Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta‐analysis of the LEAD program

Armstrong, Matthew J.; Houlihan, Diarmaid D.; Rowe, Ian; Clausen, Wan Hui Ong; Elbrønd, B; Gough, Stephen; Tomlinson, Jeremy W.; Newsome, Philip N.

doi:10.1111/apt.12149

Cited by 224 publications

(177 citation statements)

References 41 publications

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“…Yet, the primary analysis was designed as an intention-to-treat analysis. Furthermore, the rate of gastrointestinal adverse effects observed in this study was similar to those reported in the literature, and the rate of patient withdrawal was similar to that observed in larger randomized clinical trials (11,37,38).…”

Section: Limitationssupporting

confidence: 88%

“…Prior studies suggested that GLP-1 receptor agonists, such as liraglutide and exenatide, would improve liver steatosis in animal models (27,28), in human case series (29), and in prospective nonrandomized trials (30,31). However, in the setting of the randomized controlled trial Liraglutide Efficacy and Action in Diabetes (LEAD)-2 substudy, there was a nonsignificant trend toward a reduction in liver steatosis as assessed by computed tomography with the liver-tospleen attenuation ratio, but only for the 23 patients receiving higher doses (1.8 mg) of liraglutide (11,32). It is possible that the postprandial increase in insulin secretion in the portal circulation and the decrease in glucagon secretion induced by the GLP-1 analogs could favor lipogenesis and therefore explain the lack of effect of liraglutide on hepatic steatosis observed in the current study.…”

Section: Effect Of Insulin Glargine and Liraglutide On Mr-based Biomamentioning

confidence: 99%

“…Further, GLP-1 agonists may decrease liver fat by increasing fatty acid uptake and VLDL transport (10) and stimulating hepatic lipid b-oxidation (11,12), improving hepatic insulin sensitivity (10) while also reducing hepatic lipogenesis via activation of the AMPK pathway (13).…”

mentioning

confidence: 99%

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Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial

et al. 2015

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OBJECTIVEThis study determined the effects of insulin versus liraglutide therapy on liver fat in patients with type 2 diabetes inadequately controlled with oral agents therapy, including metformin. RESEARCH DESIGN AND METHODSThirty-five patients with type 2 diabetes inadequately controlled on metformin monotherapy or in combination with other oral antidiabetic medications were randomized to receive insulin glargine or liraglutide therapy for 12 weeks. The liver proton density fat fraction (PDFF) was measured by MRS. The mean liver PDFF, the total liver volume, and the total liver fat index were measured by MRI. The Student t test, the Fisher exact test, and repeated-measures ANOVA were used for statistical analysis. RESULTSInsulin treatment was associated with a significant improvement in glycated hemoglobin (7.9% to 7.2% [62.5 to 55.2 mmol/mol], P = 0.005), a trend toward a decrease in MRS-PDFF (12.6% to 9.9%, P = 0.06), and a significant decrease in liver mean MRI-PDFF (13.8% to 10.6%, P = 0.005), liver volume (2,010.6 to 1,858.7 mL, P = 0.01), and the total liver fat index (304.4 vs. 209.3 % · mL, P = 0.01). Liraglutide treatment was also associated with a significant improvement in glycated hemoglobin (7.6% to 6.7% [59.8 to 50.2 mmol/mol], P < 0.001) but did not change MRS-PDFF (P = 0.80), liver mean MRI-PDFF (P = 0.15), liver volume (P = 0.30), or the total liver fat index (P = 0.39). CONCLUSIONSThe administration of insulin glargine therapy reduced the liver fat burden in patients with type 2 diabetes. However, the improvements in the liver fat fraction and glycemia control were not significantly different from those in the liraglutide group.To reduce the risk of long-term microvascular and macrovascular complications, diabetes therapy should aim for tight glucose control as assessed by glycated hemoglobin (HbA 1c ) below 7% (53 mmol/mol) while minimizing hypoglycemia (1,2). However, most patients still do not achieve glycemic targets and thus require

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Section: Limitationssupporting

confidence: 88%

Section: Effect Of Insulin Glargine and Liraglutide On Mr-based Biomamentioning

confidence: 99%

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Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial

et al. 2015

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“…As already discussed for exenatide, this effect appears to be mediated by the favourable action of liraglutide on weight loss and glycaemic control [66] . Furthermore, a few data support a beneficial impact of liraglutide on liver inflammation markers in NAFLD patients with T2DM [67] , in obese women with polycystic ovary syndrome and NAFLD [68] and in one T2DM patient with concomitant cryptogenic cirrhosis [69] .…”

Section: Hepatic Safetymentioning

confidence: 69%

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

Scheen

2014

Clin Pharmacokinet

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SUMMARYPatients with type 2 diabetes have an increased risk of chronic liver disease such as nonalcoholic fatty liver disease and steatohepatitis, and about one third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarizes the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and -Obese patients with type 2 diabetes often have non-alcoholic fatty liver disease or steatohepatitis and the use of incretin-based therapies appears mostly favourable in these patients regarding both efficacy and safety.-There is no reported clinical experience with the use of either DPP-4 inhibitors or GLP-1 receptor agonists in diabetic patients with moderate to severe hepatic impairment, so that caution is required in patients with advanced cirrhosis.

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“…As part of studies powered to detect changes in glycaemic control in patients with type 2 diabetes and NAFLD, they caused a reduction in intrahepatic lipid as measured by MRS in addition to reductions in body weight and improved glycaemic control (98). In a separate analysis of type 2 diabetic patients treated with Liraglutide, there was a dose-dependent but non-significant improvement in hepatic steatosis, measured by liver-spleen attenuation ration as well as improvements in abnormal liver function tests (99). In an open-label study, a small cohort of patients with biopsy-proven NAFLD and diabetes were treated with exanatide, 3/8 had a histological improvement after 28 weeks of treatment (100).…”

Section: Glucagon-like Peptide-1mentioning

confidence: 99%

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

Hazlehurst

Tomlinson

2013

European Journal of Endocrinology

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Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease spanning from simple benign steatosis to steatohepatitis with fibrosis and scarring that can eventually lead to cirrhosis. Its prevalence is rising rapidly and is developing into the leading indication for liver transplantation worldwide. Abnormalities in endocrine axes have been associated with NALFD, including hypogonadism, hypothyroidism, GH deficiency and hypercortisolaemia. In some instances, correction of the endocrine defects has been shown to have a beneficial impact. While in patients with type 2 diabetes the association with NAFLD is well established and recognised, there is a more limited appreciation of the condition among common endocrine diseases presenting with hormonal excess or deficiency. In this review, we examine the published data that have suggested a mechanistic link between endocrine abnormalities and NAFLD and summarise the clinical data endorsing these observations.

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Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta‐analysis of the LEAD program

Abstract: SUMMARY Background

Cited by 224 publications

References 41 publications

Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial

Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A Randomized Trial

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

Mechanisms in endocrinology: Non-alcoholic fatty liver disease in common endocrine disorders

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