Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease

Table 1 Effects on non-alcoholic fatty liver disease of drugs that have strong evidence of benefit on heart failure

Drug	HF phenotype with evidence of benefit	Effect on NAFLD Population	Comparator	Study
ACEI	HFrEF	Reduced liver-related events, liver cancer, and cirrhosis complications[47]	Placebo	Cohort
ARB	HFrEF	Trial failed to evidence that losartan 50 mg has antifibrotic effects on NASH due to widespread use[102]	Placebo	Trial
		Patients with CKD-NAFLD taking ACEI or ARB had significantly lower liver stiffness degrees in comparison to those without those drugs[103]	Placebo	Cohort
		Losartan 100 mg in children reduced alkaline phosphatase, but not ALT at 24 wk[104]	Placebo	Trial
		Losartan 50 mg in children reduced ALT more frequently than those patients with placebo[105]	Placebo	Trial
		Telmisartan 40 mg reduced free fatty acid level and increased liver-to-spleen ratio in diabetic patients with NAFLD[106]	Losartan	Trial
		Telmisartan had similar effects to vitamin E in NAFLD histology[107]	Vitamin E	Trial
		Telmisartan 40/80 mg improved NAFLD activity score and fibrosis in NASH[108]	Lifestyle modification	Trial
		Telmisartan and olmesartan improved HOMA-IR and ALT levels[48]	Before-after comparison	Quasiexperimental
		Losartan significantly decreased steatosis degree and visceral adipose tissue, addition of simvastatin further decreased those parameters[109]	Amlodipine and simvastatin	Trial
		Amlodipine, lisinopril and rosuvastatin decreased ALT and alkaline phosphatase[110]	Therapy without rosuvastatin	Trial
Diuretics	HFrEF and congested HFpEF	In patients with NAFLD and diabetes lisinopril and hydrochlorothiazide were associated with less likelihood of advanced fibrosis, while furosemide and spironolactone had higher likelihood of it[111]	Other therapies	Cohort
		Spironolactone and vitamin E reduced NAFLD liver fat score, insulin, and HOMA-IR[55,112]	Vitamin E alone	Trial
		Five subjects received eplerenone. The study stopped early due to an unexpected increase in hepatic fat at 24 wk[113]		Open-label proof-of-concept study
SGLT2 inhibitors	HFrEF and HFpEF	Empagliflozin reduced liver stiffness measurement and steatosis (in patients with significant steatosis at baseline), liver fat level, AST, ALT and insulin in patients with NAFLD without diabetes[114]	Placebo	Trial
		Tofogliflozin significantly improved the fibrosis scores, steatosis, hepatocellular ballooning, and lobular inflammation[115]	Glimepiride	Trial
		Empagliflozin plus diabetes therapy better-improved liver fat in NAFLD patients with diabetes[116]	Diabetes therapy without empagliflozin	Trial
		Dapagliflozin and omega-3 carboxylic acids reduced liver fat[117]	Placebo	Trial
		Ipragliflozin as add-on diabetes therapy reduced liver steatosis in NAFLD patients with diabetes[118]	Metformin and pioglitazone	Trial
		Empagliflozin was associated with reduction of ALT, liver stiffness and controlled attenuation parameter in patients with NAFLD and diabetes[119]	Before-after comparison	Cohort
		Luseogliflozin improved liver-to-spleen ratio and liver fat in NAFLD patients with diabetes[120]	Metformin	Trial
		Dapagliflozin and pioglitazone significantly increased liver-to-spleen ratio. Only dapagliflozin decreased visceral fat area in patients with NAFLD and diabetes[121]	Pioglitazone and glimepiride	Trial
		Ipragliflozin reduced visceral fat area, but not AST or ALT, in patients with NAFLD and diabetes[122]	Pioglitazone	Trial

ACEI: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin receptor blockers; HFrEF: Heart failure with reduced ejection fraction; HFpEF: Heart failure preserved ejection fraction; NASH: Non-alcoholic Steatohepatitis; CKD: Chronic kidney disease; NAFLD: Nonalcoholic fatty liver disease; ALT: Alanine aminotransferases; AST: Aspartate aminotransferases; SGLT2: Sodium-glucose cotransporter 2; HOMA-IR: Homeostatic model assessment for insulin resistance.