Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Riccardo Nevola
 -- 3350 2023-05-10 19:17:47 |
2 format correct
Catherine Yang
 + 1 word(s) 3351 2023-05-12 03:37:24 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Nevola, R.; Epifani, R.; Imbriani, S.; Tortorella, G.; Aprea, C.; Galiero, R.; Rinaldi, L.; Marfella, R.; Sasso, F.C. Effects of GLP-1 Receptor Agonists on NAFLD. Encyclopedia. Available online: https://encyclopedia.pub/entry/44121 (accessed on 01 August 2024).
Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, et al. Effects of GLP-1 Receptor Agonists on NAFLD. Encyclopedia. Available at: https://encyclopedia.pub/entry/44121. Accessed August 01, 2024.
Nevola, Riccardo, Raffaella Epifani, Simona Imbriani, Giovanni Tortorella, Concetta Aprea, Raffaele Galiero, Luca Rinaldi, Raffaele Marfella, Ferdinando Carlo Sasso. "Effects of GLP-1 Receptor Agonists on NAFLD" Encyclopedia, https://encyclopedia.pub/entry/44121 (accessed August 01, 2024).
Nevola, R., Epifani, R., Imbriani, S., Tortorella, G., Aprea, C., Galiero, R., Rinaldi, L., Marfella, R., & Sasso, F.C. (2023, May 10). Effects of GLP-1 Receptor Agonists on NAFLD. In Encyclopedia. https://encyclopedia.pub/entry/44121
Nevola, Riccardo, et al. "Effects of GLP-1 Receptor Agonists on NAFLD." Encyclopedia. Web. 10 May, 2023.
Effects of GLP-1 Receptor Agonists on NAFLD
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms24021703

Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. There are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. 

NAFLD GLP-1 receptor agonist type 2 diabetes

1. Effects of GLP-1 RAs on Body Weight

To date, the only validated treatment for the management of NAFLD is weight loss, generally achieved through lifestyle changes (diet, physical activity) or bariatric surgery. Weight loss of ≥7–10% has been shown to reduce disease progression and improve steatosis, inflammation, and liver fibrosis [1][2]. However, a significant and long-lasting reduction in body weight is difficult to achieve and various dietary regimens often fail both in the long term and in highly motivated patients. Moreover, counter-regulatory mechanisms over time hinder weight loss, resulting in the recovery of body weight [3]. In addition to lifestyle changes, GLP-1 RAs have been shown to lower body weight in a range of 2–7 kg through early satiety and reduction in appetite, thus lowering caloric intake [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. Furthermore, treatment with these drugs reduces cravings for food and increases the pleasure offered by eating a meal [24]. Except for SGLT2 inhibitors, all the other hypoglycaemics drugs (including insulin) either have neutral effect or, more often, cause weight gain [25].
Mechanisms involved in this process are both central and peripheral. In the CNS, serotonin represents a crucial factor in appetite regulation. Through the stimulation of its receptor in the central nervous system, GLP-1 reduces the expression of serotonin 5-HT2A receptors in the hypothalamus, resulting in decreased appetite [26]. This role is independent from serotonin secretion, which is not affected [27]. In particular, in murin models, GLP-1 RAs have demonstrated to prevent meal-initiation-inhibiting activity on arcuate nucleus and inducing meal-ending actions on lateral parabrachial nucleus [25]. It has been hypothesized that liraglutide and semaglutide act through different neurological pathways, providing the rationale for their different efficacy in inducing weight loss [28]. The reduction in appetite is also assisted by peripheral mechanisms. In fact, GLP-1 RAs are able to delay gastric emptying and to slow intestinal motility in the gastro-intestinal tract, which enhances the feeling of early satiety at a central level [18]. However, the long-term receptor stimulation by GLP-1 over time reduces the effects on gastric emptying due to the mechanisms of tachyphylaxis [29].
The main studies on the efficacy of GLP-1 RAs in inducing weight loss are summarized in Table 1. The extent of the reduction in body weight depends on which GLP-1 RAs and which dosage are used. Moreover, the dose used to treat T2DM and obesity may differ. In fact, if the glycemic control plateau is reached with relatively low dosages, weight loss effects may require higher GLP-1 RAs dosages [25]. In contrast, the variability in interindividual response on body weight loss in patients receiving GLP-1 RAs treatment is significantly greater than the variability in glycemic control response [30]. To date, no specific predictors of long-term response to weight loss have been identified.
Table 1. Main evidences on the effect of liraglutide and semaglutide on weight loss.
