STATE OF THE ART PAPER
Pioglitazone with SGLT2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes and non-alcoholic fatty liver disease: could the combinations of an old friend with new players yield better outcomes?
1
K.M.P THERAPIS Paphos Medical Center, Internal Medicine and Diabetes Clinic, Paphos, Cyprus
2
CDA College, Paphos, Cyprus
3
Alithias Endocrinology Centre, Lakatamia, Nicosia, Cyprus
4
European University of Cyprus, Nicosia, Cyprus
5
Department of Biological Sciences, College of Science, University of North Texas, Denton, TX, US
These authors had equal contribution to this work
Submission date: 2024-11-28
Final revision date: 2025-01-11
Acceptance date: 2025-02-25
Publication date: 2025-03-14
Corresponding author
Georgios S. Papaetis
K.M.P THERAPIS Paphos Medical Center Internal Medicine and Diabetes Clinic 14 Vasileos Georgiou B St Office 201, 8010 Paphos, Cyprus CDA College 73 Democratias Avenue Paphos, Cyprus
K.M.P THERAPIS Paphos Medical Center Internal Medicine and Diabetes Clinic 14 Vasileos Georgiou B St Office 201, 8010 Paphos, Cyprus CDA College 73 Democratias Avenue Paphos, Cyprus
Arch Med Sci Atheroscler Dis 2025;10(1):1-15
KEYWORDS
non-alcoholic fatty liver diseasenon-alcoholic steatohepatitismetabolic dysfunction-associated steatotic liver diseasepioglitazoneGLP-1 receptor agonistsSGLT2 inhibitors
TOPICS
Diabetes, Diabetic complicationsDietCardiovascular preventionInflammation, oxidative stress, antioxidantsMetabolic syndromeNon-alcoholic fatty liver diseaseObesityPublic health
ABSTRACT
More than 25% of the adult population worldwide and approximately 50–75% of patients with type 2 diabetes are diagnosed with non-alcoholic fatty liver disease. Insulin resistance is one of the most crucial factors underlying its pathogenesis and a significant determinant of its progression to non-alcoholic steatohepatitis. The complex pathophysiology of non-alcoholic fatty liver disease emphasizes the need for combination treatment strategies with drug classes that target different cellular pathways, since no single agent can control all the mechanisms contributing to its development and evolution. Pioglitazone, the main thiazolidinedione in clinical practice, is the only true insulin sensitizing antidiabetic drug in our therapeutic armamentarium for the treatment of patients with type 2 diabetes. Current international practice guidelines recommend PIO as a promising therapy for patients who experience NASH and type 2 diabetes. GLP-1 receptor agonists and SGLT2 inhibitors have shown salutary cardiometabolic and renal effects in patients with type 2 diabetes, as well as beneficial liver activities in those with non-alcoholic fatty liver disease. This review discusses the pathophysiological background for the use of these three drug categories in patients with type 2 diabetes and non-alcoholic fatty liver disease. It also explores thoroughly the combinations of pioglitazone with either GLP-1 receptor agonists or SGLT2 inhibitors, as well as their future role in this setting.
REFERENCES (146)
1.
Israelsen M, Francque S, Tsochatzis EA, Krag A. Steatotic liver disease. Lancet 2024; 404: 1761-78.
2.
Utzschneider KM, Hagström H, Shang Y, Hegmar H, Nasr P. Natural history and progression of metabolic dysfunction-associated steatotic liver disease. Lancet Gastroenterol Hepatol 2024; 9: 944-56.
3.
Leung AKC, Wong AHC, Hon KL. Childhood obesity: an updated review. Curr Pediatr Rev 2024; 20: 2-26.
4.
Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut 2024; 73: 691-702.
5.
Kalavalapalli S, Leiva EG, Lomonaco R, et al. Adipose tissue insulin resistance predicts the severity of liver fibrosis in patients with type 2 diabetes and NAFLD. J Clin Endocrinol Metab 2023; 108: 1192-201.
