Abstract
Background: Non-alcoholic fatty liver disease (NAFLD), affecting over 25% of the general population worldwide, is characterized by a spectrum of clinical and histological manifestations ranging from simple steatosis (>5% hepatic fat accumulation without inflammation) to non-alcoholic steatohepatitis (NASH) which is characterized by inflammation, and finally fibrosis, often leading to liver cirrhosis, and hepatocellular carcinoma. Up to 70% of patients with type 2 diabetes mellitus (T2DM) have NAFLD, and diabetics have much higher rates of NASH compared with the general non-diabetic population.
Objective: The aim of this study is to report recent approaches to NAFLD/NASH treatment in T2DM patients. To-date, there are no approved treatments for NAFLD (apart from lifestyle measures).
Results: Current guidelines (2016) from 3 major scientific organizations suggest that pioglitazone and vitamin E may be useful in a subset of patients for adult NAFLD/NASH patients with T2DM. Newer selective PPAR-γ modulators (SPPARMs, CHRS 131) have shown to provide even better results with fewer side effects in both animal and human studies in T2DM. Newer antidiabetic drugs might also be useful, but detailed studies with histological outcomes are largely lacking. Nevertheless, prior animal and human studies on incretin mimetics, glucagon-like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD. Sodium-glucoseco-transporter-2 inhibitors (SGLT2i) have been reported to improve NAFLD/NASH. Statins, being necessary for most patients with T2DM, may also ameliorate NAFLD/NASH, and could potentially reinforce the beneficial effects of the newer antidiabetic drugs, if used in combination, but this remains to be identified.
Conclusion: Newer antidiabetic drugs (SPPARMs, GLP-1 RA and SGLT2i) alone or in combination and acting alone or with potent statin therapy which is recommended in T2DM, might contribute substantially to NAFLD/NASH amelioration, possibly reducing not only liver-specific but also cardiovascular morbidity. These observations warrant long term placebo-controlled randomized trials with appropriate power and outcomes, focusing on the general population and more specifically on T2DM with NAFLD/NASH. Certain statins may be useful for treating NAFLD/NASH, while they substantially reduce cardiovascular disease risk.
Keywords: Dipeptidyl dipeptidase-4 inhibitors, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, glucagon like peptide-1 receptor agonists, sodium-glucose co-transporter-2 inhibitors, atorvastatin, combination treatment, type 2 diabetes mellitus.
Graphical Abstract
[1]
Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103: 137-49.
[2]
El-Zayadi AR. Hepatic steatosis: A benign disease or a silent killer. World J Gastroenterol 2008; 14: 4120-6.
[3]
Charlton MR, Burns JM, Pedersen RA, et al. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 2011; 141: 1249-53.
[4]
Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015; 148: 547-55.
[5]
Musso G, Gambino R, Cassader M, et al. Meta-analysis: Natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011; 43: 617-49.
[6]
Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: A systematic review and meta-analysis. PLoS Med 2014; 11: e1001680
[7]
Agarwal AK, Jain V, Singla S, et al. Prevalence of non-alcoholic fatty liver disease and its correlation with coronary risk factors in patients with type 2 diabetes. J Assoc Physicians India 2011; 59: 351-4.
[8]
Chan WK, Goh KL. Epidemiology of a fast emerging disease in the Asia-Pacific region-non-alcoholic fatty liver disease. Hepatol Int 2013; 7: 65-71.
[9]
Targher G, Bertolini L, Padovani R, et al. Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients. Diabetes Care 2007; 30: 1212-8.
[10]
Tuttle KR, Bakris GL, Bilous RW, et al. Diabetic kidney disease: A report from an ADA Consensus Conference. Diabetes Care 2014; 37: 2864-83.
[11]
Targher G, Byrne CD. Non-alcoholic fatty liver disease: An emerging driving force in chronic kidney disease. Nat Rev Nephrol 2017; 13: 297-310.1.