Year First Author Ref. Sample Size Study Typology Evaluated Drugs Benefit Results
2009 Astrup [11] 564 non-diabetic obese Prospective double-blind Liraglutide vs orlistat vs placebo Yes Liraglutide resulted in greater weight loss than placebo or orlistat
2013 Wadden [16] 422 obese/overweight Prospective randomised Liraglutide vs placebo Yes Liraglutide plus diet and exercise maintained weight loss achieved by caloric restriction and induced further weight loss
2015 Pi-Sunyer [6] 3731 non-diabetic obese Prospective double-blind Liraglutide vs placebo Yes Liraglutide induced greater weight loss (8.4 Kg) than placebo (2.8 Kg)
2015 Davies [20] 846 obese/overweight T2DM Prospective double-blind Liraglutide vs placebo Yes Liraglutide (3.0 mg/day), compared with placebo, resulted in greater weight loss
2016 de Boer [14] 151 obese insulin-using T2DM Prospective Liraglutide or Exenatide Yes Liraglutide or Exenatide led to sustained weight reduction and daily insulin dose
2016 Blackman [17] 359 non-diabetic obese Prospective double-blind Liraglutide vs placebo Yes Liraglutide (3.0 mg/day) plus lifestyle therapy led to a greater weight loss than placebo plus lifestyle therapy
2016 Armstrong [31] 52 NASH patients Multicentre, double-blinded Liraglutide vs placebo Yes Liraglutide 1.8 mg/day led to a greater weight loss than placebo
2017 Halawi [18] 40 obese patients Prospective double-blind Liraglutide vs placebo Yes Liraglutide delays gastric emptying and reduces body weight more than placebo
2017 Petit [32] 68 uncontrolled T2DM patients Prospective single-center Liraglutide Yes Liraglutide 1.2 mg/day significantly reduced body weight
2018 Frøssing [33] 72 obese/overweight with PCOS Prospective double-blind Liraglutide vs placebo Yes Liraglutide results in greater weight loss than placebo
2019 Feng [34] 85 T2DM and NAFLD patients Prospective, randomized Liraglutide vs gliclazide Yes Liraglutide results in greater weight loss than gliclazide
2019 Yan [23] 75 NAFLD and metformin-uncontrolled T2DM patients RCT Liraglutide vs sitagliptin vs insulin glargine Yes Combined with metformin, both liraglutide and sitagliptin, but not insulin glargine, reduced body weight
2020 Kelly [13] 251 obese adolescents Prospective double-blind Liraglutide vs placebo Yes Liraglutide (3.0 mg/day) plus lifestyle therapy led to a greater weight loss than placebo plus lifestyle therapy in adolescent with obesity
2020 Wadden [15] 282 obese Prospective double-blind Liraglutide vs placebo Yes Liraglutide (3.0 mg/day) amplifies weight loss due to intensive behavioral therapy
2020 Garvey [21] 396 obese/overweight and insulin-treated T2DM patients Prospective double-blind Liraglutide vs placebo Yes Liraglutide (3.0 mg/day) led to greater weight loss than placebo
2017 Blundell [12] 28 obese Prospective double-blind Semaglutide vs placebo Yes Semaglutide resulted in lower ad libitum energy intake and greater weight loss than placebo
2018 O’Neil [4] 957 non-diabetic obese Prospective double-blind Semaglutide vs Liraglutide Yes Semaglutide (≥0.2 mg/day) resulted in greater weight loss than liraglutide (any dose)
2018 Pratley [5] 1201 T2DM patients Prospective randomised Semaglutide vs Dulaglutide Yes Semaglutide 0.5 mg/week resulted in greater weight loss than dulaglutide 0.75 mg/week. Semaglutide 1 mg/week resulted in greater weight loss than dulaglutide 1.5 mg/week
2019 Matikainen [35] 22 controlled T2DM patients Prospective single-blind Liraglutide vs placebo No Similar weight loss between 16-week liraglutide 1.8 mg/day and placebo group
2021 Wilding [7] 1961 non-diabetic obese Prospective double-blind Semaglutide vs placebo Yes Semaglutide (2.4 mg/week) plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone
2021 Davies [8] 1210 insulin-untreated diabetic obese/overweight patients Prospective double-blind Semaglutide 2.4 vs 1 mg/week vs placebo Yes Semaglutide 2.4 mg/week resulted in a greater weight loss
than Semaglutide 1.0 mg/week or placebo
2021 Wadden [9] 611 non-diabetic obese/overweight patients Prospective double-blind Semaglutide vs placebo Yes Semaglutide (2.4 mg/week) plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone
2021 Rubino [10] 902 non-diabetic obese/overweight patients Prospective double-blind Semaglutide vs placebo Yes Semaglutide (2.4 mg/week) plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone
2021 Newsome [36] 320 obese/overweight NASH patients Prospective double-blind Semaglutide vs placebo Yes Semaglutide treatment resulted in a greater reduction in BMI than placebo
2022 Rubino [19] 338 non-diabetic obese/overweight patients Prospective randomised Semaglutide vs Liraglutide Yes Semaglutide (2.4 mg/week) resulted in greater weight loss
than liraglutide (3 mg/day)
2022 Weghuber [22] 201 obese adolescents Prospective double-blind Semaglutide vs placebo Yes Semaglutide (2.4 mg/week) plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone
BMI: body mass index; BW: body weight; NA: not available; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PCOS: polycystic ovary syndrome; RCT: randomized clinical trial; T2DM: type 2 diabetes mellitus.
Liraglutide has demonstrated to determine significant weight loss, reduce pre-diabetes rate and improve obesity-related risk factors independently from the presence of T2DM [11][13][14][23][31][32][33][34]. After a year of treatment at the daily dosage of 3 mg, it was able to reduce body weight by 8.4 kg [6]. Comparing the results from the various trials [6][11][15][16][17][20][21], the average weight loss is about 3.4–6.1% of the total body weight. In particular, among treated patients, about 2/3 show a weight loss of at least 5% and 1/3 a weight loss of more than 10% [6]. Its anorectic effect starts very early; therefore, in mice, it has significantly reduced appetite within 1 h of administration [27]. To the knowledge, only one study failed to prove significant differences in weight loss between treatment with liraglutide and placebo [35].
Semaglutide is a 2nd generation GLP-1 agonist available both in oral (daily administration) and subcutaneous (weekly administration) formulation [25][37]. The treatment with semaglutide resulted in a lower energy intake and greater weight loss than placebo both in adults [4][7][8][9][10][12][36] and adolescents [22]. In particular, at a dosage of 2.4 mg per week, it has been shown to induce an average weight loss between 9.6% and 17.4%, as well as a reduction in waist circumference and arterial hypertension and an improvement of lipid profile [7][8][9][10][12]. The dose used for the treatment of obesity (2.4 mg/week) is significantly more effective in determining weight loss than that used for the treatment of T2DM (1.0 mg/week) [8]. Furthermore, the ability to induce weight loss is more pronounced for semaglutide than other GLP-1 RAs [5]. For doses equal to or greater than 0.2 mg/day (1.4 mg/week), semaglutide is also superior to liraglutide (at any dose) in causing weight loss [4]. Notably, in the recent STEP 8 randomized clinical trial [19], semaglutide (2.4 mg/week) achieved a mean weight loss of 15.8% after 68 weeks of treatment compared with 6.4% obtained with liraglutide. A weight loss greater than 10% (therapeutic target in NAFLD) was achieved in 70.9% of semaglutide-treated patients and 25.6% of liraglutide-treated patients, with comparable rates of gastrointestinal adverse events [19]. Semaglutide-related weight loss continued until weeks 28 to 44 of treatment and was sustained thereafter [36].
For these reasons, beyond T2DM, liraglutide and semaglutide have also been approved for the treatment of obesity in diabetic and non-diabetic patients [30][38]. The maximum approved dose of liraglutide for the treatment of obesity is 3 mg/day, whereas the maximum dose for the treatment of T2DM is 1.8 mg/day. The maximum dose of semaglutide used for the treatment of obesity is 2.8 mg/week (0.4 mg/day), whereas the maximum dose for the treatment of T2DM is 1 mg/week.