6.
EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). J Hepatol 2024; 81: 492-542.
7.
Noureddin M, Wei L, Castera L, Tsochatzis EA. Embracing change: from nonalcoholic fatty liver disease to metabolic dysfunction-associated steatotic liver disease under the steatotic liver disease umbrella. Clin Gastroenterol Hepatol 2024; 22: 9-11.
8.
Younossi ZM, Paik JM, Stepanova M, et al. Clinical profiles and mortality rates are similar for metabolic dysfunction-associated steatotic liver disease and non-alcoholic fatty liver disease. J Hepatol 2024; 80: 694-701.
9.
Duell PB, Welty FK, Miller M, et al.; American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease. Nonalcoholic fatty liver disease and cardiovascular risk: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol 2022; 42: e168-85.
10.
Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic steatohepatitis: a review. JAMA 2020; 323: 1175-83.
11.
Llovet JM, Willoughby CE, Singal AG, et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat Rev Gastroenterol Hepatol 2023; 20: 487-503.
12.
Feng G, Valenti L, Wong VW. Recompensation in cirrhosis: unravelling the evolving natural history of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2024; 21: 46-56.
13.
Lee HH, Lee HA, Kim EJ, et al. Metabolic dysfunction-associated steatotic liver disease and risk of cardiovascular disease. Gut 2024; 73: 533-40.
14.
Patoulias DI. Non-alcoholic fatty liver disease in patients with inflammatory bowel disease might boost cardiovascular disease burden. Arch Med Sci Atheroscler Dis 2019; 4: e250-1.
15.
Kim KS, Hong S, Han K, Park CY. Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population-based study. BMJ 2024; 384: e076388.
16.
Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol 2016; 65: 589-600.
17.
Papaetis GS, Sacharidou A, Michaelides IC, Mikellidis KC, Karvounaris SA. Insulin resistance, hyperinsulinemia and atherosclerosis: insights into pathophysiological aspects and future therapeutic prospects. Curr Cardiol Rev 2024; doi: 10.2174/011573403X314035241006185109.
18.
Taylor R. Type 2 diabetes and remission: practical management guided by pathophysiology. J Intern Med 2021; 289: 754-70.
19.
Rugivarodom M, Geeratragool T, Pausawasdi N, Charatcharoenwitthaya P. Fatty pancreas: linking pancreas pathophysiology to nonalcoholic fatty liver disease. J Clin Transl Hepatol 2022; 10: 1229-39.
20.
Petrov MS, Taylor R. Intra-pancreatic fat deposition: bringing hidden fat to the fore. Nat Rev Gastroenterol Hepatol 2022; 19: 153-68.
21.
Gao Z, Zhang X, Zuberi A, et al. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol 2004; 18: 2024-34.
22.
Sergi D, Zauli E, Celeghini C, Previati M, Zauli G. Ceramides as the molecular link between impaired lipid metabolism, saturated fatty acid intake and insulin resistance: are all saturated fatty acids to be blamed for ceramide-mediated lipotoxicity? Nutr Res Rev 2024: 1-11. doi: 10.1017/S0954422424000179.
23.
Whytock KL, Pino MF, Sun Y, et al. Comprehensive interrogation of human skeletal muscle reveals a dissociation between insulin resistance and mitochondrial capacity. Am J Physiol Endocrinol Metab 2023; 325: E291-302.
24.
Noureddin M, Sanyal AJ. Pathogenesis of NASH: the impact of multiple pathways. Curr Hepatol Rep 2018; 17: 350-60.
25.
Stefan N, Schick F, Birkenfeld AL, Häring HU, White MF. The role of hepatokines in NAFLD. Cell Metab 2023; 35: 236-52.
26.
Perakakis N, Stefanakis K, Mantzoros CS. The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease. Metabolism 2020; 111S: 154320.
27.
Zhu W. Effective roles of exercise and diet adherence in non-alcoholic fatty liver disease. World J Gastroenterol 2024; 30: 3456-60.
