Nonalcoholic fatty liver disease and the risk of metabolic comorbidities: how to manage in clinical practice

REVIEW ARTICLE NAFLD and the management of comorbidities 975 syndrome need to be examined for therisk of NAFLD and, vice versa, patients with NAFLD should be evaluated for all components of met‑ abolic syndrome.4 Physicians face thechallenge of theearly diag‑ nosis and intervention in NAFLD, and there are few pharmacological agents with proven effica‑ cy. It is necessary to proactively assess thepres‑ ence of cardiovascular disease in patients with NAFLD, regardless of thepresence or absence of classic risk factors. 5 Themanagement of themet‑ abolic overload of NAFLD, including weight loss, cardiovascular protection, insulin sensitization, and lipid reduction, is currently theonly strategy to improve hepatic and extrahepatic outcomes. In this review, we aimed to characterize theman‑ agement of themain metabolic disorders asso‑ ciated with NAFLD, such as T2D, arterial hyper‑ tension, and dyslipidemia. Introduction Nonalcoholic fatty liver disease (NAFLD) is aclinicopathological syndrome as‑ sociated with metabolic syndrome, defined as acluster of 3 of thefollowing features: increased waist circumference, abnormal fasting glucose levels or type 2 diabetes (T2D), arterial hyper‑ tension, hypertriglyceridemia, and low levels of high ‑density lipoprotein (HDL) cholesterol.1 Arecent meta ‑analysis involving 8.5 million in‑ dividuals from 22 countries has shown that more than 80% of patients with NAFLD were obese, 72% had dyslipidemia, and 44% had T2D.2 This association is due to theoverlapping of NAFLD pathogenetic mechanisms with those of meta‑ bolic syndrome, including genetic predisposition, insulin resistance (IR), oxidative stress, chronic and systemic microinflammation, and reduced adiponectin levels.3 Owing to this strong asso‑ ciation, patients who present with metabolic REVIEW ARTICLE Nonalcoholic fatty liver disease and therisk of metabolic comorbidities: how to manage in clinical practice CarolinaPerdomo 1* , PaolaD’Ingianna 2* , JavierEscalada 1,5 , SalvatorePetta 2 , ManuelRomeroGómez 3,4 , JavierAmpuero 3,4 1 Department of Endocrinology and Nutrition, Healthcare Research Institute of Navarra (IdiSNA), University of Navarra, Navarra, Spain 2 Hepatology, PROMISE (Dipartimento di Promozione della Salute, Materno Infantile, Medicina Interna e Specialistica di Eccellenza), University of Palermo, Palermo, Italy 3 Institute of Biomedicine, Virgen del Rocío University Hospital, University of Seville, Seville, Spain 4 Center for Biomedical Research Network – Liver and Digestive Diseases (CIBERehd), Madrid, Spain 5 Center for Biomedical Research Network – Physiopathology of Obesity and Nutrition (CIBERObn), Madrid, Spain Correspondence to: Javier Ampuero, MD, PhD, Virgen del Rocío University Hospital, Avenida Manuel Siurot s/n, 41013 Sevilla, Spain, phone: +34 955 015761, email: jampuero ‑[email protected] Received: June 15, 2020. Accepted: June 16, 2020. Published online: July 14, 2020. Pol Arch Intern Med. 2020; 130 (11): 975‑985 doi:10.20452/pamw.15510 Copyright by the Author(s), 2020 * CP and PD contributed equally to this work. KEy WoRds arterial hypertension, dyslipidemia, nonalcoholic fatty liver disease, type 2 diabetes AbsTRACT Nonalcoholic fatty liver disease (NAFLD) is a clinical condition that encompasses various forms of liver damage not caused by chronic alcohol consumption. In the absence of other etiologies, it ranges from ste‑ atosis to nonalcoholic steatohepatitis and cirrhosis. The prevalence of NAFLD has considerably increased over the last years owing to the current lifestyle (unhealthy diet and sedentarism). Besides, it is associated with metabolic risk factors such as obesity, arterial hypertension, dyslipidemia, and type 2 diabetes. Given the poor prognosis of patients with advanced NAFLD, a practical therapeutic approach is necessary to halt its natural history. However, no licensed drugs have been approved for this purpose to date. Nowadays, we are in a race to find the first drug able to stop the incidence of NAFLD and reverse the disease in patients at more advanced stages. Meanwhile, the management of the NAFLD metabolic overload, including weight loss, cardiovascular protection, insulin sensitization, and lipid reduction, is the only strategy to improve hepatic and extrahepatic outcomes. In this review, we aimed to describe the management of the main metabolic disorders related to NAFLD, such as type 2 diabetes, arterial hypertension, and dyslipidemia. POLISH ARCHIVES OF INTERNAL MEDICINE 2020; 130 (11)976 is essential to reduce theeffect of cardiovascular risk factors enhanced by this condition.5,8 Con‑ cerning alcohol consumption, although theeffect of some degree of regular alcohol consumption over lifetime is controversial, 13,14 alcohol intake should be discouraged in patients with NAFLD and T2D. 8 Recently, Xu et al 15 demonstrated that low ‑to ‑moderate alcohol consumption was asso‑ ciated with anincreased risk of T2D in patients with NAFLD. TheEuropean Society of Cardiology and theEu‑ ropean Society of Hypertension guidelines for themanagement of arterial hypertension suggest that ahealthy lifestyle may be sufficient to delay or prevent theneed for drug therapy in patients with grade 1 arterial hypertension.16 Therecom‑ mendations about thelifestyle associated with blood pressure (BP) reduction include weight loss, regular physical activity, smoking cessation, and dietary interventions. 