2. Effects of GLP-1 RAs on Hepatic Cytolysis

Although not highly sensitive [39], hepatic cytolysis markers (aspartate aminotransferase—AST, and, above all, alanine aminotransferase—ALT) represent the epiphenomenon of the potential hepatic inflammation in NAFLD patients. Indeed, patients with NAFLD and elevation of liver cytolysis enzymes have an increased risk of NASH and progression to cirrhosis [40]. Meanwhile, treatments that reduce the risk of NAFLD progression are all associated with a significant reduction in hepatic cytolysis [1][40][41][42]. In overweight or obese patients with NAFLD, reduction in body weight ≥7–10% improves liver enzymes together with the histological grade of disease [43][44]. Despite normalization of liver injury indices is an independent predictor of fibrosis improvement in patients with NASH [42], for several drugs this improvement is not associated with a significant histological and prognostic benefit [1][45]. Growing evidence supports the positive impact of GLP-1 RAs in reducing hepatic cytolysis enzymes [31][36][46][47][48][49][50][51][52][53][54][55][56][57][58]. Buse [46] and Klonoff [47] et al. first showed that long-term treatment with exenatide in patients with T2DM was associated with a significant improvement in biomarkers of liver injury, as well as a reduction in body weight, blood pressure and glycosylated hemoglobin levels. Notably, approximately 40% of patients with baseline liver enzyme elevations achieved normal ALT after treatment. Subsequently, Fan et al. [49] compared treatment with exenatide and metformin in diabetic patients with NAFLD. The authors showed that a 12-week treatment with exenatide was associated with a significant reduction in liver enzymes compared to treatment with metformin. Similarly, Sathyanarayana et al. [48] have also demonstrated that treatment with exenatide, as well as pioglitazone, improves liver injury rates in patients with T2DM. However, the reduction in ALT levels was significantly greater following combined treatment with pioglitazone and exenatide. A similar impact on biomarkers of liver damage has also been demonstrated for lixisenatide [52], dulaglutide [55][56], liraglutide [50][53][54] and semaglutide [36][57]. In patients with T2DM and NAFLD, dulaglutide has been shown to significantly reduce levels of liver injury biomarkers compared to placebo at 6 months of treatment [56]. As concerns liraglutide, Armstrong et al. [50] performed a meta-analysis of 4442 patients with T2DM. At a dosage of 1.8 mg/day, liraglutide has been proven to significantly lower ALT levels in patients with elevated baseline values, with a dose-dependent effect. In fact, no significant differences in the impact on biomarkers of liver injury were observed at the dosage of 0.6 and 1.2 mg/day compared to placebo. Changes in liver fat content would be directly related to the reduction in body weight, serum ALT and triglyceride levels [54]. Finally, in a post hoc analysis of two large trials on the effect of semaglutide on body weight and cardiovascular outcomes, this drug was shown to significantly reduce ALT levels in patients with T2DM and/or obesity [57]. The degree of improvement in the indices of liver damage was directly related to the dosage of semaglutide and greater for high doses. Maximal reduction in ALT levels was achieved approximately 28–30 weeks after initiation of treatment, with subsequent stabilization. These effects have been shown to be closely related to drug-induced weight loss. Recently, Newsome et al. [36] confirmed the efficacy of semaglutide in determining an improvement in hepatic cytolysis indices with a dose-dependent effect.
Another target in the treatment of NAFLD is represented by the reduction in triglycerides’ accumulation in the liver. In this regard, GLP-1 RAs have been proven to significantly improve hepatic steatosis. Preclinical studies showed that exendin-4, a GLP-1R agonist derived from the saliva of the Gila monster, was able to significantly reduce the hepatic accumulation of triglycerides both in mouse models [59] and in human hepatocytes [60] by activating the signaling cascade downstream of the insulin receptor (see below). Furthermore, the addition of exenatide to pioglitazone (already known for its benefits on NAFLD) was associated with a greater reduction in hepatic fat content compared to pioglitazone monotherapy [48].
Although inconsistent data is available [61][62], most studies subsequently confirmed the in vivo benefit of GLP-1 RAs on fatty liver disease [23][31][32][33][36][48][51][53][54][58][61][62][63][64][65][66][67]. Compared with other hypoglycemic agents, exenatide significantly reduces the hepatic triglyceride content and epicardial adipose tissue related to weight loss [65]. Braslov et al. [51] underlined that the improvement of hepatic fat accumulation (assessed using the fatty liver index—FLI) induced by exenatide is not detectable for the other oral hypoglycemic agents. In addition to GLP-1 RAs, a similar impact on steatosis (assessed by FLI) was also showed by SGLT2i [58].
Vanderheiden [66], Petit [32] and Yan [23] et al. demonstrated through magnetic resonance imaging a significant reduction in hepatic and subcutaneous fat in patients treated with liraglutide. Treatment with liraglutide would reduce liver fat content by 44% [33]. In addition to the effect on liver fat, liraglutide treatment is also associated with a greater reduction in total fat mass than treatment with sulfonylurea [34][54]. In this setting, the study by Armstrong et al. is very interesting [31]. Through a multicenter, double-blind, placebo-controlled phase 2 trial, the authors evaluated the impact of liraglutide on liver histology in patients with NASH. Treatment with liraglutide (1.8 mg/day) resulted in a greater improvement in steatosis and hepatocyte ballooning compared to placebo. Particularly, liraglutide has been shown to achieve histological resolution of steatohepatitis in 39% of cases after 48 weeks of treatment, compared to 9% of cases in the placebo group. Patients treated with liraglutide had a relative risk of 4.5 (95% CI: 1.1–18.9; p = 0.017) of achieving resolution of NASH compared with placebo, regardless of the presence of T2DM. However, NAFLD activity score (NAS) was not significantly different between the two groups, although there may be additional benefits associated with liraglutide dosages >1.8 mg/day, not evaluated in this trial. No significant differences in weight loss and improvement in glycosylated hemoglobin levels were found between liraglutide responders and non-responders. A similar effect of liraglutide in patients with NASH was also highlighted by Eguchi et al. [53]. Recently, the effects of semaglutide treatment on patients with biopsy-proven NASH have been evaluated [36]. After 72 weeks, treatment with semaglutide at a dose of 0.4 mg/day resulted in the histological resolution of NASH without progression of fibrosis in 59% of patients, compared with 17% in the placebo group. Furthermore, an improvement in NAS was observed in 83% of patients treated with semaglutide 0.4 mg/day, 80% of those treated with 0.2 mg/day, 71% of those treated with 0.1 mg/day and only 44% of those treated with placebo.