28.
Koutekites DA, Astbury NM, Tudor KE, et al. Association of weight loss interventions with changes in biomarkers of non-alcoholic fatty liver disease: a systematic review and meta-analysis. JAMA Intern Med 2019; 179: 1262e1271.
29.
Younus Z, Stepanova M, Sanyal AJ, et al. The conundrum of cryptogenic cirrhosis: adverse outcomes without treatment options. J Hepatol 2018; 69: 1365-70.
30.
Xue Y, Peng Y, Zhang L, Ba Y, Jin G, Liu G. Effect of different exercise modalities on nonalcoholic fatty liver disease: a systematic review and network meta-analysis. Sci Rep 2024; 14: 6212.
31.
Ryan DH. Lifestyle-based obesity care. Gastroenterol Clin North Am 2023; 52: 645-60.
32.
Delahanty LM, Tried PM, Cibula DA, Weinstock RS. Barriers to weight loss and physical activity, and coach approaches to addressing barriers, in a real-world adaptation of the DPP lifestyle intervention: a process analysis. Diabetes Educe 2019; 45: 596-606.
33.
Fakhry TK, Mhaskar R, Switala T, Muradova E, Gonzalvo JP, Murr MM. Bariatric surgery improves non-alcoholic fatty liver disease: a contemporary systematic review and meta-analysis. Surg Obes Relate Dis 2019; 15: 502-11.
34.
Pais R, Aron-Wisnewsky J, Bedossa P, et al. Persistence of severe liver fibrosis despite substantial weight loss with bariatric surgery. Hepatology 2022; 76: 456-68.
35.
Lassailly G, Caiazzo R, Ntandja-Wandji LC, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 2020; 159: 1290-301.e5.
36.
Lazaridis II, Delko T. Bariatric surgery and metabolic dysfunction-associated fatty liver disease: a 2022 update. Praxis (Bern 1994) 2023; 112: 97-102.
37.
Morin-Papunen L. Bariatric surgery in women with PCOS and obesity. Lancet 2024; 403: 2456-57.
38.
Papaetis GS. GLP-1 receptor agonists, SGLT-2 inhibitors and obstructive sleep apnea: can new allies face an old enemy? Arch Med Sci Atheroscler Dis 2023; 8: e19-34.
39.
Athanasiadis DI, Martin A, Kaanapali’s P, Monfared S, Stefanidis D. Factors associated with weight regain post-bariatric surgery: a systematic review. Surg Endosc 2021; 35: 4069-84.
40.
Cusi K, Isaacs S, Barb D, et al. American Association of Clinical Endocrinology Clinical Practice Guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings: co-sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract 2022; 28: 528-62.
41.
Wang YD, Wu LL, Qi XY, et al. New insight of obesity-associated NAFLD: Dysregulated “crosstalk” between multi-organ and the liver? Genes Dis 2022; 10: 799-812.
42.
Johnston MP, Patel J, Byrne CD. Multi-drug approaches to NASH: what’s in the development pipeline? Expert Opin Investig Drugs 2020; 29: 143-50.
43.
Koureta E, Cholongitas E. Combination therapies in nonalcoholic fatty liver disease using antidiabetic and disease-specific drugs. Ann Gastroenterol 2023; 36: 378-91.
44.
Zhang F, Pan X, Zhang X, Tong N. The effect of thiazolidinediones on body fat redistribution in adults: a systematic review and meta-analysis of randomized controlled trials. Obes Rev 2024; 25: e13675.
45.
DeFronzo RA, Inzucchi S, Abdul-Ghani M, et al. Pioglitazone: the forgotten, cost-effective cardioprotective drug for type 2 diabetes. Diab Vasc Dis Res 2019; 16: 133-43.
46.
Papaetis GS. Pioglitazone, bladder cancer and the presumption of innocence. Curr Drug Saf 2022; 7: 294-318.
47.
