The obesity epidemic is closely associated with the rising prevalence and severity of nonalcoholic fatty liver disease (NAFLD): obesity has been linked not only with simple steatosis (SS), but also with advanced disease, i.e., nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis and hepatocellular carcinoma. As a consequence, apart from increasing all-cause mortality, obesity seems to increase liver-specific mortality in NAFLD patients. Given the lack of approved pharmacological interventions for NAFLD, targeting obesity is a rational option for its management. As the first step, lifestyle modification (diet and exercise) is recommended, although it is difficult to achieve and sustain. When the first step fails, adding pharmacotherapy is recommended. Several anti-obesity medications have been investigated in NAFLD (e.g., orlistat, glucagon-like peptide-1 analogs), other anti-obesity medications have not been investigated (e.g., lorcaserin, phentermine hydrochloric, phentermine/topiramate and naltrexone/bupropion), whereas some medications with weight-lowering efficacy have not been approved for obesity (e.g., sodium-glucose cotransporter-2 inhibitors, farnesoid X receptor ligands). If the combination of lifestyle modification and pharmacotherapy also fails, then bariatric surgery should be considered in selected morbidly obese individuals. This review summarizes best evidence linking obesity with NAFLD and presents related therapeutic options.

Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics.

The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly. It is nowadays recognized as the most frequent liver disease, affecting a quarter of global population and regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity, and cardiovascular disease. In a more simplistic view, NAFLD could be defined as an increase in liver fat content, in the absence of secondary cause of steatosis. In fact, the clinical onset of the disease is a much more complex process, closely related to insulin resistance, limited expandability and dysfunctionality of adipose tissue. A fatty liver is a main driver for a new recognized liver-pancreatic α-cell axis and increased glucagon, contributing to diabetes pathophysiology. This review will focus on the clinical and pathophysiological connections between NAFLD, insulin resistance and type 2 diabetes. We reviewed non-invasive methods and several scoring systems for estimative of steatosis and fibrosis, proposing a multistep process for NAFLD evaluation. We will also discuss treatment options with a more comprehensive view, focusing on the current available therapies for obesity and/or type 2 diabetes that impact each stage of NAFLD. The proper understanding of NAFLD spectrum—as a continuum from obesity to metabolic syndrome and diabetes—may contribute to the early identification and for establishment of targeted treatment.

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NAFLD as a continuum: from obesity to metabolic syndrome and diabetes

In healthy individuals, the incretin hormone glucagon-like peptide 1 (GLP1) potentiates insulin release and suppresses glucagon secretion in response to the ingestion of nutrients. GLP1 also delays gastric emptying and increases satiety. In patients with type 2 diabetes mellitus (T2DM), supraphysiological doses of GLP1 normalize the endogenous insulin response during a hyperglycaemic clamp. Owing to the short plasma half-life of native GLP1, several GLP1 receptor agonists (GLP1RAs) with longer half-lives have been developed for the treatment of T2DM. These compounds vary in chemical structure, pharmacokinetics and size, which results in different clinical effects on hyperglycaemia and body weight loss; these variations might also explain the difference in cardiovascular effect observed in large-scale cardiovascular outcome trials, in which certain GLP1RAs were shown to have a positive effect on cardiovascular outcomes. Owing to their metabolic effects, GLP1RAs are also considered for the treatment of several other lifestyle-induced conditions, such as obesity, prediabetes and liver disease. This Review provides insights into the physiology of GLP1 and its involvement in the pathophysiology of T2DM and an overview of the currently available and emerging GLP1RAs. Furthermore, we review the results from the currently available large-scale cardiovascular outcome trials and the use of GLP1RAs for other indications.

Glucagon-like peptide 1 in health and disease.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) remain as one of the most global problematic metabolic diseases with rapidly increasing prevalence and incidence. Epidemiological studies noted that T2DM patients have by two-fold increase to develop NAFLD, and vice versa. This complex and intricate association is supported and mediated by insulin resistance (IR). In this review, we discuss the NAFLD immunopathogenesis, connection with IR and T2DM, the role of screening and noninvasive tools, and mostly the impact of the current antidiabetic drugs on steatosis liver and new potential therapeutic targets.

/pdf/the-intricate-relationship-between-type-2-diabetes-mellitus-4s6cbvtvhv.pdf

The Intricate Relationship between Type 2 Diabetes Mellitus (T2DM), Insulin Resistance (IR), and Nonalcoholic Fatty Liver Disease (NAFLD).