Although not fully clarified, the mechanism of action of GLP-1 RAs on fatty liver disease may be multifactorial. If the reduction in body weight and the improvement of glycemic control are crucial factors in determining the effects of GLP-1 on NAFLD, direct pharmacological mechanisms could also be involved. Indeed, in liraglutide-treated mice, the reduction in hepatic steatosis and endoplasmic reticulum oxidative stress occurred regardless of body weight loss (see below) [68][69].

3. Effects of GLP-1 RAs on Liver Fibrosis

Liver fibrosis is the main determinant of clinical outcomes in patients with NASH [70][71]. In particular, clinically relevant fibrosis is detectable in about 15% of diabetic patients [72]. A treatment for NAFLD must be able to impact liver fibrosis, aiming to reduce the rates of mortality, liver transplantation and liver-related events.
To date, few studies that evaluated the efficacy of GLP-1 RAs on NAFLD-related liver fibrosis are available [31][36][58][73][74][75]. Moreover, most of the data are obtained from indirect markers of fibrosis, such as the APRI (AST-to-platelet count ratio index), the NFS (NAFLD fibrosis score), the FIB-4 (fibrosis index based on 4 factors) or from the assessment of liver stiffness (LSM). In this regard, Ohki et al. [74] observed a significant reduction in APRI in patients treated with liraglutide, similar to those treated with pioglitazone. Recently, Colosimo et al. [58] confirmed a significant reduction in FIB-4 in diabetic patients treated with GLP-1 RAs, similar to those treated with SGLT2i. Finally, Tan et al. [75] found that diabetic patients treated with liraglutide showed a significant reduction in NFS, FIB-4 and LSM after a 12-month follow-up compared to patients treated with other hypoglycemic agents.
Few studies evaluated the impact of GLP-1 RAs on histologically detected liver fibrosis [31][36][73]. Significant data emerged in this regard from the previously discussed trial by Armstrong et al. [31]. In addition to the reduction in body weight, improvement in liver injury rates and resolution of steatohepatitis in 39% of cases, treatment with liraglutide was associated with lower progression of liver fibrosis compared to placebo. Indeed, despite the short duration of the trial (48 weeks), progression of fibrosis was detected in 9% of patients treated with liraglutide and 36% of patients treated with placebo (p = 0.04). However, patients with more severe fibrosis at baseline appear to have a lower response to liraglutide. Thus, early treatment of NASH with GLP-1 RAs may be more effective. Recently, Newsome et al. [36] carried out a 72-week trial on the effects of semaglutide on NASH assessed by liver biopsy before and after treatment. If semaglutide at a dosage of 0.4 mg/day leads to resolution of steatohepatitis in 59% of cases, no significant difference emerged in the improvement of fibrosis compared to placebo. However, the treatment was shown to be effective in reducing the progression of fibrosis (5% vs. 19% of the placebo group), in accordance with what previously demonstrated [31].
The protective role on fibrosis progression demonstrated by GLP-1 RAs could be explained by the effect in reducing the expression of three out of five collagen genes [76]. In fact, this effect demonstrated on mouse models exposed to semaglutide exclusively impacts the de novo production of collagen and does not affect the pre-treatment liver fibrosis. In this regard, in the researcher's opinion, it can be assumed that longer-lasting treatments could also show a significant effect on the regression of pre-existing NASH-related fibrosis. In fact, if the drug-induced reduction in hepatic fat content and the consequent lipotoxicity can determine a resolution of the steatohepatitis in the medium-term, avoiding the progression of liver damage, longer times are probably needed for the clearance of the pre-existing fibrosis.
Finally, preclinical data suggest that treatment with GLP-1 RAs could result in lower incidence of NASH-related hepatocellular carcinoma (HCC) [77]. In mouse models, liraglutide has been shown to completely suppress hepatocarcinogenesis. The protective effect on the development of HCC could be mediated both by the improvement of steatohepatitis (steatosis, inflammation, and hepatocyte ballooning) and the better glycemic compensation and weight loss, with reduced systemic inflammatory state and oxidative stress [78][79]. Moreover, in conditions of insulin resistance (such as during NAFLD), a significant imbalance in the levels of adipokines is determined, with lower levels of adiponectin and an increase in those of leptin [80]. It has been demonstrated that this imbalance favors hepatocarcinogenesis [81]. In particular, leptin promotes the proliferation and migration of neoplastic cells. GLP-1 RAs are able to increase adiponectin levels and restore the balance among adipokines [59][80][82]. This pathway could represent one of the protective mechanisms against HCC development exerted by GLP-1 RAs.

References

  1. European Association for the Study of the Liver (EASL); European Association 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.
  2. Associazione Italiana per lo Studio del Fegato (AISF), Società Italiana di Diabetologia (SID) and Società Italiana dell’Obesità (SIO); Members of the Guidelines Panel; Coordinator; AISF Members; SID Members; SIO Members; Metodologists. Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Dig. Liver Dis. 2022, 54, 170–182.
  3. Lingvay, I.; Sumithran, P.; Cohen, R.V.; le Roux, C.W. Obesity management as a primary treatment goal for type 2 diabetes: Time to reframe the conversation. Lancet 2022, 399, 394–405, Erratum in Lancet 2022, 399, 358.
  4. O’Neil, P.M.; Birkenfeld, A.L.; McGowan, B.; Mosenzon, O.; Pedersen, S.D.; Wharton, S.; Carson, C.G.; Jepsen, C.H.; Kabisch, M.; Wilding, J.P.H. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: A randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet 2018, 392, 637–649.
  5. Pratley, R.E.; Aroda, V.R.; Lingvay, I.; Lüdemann, J.; Andreassen, C.; Navarria, A.; Viljoen, A.; SUSTAIN 7 Investigators. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): A randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018, 6, 275–286.