Papaetis GS. Pioglitazone and diabetic kidney disease: forgotten but not gone. Arch Med Sci Atheroscler Dis 2022; 7: e78-93.
48.
Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006; 355: 2297e2307.
49.
Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016; 165: 305e315.
50.
Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med 2017; 177: 633-40.
51.
Tang W, Xu Q, Hong T, et al. Comparative efficacy of anti-diabetic agents on nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized and non-randomized studies. Diabetes Metab Res Rev 2016; 32: 200-16.
52.
Kumar J, Memon RS, Shahid I, et al. Antidiabetic drugs and non-alcoholic fatty liver disease: a systematic review, meta-analysis and evidence map. Dig Liver Dis 2021; 53: 44-51.
53.
Panunzi S, Maltese S, Verrastro O, et al. Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: a hierarchical network meta-analysis. Diabetes Obes Metab 2021; 23: 980-90.
54.
Della Pepa G, Russo M, Vitale M, et al. Pioglitazone even at low dosage improves NAFLD in type 2 diabetes: clinical and pathophysiological insights from a subgroup of the TOSCA.IT randomised trial. Diabetes Res Clin Pract 2021; 178: 108984.
55.
European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016; 64: 1388-402.
56.
Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American association for the study of liver diseases. Hepatology 2018; 67: 328-57.
57.
Abdul-Ghani M, Maffei P, DeFronzo RA. Managing insulin resistance: the forgotten pathophysiological component of type 2 diabetes. Lancet Diabetes Endocrinol 2024; 12: 674-80.
58.
Palavicini JP, Chavez-Velazquez A, Fourcaudot M, et al. The insulin-sensitizer pioglitazone remodels adipose tissue phospholipids in humans. Front Physiol 2021; 12: 784391.
59.
Rohm TV, Castellani Gomes Dos Reis F, Isaac R, et al. Adipose tissue macrophages secrete small extracellular vesicles that mediate rosiglitazone-induced insulin sensitization. Nat Metab 2024; 6: 880-98.
60.
Ranade SD, Alegaon SG, Khatib NA, Gharge S, Kavalapure RS, Kumar BRP. Reversal of insulin resistance to combat type 2 diabetes mellitus by newer thiazolidinedione’s in fructose induced insulin resistant rats. Eur J Med Chem 2024; 280: 116939.
61.
Shannon CE, Ragavan M, Palavicini JP, et al. Insulin resistance is mechanistically linked to hepatic mitochondrial remodeling in non-alcoholic fatty liver disease. Mol Metab 2021; 45: 101154.
62.
Shannon CE, Daniele G, Galindo C, Abdul-Ghani MA, DeFronzo RA, Norton L. Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes. FEBS J 2017; 284: 451-65.
63.
Lefere S, Puengel T, Hundertmark J, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J Hepatol 2020; 73: 757-70.
64.
Mazhar IJ, Yasir M, Sarfraz S, et al. Vitamin E and pioglitazone: a comprehensive systematic review of their efficacy in non-alcoholic fatty liver disease. Cureus 2023; 15: e43635.
65.
Ratziu V, Giral P, Jacqueminet S, et al. Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled Fatty Liver Improvement with Rosiglitazone Therapy (FLIRT). Gastroenterology 2008; 135: 100-10.
66.
Mullur N, Morissette A, Morrow NM, Mulvihill EE. GLP-1 receptor agonist-based therapies and cardiovascular risk: a review of mechanisms. J Endocrinol 2024; 263: e240046.
67.
Davies MJ, Bergenstal R, Bode B, et al.; NN8022-1922 Study Group. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA 2015; 314: 687-99.
68.
Papaetis GS. Liraglutide therapy in a prediabetic state: rethinking the evidence. Curr Diabetes Rev 2020; 16: 699-715.
69.
Papaetis GS, Filippou PK, Constantinidou KG, Stylianou CS. Liraglutide: new perspectives for the treatment of polycystic ovary syndrome. Clin Drug Investig 2020; 40: 695-713.
70.