[12]
Targher G, Chonchol M, Pichiri I, et al. Risk of cardiovascular disease and chronic kidney disease in diabetic patients with non-alcoholic fatty liver disease: Just a coincidence? J Endocrinol Invest 2011; 34: 544-51.
[13]
Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 1296-305.
[14]
Harper CR, Jacobson TA. Managing dyslipidemia in chronic kidney disease. J Am Coll Cardiol 2008; 51: 2375-84.
[15]
Parfrey PS, Foley RN, Harnett JD, et al. Outcome and risk factors of ischemic heart disease in chronic uremia. Kidney International 1996; 49: 1428-34.
[16]
Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: A statement from the american heart association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Hypertension 2003; 42: 1050-65.
[17]
National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification and stratification. Am J Kidney Dis 2002; 39(2)(Suppl. 1): S1-S266.
[18]
Metsärinne K, Bröijersen A, Kantola I, et al. High prevalence of chronic kidney disease in Finnish patients with type 2 diabetes treated in primary care. Prim Care Diabetes 2015; 9: 31-8.
[19]
Li Y, Zhu S, Li B, et al. Association between non-alcoholic fatty liver disease and chronic kidney disease in population with prediabetes or diabetes. Int Urol Nephrol 2014; 46: 1785-91.
[20]
Nguyen V, George J. Nonalcoholic fatty liver disease management: dietary and lifestyle modifications. Semin Liver Dis 2015; 35: 318-37.
[21]
Athyros VG, Tziomalos K, Katsiki N, et al. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: An update. World J Gastroenterol 2015; 21: 6820-34.
[22]
EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. 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 2016; 64: 1388-402.
[23]
Polyzos SA, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: A systematic review. Metabolism 2016; 65: 1297-306.
[24]
Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism 2016; 65: 1062-79.
[25]
Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis. N Engl J Med 2010; 362: 1675-85.
[26]
Polyzos SA, Kountouras J, Mantzoros CS, et al. Effects of combined low-dose spironolactone plus vitamin E vs. vitamin E monotherapy on insulin resistance, non-invasive indices of steatosis and fibrosis, and adipokine levels in non-alcoholic fatty liver disease: A randomized controlled trial. Diabetes Obes Metab 2017; 19: 1805-9.
[27]
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: 2297-307.
[28]
Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 2008; 135: 1176-84.
[29]
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). Trial Gastroenterology 2008; 135: 100-10.
[30]
Ratziu V, Charlotte F, Bernhardt C, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: Results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51: 445-53.
[31]
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: 305-15.
[32]
Skat-Rørdam J, Højland Ipsen D, Lykkesfeldt J, Tveden-Nyborg P. A role of peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease. Basic Clin Pharmacol Toxicol 2019; 124(5): 528-37.
[33]
Raschi E, Mazzotti A, Poluzzi E, De Ponti F, Marchesini G. Pharmacotherapy of type 2 diabetes in patients with chronic liver disease: focus on nonalcoholic fatty liver disease. Expert Opin Pharmacother 2018; 19(17): 1903-14.
[34]
Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes. Cell Metab 2014; 20: 573-91.
[35]
Sahebkar A, Chew GT, Watts GF. New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opin Pharmacother 2014; 15: 493-503.
[36]
Higgins LS, Mantzoros CS. The development of INT131 as a selective PPAR gamma modulator: Approach to a safer insulin sensitizer. PPAR Res 2008; 2008: 936906
[37]
Chiarelli F, Di Marzio D. Peroxisome proliferator-activated receptor-gamma agonists and diabetes: Current evidence and future perspectives. Vasc Health Risk Manag 2008; 4: 297-304.
[38]
Polyzos SA, Kountouras J, Mantzoros CS. Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol 2017; 42: 92-108.
[39]
Boutari C, Perakakis N, Mantzoros CS. Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinol Metab (Seoul) 2018; 33: 33-43.