  6. Pi-Sunyer, X.; Astrup, A.; Fujioka, K.; Greenway, F.; Halpern, A.; Krempf, M.; Lau, D.C.; le Roux, C.W.; Violante Ortiz, R.; Jensen, C.B.; et al. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management. N. Engl. J. Med. 2015, 373, 11–22.
  7. Wilding, J.P.H.; Batterham, R.L.; Calanna, S.; Davies, M.; Van Gaal, L.F.; Lingvay, I.; McGowan, B.M.; Rosenstock, J.; Tran, M.T.D.; Wadden, T.A.; et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N. Engl. J. Med. 2021, 384, 989–1002.
  8. Davies, M.; Færch, L.; Jeppesen, O.K.; Pakseresht, A.; Pedersen, S.D.; Perreault, L.; Rosenstock, J.; Shimomura, I.; Viljoen, A.; Wadden, T.A.; et al. STEP 2 Study Group. Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): A randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021, 397, 971–984.
  9. Wadden, T.A.; Bailey, T.S.; Billings, L.K.; Davies, M.; Frias, J.P.; Koroleva, A.; Lingvay, I.; O’Neil, P.M.; Rubino, D.M.; Skovgaard, D.; et al. Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial. JAMA 2021, 325, 1403–1413.
  10. Rubino, D.; Abrahamsson, N.; Davies, M.; Hesse, D.; Greenway, F.L.; Jensen, C.; Lingvay, I.; Mosenzon, O.; Rosenstock, J.; Rubio, M.A.; et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA 2021, 325, 1414–1425.
  11. Astrup, A.; Rössner, S.; Van Gaal, L.; Rissanen, A.; Niskanen, L.; Al Hakim, M.; Madsen, J.; Rasmussen, M.F.; Lean, M.E.; NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: A randomised, double-blind, placebo-controlled study. Lancet 2009, 374, 1606–1616, Erratum in Lancet 2010, 375, 984.
  12. Blundell, J.; Finlayson, G.; Axelsen, M.; Flint, A.; Gibbons, C.; Kvist, T.; Hjerpsted, J.B. Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes. Metab. 2017, 19, 1242–1251.
  13. Kelly, A.S.; Auerbach, P.; Barrientos-Perez, M.; Gies, I.; Hale, P.M.; Marcus, C.; Mastrandrea, L.D.; Prabhu, N.; Arslanian, S.; NN8022-4180 Trial Investigators. A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity. N. Engl. J. Med. 2020, 382, 2117–2128.
  14. de Boer, S.A.; Lefrandt, J.D.; Petersen, J.F.; Boersma, H.H.; Mulder, D.J.; Hoogenberg, K. The effects of GLP-1 analogues in obese, insulin-using type 2 diabetes in relation to eating behaviour. Int. J. Clin. Pharm. 2016, 38, 144–151.
  15. Wadden, T.A.; Tronieri, J.S.; Sugimoto, D.; Lund, M.T.; Auerbach, P.; Jensen, C.; Rubino, D. Liraglutide 3.0 mg and Intensive Behavioral Therapy (IBT) for Obesity in Primary Care: The SCALE IBT Randomized Controlled Trial. Obesity 2020, 28, 529–536.
  16. Wadden, T.A.; Hollander, P.; Klein, S.; Niswender, K.; Woo, V.; Hale, P.M.; Aronne, L.; NN8022-1923 Investigators. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: The SCALE Maintenance randomized study. Int. J. Obes. 2013, 37, 1443–1451, Erratum in Int. J. Obes. 2013, 37, 1514Erratum in Int. J. Obes. 2015, 39, 187.
  17. Blackman, A.; Foster, G.D.; Zammit, G.; Rosenberg, R.; Aronne, L.; Wadden, T.; Claudius, B.; Jensen, C.B.; Mignot, E. Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: The SCALE Sleep Apnea randomized clinical trial. Int. J. Obes. 2016, 40, 1310–1319.
  18. Halawi, H.; Khemani, D.; Eckert, D.; O’Neill, J.; Kadouh, H.; Grothe, K.; Clark, M.M.; Burton, D.D.; Vella, A.; Acosta, A.; et al. Effects of liraglutide on weight, satiation, and gastric functions in obesity: A randomised, placebo-controlled pilot trial. Lancet Gastroenterol. Hepatol. 2017, 2, 890–899.
  19. Rubino, D.M.; Greenway, F.L.; Khalid, U.; O’Neil, P.M.; Rosenstock, J.; Sørrig, R.; Wadden, T.A.; Wizert, A.; Garvey, W.T.; STEP 8 Investigators. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA 2022, 327, 138–150.
  20. Davies, M.J.; Bergenstal, R.; Bode, B.; Kushner, R.F.; Lewin, A.; Skjøth, T.V.; Andreasen, A.H.; Jensen, C.B.; DeFronzo, R.A.; NN8022-1922 Study Group. Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial. JAMA 2015, 314, 687–699, Erratum in JAMA 2016, 315, 90.
  21. Garvey, W.T.; Birkenfeld, A.L.; Dicker, D.; Mingrone, G.; Pedersen, S.D.; Satylganova, A.; Skovgaard, D.; Sugimoto, D.; Jensen, C.; Mosenzon, O. Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial. Diabetes Care 2020, 43, 1085–1093.
  22. Weghuber, D.; Barrett, T.; Barrientos-Pérez, M.; Gies, I.; Hesse, D.; Jeppesen, O.K.; Kelly, A.S.; Mastrandrea, L.D.; Sørrig, R.; Arslanian, S.; et al. Once-Weekly Semaglutide in Adolescents with Obesity. N. Engl. J. Med. 2022. Epub ahead of print.
  23. Yan, J.; Yao, B.; Kuang, H.; Yang, X.; Huang, Q.; Hong, T.; Li, Y.; Dou, J.; Yang, W.; Qin, G.; et al. Liraglutide, Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease. Hepatology 2019, 69, 2414–2426.
  24. van Bloemendaal, L.; Veltman, D.J.; Ten Kulve, J.S.; Groot, P.F.; Ruhé, H.G.; Barkhof, F.; Sloan, J.H.; Diamant, M.; Ijzerman, R.G. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans. Diabetes Obes. Metab. 2015, 17, 878–886.