Papaetis GS, Kyriacou A. GLP-1 receptor agonists, polycystic ovary syndrome, and reproductive dysfunction: current research and future horizons. Adv Clin Exp Med 2022; 31: 1265-74.
71.
Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet 2022; 399: 259-69.
72.
Weghuber D, Barrett T, Barrientos-Pérez M, et al.; STEP TEENS Investigators. Once-weekly semaglutide in adolescents with obesity. N Engl J Med 2022; 387: 2245-57.
73.
Gabery S, Salinas CG, Paulsen SJ, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 2020; 5: e13342.
74.
Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016; 387: 679-90.
75.
Newsome PN, Buchholtz K, Cusi K, et al.; NN9931-4296 Investigators. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 2021; 384: 1113-24.
76.
Mantovani A, Byrne CD, Scorletti E, Mantzoros CS, Targher G. Efficacy and safety of anti-hyperglycemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: an updated systematic review of randomized controlled trials. Diabetes Metab 2020; 46: 427-41.
77.
Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Targher G. Glucagon-like peptide-1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta-analysis of randomized controlled trials. Metabolites 2021; 11: 73.
78.
Patel Chavez C, Cusi K, Kadiyala S. The emerging role of glucagon-like peptide-1 receptor agonists for the management of NAFLD. J Clin Endocrinol Metab 2022; 107: 29-38.
79.
Somm E, Montandon SA, Loizides-Mangold U, et al. The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet. Transl Res 2021; 227: 75-88.
80.
Goldenberg RM, Gilbert JD, Manjoo P, Pedersen SD, Woo VC, Lovshin JA. Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high-dose GLP-1 receptor agonists and GLP-1 receptor-based co-agonists. Obes Rev 2024; 25: e13663.
81.
Yabut JM, Drucker DJ. Glucagon-like peptide-1 receptor-based therapeutics for metabolic liver disease Endocr Rev 2023; 44: 14-32.
82.
Pyke C, Heller RS, Kirk RK, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 2014; 155: 1280-90.
83.
Hoffman S, Adeli K. Glucagon-like peptide (GLP)-1 regulation of lipid and lipoprotein metabolism. Med Rev 2024; 4: 301-11.
84.
Tsiampali C, Vachliotis ID, Goulas A, Polyzos SA. Animal studies on glucagon-like peptide-1 receptor agonists and related polyagonists in nonalcoholic fatty liver disease. Hormones (Athens) 2024; 23: 611-9.
85.
Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol Metab 2021; 46: 101090.
86.
Moreira GV, Azevedo FF, Ribeiro LM, et al. Liraglutide modulates gut microbiota and reduces NAFLD in obese mice. J Nutr Biochem 2018; 62: 143-54.
87.
Park MJ, Kim H, Kim MG, Kim K. Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: a network meta-analysis. Clin Mol Hepatol 2023; 29: 693-704.
88.
Papaetis GS. Empagliflozin and the diabetic kidney: pathophysiological concepts and future challenges. Endocr Metab Immune Disord Drug Targets 2021; 21: 1555-89.
89.
Papaetis GS. SGLT2 inhibitors and diabetic kidney disease: targeting multiple and interrelated signaling pathways for renal protection. Curr Mol Pharmacol 2023; doi: 10.2174/0118761429261105231011101200.
90.
Papaetis GS. SGLT2 inhibitors, intrarenal hypoxia and the diabetic kidney: insights into pathophysiological concepts and current evidence. Arch Med Sci Atheroscler Dis 2023; 8: e155-68.
91.
Liu S, Lam A, Wazir A, Cheema AN. SGLT2 inhibitors and the changing landscape for treatment of diabetes. Ther Clin Risk Manag 2019; 15: 861-7.
92.
Xiao L, Nie X, Cheng Y, Wang N. Sodium-glucose cotransporter-2 inhibitors in vascular biology: cellular and molecular mechanisms. Cardiovasc Drugs Ther 2021; 35: 1253-67.
93.