The global prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be 25% and continues to rise worldwide in the setting of the obesity epidemic. This increase is especially concerning because NAFLD is often a progressive disease that can be associated with significant complications such as liver cirrhosis, hepatocellular carcinoma, and an increase in liver-related and overall mortality. Because of the devastating complications and comorbidities, NAFLD is a very costly disease for the healthcare system, with estimated annual direct medical costs exceeding $100 billion in the United States alone. Given this progressive course, it is imperative to make the diagnosis in patients with risk factors (metabolic syndrome, weight gain, and insulin resistance/diabetes). Once the diagnosis is made, the focus should shift to treatment and monitoring for the development of associated complications. Given that currently no pharmaceutical intervention is approved for the treatment of NAFLD, focus shifts instead to mitigation of risk factors through avoidance of foods that are rich in red meat, trans fats, refined carbohydrates, and high-fructose corn syrup; are low fiber; and have high energy density. The landmark of treatment, however, continues to be weight loss and improvement of insulin resistance, often through a multimodality approach. The current manuscript reviews the clinical phenotypes of NAFLD, its risk factors, and pathogenesis, as well as treatment options including lifestyle modifications and dietary interventions, medical therapies, endoscopic bariatric interventions, and bariatric surgery.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ncp.10449

Evolution of NAFLD and Its Management

BACKGROUND & AIMS We compared the effects of weight loss induced with the glucagon-like peptide-1 agonist liraglutide, with that of lifestyle modification, followed by weight maintenance after discontinuing intervention, in obese adults with non-alcoholic fatty liver disease (NAFLD). METHODS Thirty obese (mean age 40.7 ± 9.1 years, BMI 33.2 ± 3.6 kg/m2 , 90% male) adults with NAFLD defined as liver fat fraction (LFF) > 5% on magnetic resonance imaging without other causes of hepatic steatosis were randomized to a supervised programme of energy restriction plus moderate-intensity exercise to induce ≥ 5% weight loss (DE group, n = 15), or liraglutide 3 mg daily (LI group, n = 15) for 26 weeks, followed by 26 weeks with only advice to prevent weight regain. RESULTS Diet and exercise and LI groups had significant (P < 0.01) and similar reductions in weight (-3.5 ± 3.3 vs -3.0 ± 2.2 kg), LFF (-8.1 ± 13.2 vs -7.0 ± 7.1%), serum alanine aminotransferase (-39 ± 35 vs -26 ± 33 U/L) and caspase-cleaved cytokeratin-18 (cCK-18) (-206 ± 252 vs -130 ± 158 U/L) at 26 weeks. At 52 weeks, the LI group significantly (P < 0.05) regained weight (1.8 ± 2.1 kg), LFF (4.0 ± 5.3%) and cCK-18 (72 ± 126 U/L), whereas these were unchanged in the DE group. CONCLUSIONS Liraglutide was effective for decreasing weight, hepatic steatosis and hepatocellular apoptosis in obese adults with NAFLD, but benefits were not sustained after discontinuation, in contrast with lifestyle modification. Continuing the exercise learned in the structured programme contributed to the maintenance of liver fat reduction.

Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease.

We compared the effects of weight loss induced by the glucagon-like peptide 1-agonist liraglutide with a structured lifestyle intervention in obese adults with non-alcoholic fatty liver disease (NAFLD) Obese (body mass index ≥30 kg/m2 , mean weight 960 ± 163 kg) non-diabetic Asian adults, with NAFLD diagnosed by liver fat fraction (LFF) ≥ 55% on magnetic resonance imaging without other causes of hepatic steatosis, were randomized to a supervised program of dieting (restriction by 400 kilocalories/d) plus moderate-intensity aerobic exercise (~200 min/wk; DE group, n = 12), or liraglutide at the 3 mg daily dose approved for weight loss (LI group, n = 12), for 26 weeks Both DE and LI groups had significant (P < 01) and similar reductions in weight (-35 ± 33 vs -35 ± 21 kg, respectively, P = 72), LFF (-89 ± 134 vs -72% ± 71%, P = 70), serum alanine aminotransferase (-42 ± 46 vs -34 ± 27 U/L, P = 52) and aspartate aminotransferase (-23 ± 24 vs -18 ± 15 U/L, P = 53) In this first randomized study comparing the 2 weight-loss modalities for improving NAFLD, liraglutide was as effective as structured lifestyle modification

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: A pilot randomized trial.

Weight loss through lifestyle modification or liraglutide is associated with improvement of NAFLD severity and changes in amino acid concentrations

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Randomized trial comparing effects of weight loss by liraglutide with lifestyle modification in non-alcoholic fatty liver disease.

Comparative effects of liraglutide 3 mg vs structured lifestyle modification on body weight, liver fat and liver function in obese patients with non-alcoholic fatty liver disease: A pilot randomized trial.

Weight loss through lifestyle modification or liraglutide is associated with improvement of NAFLD severity and changes in amino acid concentrations