16 Weight loss and themain‑ tenance of an optimal body mass index (BMI) (approximately 20–25kg/m2)17 are recommend‑ ed to prevent hypertension, reduce BP, and im‑ prove theefficacy of medication in hypertensive patients.16 Epidemiological studies have shown that thetreatment and prevention of hyperten‑ sion may be enhanced by regular aerobic phys‑ ical activity, which also reduces cardiovascular risk and mortality.17 Agrowing body of evidence has suggested that hypertensive patients should The first step to manage nonalcoholic fatty liver disease Lifestyle interventions Themost critical in‑ tervention is to endorse ahealthy lifestyle that promotes weight loss and control of cardiovas‑ cular risk factors (see FIguRE 1).6,7 TheEurope‑ an and American guidelines emphasize theim‑ portance of modifying lifestyle in theabsence of approved pharmacological agents for thetreat‑ ment of NAFLD. 5,8,9 Asingle randomized con‑ trolled trial examined theeffect of lifestyle in‑ tervention using acombination of diet and exer‑ cise (200 min/week).10 After 48 weeks of inter‑ vention, aweight reduction greater than 7% led to asignificant improvement in theNAFLD Ac‑ tivity Score (NAS). Vilar ‑Gomez et al11 reported similar results, with thehighest rates of NAS re‑ duction and fibrosis regression in patients who achieved weight loss greater than 10%. Based on these studies, atthe early stages of NAFLD, rec‑ ommending aloss of 5% to 7% of body weight might be sufficient. In thecase of T2D, pharmacological treatment should be started as anadjunct to recommending reduction of body weight greater than 7%. 5,8,12 Be‑ sides, interventions that improve metabolic ab‑ normalities in patients with T2D have been prov‑ en to be beneficial in NAFLD (FIguRE 2). Further‑ more, it should be considered that smoking is as‑ sociated with advanced liver fibrosis mediated by anincrease in IR. Therefore, smoking cessation FIguRE 1 The suggested algorithm for the management of type 2 diabetes and prediabetes in the non alcoholic fatty liver disease scenario Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; GLP ‑1, glucagon ‑like peptide 1; HbA1C, hemoglobin A1C; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; SGLT ‑2, sodium ‑glucose cotransporter 2; TG, triglyceride; T2D, type 2 diabetes NAFLD + T2D* Liver-focused therapeutic measures Lifestyle intervention target: weight loss by 5%–10% If BMI >30 kg/m2or weight target not achieved: consider antiobesity drugs or metabolic endoscopy and /or surgery Smoking cessation and alcohol consumption avoidance Pharmacological treatment (pioglitazone) If BMI >25 kg/m2 or no response: consider GLP-1 agonists, SGLT-2 inhibitors Manage cardiovascular risk Optimize HbA1C (metformin) Add pioglitazone, GLP-1 agonists, SGLT-2 inhibitors Optimize blood pressure control (ARBs/ACEIs) Consider calcium blockers or diuretics Treat dyslipidemia (statins) Start fibrates if ↑TG or ezetimibe if TG not at the target level * High risk of fibrosis: referral to a hepatologist NAFLD: Non-alcoholic Fatty Liver Disease; T2DM: Type 2 Diabetes Mellitus; NASH: Non-Alcoholic Steatohepatitis; BMI: Body mass index; GLP-1: Glucagon-like Peptide-1; SGLT2: Sodium–glucose cotransporter 2; ARB: Angiotensin-IIreceptorantagonistsorblockers; ACE: Angiotensin converting enzyme; TG: Triglycerides REVIEW ARTICLE NAFLD and the management of comorbidities 977 thedietary treatment of NAFLD, it is important to provide practical highlights customizing thediet to theindividual’s taste. Some studies have iden ‑ tified dietary habits that may promote NAFLD directly by modulating hepatic triglyceride accu‑ mulation and antioxidant activity and, indirect‑ ly, by affecting insulin sensitivity and postpran‑ dial triglyceride metabolism. 25 TheWestern diet, which is generally characterized by ahigh con‑ sumption of carbohydrates, simple sugars, satu‑ rated fats, trans fats, animal proteins (red meat), processed food, and low fiber intake, is associat‑ ed with NAFLD development and progression.26 Dietary advice should include caloric restric‑ tion and adherence to themacronutrient com‑ position typical of theMediterranean diet.5,24 TheMediterranean diet is adietary pattern sup‑ ported by probably thegreatest body of evidence of long ‑term cardiometabolic benefits.18,24 How‑ ever, the number of randomized trials examining theeffect of theMediterranean diet on liver his‑ tology is limited. 24 Long ‑term trials on standard‑ ized nutritional interventions, evaluating theef‑ fect on fibrosis, are necessary. 5,24 In NAFLD, car‑ bohydrate intake should include whole grains, unprocessed cereals, and low–glycemic index foods24; fat intake should aim athigh monoun‑ saturated fatty acid and omega ‑3 polyunsaturat‑ ed fatty acid consumption; protein intake should favor vegetable protein, seafood, egg, and white meat consumption. Theintake of prebiotic fiber and probiotic ‑enriched products may be recom‑ mended to promote areduced caloric intake and favorable microbiota, respectively. 24 Informa‑ tion on dietary treatment in NAFLD is summa‑ rized in FIguRE 3.24 be advised to participate in atleast 30 ‑minute moderate ‑intensity aerobic exercise sessions (walking, jogging, cycling, or swimming) on 5 to 7 days per week. 17 Regarding dietary changes, hy‑ pertensive patients should be recommended to follow ahealthy, balanced diet containing vege‑ tables, legumes, fresh fruit, low ‑fat dairy prod‑ ucts, whole grains, fish, and unsaturated fatty acids (especially olive oil) and promoting alow consumption of red meat and saturated fatty ac‑ ids.18,19 TheMediterranean diet, which includes many of these nutrients,18,19 significantly reduc‑ es blood pressure20 and has similar beneficial ef‑ fects on blood glucose and lipid levels. Physical exercise Regardless of weight loss, phys‑ ical exercise reduces IR and metabolic risk fac‑ tors in patients with NAFLD. 