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Patients with NAFLD are managed using several modalities that address both liver disease and related comorbidities such as obesity, type 2 diabetes mellitus, and dyslipidemia. In general, pharmacologic interventions aimed at improving liver disease should be reserved for patients with NASH and fibrosis.
The mainstay of treatment is to counsel regarding changes in dietary intake and exercise, although it is important to be aware of the limitations of such approaches. Unlike most other liver conditions, there are no specific pharmacotherapies that are approved for routine clinical use in patients with NAFLD or NASH, although many are in clinical development. In select cases, bariatric surgery may be recommended to help patients lose weight, which may have an impact on NAFLD/NASH and related comorbidities.
Large studies of diet and exercise in patients with NAFLD are few, with the most robust study showing marked improvement in liver histology with weight loss. This study enrolled 293 patients with NASH into a 12-month program of calorie reduction (750 kcal reduction per day), exercise (200 minutes of brisk exercise per week), and 8 weekly behavioral sessions. After 52 weeks, 30% of participants achieved ≥ 5% weight loss. The greatest liver-related benefits were found in the 29 patients who achieved ≥ 10% weight loss; 90% of these patients experienced resolution of NASH compared with 25% of patients overall. Notably, no patient who achieved ≥ 10% weight loss experienced progression of liver fibrosis compared with 16% of patients overall. These data support the role of diet and exercise strategies, although it remains unclear how long such weight loss can be sustained. Other studies have suggested that up to two thirds of patients who have lost weight on a reduced-calorie dietary regimen return to a higher weight than they had before the diet commenced. The European Association for the Study of the Liver recommends that patients with NAFLD who are overweight or obese should aim for a weight loss of 7% to 10% to improve both liver enzymes and histologic parameters.
Although there are no FDA-approved therapies specifically indicated for the management of NAFLD or NASH, some agents are recommended by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL).[1,34] For most patients with NAFLD and NASH, the priority is optimizing medical management of coexisting components of the metabolic syndrome.
Management of Common Comorbidities. In many patients with NAFLD and NASH, both the individual’s liver health and overall well-being benefit from management of comorbidities associated with metabolic syndrome, such as dyslipidemia, hypertension, and T2DM.
The decision to start lipid-lowering pharmacotherapy depends on the patient’s lipid profile and risk factors for atherosclerotic cardiovascular disease (ASCVD). Patients with diabetes or with impaired glucose tolerance exhibit an increased risk for cardiovascular events; therefore, lipid-lowering therapy should be started at lower levels of dyslipidemia. Conventional therapy includes statins with gradual titration to ensure correction of dyslipidemia while minimizing risks of drug toxicity. In those patients with diabetes and a previous cardiovascular event (eg, myocardial infarction, angina, stroke), consideration should be given to add the cholesterol absorption inhibitor ezetimibeat 10 mg/day to the statin to further reduce serum cholesterol. If serum triglyceride levels are consistently high (200-499 mg/dL), then the use of fibrates should be considered.
The 2018 American College of Cardiology/American Heart Association guidelines on managing blood cholesterol have identified 4 groups who would be most likely to have a beneficial reduction in ASCVD risk with moderate-intensity to high-intensity statin therapy. Patients with NAFLD or NASH often share many characteristics with these groups, which are defined as individuals with:
Blood pressure should be maintained below 130/80 mm Hg, the threshold for defining hypertension according to the American College of Cardiology, American Heart Association, and other professional medical organizations Selecting an approach for pharmacologic management of hypertension depends on the presence or absence of comorbidities such as proteinuria. To assess proteinuria, the patient should bring in three 24-hour collections from home. Patients without proteinuria can be assessed with 24-hour ambulatory blood pressure monitoring.
The main goal of treating patients with T2DM is to improve glycemic control while avoiding weight gain. In those with T2DM and an estimated glomerular filtration rate (eGFR) > 45 mL/min, metformin should be initiated and the dose titrated as tolerated up to 2 g/day. Metformin should not be administered to those with an eGFR < 30 mL/min and is not recommended in those with an eGFR between 30 and 45 mL/min. If glycemic control is not achieved with metformin monotherapy, the patient should receive dual therapy with weight-neutral or weight-reducing agents approved by the FDA for this setting, such as SGLT2 inhibitors or GLP-1 analogues. Preliminary data suggest that SGLT2 inhibitors may have some beneficial effects on NAFLD, but larger, histology-based clinical trials are needed. GLP-1 analogues are supported by clinical trial data. Notably, the randomized, placebo-controlled phase II LEAN trial reported that the GLP-1 analogue liraglutide was associated with a significantly higher rate of NASH resolution (39% vs 9% with placebo; P = .04). Extensive guidance on the management of T2DM is available from the American Diabetes Association.
Bariatric Surgery. Although hypocaloric diets and exercise can induce weight loss and improvements in insulin resistance in patients with NAFLD, long-term results have not been reported, and weight loss is difficult to maintain. Bariatric surgery is very effective for weight loss. In a large meta-analysis of more than 160,000 patients who underwent bariatric surgery, the 5-year reduction in BMI was 12-17 kg/m2. Data on liver-related outcomes following bariatric surgery in patients with NASH are restricted to observational studies, with a number of systematic reviews showing marked improvement in histological features of NAFLD. Bariatric surgery is sometimes performed in patients with liver cirrhosis, although there are concerns about increased operative risk. This is particularly relevant in patients with decompensated liver cirrhosis, where mortality rates of up to 41% have been reported.
