Lifestyle interventions

The most critical intervention is to endorse a healthy lifestyle that promotes weight loss and control of cardiovascular risk factors (see figure 1).^6,7 The European and American guidelines emphasize the importance of modifying lifestyle in the absence of approved pharmacological agents for the treatment of NAFLD.^5,8,9 A single randomized controlled trial examined the effect of lifestyle intervention using a combination of diet and exercise (200 min/week).¹⁰ After 48 weeks of intervention, a weight reduction greater than 7% led to a significant improvement in the NAFLD Activity Score (NAS). Vilar‑Gomez et al¹¹ reported similar results, with the highest rates of NAS reduction and fibrosis regression in patients who achieved weight loss greater than 10%. Based on these studies, at the early stages of NAFLD, recommending 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 Besides, interventions that improve metabolic abnormalities in patients with T2D have been proven to be beneficial in NAFLD (figure 2). Furthermore, it should be considered that smoking is associated with advanced liver fibrosis mediated by an increase in IR. Therefore, smoking cessation is essential to reduce the effect of cardiovascular risk factors enhanced by this condition.^5,8 Concerning 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 al¹⁵ demonstrated that low‑to‑moderate alcohol consumption was associated with an increased risk of T2D in patients with NAFLD.

The European Society of Cardiology and the European 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 recommendations 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 maintenance of an optimal body mass index (BMI) (approximately 20–25 kg/m²)¹⁷ are recommended to prevent hypertension, reduce BP, and improve the efficacy of medication in hypertensive patients.¹⁶ Epidemiological studies have shown that the treatment and prevention of hypertension may be enhanced by regular aerobic physical activity, which also reduces cardiovascular risk and mortality.¹⁷ A growing body of evidence has suggested that hypertensive patients should 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, hypertensive patients should be recommended to follow a healthy, balanced diet containing vegetables, legumes, fresh fruit, low‑fat dairy products, whole grains, fish, and unsaturated fatty acids (especially olive oil) and promoting a low consumption of red meat and saturated fatty acids.^18,19 The Mediterranean diet, which includes many of these nutrients,^18,19 significantly reduces blood pressure²⁰ and has similar beneficial effects on blood glucose and lipid levels.

Dietary treatment

Reduced caloric intake and improved macronutrient composition may prevent NAFLD progression, independently of weight loss.²⁴ Dietary adherence is an essential determinant of weight loss sustainability. Therefore, in the dietary treatment of NAFLD, it is important to provide practical highlights customizing the diet to the individual’s taste. Some studies have identified dietary habits that may promote NAFLD directly by modulating hepatic triglyceride accumulation and antioxidant activity and, indirectly, by affecting insulin sensitivity and postprandial triglyceride metabolism.²⁵ The Western diet, which is generally characterized by a high consumption of carbohydrates, simple sugars, saturated fats, trans fats, animal proteins (red meat), processed food, and low fiber intake, is associated with NAFLD development and progression.²⁶

Dietary advice should include caloric restriction and adherence to the macronutrient composition typical of the Mediterranean diet.^5,24 The Mediterranean diet is a dietary pattern supported by probably the greatest body of evidence of long‑term cardiometabolic benefits.^18,24 However, the number of randomized trials examining the effect of the Mediterranean diet on liver histology is limited.²⁴ Long‑term trials on standardized nutritional interventions, evaluating the effect on fibrosis, are necessary.^5,24 In NAFLD, carbohydrate intake should include whole grains, unprocessed cereals, and low–glycemic index foods²⁴; fat intake should aim at high monounsaturated fatty acid and omega‑3 polyunsaturated 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 recommended to promote a reduced caloric intake and favorable microbiota, respectively.²⁴ Information on dietary treatment in NAFLD is summarized in figure 3.²⁴

How to assess diabetes in nonalcoholic fatty liver disease

The diagnosis of T2D is established based on the abnormal levels of the following parameters: fasting plasma glucose level ≥126 mg/dl (7 mmol/l), 2‑hour plasma glucose level during a 75‑g oral glucose tolerance test ≥200 mg/dl (11.1 mmol/l), or hemoglobin A_1C 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 deficiency, recent blood loss or transfusion, HIV, in pregnancy, and in those undergoing hemodialysis or receiving erythropoietin therapy. Patients 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 recommended if the patient is considered to be a candidate for bariatric surgery, has advanced micro- or macrovascular complications, and HbA_1C target levels have not been achieved following intensified oral antidiabetic treatment at the primary care level.^5,27 The target level of HbA_1C is individually established in view of comorbidities, life expectancy, risk of hypoglycemia, and micro- and macrovascular complications.²⁷ In general, a target 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 treatment 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 antidiabetic drugs with proven histological efficacy (table 1). In a systematic review of 11 international guidelines for the treatment of NAFLD, the initiation of pharmacotherapy was recommended when the patient presented with NASH 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 mediated, 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 steatosis has been reported in small studies.²⁸