9,21 Theintensity and duration of physical exercise necessary to significantly reduce liver fat have not been de‑ fined yet. Guidelines recommend patients to do moderate aerobic exercise for 150 to 250 min‑ utes per week,22 although better results may be achieved with exercising longer than 250 minutes per week.21 Similarly, resistance or high ‑intensity interval training (3 series of 10 repetitions at70% to 80% of themaximum amount of weight that aperson can possibly lift during asingle repeti‑ tion, with 1 minute of recovery between series) are also beneficial for patients with NAFLD.23 Dietary treatment Reduced caloric intake and im‑ proved macronutrient composition may prevent NAFLD progression, independently of weight loss. 24 Dietary adherence is anessential determi‑ nant of weight loss sustainability. Therefore, in FIguRE 2 The recommended management of type 2 diabetes in the nonalcoholic fatty liver disease scenario Abbreviations: eGFR, estimated glomerular filtration rate; others, see FIguRE 1 Liver fibrosis assessment First step: fibrosis serum markers Second step: transient elastography Lifestyle interventions 5%–10% weight loss: Mediterranean diet and physical excercise Smoking cessation No alcohol consumption BMI <25 kg/m2BMI, 25–30 kg/m2BMI >30 kg/m2 Pioglitazone: avoid if high fracture risk or heart failure GLP-1 analogues: contraindicated if history of pancreatitis Metabolic endoscopy or surgery SGLT-2 inhibitors: monitor genital fungal infections (canagliflozin: avoid if high fracture risk) Established heart disease: empagliflozin, canagliflozin, lirgalutide or semaglutide Heart failure: empagliflozin, canagliflozin, dapagliflozin Diabetic kidney disease: empagliflozin (eGFR >45 ml/min/1.73 m2), canagliflozin (eGFR >45 ml/min/1.73 m2), dapagliflozin (eGFR >60 ml/min/1.73 m2), lirgalutide or semaglutide (eGFR >15 ml/min/1.73 m2) Cerebrovascular disease: semaglutide Cardiovascular risk factor control Dyslipidemia Arterial hypertension (<140/90 mm Hg) Secondary prevention (antiplatelet therapy) Consider dual therapy if HbA1C >7.5% (consider metformin) and triple therapy if HbA1C >9% (basal insulin if cardinal symptoms are noted) Treatment of hyperglycemia POLISH ARCHIVES OF INTERNAL MEDICINE 2020; 130 (11)978 in pregnancy, and in those undergoing hemo‑ dialysis or receiving erythropoietin therapy. Pa‑ tients with the classic symptoms of hyperglycemia and arandom plasma glucose level≥200mg/dl (11.1mmol/l) do not need to meet any further criteria to be diagnosed with T2D. Referral to anendocrinologist is recommend‑ ed if thepatient is considered to be acandidate for bariatric surgery, has advanced micro‑ or mac‑ rovascular complications, and HbA1C target lev‑ els have not been achieved following intensified oral antidiabetic treatment atthe primary care level.5,27 Thetarget level of HbA1C is individual‑ ly established in view of comorbidities, life ex‑ pectancy, risk of hypoglycemia, and micro‑ and macrovascular complications. 27 In general, a tar‑ get level of HbA 1C <7% is appropriate, but the target level<8% may be appropriate for patients with ahistory of severe hypoglycemia, limited life expectancy, or significant comorbid conditions. Pharmacological treatment Pharmacological treat‑ ment should always be considered in T2D and NAFLD, especially if lifestyle recommendations are unsuccessful or challenging to maintain.8 In patients with T2D, glycemic control is essential to prevent NAFLD progression. For now, no drug has been approved by international agencies for thetreatment of NAFLD, although there are an‑ tidiabetic drugs with proven histological effica‑ cy (TAbLE 1). In asystematic review of 11 interna‑ tional guidelines for thetreatment of NAFLD, theinitiation of pharmacotherapy was recom‑ mended when thepatient presented with NASH specific management of type 2 diabetes in nonalcoholic fatty liver disease Thecoexistence of NAFLD and T2D is dangerous, because it seems to favor quick progression towards more aggressive liver conditions such as nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcino‑ ma,5,6 especially in patients with other metabol‑ ic comorbidities (arterial hypertension, dyslipid‑ emia, and obesity). 5 However, unfortunately, pa‑ tients and clinicians are unaware of thepotential ‑ ly serious NASH.8 It has been reported that up to 66% of patients with T2D or obesity who are old‑ er than 50 years of age have NASH21 and it seems to be anadditional independent risk factor for cardiovascular disease.7,8,21 Moreover, patients with T2D and NAFLD have more micro‑ and / or macrovascular complications in relation to worse glycemic control and atherogenic dyslipidemia. In high ‑risk patients, referral to ahepatologist is required in order to rule out other causes of liv‑ er disease, perform liver biopsy if necessary, and maintain closer follow ‑up.5,6,8 How to assess diabetes in nonalcoholic fatty liver disease The diagnosis of T2D is estab‑ lished based on the abnormal levels of thefol‑ lowing parameters: fasting plasma glucose lev‑ el≥126mg/dl (7mmol/l), 2 ‑hour plasma glu‑ cose level during a75 ‑g oral glucose tolerance test≥200mg/dl (11.1mmol/l), or hemoglobin A1C level (HbA 1C )≥6.5% (48mmol/mol). 27 TheHbA 1C criteria cannot be used in patients with sickle cell disease, glucose ‑6‑phosphate dehydrogenase de ‑ ficiency, recent blood loss or transfusion, HIV, SATURATED PUFA OMEGA-6 Animal products (red meat, butter, and dairy products), vegetable oils (palm oil), and processed foods (sausages, desserts) Vegetable oils (canola and cottonseed), cereal grains (wheat, corn, and rice) PUFA OMEGA-3 MUFA Olive oil, avocados, nuts, and nut oils Seafood, certain vegetable oils (flaxseed oil) and, to a much lesser extent, eggs and meat ANIMAL NATURE Red meat and processed meat (sausages) PLANT-BASED NATURE FATS Recommended Avoid Whole grains, cereals, seeds, nuts, legumes, vegetables, soybeans, peas PROTEINS Avoid Nondigestible CHO found in garlic, asparagus, leeks, onions, and cereals Recommended Recommended DIETARY FIBER Fructose (soft drinks and fruit juices) and refined CHO (sucrose, honey, syrup) SIMPLE CHO CARBOHYDRATES Avoid