  25. Nauck, M.A.; Quast, D.R.; Wefers, J.; Meier, J.J. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol. Metab. 2021, 46, 101102.
  26. Nonogaki, K.; Kaji, T. Liraglutide, a GLP-1 Receptor Agonist, Which Decreases Hypothalamic 5-HT2A Receptor Expression, Reduces Appetite and Body Weight Independently of Serotonin Synthesis in Mice. J. Diabetes Res. 2018, 2018, 6482958.
  27. Nonogaki, K.; Kaji, T. The acute anorexic effect of liraglutide, a GLP-1 receptor agonist, does not require functional leptin receptor, serotonin, and hypothalamic POMC and CART activities in mice. Diabetes Res. Clin. Pract. 2016, 120, 186–189.
  28. Gabery, S.; Salinas, C.G.; Paulsen, S.J.; Ahnfelt-Rønne, J.; Alanentalo, T.; Baquero, A.F.; Buckley, S.T.; Farkas, E.; Fekete, C.; Frederiksen, K.S.; et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight 2020, 5, e133429.
  29. Umapathysivam, M.M.; Lee, M.Y.; Jones, K.L.; Annink, C.E.; Cousins, C.E.; Trahair, L.G.; Rayner, C.K.; Chapman, M.J.; Nauck, M.A.; Horowitz, M.; et al. Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia. Diabetes 2014, 63, 785–790.
  30. Jensterle, M.; Rizzo, M.; Haluzík, M.; Janež, A. Efficacy of GLP-1 RA Approved for Weight Management in Patients With or Without Diabetes: A Narrative Review. Adv. Ther. 2022, 39, 2452–2467.
  31. Armstrong, M.J.; Gaunt, P.; Aithal, G.P.; Barton, D.; Hull, D.; Parker, R.; Hazlehurst, J.M.; Guo, K.; Abouda, G.; Aldersley, M.A.; et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2016, 387, 679–690.
  32. Petit, J.M.; Cercueil, J.P.; Loffroy, R.; Denimal, D.; Bouillet, B.; Fourmont, C.; Chevallier, O.; Duvillard, L.; Vergès, B. Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study. J. Clin. Endocrinol. Metab. 2017, 102, 407–415.
  33. Frøssing, S.; Nylander, M.; Chabanova, E.; Frystyk, J.; Holst, J.J.; Kistorp, C.; Skouby, S.O.; Faber, J. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial. Diabetes Obes. Metab. 2018, 20, 215–218.
  34. Feng, W.H.; Bi, Y.; Li, P.; Yin, T.T.; Gao, C.X.; Shen, S.M.; Gao, L.J.; Yang, D.H.; Zhu, D.L. Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non-alcoholic fatty liver disease: A randomized trial. J. Diabetes Investig. 2019, 10, 399–407.
  35. Matikainen, N.; Söderlund, S.; Björnson, E.; Pietiläinen, K.; Hakkarainen, A.; Lundbom, N.; Taskinen, M.R.; Borén, J. Liraglutide treatment improves postprandial lipid metabolism and cardiometabolic risk factors in humans with adequately controlled type 2 diabetes: A single-centre randomized controlled study. Diabetes Obes. Metab. 2019, 21, 84–94.
  36. Newsome, P.N.; Buchholtz, K.; Cusi, K.; Linder, M.; Okanoue, T.; Ratziu, V.; Sanyal, A.J.; Sejling, A.S.; Harrison, S.A.; NN9931-4296 Investigators. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N. Engl. J. Med. 2021, 384, 1113–1124.
  37. Trujillo, J.M.; Nuffer, W.; Smith, B.A. GLP-1 receptor agonists: An updated review of head-to-head clinical studies. Ther. Adv. Endocrinol. Metab. 2021, 12, 2042018821997320.
  38. Del Prato, S.; Gallwitz, B.; Holst, J.J.; Meier, J.J. The incretin/glucagon system as a target for pharmacotherapy of obesity. Obes. Rev. 2022, 23, e13372.
  39. Portillo-Sanchez, P.; Bril, F.; Maximos, M.; Lomonaco, R.; Biernacki, D.; Orsak, B.; Subbarayan, S.; Webb, A.; Hecht, J.; Cusi, K. High Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus and Normal Plasma Aminotransferase Levels. J. Clin. Endocrinol. Metab. 2015, 100, 2231–2238.
  40. Ekstedt, M.; Franzén, L.E.; Mathiesen, U.L.; Thorelius, L.; Holmqvist, M.; Bodemar, G.; Kechagias, S. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006, 44, 865–873.
  41. Neuschwander-Tetri, B.A.; Loomba, R.; Sanyal, A.J.; Lavine, J.E.; Van Natta, M.L.; Abdelmalek, M.F.; Chalasani, N.; Dasarathy, S.; Diehl, A.M.; Hameed, B.; et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial. Lancet 2015, 385, 956–965, Erratum in Lancet 2015, 385, 946Erratum in Lancet 2016, 387, 1618.
  42. Vilar-Gomez, E.; Calzadilla-Bertot, L.; Friedman, S.L.; Gra-Oramas, B.; Gonzalez-Fabian, L.; Lazo-Del Vallin, S.; Diago, M.; Adams, L.A. Serum biomarkers can predict a change in liver fibrosis 1 year after lifestyle intervention for biopsy-proven NASH. Liver Int. 2017, 37, 1887–1896.
  43. Promrat, K.; Kleiner, D.E.; Niemeier, H.M.; Jackvony, E.; Kearns, M.; Wands, J.R.; Fava, J.L.; Wing, R.R. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010, 51, 121–129.
  44. Vilar-Gomez, E.; Martinez-Perez, Y.; Calzadilla-Bertot, L.; Torres-Gonzalez, A.; Gra-Oramas, B.; Gonzalez-Fabian, L.; Friedman, S.L.; Diago, M.; Romero-Gomez, M. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 2015, 149, 367–378.e5, quiz e14–e15.
  45. Friedman, S.L.; Ratziu, V.; Harrison, S.A.; Abdelmalek, M.F.; Aithal, G.P.; Caballeria, J.; Francque, S.; Farrell, G.; Kowdley, K.V.; Craxi, A.; et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology 2018, 67, 1754–1767.