[40]
Blüher M, Mantzoros CS. From leptin to other adipokines in health and disease: Facts and expectations at the beginning of the 21st century. Metabolism 2015; 64: 131-45.
[41]
Lee DH, Huang H, Choi K, et al. Selective PPARγ modulator INT131 normalizes insulin signaling defects and improves bone mass in diet-induced obese mice. Am J Physiol Endocrinol Metab 2012; 302: E552-60.
[42]
Xie X, Chen W, Zhang N, et al. Selective tissue distribution mediates tissue-dependent PPARg activation and insulin sensitization by INT131, a selective PPARg modulator. Front Pharmacol 2017; 8: 317.
[43]
DePaoli AM, Higgins LS, Henry RR, et al. INT131-007 Study Group. Can a selective PPARγ modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone? Diabetes Care 2014; 37: 1918-23.
[44]
Boutari C, Mantzoros CS. Inflammation: A key player linking obesity with malignancies. Metabolism 2018; 81: A3-6.
[45]
Ríos-Vázquez R, Marzoa-Rivas R, Gil-Ortega I, et al. Peroxisome proliferator-activated receptor-gamma agonists for management and prevention of vascular disease in patients with and without diabetes mellitus. Am J Cardiovasc Drugs 2006; 6: 231-42.
[46]
Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 2016; 150: 1147-59.
[47]
Lee YH, Kim JH, Kim SR, et al. Lobeglitazone, a novel thiazolidinedione, improves non-alcoholic fatty liver disease in type 2 diabetes: its efficacy and predictive factors related to responsiveness. J Korean Med Sci 2017; 32: 60-9.
[48]
Jespersen MJ, Knop FK, and Christensen M. GLP-1 agonists for type 2 diabetes: Pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 2013; 9: 17-29.
[49]
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.
[50]
Wong VW, Wong GL. A LEAN treatment for non-alcoholic steatohepatitis. Lancet 2016; 387: 628-30.
[51]
Guss DA, Mohanty SR. Liraglutide’s use in treatment of non-alcoholic fatty liver: An evaluation of the non-alcoholic steatohepatitis study. Hepatobiliary Surg Nutr 2016; 5: 515-8.
[52]
Gaborit B, Darmon P, Ancel P, et al. Liraglutide for patients with non-alcoholic steatohepatitis. Lancet 2016; 387: 2378-9.
[53]
Ohki T, Isogawa A, Iwamoto M, et al. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. ScientificWorldJournal 2012; 2012: 496453
[54]
Armstrong MJ, Houlihan DD, Rowe IA, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: Individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther 2013; 37: 234-42.
[55]
Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER steering committee; LEADER trial investigators. liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-22.
[56]
Feng W, Gao C, Bi Y, et al. Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease. J Diabetes 2017; 9: 800-9.
[57]
Bouchi R, Nakano Y, Fukuda T, et al. Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: A randomized control trial. Endocr J 2017; 64: 269-81.
[58]
Rizvi AA, Patti AM, Giglio RV, et al. Liraglutide improves carotid intima-media thickness in patients with type 2 diabetes and non-alcoholic fatty liver disease: An 8-month prospective pilot study. Expert Opin Biol Ther 2015; 15: 1391-7.
[59]
Li S, Wang X, Zhang J, et al. Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease. Braz J Med Biol Res 2018; 51: e7299
[60]
Fan H, Pan Q, Xu Y, et al. Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. Arq Bras Endocrinol Metabol 2013; 57: 702-8.
[61]
Shao N, Kuang HY, Hao M, et al. Benefits of exenatide on obesity and non-alcoholic fatty liver disease with elevated liver enzymes in patients with type 2 diabetes. Diabetes Metab Res Rev 2014; 30: 521-9.
[62]
Liu J, Wang G, Jia Y, et al. GLP-1 receptor agonists: Effects on the progression of non-alcoholic fatty liver disease. Diabetes Metab Res Rev 2015; 31: 329-35.