FIguRE 3 Dietary treatment according to macronutrient composition in the treatment of nonalcoholic fatty liver disease and type 2 diabetes Abbreviations: CHO, carbohydrates; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid REVIEW ARTICLE NAFLD and the management of comorbidities 979 in patients with unknown diastolic dysfunction or patients with established heart failure, and its controversial relationship with bladder can‑ cer. 31,32 However, various trials have been car‑ ried out to establish the cardiovascular safety of the drugs. Recently, theefficacy and safety of pi‑ oglitazone (45mg/d) in 101 patients with T2D and NAFLD have been proven after 36 months of treatment without significant adverse effects in‑ cluding amean weight gain of 3.1kg. 33 Addition‑ ally, asubsequent meta ‑analysis (n = 516) con‑ firmed theefficacy and safety of pioglitazone in thetherapeutic management of NAFLD. 34 No ma‑ jor adverse events were reported during thetri‑ als, and theadverse effects observed included aslight weight gain and lower extremity edema. Moreover, pioglitazone has been shown to reduce theincidence of stroke and fatal or nonfatal myo‑ cardial infarction by 24% in patients with ahis‑ tory of ischemic stroke or transient ischemic at‑ tack.35 Furthermore, theuse of pioglitazone re‑ duced theprogression from prediabetes to T2D by 50% to 70%.8 Glucagon ‑like peptide ‑1 agonists Glucagon ‑like peptide ‑1 agonists promote insulin secretion, decrease postprandial glucagon levels, reduce he‑ patic glucose production, and induce satiety and weight loss.36 Commercially available GLP ‑1 ag‑ onists include liraglutide, semaglutide, exena‑ tide, lixisenatide, and dulaglutide, all of which are approved for thetreatment of T2D. TheLEAN (Liraglutide Efficacy and Action in NASH) trial showed ahistological benefit in 52 patients treat‑ ed with liraglutide for 48 weeks (39% resolution of NASH versus 9% with placebo). 37 TheLEAD (Liraglutide Effect and Action in Diabetes) pro‑ gram team performed individual patient data meta ‑analysis, in which liver enzyme reduction, weight loss, and glycemic control were achieved. 38 In summary, based on thecurrent evidence and mainly because it induces weight loss, liraglutide use is recommended in T2D and NAFLD.6 Simi‑ lar outcomes have been reported for other GLP‑ ‑1 agonists.32 Atrial demonstrated that exena‑ tide versus insulin therapy during 8 weeks was associated with greater reversal of liver fat (as‑ sessed by ultrasonography), 39 and similar results have been recently reported, although liver fat was assessed by magnetic resonance spectros‑ copy after 24 ‑week treatment.40 Regarding nov‑ el agents, GLP ‑1 and dual glucose ‑dependent in‑ sulinotropic polypeptide receptor agonists im‑ proved NASH and facilitated liver regeneration in mice41 as well as significantly decreased fibro‑ sis biomarkers and increased adiponectin levels in patients with T2D.42 Both liraglutide and sema‑ glutide have been shown to reduce cardiovascu‑ lar risk in patients with T2D.43,44 Sodium ‑glucose cotransporter 2 inhibitors Sodium‑ ‑glucose cotransporter 2 inhibitors are themajor cotransporters involved in glucose reabsorption in thekidney and they are blocked by empagliflozin, or risk factors for arapid progression of NAFLD, such as thecoexistence with T2D.22 Theeffect of various antidiabetics on NAFLD was compared in arecent systematic review.28 Pioglitazone and glucagon ‑like peptide ‑1 (GLP ‑1) analogues are antidiabetic drugs having thebest effect on liver histology,5,28 and sodium ‑glucose cotransporter 2 (SGLT ‑2) inhibitors have also been proven to be beneficial, although drug efficacy may be me‑ diated, atleast in part, by weight loss. 6 Among thepharmacological agents for thetreatment of T2D, neither insulin, metformin, sulfonylureas, dipeptidyl peptidase–4 (DPP ‑4) inhibitors, nor acarbose are believed to significantly improve NASH or liver fibrosis, although reduced steato‑ sis has been reported in small studies.28 Thiazolidinediones Pioglitazone is anagonist of theperoxisome proliferator–activated receptor γ, which improves insulin sensitivity and mitochon‑ drial dysfunction in hepatocytes.7 ThePIVENS (Pioglitazone Versus Vitamin E Versus Placebo for the Treatment of Nondiabetic Patients with Non‑ alcoholic Steatohepatitis) trial team compared theuse of pioglitazone 30mg/d with vitamin E and placebo for 2 years in patients without diabe‑ tes. 29 Pioglitazone significantly reduced steatosis and inflammation, but there was no evidence for fibrosis reduction. In T2D, asingle randomized controlled trial included 55 patients with predi‑ abetes or T2D with confirmed NASH who were assigned to either receive ahypocaloric diet and placebo or ahypocaloric diet and pioglitazone 45mg/d. 30 After only 6 months of treatment, pi‑ oglitazone showed asignificant reduction in ste‑ atosis, ballooning necrosis, and inflammation. In clinical practice, there is still some reluctance to prescribe this medication, probably due to its known adverse effects: weight gain, bone mineral density reduction, heart failure decompensation TAbLE 1 The histological effects of antidiabetic treatment in patients with type 2 diabetes and nonalcoholic fatty liver disease Antidiabetic agent Steatosis Inflammation Fibrosis Pioglitazone 45 mg ↓ ↓ ↓ Pioglitazone 30 mg ↓ ↓ ⇆ Liraglutide ↓ ↓ ⇆ Exenatide ↓aNA NA Empagliflozin ↓aNA NA Canagliflozin ↓aNA ⇆a Dapagliflozin ↓aNA ⇆a Ipragliflozin ↓aNA ↓ Luseogliflozin ↓aNA ⇆a Metformin ⇆ ⇆ NA Sitagliptin ⇆ ⇆ ⇆ Vildagliptin ↓aNA NA Saxagliptin ↓aNA NA a No histological evidence Abbreviations: NA, no data available; ↓, decrease; ⇆, neutral effect POLISH ARCHIVES OF INTERNAL MEDICINE 2020; 130 (11)980 obese patients (with BMI >40kg/m2 or ranging between 35 to 40kg/m2 and comorbidities).58 It has been suggested to expand theindications for metabolic surgery to theBMI as low as 30kg/m2 in patients with T2D who do not achieve perma‑ nent weight loss and comorbidity improvement with nonsurgical treatments.58 Bariatric surgery may induce a25% weight loss even 10 years af‑ ter theprocedure.59 Additionally, bariatric sur‑ gery facilitates better glycemic, lipid, and blood pressure control. A long ‑term reversal of NASH has been reported regardless of thefibrosis stage and through various types of surgical interven‑ tions.8,21 Aprospective study provided evidence on an85% fibrosis improvement ayear after thesurgery. 