Papaetis GS. Empagliflozin therapy and insulin resistance-associated disorders: effects and promises beyond a diabetic state. Arch Med Sci Atheroscler Dis 2021; 6: e57-78.
94.
Neeland IJ, McGuire DK, Chilton R, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2016; 13: 119-26.
95.
Katsimardou A, Theofilis P, Vordoni A, Doumas M, Kalaitzidis RG. The effects of SGLT2 inhibitors on blood pressure and other cardiometabolic risk factors. Int J Mol Sci 2024; 25: 12384.
96.
Teo YH, Teo YN, Syn NL, et al. Effects of sodium/glucose cotransporter 2 (SGLT2) inhibitors on cardiovascular and metabolic outcomes in patients without diabetes mellitus: a systematic review and meta-analysis of randomized-controlled trials. J Am Heart Assoc 2021; 10: e019463.
97.
Dokmak A, Almeqdadi M, Trivedi H, Krishnan S. Rise of sodium-glucose cotransporter 2 inhibitors in the management of nonalcoholic fatty liver disease. World J Hepatol 2019; 11: 562-73.
98.
Raj H, Durgia H, Palui R, et al. SGLT-2 inhibitors in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus: a systematic review. World J Diabetes 2019; 10: 114-32.
99.
Li B, Wang Y, Ye Z, et al. Effects of canagliflozin on fatty liver indexes in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. J Pharm Pharm Sci 2018; 21: 222-35.
100.
Ong Lopez AMC, Pajimna JAT. Efficacy of sodium glucose cotransporter 2 inhibitors on hepatic fibrosis and steatosis in non-alcoholic fatty liver disease: an updated systematic review and meta-analysis. Sci Rep 2024; 14: 2122.
101.
Alfayez AI, Alfallaj JM, Mobark MA, Alalwan AA, Alfayez OM. An update on the effect of sodium glucose cotransporter 2 inhibitors on non-alcoholic fatty liver disease: a systematic review of clinical trials. Curr Diabetes Rev 2024; 20: e250523217349.
102.
Lombardi R, Mantovani A, Cespiati A, et al. Evolution of liver fibrosis in diabetic patients with NAFLD in a follow-up study: hepatoprotective effects of sodium-glucose co-transporter-2 inhibitors. Dig Liver Dis 2024; 56: 551-8.
103.
Takahashi H, Kessoku T, Kawanaka M, et al. Ipragliflozin improves the hepatic outcomes of patients with diabetes with NAFLD. Hepatol Commun 2022; 6: 120-32.
104.
Shimizu M, Suzuki K, Kato K, et al. Evaluation of the effects of dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on hepatic steatosis and fibrosis using transient elastography in patients with type 2 diabetes and non-alcoholic fatty liver disease. Diabetes Obes Metab 2019; 21: 285-92.
105.
Akuta N, Kawamura Y, Watanabe C, et al. Impact of sodium glucose cotransporter 2 inhibitor on histological features and glucose metabolism of non-alcoholic fatty liver disease complicated by diabetes mellitus. Hepatol Res 2019; 49: 531-9.
106.
Lai LL, Vethakkan SR, Nik Mustapha NR, Mahadeva S, Chan WK. Empagliflozin for the treatment of nonalcoholic steatohepatitis in patients with type 2 diabetes mellitus. Dig Dis Sci 2020; 65: 623-31.
107.
Scheen AJ. Beneficial effects of SGLT2 inhibitors on fatty liver in type 2 diabetes: a common comorbidity associated with severe complications. Diabetes Metab 2019; 45: 213-23.
108.
Wakamatsu S, Jojima T, Hashiguchi M, et al. Inhibition of IL-33 signaling ameliorate hepatic fibrosis with decreasing MCP-1 in a mouse model of diabetes and non-alcoholic steatohepatitis; comparison for luseogliflozin, an SGLT2 inhibitor. Diabetes Complications 2024; 38: 108650.
109.
Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, et al. Empagliflozin attenuates non-alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE(-/-) mice by activating autophagy and reducing ER stress and apoptosis. Int J Mol Sci 2021; 22: 818.
110.
Hsiang JC, Wong VW. SGLT2 inhibitors in liver patients. Clin Gastroenterol Hepatol 2020; 18: 2168-72.e2.
111.
Zhang E, Zhao Y, Hu H. Impact of sodium glucose cotransporter 2 inhibitors on nonalcoholic fatty liver disease complicated by diabetes mellitus. Hepatol Commun 2021; 5: 736-48.
112.
Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite -hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 2015; 21: 263-9.
113.
Tahara A, Takasu T. SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model. Physiol Rep 2019; 7: e14286.
114.
Tahara A. Effects of SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone on fluid retention in type 2 diabetic mice with NASH. Eur J Pharmacol 2021; 901: 174076.
115.
Shaaban HH, Alzaim I, El-Mallah A, Aly RG, El-Yazbi AF, Wahid A. Metformin, pioglitazone, dapagliflozin and their combinations ameliorate manifestations associated with NAFLD in rats via anti-inflammatory, anti-fibrotic, anti-oxidant and anti-apoptotic mechanisms. Life Sci 2022; 308: 120956.
116.
Yoneda M, Kobayashi T, Honda Y, et al. Combination of tofogliflozin and pioglitazone for NAFLD: extension to the ToPiND randomized controlled trial. Hepatol Commun 2022; 6: 2273-85.
117.
Yoneda M, Honda Y, Ogawa Y, et al. Comparing the effects of tofogliflozin and pioglitazone in non-alcoholic fatty liver disease patients with type 2 diabetes mellitus (ToPiND study): a randomized prospective open-label controlled trial. BMJ Open Diabetes Res Care 2021; 9: e001990.
118.
Pirola CJ, Garaycoechea M, Flichman D, Castaño GO, Sookoian S. Liver mitochondrial DNA damage and genetic variability of Cytochrome b – a key component of the respirasome – drive the severity of fatty liver disease. J Intern Med 2021; 289: 84-96.
119.
de Alteriis G, Pugliese G, Di Sarno A, et al. Visceral obesity and cytokeratin-18 antigens as early biomarkers of liver damage. Int J Mol Sci 2023; 24: 10885.
120.
Lim S, Lee SH, Min KW, et al. A multicentre, double-blind, placebo-controlled, randomized, parallel comparison, phase 3 trial to evaluate the efficacy and safety of pioglitazone add-on therapy in type 2 diabetic patients treated with metformin and dapagliflozin. Diabetes Obes Metab 2024; 26: 2188-98.
121.
Effect of Oral Anti-diabetic Medication on Liver Fat in Subjects With Type II Diabetes and Non-alcoholic Fatty Liver. ClinicalTrials.gov. NCT04976283.
122.
Comparison of The Effects of Thiazolidinediones(TZD), Sodium- Glucose Cotransporter 2 Inhibitors(SGLT2i) Alone and TZD/SGLT2i Combination Therapy on Non-alcoholic Fatty Liver Disease in Type 2 Diabetic Patients With Fatty Liver. ClinicalTrials.gov. NCT03646292.
123.
Efficacy of Empagliflozin and Pioglitazone in Diabetic Patients With NAFLD. ClinicalTrials.gov.
124.
Sathyanarayana P, Jogi M, Muthupillai R, Krishnamurthy R, Samson SL, Bajaj M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity (Silver Spring) 2011; 19: 2310-5.
125.
Ritchie M, Hanouneh IA, Noureddin M, Rolph T, Alkhouri N. Fibroblast growth factor (FGF)-21 based therapies: a magic bullet for nonalcoholic fatty liver disease (NAFLD)? Expert Opin Investig Drugs 2020; 29: 197-204.
126.
Samson SL, Sathyanarayana P, Jogi M, et al. Exenatide decreases hepatic fibroblast growth factor 21 resistance in non-alcoholic fatty liver disease in a mouse model of obesity and in a randomised controlled trial. Diabetologia 2011; 54: 3093-100.