At this time, the AASLD recommends considering foregut bariatric surgery in obese individuals with NAFLD or NASH who are otherwise eligible for the procedure. Guidance from the EASL notes that bariatric surgery is an option for those unresponsive to pharmacotherapy and lifestyle modifications and that the procedure is likely to retard NASH progression while improving histologic lesions, including fibrosis.
Pharmacologic Management of NASH. Currently, the FDA has not approved any agent for treatment of NAFLD or NASH. However, guidelines from both the AASLD and the EASL recommend specific pharmacotherapies for individuals with NASH, but not NAFLD (Table 4).[1,34] These agents may also be considered for individuals with NAFLD at a high risk for disease progression.
Table 4. Pharmacotherapies Recommended by the AASLD and EASL for Treatment of NASH[1,34]
PPARγ agonists such as pioglitazone were originally developed for the management of T2DM but have also been widely studied in patients with NASH. Pioglitazone has been shown to improve steatohepatitis in patients with NASH with and without T2DM.[64,65] However, this agent has not been tested in phase III clinical trials assessing outcomes prescribed by regulatory agencies. Enthusiasm for use of pioglitazone has been dampened by its associated adverse events, although many of these may be manageable. Weight gain is the most common adverse event associated with pioglitazone; a gain of 3-5 kg after 3 years of therapy in patients with NASH may be expected. Peripheral edema also occurs in approximately 5% to 10% of patients and may be more likely in patients receiving insulin. Pioglitazone reduces the risk of cardiovascular events, but it must be avoided in patients with congestive cardiac failure or diastolic dysfunction. There are also effects on bone metabolism, which are associated with an increased risk of bone fractures, particularly in postmenopausal women. Finally, there remains controversy about the link between pioglitazone and bladder cancer. A recent meta-analysis of 26 studies found that only 5 studies reported an association with bladder cancer; all of these studies were considered to be of low quality.
The antioxidant vitamin E has been shown to effect improvement in histologic features of NAFLD in 2 large, randomized, controlled trials, TONIC and PIVENS, which were conducted in nondiabetic, noncirrhotic pediatric and adult populations, respectively.[64,68] Although these studies showed a significant improvement in hepatocellular inflammation and ballooning after use of vitamin E, they were not designed as registration trials. There remains uncertainty about use of vitamin E in patients with diabetes and whether the use of vitamin E at ≥ 400 IU/day may increase all-cause mortality, although a meta-analysis of 57 trials covering 246,371 individuals reported no relationship between vitamin E dose and mortality.
Investigational Agents. There are numerous ongoing clinical trials of investigational agents that may be effective in patients with NAFLD and NASH, including agents in late-phase clinical investigation.
The farnesoid X nuclear receptor (FXR), which is activated by bile acids, is highly expressed in the intestine, liver, kidney, and adrenal glands and regulates transcription of genes involved in a number of metabolic pathways. The randomized, placebo-controlled phase II FLINT trial reported that in patients with noncirrhotic NASH, the FXR agonist obeticholic acid was associated with a significantly higher rate of improved liver histology compared with placebo (45% vs 21%, respectively; P = .0002), although there was no difference in rates of NASH resolution. The ongoing phase III REGENERATE trial is evaluating obeticholic acid in patients with NASH, with data also showing an antifibrotic effect (Capsule Summary). Other FXR agonists under development include tropifexor (LJN452) and cilofexor (GS-9674), which have slightly different structures than obeticholic acid; these structural differences may affect the safety profile.
Elafibranor is a dual PPAR-α and PPAR-δ agonist. Both of these receptors are important to hepatic lipid and lipoprotein metabolism, insulin sensitivity, lipid and glucose homeostasis, and modulation of inflammation. The GOLDEN-505 trial compared 2 different doses of elafibranor vs placebo over 52 weeks of therapy in 247 patients. Although this study did not meet its predefined primary endpoint of NASH resolution for either dose, post hoc analyses in the subgroup with NAFLD Activity Score ≥ 4 observed a significant effect at the 120-mg dose (NASH resolution in 19% with elafibranor vs 12% with placebo; P = .045). A phase III study of elafibranor, RESOLVE-IT, is ongoing.
Acetyl-coenzyme A carboxylase (ACC) catalyzes the initial step of de novo lipogenesis. Firsocostat (GS-0976), an inhibitor of ACC in the liver, was evaluated in a randomized, placebo-controlled phase II trial. This 12-week study reported that treatment with firsocostat decreased hepatic steatosis, selected markers of fibrosis, and liver enzymes.
Within the context of oxidative stress, apoptosis signal–regulating kinase 1 (ASK1) activation promotes stress response pathways that exacerbate hepatic inflammation and fibrosis. Selonsertib, an ASK1 inhibitor, was compared at different doses as monotherapy, in combination with the investigational antifibrotic agent simtuzumab, and in comparison to simtuzumab alone in a randomized phase II trial that enrolled 72 patients with NASH and stage 2/3 liver fibrosis. After 24 weeks of treatment, this trial observed a dose-dependent relationship between selonsertib and fibrosis regression, with a reduction of ≥ 1 fibrosis stage observed in 43% of those who received selonsertib at 18 mg, in 30% with selonsertib at 6 mg, and 20% in the simtuzumab monotherapy group. Despite these early promising results, the phase III STELLAR 3 and STELLAR 4 trials of selonsertib were recently ended due to lack of evidence of efficacy after 48 weeks of therapy.