60 However, no randomized controlled trials have evaluated theeffect of different surgi‑ cal approaches versus lifestyle intervention plus pharmacological treatment on T2D and NAFLD. Of note, bariatric surgery should be performed in high ‑volume centers and by amultidisciplinary team to ensure patient safety.61 specific management of arterial hypertension in nonalcoholic fatty liver disease Theglobal prevalence of hypertension was estimated at 1.3 billion in 2015, with aprevalence of 150 million cases in Central and Eastern Europe; in adults, theprev‑ alence is around 45% and becomes more frequent with advancing age, adopting amore sedentary life, and increasing body weight.62 Several epidemiological studies have shown therelationship between NAFLD and essential hypertension, estimating that around 50% of pa‑ tients with NAFLD suffer from this condition.63 Moreover, fatty liver is significantly more preva‑ lent in nondiabetic hypertensive patients (31%) compared with normotensive controls (13%). 64 Besides, hypertension is associated with thede‑ velopment of severe NAFLD.64 How to assess arterial hypertension in nonalcoholic fatty liver disease Hypertension is predominant‑ ly anasymptomatic condition detected by screen‑ ing programs or an incidental measurement of BP and, therefore, patients with NAFLD should un‑ dergo screening for hypertension. Hypertension is defined as office systolic BP (SBP) of atleast 140mmHg and / or diastolic BP (DBP) of atleast 90mmHg, although thelast European Society of Cardiology / European Society of Hypertension guidelines 65 considered SBP of 130 to 139mmHg and / or DBP of 80 to 89mmHg as high ‑normal values, SBP of 120 to 129mmHg and DBP of 80 to 84mmHg as normal values, and SBP above 120mmHg and DBP below 80mmHg as opti‑ mal values. Arterial hypertension should be eval‑ uated periodically, depending on severity, rang‑ ing from every 3 months to 5 years.65 Pharmacological treatment Apart from life‑ style modification, a wide range of agents has been tested for thetreatment of NAFLD (TAbLE 2). Alarge body of evidence has suggested dapagliflozin, canagliflozin, tofogliflozin, luseo‑ gliflozin, ertugliflozin, and ipragliflozin, which induce glucosuria in theproximal renal tubule. 45 Based on the evidence of low ‑to ‑moderate qual‑ ity, 2 recent systematic reviews concluded that SGLT ‑2 inhibitors improve liver enzymes and re‑ duce liver and visceral fat, providing additional beneficial effects on various metabolic parame‑ ters in T2D patients with NAFLD.46,47 In Japan, ipragliflozin has been shown to have asimilar ef‑ fect on hepatic fat content (measured by comput‑ ed tomography) as compared with pioglitazone.48 Similarly, luseogliflozin has been found to be su‑ perior to metformin in reducing hepatic fat con‑ tent (measured by computed tomography).49 There have been no studies evaluating theeffect of SGLT ‑2 inhibitors on liver histology, but these drugs show promising results due to their po‑ tential to promote weight reduction (2%–4%), improve glycemic control, improve cardiovas‑ cular disease (dapagliflozin and empagliflozin), and slow theprogression of chronic kidney dis‑ ease in T2D.45,50 Other antidiabetic agents Metformin is thefirst‑ ‑line drug in themanagement of T2D. Despite thefact that its main function is to improve in‑ sulin sensitivity, metformin did not cause histo‑ logical improvement of steatosis,51 although it has been recently shown to prevent thedevelop‑ ment of NAFLD in amice model.52 Its use, togeth‑ er with pioglitazone or liraglutide, is recommend‑ ed in thetreatment of NAFLD owing to its recog‑ nized effect on glycemic control8 and associated weight loss.31,32 There are few studies evaluating theeffect of sulfonylureas on NAFLD. Paradoxi‑ cally, anassociation with advanced liver disease and anincreased risk of hepatocellular carcino‑ ma has been found, since hyperinsulinemia may promote cancer progression.53 However, insulin has recently been demonstrated to reduce liver fat content assessed by magnetic resonance spec ‑ troscopy in patients with T2D and NAFLD.40 Di‑ peptidyl peptidase–4 inhibitors (sitagliptin, lin‑ agliptin, vildagliptin, saxagliptin, teneligliptin, and alogliptin) act by blocking theenzyme that breaks down GLP ‑1, enhancing the effects of in‑ cretins and duration of their activity. 45 They have been proven to help achieve good glycemic con‑ trol in T2D31; however, large randomized con‑ trolled trials with sitagliptin failed to show ben‑ efit in NAFLD.54,55 Conversely, vildagliptin seems to improve steatosis assessed by ultrasonography after 12 weeks of treatment compared with pla‑ cebo,56 and, more recently, preliminary data have shown that saxagliptin improved IR as well as re‑ duced IL ‑6 levels and liver steatosis.57 Based on thecurrent evidence and owing to thefact that they do not induce weight loss, DPP ‑4 inhibitors should not be thefirst ‑line therapy in theNAFLD treatment of T2D. Nonpharmacological treatment Bariatric surgery Bariatric surgery should be considered in severely REVIEW ARTICLE NAFLD and the management of comorbidities 981 data about their role in NAFLD, particularly re‑ garding ACEIs. Gillespie et al67 reported that ACEIs improved theinsulin sensitivity index by a mean(SD) of 12.1% (15.8%) in