  46. Buse, J.B.; Klonoff, D.C.; Nielsen, L.L.; Guan, X.; Bowlus, C.L.; Holcombe, J.H.; Maggs, D.G.; Wintle, M.E. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: An interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin. Ther. 2007, 29, 139–153.
  47. Klonoff, D.C.; Buse, J.B.; Nielsen, L.L.; Guan, X.; Bowlus, C.L.; Holcombe, J.H.; Wintle, M.E.; Maggs, D.G. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr. Med. Res. Opin. 2008, 24, 275–286.
  48. Sathyanarayana, P.; Jogi, M.; Muthupillai, R.; Krishnamurthy, R.; Samson, S.L.; Bajaj, M. Effects of combined exenatide and pioglitazone therapy on hepatic fat content in type 2 diabetes. Obesity 2011, 19, 2310–2315.
  49. Fan, H.; Pan, Q.; Xu, Y.; Yang, X. Exenatide improves type 2 diabetes concomitant with non-alcoholic fatty liver disease. Arq. Bras. Endocrinol. Metabol. 2013, 57, 702–708.
  50. Armstrong, M.J.; Houlihan, D.D.; Rowe, I.A.; Clausen, W.H.; Elbrønd, B.; Gough, S.C.; Tomlinson, J.W.; Newsome, P.N. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: Individual patient data meta-analysis of the LEAD program. Aliment. Pharmacol. Ther. 2013, 37, 234–242.
  51. Blaslov, K.; Zibar, K.; Bulum, T.; Duvnjak, L. Effect of exenatide therapy on hepatic fat quantity and hepatic biomarkers in type 2 diabetic patients. Clin. Res. Hepatol. Gastroenterol. 2014, 38, e61–e63.
  52. Gluud, L.L.; Knop, F.K.; Vilsbøll, T. Effects of lixisenatide on elevated liver transaminases: Systematic review with individual patient data meta-analysis of randomised controlled trials on patients with type 2 diabetes. BMJ Open 2014, 4, e005325.
  53. Eguchi, Y.; Kitajima, Y.; Hyogo, H.; Takahashi, H.; Kojima, M.; Ono, M.; Araki, N.; Tanaka, K.; Yamaguchi, M.; Matsuda, Y.; et al. Pilot study of liraglutide effects in non-alcoholic steatohepatitis and non-alcoholic fatty liver disease with glucose intolerance in Japanese patients (LEAN-J). Hepatol. Res. 2015, 45, 269–278.
  54. Feng, W.; Gao, C.; Bi, Y.; Wu, M.; Li, P.; Shen, S.; Chen, W.; Yin, T.; Zhu, D. Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non-alcoholic fatty liver disease. J. Diabetes 2017, 9, 800–809.
  55. Seko, Y.; Sumida, Y.; Tanaka, S.; Mori, K.; Taketani, H.; Ishiba, H.; Hara, T.; Okajima, A.; Umemura, A.; Nishikawa, T.; et al. Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus. Hepatol. Res. 2017, 47, 1206–1211.
  56. Cusi, K.; Sattar, N.; García-Pérez, L.E.; Pavo, I.; Yu, M.; Robertson, K.E.; Karanikas, C.A.; Haupt, A. Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: A post hoc analysis of the AWARD programme. Diabet. Med. 2018, 35, 1434–1439.
  57. Newsome, P.; Francque, S.; Harrison, S.; Ratziu, V.; Van Gaal, L.; Calanna, S.; Hansen, M.; Linder, M.; Sanyal, A. Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Aliment. Pharmacol. Ther. 2019, 50, 193–203.
  58. Colosimo, S.; Ravaioli, F.; Petroni, M.L.; Brodosi, L.; Marchignoli, F.; Barbanti, F.A.; Sasdelli, A.S.; Marchesini, G.; Pironi, L. Effects of antidiabetic agents on steatosis and fibrosis biomarkers in type 2 diabetes: A real-world data analysis. Liver Int. 2021, 41, 731–742.
  59. Ding, X.; Saxena, N.K.; Lin, S.; Gupta, N.A.; Anania, F.A. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/ob mice. Hepatology 2006, 43, 173–181, Erratum in Hepatology 2006, 44, 515.
  60. Gupta, N.A.; Mells, J.; Dunham, R.M.; Grakoui, A.; Handy, J.; Saxena, N.K.; Anania, F.A. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010, 51, 1584–1592.
  61. Smits, M.M.; Tonneijck, L.; Muskiet, M.H.; Kramer, M.H.; Pouwels, P.J.; den Pieters-van Bos, I.C.; Hoekstra, T.; Diamant, M.; van Raalte, D.H.; Cahen, D.L. Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: A randomised placebo-controlled trial. Diabetologia 2016, 59, 2588–2593.
  62. Tang, A.; Rabasa-Lhoret, R.; Castel, H.; Wartelle-Bladou, C.; Gilbert, G.; Massicotte-Tisluck, K.; Chartrand, G.; Olivié, D.; Julien, A.S.; de Guise, J.; et al. Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial. Diabetes Care 2015, 38, 1339–1346.
  63. Jendle, J.; Nauck, M.A.; Matthews, D.R.; Frid, A.; Hermansen, K.; Düring, M.; Zdravkovic, M.; Strauss, B.J.; Garber, A.J.; LEAD-2 and LEAD-3 Study Groups. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes. Metab. 2009, 11, 1163–1172.
  64. Cuthbertson, D.J.; Irwin, A.; Gardner, C.J.; Daousi, C.; Purewal, T.; Furlong, N.; Goenka, N.; Thomas, E.L.; Adams, V.L.; Pushpakom, S.P.; et al. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS ONE 2012, 7, e50117.
  65. Dutour, A.; Abdesselam, I.; Ancel, P.; Kober, F.; Mrad, G.; Darmon, P.; Ronsin, O.; Pradel, V.; Lesavre, N.; Martin, J.C.; et al. Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: A prospective randomized clinical trial using magnetic resonance imaging and spectroscopy. Diabetes Obes. Metab. 2016, 18, 882–891.