[63]
Ding X, Saxena NK, Lin S, et al. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006; 43: 173-81.
[64]
Valdecantos MP, Pardo V, Ruiz L, et al. A novel glucagon-like peptide 1/glucagon receptor dual agonist improves steatohepatitis and liver regeneration in mice. Hepatology 2017; 65: 950-68.
[65]
Iogna Prat L, Tsochatzis EA. The effect of antidiabetic medications on non-alcoholic fatty liver disease (NAFLD). Hormones (Athens) 2018; 17: 219-29.
[66]
Yilmaz Y, Yonal O, Deyneli O, et al. Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis. Acta Gastroenterol Belg 2012; 75: 240-4.
[67]
Nakamura K, Fukunishi S, Yokohama K, et al. A long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, as a preventive drug for the development of hepatic steatosis in high-fructose diet-fed ob/ob mice. Int J Mol Med 2017; 39: 969-83.
[68]
Cui J, Philo L, Nguyen P, et al. Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial. J Hepatol 2016; 65: 369-76.
[69]
Joy TR, McKenzie CA, Tirona RG, et al. Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial. World J Gastroenterol 2017; 23: 141-50.
[70]
Barb D, Portillo-Sanchez P, Cusi K. Pharmacological management of nonalcoholic fatty liver disease. Metabolism 2016; 65: 1183-95.
[71]
Wells RG, Mohandas TK, Hediger MA. Localization of the Na+/glucose co-transporter gene SGLT2 to human chromosome 16 close to the centromere. Genomics 1993; 17: 787-9.
[72]
Haas B, Eckstein N, Pfeifer V, et al. Efficacy, safety and regulatory status of SGLT2 inhibitors: Focus on canagliflozin. Nutr Diabetes 2014; 4: e143
[73]
Stenlof K, Cefalu WT, Kim KA, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013; 15: 372-82.
[74]
Honda Y, Imajo K, Kato T, et al. The selective SGLT2 inhibitor ipragliflozin has a therapeutic effect on nonalcoholic steatohepatitis in mice. PLoS One 2016; 11: e0146337
[75]
Hayashizaki-Someya Y, Kurosaki E, Takasu T, et al. Ipragliflozin, an SGLT2 inhibitor, exhibits a prophylactic effect on hepatic steatosis and fibrosis induced by choline-deficient l-amino acid-defined diet in rats. Eur J Pharmacol 2015; 754: 19-24.
[76]
Jojima T, Tomotsune T, Iijima T, et al. Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes. Diabetol Metab Syndr 2016; 8: 45.
[77]
Kern M, Klöting N, Mark M, Mayoux E, Klein T, Blüher M. The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as mono therapy and in combination with linagliptin. Metabolism 2016; 65: 114-23.
[78]
Cheng ST, Chen L, Li SY, et al. The Effects of empagliflozin, an SGLT2 inhibitor, on pancreatic β-Cell mass and glucose homeostasis in type 1 diabetes. PLoS One 2016; 11: e0147391
[79]
Kern M, Klöting N, Mark M, et al. The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as mono therapy and in combination with linagliptin. Metabolism 2016; 65: 114-23.
[80]
Kuchay MS, Krishan S, Mishra SK, et al. Effect of empagliflozin
on liver fat in patients with type 2 diabetes and nonalcoholic fatty
liver disease: A randomized controlled trial (E-LIFT Trial) diabetes
care 2018; 41: 1801-8.
[81]
Kurinami N, Sugiyama S, Yoshida A, et al. Dapagliflozin significantly reduced liver fat accumulation associated with a decrease in abdominal subcutaneous fat in patients with inadequately controlled type 2 diabetes mellitus. Diabetes Res Clin Pract 2018; 142: 254-63.
[82]
Sugiyama S, Jinnouchi H, Kurinami N, et al. Dapagliflozin reduces fat mass without affecting muscle mass in type 2 diabetes. J Atheroscler Thromb 2018; 25: 467-76.