127.
Abdul-Ghani A, Puckett C, Adams J, et al. Durability of triple combination therapy versus stepwise addition therapy in new onset T2DM subjects: 3-year follow-up of EDICT. Diabetes Care 2021; 44: 433-9.
128.
Lavynenko O, Abdul-Ghani M, Alatrach M, et al. Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT). Diabetes Obes Metab 2022; 24: 899-907.
129.
Harrison SA, Loomba R, Dubourg J, Ratziu V, Noureddin M. Clinical trial landscape in NASH. Clin Gastroenterol Hepatol 2023; 21: 2001-14.
130.
Nassir F. NAFLD: mechanisms, treatments, and biomarkers. Biomolecules 2022; 12: 824.
131.
Papaetis GS, Mikellidis KC. Insulin degludec in pregestational diabetes: evidence and perspectives. Arch Med Sci Atheroscler Dis 2024; 9: e86-93.
132.
Harrison SA, Allen AM, Dubourg J, Noureddin M, Alkhouri N. Challenges and opportunities in NASH drug development. Nat Med 2023; 29: 562-73.
133.
Rong L, Zou J, Ran W, et al. Advancements in the treatment of non-alcoholic fatty liver disease (NAFLD). Front Endocrinol (Lausanne) 2023; 13: 1087260.
134.
Miyake T, Yoshida O, Matsuura B, et al. Additional effect of luseogliflozin on semaglutide in nonalcoholic steatohepatitis complicated by type 2 diabetes mellitus: an open-label, randomized, parallel-group study. Diabetes Ther 2022; 13: 1083-96.
135.
Lin YH, Zhang ZJ, Zhong JQ, et al. Semaglutide combined with empagliflozin vs. monotherapy for non-alcoholic fatty liver disease in type 2 diabetes: Study protocol for a randomized clinical trial. PLoS One 2024; 19: e0302155.
136.
Gastaldelli A, Cusi K, Fernandez Lando L, et al. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol 2022; 10: 393-406.
137.
Loomba R, Hartman ML, Lawitz EJ, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med 2024; 391: 299-310.
138.
Ciardullo S, Muraca E, Vergani M, Invernizzi P, Perseghin G. Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions. Gastroenterol Rep (Oxf) 2024; 12: goae029.
139.
Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. Endocrinol Metab Clin North Am 2005; 34: 49-62.
140.
Anson M, Henney AE, Zhao SS, et al. Effect of combination pioglitazone with sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide-1 receptor agonists on outcomes in type 2 diabetes: a systematic review, meta-analysis, and real-world study from an international federated database. Diabetes Obes Metab 2024; 26: 2606-23.
141.
Moon JS, Hong JH, Jung YJ, Ferrannini E, Nauck MA, Lim S. SGLT-2 inhibitors and GLP-1 receptor agonists in metabolic dysfunction-associated fatty liver disease. Trends Endocrinol Metab 2022; 33: 424-42.
142.
Abdelmalek MF, Harrison SA, Sanyal AJ. The role of glucagon-like peptide-1 receptor agonists in metabolic dysfunction-associated steatohepatitis. Diabetes Obes Metab 2024; 26: 2001-16.
143.
Ye Q, Zou B, Yeo YH, et al. Global prevalence, incidence, and outcomes of non-obese or lean non-alcoholic fatty liver disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2020; 5: 739-52.
144.
Wei S, Wang L, Evans PC, Xu S. NAFLD and NASH: etiology, targets and emerging therapies. Drug Discov Today 2024; 29: 103910.
145.
Parola M, Pinzani M. Liver fibrosis in NAFLD/NASH: from pathophysiology towards diagnostic and therapeutic strategies. Mol Aspects Med 2024; 95: 101231.
146.
Ratziu V, Charlton M. Rational combination therapy for NASH: Insights from clinical trials and error. J Hepatol 2023; 78: 1073-9.
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