the analysis of 20 clinical trials, while Abuissa et al68 performed ameta ‑analysis of 12 randomized controlled clini‑ cal trials and concluded that ACEIs reduced thein‑ cidence of diabetes by 27%. Astudy that exam‑ ined thein vivo effect of perindopril on pig se‑ rum–induced liver fibrosis development in rats showed that this drug significantly blocked hepat‑ ic fibrosis induced by pig serum.69 Thesame study showed that captopril inhibited thegrowth of fi‑ broblasts in vitro and also reduced collagen accu‑ mulation in themodel of pig serum–induced liver fibrosis. In arabbit model, ramipril significantly reduced thedevelopment of steatosis, lobular in‑ flammation, and hepatic fibrosis as well as signif‑ icantly diminished thedevelopment of NASH.70 However, data on theevaluation of theimpact of ACEIs in NAFLD patients are too scarce to make any recommendation about their role in this population. Angiotensin II receptor blockers Losartan and telmisartan are themost commonly investigat‑ ed ARBs in thescenario of NAFLD, demonstrat‑ ing anexcellent side ‑effect profile.71,72 Losartan (50mg/d for 48 weeks) was tested in 3 small hu‑ man studies (a total of 19 patients) that evaluated biochemical parameters and histological markers in patients with biopsy ‑proven NASH.73 Yokoha‑ ma et al 74 included 7 biopsy ‑NAFLD patients and found animprovement of hepatic necroinflam‑ mation in 5 patients, reduction of hepatic fibro‑ sis in 4, and resolution of iron deposition in2. Besides, another study assessing 48 ‑week losar‑ tan treatment showed aremarkable decrease in thenumber of activated hepatic stellate cells and amild increase in quiescent phenotypes in 7 pa‑ tients.75 Despite these findings, further studies are needed to make any recommendations about theuse of losartan as NAFLD treatment. Telmisartan and valsartan were assessed in ablinded pilot study including 54 patients with biopsy ‑proven NASH and mild or moderate ar‑ terial hypertension.76 Paired blinded biopsies were performed atthe beginning and theend of theexperimental treatment period. Asignifi‑ cant improvement in cytolysis was noted in all pa‑ tients, similar for telmisartan and valsartan. Be‑ sides, both valsartan and telmisartan improved IR, although theeffect was more remarkable with thelatter drug; patients receiving telmisartan had animproved NAS and fibrosis stage.76 An ‑ other randomized clinical trial assessed therole of prescribing telmisartan in 50 patients with biopsy ‑proven NASH who underwent lifestyle modification. Adding telmisartan improved the NAS and fibrosis scores in NASH and was asso‑ ciated with nonsignificant adverse events.77 On theother hand, olmesartan 20mg/d and telmisar‑ tan 40mg/d were tested in patients with NAFLD for 6 months, and thestudy demonstrated that that therenin–angiotensin system (RAS) may play arelevant role in thepathogenesis of NAFLD and indicated angiotensin ‑converting enzyme inhibi‑ tors (ACEIs) and angiotensin II receptor blockers (ARBs) as potential therapeutic drugs.66 In fact, ACEIs and ARBs are themost widely used anti‑ hypertensive drugs.65 Consistent data have shown that RAS inter‑ vention in NAFLD could influence adipogenesis as well as adipokine and cytokine production, in‑ teract with insulin receptors and intracellular sig‑ naling pathways, and interfere with pancreatic β ‑cell insulin secretion.66 Thelocal hepatic effect is mediated by angiotensin II receptor 1, which is localized in hepatocytes, bile duct cells, he‑ patic stellate cells, and vascular endothelial cells (where it mediates theaction of angiotensin II in theliver).66 On theother hand, angiotensin II re‑ ceptor2 has antifibrogenic effects. Hence, thein‑ hibition of theRAS could improve theactivity of intracellular signaling pathways, adipose tissue proliferation, and adipokine production, as well as lead to amore stable release of cytokines and chemoattractant factors.66 Angiotensin ‑converting enzyme inhibitors There are 2 classes of agents to antagonize theRAS: ACEIs and ARBs. Unfortunately, there are little TAbLE 2 The histological effects of antihypertensive treatment in patients with arterial hypertension and nonalcoholic fatty liver disease Antihypertensive agent Steatosis Inflammation Fibrosis Atorvastatin ↓a↓a⇆ Rosuvastatin ↓a↓a⇆ Pitavastatin ⇆ ⇆ ⇆ Ezetimibe ⇆ ⇆ ⇆ Fibrates ⇆ ⇆ ⇆ Omega ‑3 fatty acid supplements ⇆ ⇆ ⇆ PCSK9 inhibitors NA NA NA a No histological evidence Abbreviations: PCSK9, proprotein convertase subtilisin / kexin type 9; others, see TAbLE 1 TAbLE 3 The histological effects of lipid‑lowering treatment in patients with dyslipidemia and nonalcoholic fatty liver disease Lipid‑lowering agent Steatosis Inflammation Fibrosis Telmisartan ↓ ↓ ↓b Losartan ⇆ ⇆ ⇆ Olmesartan ⇆ ↓a⇆ Valsartan ↓ ⇆ ⇆ Candesartan NA NA NA Ramipril NA NA NA Perindopril NA NA NA Captopril NA NA NA a No histological evidence b Insufficient data to make recommendations Abbreviations: see TAbLE 1 POLISH ARCHIVES OF INTERNAL MEDICINE 2020; 130 (11)982 demonstrated in several controlled trials.81,82 Moreover, their anti ‑inflammatory, antioxidant, and antifibrotic effects would make them excel‑ lent drugs for thetreatment of NASH, but theuse of statins has long been limited due to their po‑ tential hepatotoxicity in patients with liver dis‑ ease. Statin metabolism takes place in theliver, and theuse of these drugs has been related to higher transaminase levels.83 Liver toxicity as‑ sociated with statins is rare, and theincidence of acute liver failure is estimated to be similar in subjects exposed and unexposed to statins.84 In 2006, data from anextensive analysis of the Dal‑ las Heart Study suggested that no damage should be expected for thestatin use in individuals with liver disease, including patients with fatty liv‑ er. 85 Currently, the European Society of Cardi‑ ology / European Atherosclerosis Society guide‑ lines for themanagement of hypertension sug‑ gest that statin therapy may be continued if ala‑ nine transaminase levels are lower than or equal to the 3‑fold value of the upper limit of normal and may be reduced or discontinued if alanine transaminase levels riseabove this value.86 Statins have been proposed to treat NAFLD and NASH because of their anti ‑inflammatory, antiox‑ idant, and antithrombotic effects. Nevertheless, unfortunately, only afew and limited studies have tested thebenefits of statins in thetreatment of NAFLD (TAbLE 3). In across ‑sectional study from 2015, the statin use was associated with protec‑ tion from steatosis, NASH, and significant fibro‑ sis.87 Atorvastatin and rosuvastatin have shown abeneficial effect on both biochemical and ul‑ trasonographic evidence of NAFLD.88,89 Besides, numerous studies have confirmed that statins may reduce therisk of advanced liver disease and mortality as well as might reduce portal hyper‑ tension, promoting fibrosis regression and stop‑ ping disease progression.90 NAFLD Clinical Prac‑ tice Guidelines,5 published by theEuropean As‑ sociation of Liver Disease, strongly recommend theuse of statins to strictly control thecardio‑ vascular risk, but they do not recommend them as atherapeutic therapy for NAFLD. Ezetimibe Ezetimibe is aselective inhibitor of the Niemann –Pick C1 ‑like 1 protein that regu‑ lates cholesterol absorption from thesmall intes‑ tine to enterocytes and it has been demonstrat‑ ed to significantly reduce LDL cholesterol levels and cardiovascular risk, especially in combina‑ tion with statins. 91 It has also been reported that ezetimibe reduces lipid levels, IR, and cardiovas ‑ cular risk as well as improves liver function and hepatic histology in NAFLD.91 In anexperimen‑ tal study, ezetimibe was found to improve diet‑ ‑induced steatosis and fibrosis, while attenuating dyslipidemia in obesity and the insulin ‑resistant animal model.92 In theMOZART (Magnetic Res‑ onance Imaging and Elastography in Ezetimibe Versus Placebo for the Assessment of Response to Treatment in NASH) trial, arandomized, double‑ ‑blind, placebo ‑controlled trial, 50 patients with both drugs significantly improved IR and trans‑ aminase levels.78 Therefore, ARBs are effective drugs for arteri‑ al hypertension, which have shown theability to improve insulin sensitivity, and could play apar‑ tial role in thenecroinflammatory activity.78 They could be anexcellent choice to treat arterial hy‑ pertension in patients with NAFLD (telmisartan in particular), probably better than ACEIs. How‑ ever, their use as NAFLD treatment needs fur‑ ther large clinical trials to establish their effica‑ cy in this entity. specific management of dyslipidemia in nonalcoholic fatty liver disease Dyslipidemia is frequent in individuals with NAFLD, which, in turn, is inde‑ pendently associated with increased triglyceride and low ‑density lipoprotein (LDL) cholesterol lev‑ els, and decreased HDL cholesterol levels. 79 On theother hand, hypertriglyceridemia is present in 20% to 80% of patients with NAFLD. How to assess dyslipidemia in nonalcoholic fatty liver disease Themain aim of lipid management is to reduce theatherosclerotic risk by substantial‑ ly lowering LDL cholesterol levels. For patients atvery high cardiovascular risk (in secondary pre‑ vention or rarely in primary prevention), anLDL cholesterol reduction greater than 50% from base‑ line or lower than 55mg/dl is recommended.80 For people athigh cardiovascular risk, anLDL cho‑ lesterol reduction greater than 50% from base‑ line and anLDL cholesterol level below 70mg/dl are recommended. In patients atmoderate car‑ diovascular risk, thegoal should be anLDL cho‑ lesterol level below 100mg/dl, while thethera‑ peutic goal for individuals atlow cardiovascu‑ lar risk should be anLDL cholesterol level below 116mg/dl. For HDL cholesterol, thespecific goal should be 30mg/dl higher than thecorrespond‑ ing LDL target level.80 Moreover, thelevel of non– HDL cholesterol, which is ameasure of athero‑ genic lipoproteins (including very low–density lipoproteins, intermediate ‑density lipoproteins, and lipoprotein A), is increased in patients with NASH. Thenon–HDL cholesterol level is calculat‑ ed from thestandard formula (non–HDL choles‑ terol = total cholesterol – HDL cholesterol). Guide‑ lines provide its values as ranging between less than 85mg/dl and 100 to 130mg/dl for patients atvery high, high, and moderate cardiovascular risk (as asecondary target for lipid ‑lowering ther‑ apy). On theother hand, no specific goals for tri‑ glyceride levels have been determined in clinical trials, but values below 150mg/dl indicated low‑ er cardiovascular risk.80 Pharmacological treatment Statins Statins are among the most frequently prescribed drugs worldwide. Reducing cholester‑ ol biosynthesis in the liver by inhibiting 3 ‑hydroxy ‑3‑methylglutaryl –coenzyme A re‑ ductase is thefulcrum in the primary and sec‑ ondary prevention of cardiovascular risk, as REVIEW ARTICLE NAFLD and the management of comorbidities 983 Conclusions NAFLD could be regarded as theliv‑ er component of metabolic syndrome, because it is closely related to comorbidities such as di ‑ abetes, arterial hypertension, dyslipidemia, and obesity. Also, we should consider thescreening of metabolic syndrome features and cardiovas‑ cular risk in patients with NAFLD. Anunhealthy lifestyle plays akey role in theprogression of this condition, thus requiring prompt and effective therapeutic interventions to avoid hepatic and extra ‑hepatic complications. While no pharmacological treatment has been approved by international agencies for thetreat‑ ment of NAFLD, thetherapeutic strategy includes lifestyle change and pharmacological treatment of metabolic syndrome components. In this set‑ ting, lifestyle intervention is still themost crucial