  66. Vanderheiden, A.; Harrison, L.B.; Warshauer, J.T.; Adams-Huet, B.; Li, X.; Yuan, Q.; Hulsey, K.; Dimitrov, I.; Yokoo, T.; Jaster, A.W.; et al. Mechanisms of Action of Liraglutide in Patients With Type 2 Diabetes Treated With High-Dose Insulin. J. Clin. Endocrinol. Metab. 2016, 101, 1798–1806.
  67. Bouchi, R.; Nakano, Y.; Fukuda, T.; Takeuchi, T.; Murakami, M.; Minami, I.; Izumiyama, H.; Hashimoto, K.; Yoshimoto, T.; Ogawa, Y. Reduction of visceral fat by liraglutide is associated with ameliorations of hepatic steatosis, albuminuria, and micro-inflammation in type 2 diabetic patients with insulin treatment: A randomized control trial. Endocr. J. 2017, 64, 269–281.
  68. Sharma, S.; Mells, J.E.; Fu, P.P.; Saxena, N.K.; Anania, F.A. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 2011, 6, e25269.
  69. Mells, J.E.; Fu, P.P.; Sharma, S.; Olson, D.; Cheng, L.; Handy, J.A.; Saxena, N.K.; Sorescu, D.; Anania, F.A. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. Am. J. Physiol. Gastrointest. Liver Physiol. 2012, 302, G225–G235.e10.
  70. Angulo, P.; Kleiner, D.E.; Dam-Larsen, S.; Adams, L.A.; Bjornsson, E.S.; Charatcharoenwitthaya, P.; Mills, P.R.; Keach, J.C.; Lafferty, H.D.; Stahler, A.; et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2015, 149, 389–397.e10.
  71. Taylor, R.S.; Taylor, R.J.; Bayliss, S.; Hagström, H.; Nasr, P.; Schattenberg, J.M.; Ishigami, M.; Toyoda, H.; Wai-Sun Wong, V.; Peleg, N.; et al. Association Between Fibrosis Stage and Outcomes of Patients With Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Gastroenterology 2020, 158, 1611–1625.e12.
  72. Lomonaco, R.; Godinez Leiva, E.; Bril, F.; Shrestha, S.; Mansour, L.; Budd, J.; Portillo Romero, J.; Schmidt, S.; Chang, K.L.; Samraj, G.; et al. Advanced Liver Fibrosis Is Common in Patients With Type 2 Diabetes Followed in the Outpatient Setting: The Need for Systematic Screening. Diabetes Care 2021, 44, 399–406.
  73. Kenny, P.R.; Brady, D.E.; Torres, D.M.; Ragozzino, L.; Chalasani, N.; Harrison, S.A. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: A case series. Am. J. Gastroenterol. 2010, 105, 2707–2709.
  74. Ohki, T.; Isogawa, A.; Iwamoto, M.; Ohsugi, M.; Yoshida, H.; Toda, N.; Tagawa, K.; Omata, M.; Koike, K. The effectiveness of liraglutide in nonalcoholic fatty liver disease patients with type 2 diabetes mellitus compared to sitagliptin and pioglitazone. Sci. World J. 2012, 2012, 496453.
  75. Tan, Y.; Zhen, Q.; Ding, X.; Shen, T.; Liu, F.; Wang, Y.; Zhang, Q.; Lin, R.; Chen, L.; Peng, Y.; et al. Association between use of liraglutide and liver fibrosis in patients with type 2 diabetes. Front. Endocrinol. 2022, 13, 935180.
  76. Rakipovski, G.; Rolin, B.; Nøhr, J.; Klewe, I.; Frederiksen, K.S.; Augustin, R.; Hecksher-Sørensen, J.; Ingvorsen, C.; Polex-Wolf, J.; Knudsen, L.B. The GLP-1 Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE-/- and LDLr-/- Mice by a Mechanism That Includes Inflammatory Pathways. JACC Basic Transl. Sci. 2018, 3, 844–857.
  77. Kojima, M.; Takahashi, H.; Kuwashiro, T.; Tanaka, K.; Mori, H.; Ozaki, I.; Kitajima, Y.; Matsuda, Y.; Ashida, K.; Eguchi, Y.; et al. Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis. Int. J. Mol. Sci. 2020, 21, 5722.
  78. Di Francia, R.; Rinaldi, L.; Troisi, A.; Di Benedetto, F.; Berretta, M. Effect of anti-oxidant agents in patients with hepatocellular di-seases. Eur. Rev. Med. Pharmacol. Sci. 2015, 19, 3993–3995.
  79. Di Francia, R.; Rinaldi, L.; Cillo, M.; Varriale, E.; Facchini, G.; D’Aniello, C.; Marotta, G.; Berretta, M. Antioxidant diet and geno-typing as tools for the prevention of liver disease. Eur. Rev. Med. Pharmacol. Sci. 2016, 20, 5155–5163.
  80. Savvidou, S.; Karatzidou, K.; Tsakiri, K.; Gagalis, A.; Hytiroglou, P.; Goulis, J. Circulating adiponectin levels in type 2 diabetes mellitus patients with or without non-alcoholic fatty liver disease: Results of a small, open-label, randomized controlled intervention trial in a subgroup receiving short-term exenatide. Diabetes Res. Clin. Pract. 2016, 113, 125–134.
  81. Sharma, D.; Wang, J.; Fu, P.P.; Sharma, S.; Nagalingam, A.; Mells, J.; Handy, J.; Page, A.J.; Cohen, C.; Anania, F.A.; et al. Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology 2010, 52, 1713–1722.
  82. Samson, S.L.; Gonzalez, E.V.; Yechoor, V.; Bajaj, M.; Oka, K.; Chan, L. Gene therapy for diabetes: Metabolic effects of helper-dependent adenoviral exendin 4 expression in a diet-induced obesity mouse model. Mol. Ther. 2008, 16, 1805–1812, Erratum in Mol. Ther. 2009, 17, 1831.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Gastroenterology & Hepatology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Riccardo Nevola
,
Raffaella Epifani
,
Simona Imbriani
,
Giovanni Tortorella
,
Concetta Aprea
,
Raffaele Galiero
,
Luca Rinaldi
,
Raffaele Marfella
,
Ferdinando Carlo Sasso
View Times: 252
Revisions: 2 times (View History)
Update Date: 12 May 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback