Liraglutide and the Preservation of Pancreatic β-Cell Function in Early Type 2 Diabetes: The LIBRA Trial

Retnakaran, Ravi; Kramer, Caroline; Choi, Haysook; Swaminathan, Balakumar; Zinman, Bernard

doi:10.2337/dc14-0893

Cited by 123 publications

(104 citation statements)

References 37 publications

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“…Following cessation of GLP-1 treatment after one year (when improvements in beta-cell function were evident), the benefit was lost within weeks as beta-cell function returned to pre-treatment values. 113 In contrast, individuals treated with exenatide for three years had sustained improvement in betacell function after a four-week washout compared with those receiving three years of insulin. 116 …”

Section: Sglt-2 Inhibitorsmentioning

confidence: 92%

“…[109][110][111][112] In the Liraglutide and the Preservation of Pancreatic β-Cell Function in Early Type 2 Diabetes (LIBRA) trial, following elimination of glucotoxicity with four weeks of IIT, treatment with liraglutide for 48 weeks led to further improvement in baseline adjusted insulin secretion to OGTT in patients with T2D. 113 In animal studies, the protective effects of liraglutide on betacell function were more pronounced in the early stages of T2D than in the advanced stages. 114 This reflects clinical studies in which the effect size of GLP-1 agonists on glycaemic control correlates with duration of T2D.…”

Section: Sglt-2 Inhibitorsmentioning

confidence: 99%

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Targeting beta-cell preservation in the management of type 2 diabetes

2017

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Type 2 diabetes (T2D) is widely considered a chronic and progressive disease without cure. As beta-cell function progressively declines over time, blood glucose rises. Current management of T2D involves incremental introduction of dietary and drug therapies to achieve normoglycaemia. However, recent studies have demonstrated remission of T2D following bariatric surgery, very low calorie diet or intensive insulin therapy, raising the possibility that the declining beta-cell function in T2D may be arrested or even reversed. The point at which such interventions are introduced in the course of T2D is key for clinical benefit. Future treatment strategies should be revised to target early betacell preservation and thus disease remission. This article reviews the pathogenesis of beta-cell dysfunction and evidence for the clinical benefit of preserving beta-cell function in T2D, and discusses the evidence for beta-cell preservation of current glucose-lowering therapies with particular reference to their effect when initiated at the time of diagnosis of T2D. Br J Diabetes 2017;17:134-144

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Section: Sglt-2 Inhibitorsmentioning

confidence: 92%

Section: Sglt-2 Inhibitorsmentioning

confidence: 99%

Targeting beta-cell preservation in the management of type 2 diabetes

2017

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“…The significant inverse correlations of insulin secretion at 8 mmol/L glucose and glucose sensitivity after 3 years of EXE treatment with HbA1c demonstrate the importance of β-cell function in glycaemic control with GLP1 receptor agonist treatment. # GLP1 receptor agonists have previously been shown to improve β-cell function in type 2 diabetic patients using both static and dynamic tests; the latter includes hyperglycaemic clamps (5,20) and oral glucose or meal tolerance tests (9,18,19). However, these studies were limited by the relatively short treatment duration (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…GLP1 receptor agonists mainly lower blood glucose levels by inhibiting gastric emptying (postprandial), increasing insulin secretion and decreasing glucagon secretion, in a glucose-dependent manner (5,6). Although in a number of rodent models, GLP1 receptor agonist treatment durably improved β-cell function, and also increased β-cell mass (7), there is no evidence for increased functional β-cell mass following GLP1 receptor agonist treatment in humans (8,9). The extent to which the improvement in β-cell function by GLP1 receptor agonists is sustained over time (i.e.…”