measure. However, it is necessary to implement pharmacological therapies that improve glycolip‑ id metabolism and blood pressure. On theother hand, thecurrent understanding of the NAFLD pathophysiology has expanded thepossibilities of treatment, so several promising drugs are be‑ ing studied in randomized controlled trials. We expect that they will facilitate early intervention in NAFLD, leading to individualized treatment for all patients. ARTICLE INFoRmATIoN ACKNoWLEdgmENTs This project was partially funded by the “Conse‑ jería de Salud de la Junta de Andalucía” (PI ‑0075 ‑2014; to JA), the “Span‑ ish Ministry of Economy, Innovation and Competition, Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI17/00535, and GLD19/00100; to JA). The funders were not involved in the design, analysis, writing, or interpre‑ tation of this study. CoNFLICT oF INTEREsT None declared. oPEN ACCEss This is an Open Access article distributed under the terms of the Creative Commons Attribution ‑NonCommercial ‑ShareAlike 4.0 Inter‑ national License (CC BY ‑NC ‑SA 4.0), allowing third parties to copy and re‑ distribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited, distrib‑ uted under the same license, and used for noncommercial purposes only. For commercial use, please contact the journal office at [email protected]. HoW To CITE Perdomo C, D’Ingianna P, Escalada J, et al. Nonalcoholic fatty liver disease and the risk of metabolic comorbidities: how to manage in clinical practice. Pol Arch Intern Med. 2020; 130: 975‑985. doi:10.20452/ pamw.15510 REFERENCEs 1 Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liv‑ er, steatohepatitis, and the metabolic syndrome. Hepatology. 2003; 37: 917‑923.  2 Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of non‑ alcoholic fatty liver disease – meta ‑analytic assessment of prevalence, inci‑ dence, and outcomes. Hepatology. 2016; 64: 73‑84.  3 Abenavoli L, Milic N, Renzo L Di, et al. Metabolic aspects of adult pa‑ tients with nonalcoholic fatty liver disease. WJG. 2016; 22: 7006‑7016.  4 Ampuero J, Aller R, Gallego ‑Durán R, et al. Significant fibrosis pre‑ dicts new ‑onset diabetes mellitus and arterial hypertension in patients with NASH. J Hepatology. 2020; 73: 17‑25.  5 European Association for the Study of the Liver (EASL); European As‑ sociation 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: 1388‑1402.  6 American Diabetes Association. Comprehensive medical evaluation and assessment of comorbidities: standards of medical care in diabetes. Diabe‑ tes Care. 2020; 43: S37 ‑S47.  7 Budd J, Cusi K. Non ‑alcoholic fatty liver disease: what does the primary care physician need to know? AJM. 2020; 133: 536‑543.  8 Bril F, Cusi K. Management of nonalcoholic fatty liver disease in patients with type 2 diabetes: a call to action. Diabetes Care. 2017; 40: 419‑430.  biopsy ‑proven NASH were randomized to either oral ezetimibe 10mg/d or placebo for 24 weeks.93 Theaim of the study was to examine theefficacy of ezetimibe versus placebo in reducing liver fat assessed by magnetic resonance imaging–proton density fat fraction and liver histology in patients with biopsy ‑proven NASH. Ezetimibe did not sig‑ nificantly reduce liver fat in NASH, and there were no significant differences in histologic response rates between theexperimental drug and place‑ bo.93 Therefore, ezetimibe is not recommended for the treatment of patients with NAFLD be‑ yond themanagement of dyslipidemia. Fibrates and omega ‑3 fatty acid supplements Fibrates are the first ‑line pharmacological therapy in pa‑ tients with severe hypertriglyceridemia. Their pri‑ mary function is to decrease plasma triacylglycer‑ ol levels, increase HDL synthesis, and increase re‑ verse cholesterol transport. Furthermore, fibrates may ameliorate insulin sensitivity 94 as well as vas‑ cular and systemic inflammation.95 In a study by Fernández ‑Miranda et al,96 fenofibrate was admin‑ istered in 16 patients with NAFLD for 48 weeks, and theauthors noted that thetransaminase levels decreased and ballooning improved, but no effect on histological steatosis, inflammation, or fibrosis was observed. Another placebo ‑controlled study using fenofibrate for NAFLD did not show any ef‑ fect on hepatic triglyceride content.97 Therefore, fibrates are not recommended in NAFLD guide‑ lines. On theother hand, omega ‑3 polyunsaturat‑ ed fatty acids reduce plasma and liver lipid levels, but they have not demonstrated the ability to im‑ prove histological outcomes, which would support their use in patients with NAFLD. 98 Proprotein convertase subtilisin / kexin type 9 inhibitors Proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibition is apromising therapeutic option for patients with familial hypercholester‑ olemia or statin intolerance. These drugs signifi ‑ cantly decrease LDL cholesterol and triglyceride levels, increase HDL cholesterol levels, and reduce the number of cardiovascular events. Thelink between PCSK9 inhibitors and liver steatosis remains unclear. Numerous studies have indicated that ahigh level of intrahepatic and cir‑ culating PCSK9 increase liver lipid storage, adi‑ pose energy, and hepatic fatty acid storage as well as triglyceride secretion and storage.99 In 201 con‑ secutive patients with biopsy ‑confirmed NASH, circulating PCSK9 levels were associated with the steatosis grade, necroinflammation, balloon‑ ing, and the fibrosis stage.100 Indeed, circulating PCSK9 levels increase with hepatic fat accumu ‑ lation and correlate with theseverity of steato‑ sis. Therefore, reducing thePCSK9 expression by using PCSK9 inhibitors seems to protect theliver from NAFLD by decreasing IR. 99 Thus, themodu‑ lation of thePCSK9 synthesis and release might be used to treat NAFLD. However, further re‑ search is needed to establish thedefinite role of PCSK9 inhibitors in themanagement of NAFLD.