[83]
Lee PCH, Gu Y, Yeung MY, et al. Dapagliflozin and empagliflozin ameliorate hepatic dysfunction among chinese subjects with diabetes in part through glycemic improvement: A single-center, retrospective, observational study. Diabetes Ther 2018; 9: 285-95.
[84]
Tang L, Wu Y, Tian M, et al. Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes. Am J Physiol Endocrinol Metab 2017; 313: E563-76.
[85]
Terami N, Ogawa D, Tachibana H, et al. Long-term treatment with the sodium glucose co-transporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One 2014; 9: e100777
[86]
Sugiyama S, Jinnouchi H, Kurinami N, et al. Impact of dapagliflozin therapy on renal protection and kidney morphology in patients with uncontrolled type 2 diabetes mellitus. J Clin Med Res 2018; 10: 466-77.
[87]
Cherney D, Lund SS, Perkins BA, et al. The effect of sodium glucose co-transporter 2 inhibition with empagliflozin on micro albuminuria and macro albuminuria in patients with type 2 diabetes. Diabetologia 2016; 59: 1860-70.
[88]
Wanner C, Inzucchi SE, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323-34.
[89]
Zinman B, Wanner C, Lachin JM, et al. Empa-Reg Outcome Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-28.
[90]
Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and heart failure in type 2 diabetes mellitus: Results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018; 138: 458-68.
[91]
Layton AT, Vallon V. SGLT2 inhibition in a kidney with reduced nephron number: Modeling and analysis of solute transport and metabolism. Am J Physiol Renal Physiol 2018; 314: F969-84.
[92]
Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation 2017; 136: 1643-58.
[93]
Athyros VG, Alexandrides TK, Bilianou H, et al. The use of statins alone, or in combination with pioglitazone and other drugs, for the treatment of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and related cardiovascular risk. An Expert Panel Statement. Metabolism 2017; 71: 17-32.
[94]
Athyros VG, Tziomalos K, Gossios TD, et al. GREACE study collaborative group. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: A post-hoc analysis. Lancet 2010; 376: 1916-22.
[95]
Tikkanen MJ, Fayyad R, Faergeman O, et al. IDEAL investigators. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol 2013; 168: 3846-52.
[96]
Athyros VG, Elisaf MS, Alexandrides T, et al. Assessing the Treatment Effect in Metabolic Syndrome without Perceptible Diabetes (ATTEMPT) collaborative group. Long-term impact of multifactorial treatment on new-onset diabetes and related cardiovascular events in metabolic syndrome: A post hoc ATTEMPT analysis. Angiology 2012; 63: 358-66.
[97]
Kargiotis K, Athyros VG, Giouleme O, et al. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome. World J Gastroenterol 2015; 21: 7860-8.
[98]
Dongiovanni P, Petta S, Mannisto V, et al. Statin use and non-alcoholic steatohepatitis in at risk individuals. J Hepatol 2015; 63: 705-12.
[99]
Nascimbeni F, Aron-Wisnewsky J, Pais R, et al. Statins, antidiabetic medications and liver histology in patients with diabetes with non-alcoholic fatty liver disease. BMJ Open Gastroenterol 2016; 3: e000075
[100]
Bril F, Portillo Sanchez P, et al. Liver safety of statins in prediabetes or t2dm and nonalcoholic steatohepatitis: Post hoc analysis of a randomized trial. J Clin Endocrinol Metab 2017; 102: 2950-61.
[101]
Mills EP, Brown KPD, Smith JD, et al. Treating nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: A review of efficacy and safety. Ther Adv Endocrinol Metab 2018; 9: 15-28.
[102]
Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol 2004; 57: 728-34.
[103]
Shepherd J, Kastelein JJ, Bittner V, et al. TNT (Treating to New Targets) Investigators. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: The TNT (Treating to New Targets) study. J Am Coll Cardiol 2008; 51: 1448-54.
[104]
Shepherd J, Kastelein JJ, Bittner V, et al. Treating to new targets investigators. effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: The treating to new targets (TNT) study. Clin J Am Soc Nephrol 2007; 2: 1131-9.
[105]
Shepherd J, Breazna A, Deedwania PC, et al. Treating to new targets steering committee and investigators. Relation between change in renal function and cardiovascular outcomes in atorvastatin-treated patients (from the treating to new targets [TNT] study). Am J Cardiol 2016; 117: 1199-205.
[106]
Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015; 19: 361-79.
[107]
Wild SH, Walker JJ, Morling JR, et al. Scottish diabetes research network epidemiology group. Cardiovascular disease, cancer, and mortality among people with type 2 diabetes and alcoholic or nonalcoholic fatty liver disease hospital admission. Diabetes Care 2018; 41: 341-7.
[108]
Pang Y, Kartsonaki C, Turnbull I, et al. Diabetes, plasma glucose and incidence of fatty liver, cirrhosis and liver cancer: A prospective study of 0.5 million people. Hepatology 2018; 68: 1308-18.
[109]
Noureddin M, Rinella ME. Nonalcoholic fatty liver disease, diabetes, obesity, and hepatocellular carcinoma. Clin Liver Dis 2015; 19: 361-79.
[110]
Yokohama K, Fukunishi S, Ii M, Nakamura K, et al. Rosuvastatin as a potential preventive drug for the development of hepatocellular carcinoma associated with non-alcoholic fatty liver disease in mice. Int J Mol Med 2016; 38: 1499-506.
[111]
Carbone LJ, Angus PW, Yeomans ND. Incretin-based therapies for the treatment of non-alcoholic fatty liver disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2016; 31: 23-31.
[112]
Seko Y, Sumida Y, Tanaka S, et al. Effect of sodium glucose co-transporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol Res 2017; 47: 1072-8.
[113]
Doumas M, Imprialos K, Stavropoulos K, et al. Combination of SGLT-2 inhibitors and GLP-1 receptor agonists: Potential benefits in surrogate and hard endpoints. Curr Pharm Des 2018; 24: 1879-86.
[114]
Busch RS, Kane MP. Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: A complementary approach to the treatment of type 2 diabetes. Postgrad Med 2017; 129: 686-97.
[115]
Katsiki N, Mikhailidis DP, Theodorakis MJ. Sodium-glucose cotransporter 2 inhibitors (SGLT2i): Their role in cardiometabolic risk management. Curr Pharm Des 2017; 23(10): 1522-32.
[116]
Marso SP, Daniels GH, Brown-Frandsen K, et al. LEADER steering committee; LEADER trial investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-22.
[117]
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-57.
[118]
Yuan Z, DeFalco FJ, Ryan PB, et al. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: A retrospective cohort study. Diabetes Obes Metab 2018; 20: 582-9.
[119]
Inzucchi SE, Iliev H, Pfarr E, et al. Empagliflozin and assessment of lower-limb amputations in the Empa-Reg Outcome Trial. Diabetes Care 2018; 41: e4-5.
[120]
Kohler S, Zeller C, Iliev H, et al. Safety and tolerability of empagliflozin in patients with type 2 diabetes. Pooled Analysis of Phase I-III Clinical Trials Adv Ther 2017; 34: 1707-26.
Call for Papers in Thematic Issues
31 January, 2025
TREATMENT OF CARDIOVASCULAR DISEASE IN CHRONIC AND END STAGE KIDNEY DISEASE
Cardiovascular disease still remains the leading cause of death in Chronic and End Stage Kidney Disease, accounting for more than half of all deaths in dialysis patients. During the past decade, research has been focused on novel therapeutic agents that might delay or even reverse cardiovascular disease and vascular calcification, ...read more
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