabetol 2022;59(4):519-533 View Article PubMed/NCBI
  10. Ng CH, Lin SY, Chin YH, Lee MH, Syn N, Goh XL, et al. Antidiabetic Medications for Type 2 Diabetics with Nonalcoholic Fatty Liver Disease: Evidence From a Network Meta-Analysis of Randomized Controlled Trials. Endocr Pract 2022;28(2):223-230 View Article PubMed/NCBI
  11. Akuta N, Kawamura Y, Fujiyama S, Saito S, Muraishi N, Sezaki H, et al. Favorable impact of long-term SGLT2 inhibitor for NAFLD complicated by diabetes mellitus: A 5-year follow-up study. Hepatol Commun 2022 View Article PubMed/NCBI
  12. Gao Y, Wei L, Zhang DD, Chen Y, Hou B. SGLT2 Inhibitors: A New Dawn for Recurrent/Refractory Cirrhotic Ascites. J Clin Transl Hepatol 2021;9(6):795-797 View Article PubMed/NCBI
  13. Montalvo-Gordon I, Chi-Cervera LA, García-Tsao G. Sodium-Glucose Cotransporter 2 Inhibitors Ameliorate Ascites and Peripheral Edema in Patients With Cirrhosis and Diabetes. Hepatology 2020;72(5):1880-1882 View Article PubMed/NCBI
  14. Simon TG, Patorno E, Schneeweiss S. Glucagon-Like Peptide-1 Receptor Agonists and Hepatic Decompensation Events in Patients With Cirrhosis and Diabetes. Clin Gastroenterol Hepatol 2022;20(6):1382-1393.e19 View Article PubMed/NCBI
  15. Mantsiou C, Karagiannis T, Kakotrichi P, Malandris K, Avgerinos I, Liakos A, et al. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab 2020;22(10):1857-1868 View Article PubMed/NCBI
  16. Patoulias D, Papadopoulos C, Karagiannis A, Doumas M. Which one should I choose, a glucagon-like peptide-1 receptor agonist or a sodium-glucose cotransporter 2 inhibitor? Or maybe both?. Eur J Intern Med 2022;98:125-127 View Article PubMed/NCBI
  17. Zhu Y, Xu J, Zhang D, Mu X, Shi Y, Chen S, et al. Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021;12:769069 View Article PubMed/NCBI
  18. Wei Q, Xu X, Guo L, Li J, Li L. Effect of SGLT2 Inhibitors on Type 2 Diabetes Mellitus With Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Front Endocrinol (Lausanne) 2021;12:635556 View Article PubMed/NCBI
  19. Ohki T, Isogawa A, Toda N, Tagawa K. Effectiveness of Ipragliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor, as a Second-line Treatment for Non-Alcoholic Fatty Liver Disease Patients with Type 2 Diabetes Mellitus Who Do Not Respond to Incretin-Based Therapies Including Glucagon-like Peptide-1 Analogs and Dipeptidyl Peptidase-4 Inhibitors. Clin Drug Investig 2016;36(4):313-319 View Article PubMed/NCBI
  20. Negi CK, Babica P, Bajard L, Bienertova-Vasku J, Tarantino G. Insights into the molecular targets and emerging pharmacotherapeutic interventions for nonalcoholic fatty liver disease. Metabolism 2022;126:154925 View Article PubMed/NCBI
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