Section: Introductionmentioning

confidence: 99%

Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

Raalte

Bunck

Hoekstra

et al. 2016

European Journal of Endocrinology

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Objective: Glucagon-like peptide (GLP)-1 receptor agonist treatment improves β-cell function. In this study, we investigated whether the improvements are sustained during a 3-year treatment period. Research design and methods: Sixty-nine metformin-treated type 2 diabetes patients were randomised to the GLP1 receptor agonist, exenatide (EXE) twice daily (BID) or to insulin glargine (GLAR). β-cell function parameters were derived using the Mari model from standardised breakfast and lunch meals that were administered before treatment, and after 1 and 3 years of treatment. EXE was administered before breakfast. Results: Fifty-nine (EXE: n = 30; GLAR: n = 29) and thirty-six (EXE: n = 16; GLAR: n = 20) patients completed the meal at 1-and 3-year treatment respectively. After 3 years, groups had comparable glycaemic control (HbA1c: EXE 6.6 ± 0.2% and GLAR 6.9 ± 0.2%; P = 0.216). Compared with GLAR, at 1 and 3 years, EXE induced a stronger reduction in post-breakfast glucose concentrations (P < 0.001), with lower C-peptide levels (P < 0.001). Compared with GLAR, EXE increased insulin secretion at 8 mmol/L glucose throughout the study period (P < 0.01). Both treatments improved β-cell glucose sensitivity after 1-year treatment. However, only EXE treatment sustained this improvement for 3 years. No consistent changes in other β-cell parameters including rate sensitivity and potentiation were observed. Conclusions: Compared with GLAR, EXE improved the parameters of β-cell function, especially insulin secretion at 8 mmol/L glucose and β-cell glucose sensitivity, which was sustained during the 3-year treatment period.

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“…The randomized controlled LIBRA (Liraglutide and β-Cell Repair) trial investigated the effects of liraglutide on preservation of β-cell function in patients (N=51) with early T2D (duration of 2.6 years), using the Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test [42]. After 48 weeks, baseline-adjusted ISSI-2 was significantly higher with liraglutide versus placebo (339.8 vs. 229.3; p=0.008).…”

Section: Effects Of Liraglutide Once Daily On β-Cell Functionmentioning

confidence: 99%

Effects of Glucagon-Like Peptide-1 Receptor Agonists on β-Cell Function in Patients with Type 2 Diabetes

Grandy¹,

Shaunik²

2015

J Diabetes Metab

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Type 2 diabetes (T2D) is characterized by insulin resistance and a progressive decline in pancreatic β-cell function. Over time, upregulation of insulin secretion is no longer sufficient to compensate for insulin resistance, leading to fasting hyperglycemia, while β-cell function continues to deteriorate. Effective treatments targeting the underlying pathophysiology of T2D involve early lifestyle interventions and a combination of therapies to counteract insulin resistance and progressive deterioration of β cells. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are one class of antihyperglycemic agents that target multiple pathways, mediating clinical benefits for patients with T2D. This review summarizes the effects of treatment with various GLP-1RAs, including exenatide (twice daily and once weekly), liraglutide, dulaglutide, and lixisenatide, on β-cell function in patients with T2D. β-cell function was assessed in randomized controlled trials and their extension studies using a variety of methods, including glucose and arginine clamp techniques, proinsulin-to-insulin ratio, and homeostatic model assessment of β-cell function (HOMA-B). Exenatide twice daily and liraglutide both improved first-and second-phase insulin secretory responses. In addition, numerous studies reported significant improvements in HOMA-B with exenatide (twice daily and once weekly; range of relative change from baseline: +28-50%; range of absolute change: +5-40%) or liraglutide (range of change vs. placebo: +13-43%). Improvements in HOMA-B were also observed with the newer GLP-1RAs dulaglutide and lixisenatide. In contrast to the effects on HOMA-B, treatment with GLP-1RAs had a lesser effect on insulin sensitivity. Taken together, the results suggest that glucagon-like peptide-1 analogs have a greater effect on β-cell function than insulin sensitivity.

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Liraglutide and the Preservation of Pancreatic β-Cell Function in Early Type 2 Diabetes: The LIBRA Trial

Cited by 123 publications

References 37 publications

Targeting beta-cell preservation in the management of type 2 diabetes

Targeting beta-cell preservation in the management of type 2 diabetes

Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial

Effects of Glucagon-Like Peptide-1 Receptor Agonists on β-Cell Function in Patients with Type 2 Diabetes

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