LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial
Baylor College of Medicine, Houston, TX, USA. The Lancet
(Impact Factor: 45.22).
10/2008; 373(9662):473-81. DOI: 10.1016/S0140-6736(08)61246-5
New treatments for type 2 diabetes mellitus are needed to retain insulin-glucose coupling and lower the risk of weight gain and hypoglycaemia. We aimed to investigate the safety and efficacy of liraglutide as monotherapy for this disorder.
In a double-blind, double-dummy, active-control, parallel-group study, 746 patients with early type 2 diabetes were randomly assigned to once daily liraglutide (1.2 mg [n=251] or 1.8 mg [n=247]) or glimepiride 8 mg (n=248) for 52 weeks. The primary outcome was change in proportion of glycosylated haemoglobin (HbA(1c)). Analysis was done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NTC00294723.
At 52 weeks, HbA(1c) decreased by 0.51% (SD 1.20%) with glimepiride, compared with 0.84% (1.23%) with liraglutide 1.2 mg (difference -0.33%; 95% CI -0.53 to -0.13, p=0.0014) and 1.14% (1.24%) with liraglutide 1.8 mg (-0.62; -0.83 to -0.42, p<0.0001). Five patients in the liraglutide 1.2 mg, and one in 1.8 mg groups discontinued treatment because of vomiting, whereas none in the glimepiride group did so.
Liraglutide is safe and effective as initial pharmacological therapy for type 2 diabetes mellitus and leads to greater reductions in HbA(1c), weight, hypoglycaemia, and blood pressure than does glimepiride.
Available from: Bernt Johan von Scholten
- "Three dosages of liraglutide, 0.6 mg daily, 1.2 mg daily and 1.8 mg daily, were compared with active comparator or placebo for efficacy and safety assessments. The active comparators were insulin glargine (Russell-Jones et al., 2009), glimepiride (sulfonylurea) (Garber et al., 2009), exenatide (GLP-1 receptor agonist) (Buse et al., 2009), rosiglitazone (glitazone) (Marre et al., 2009) and sitagliptin (DPP-4 inhibitor) (Pratley et al., 2012). In the LEAD studies including a placebo arm, placebo-treated patients also received background oral antidiabetic drug therapy. "
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Estimation of kidney function (eGFR) is essential in monitoring of patients with kidney disease. Estimates of kidney function based on serum creatinine are derived from cross-sectional studies. If body weight (BW) changes, this might affect creatinine and eGFR. The Cockcroft-Gault (CG) equation includes creatinine and BW, whereas the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations only include creatinine.
Data were pooled from the six LEAD (Liraglutide Effect and Action in Diabetes) trials and the LIRA-DPP4 trial. The trials were conducted in patients with type 2 diabetes and of 26weeks duration. We investigated changes in eGFR for patients treated with liraglutide, and for patients treated with glucose-lowering medications with less weight-reducing effects (insulin glargine, glimepiride, exenatide and rosiglitazone).
We included 5100 patients (liraglutide n=3173, comparator n=1927). Mean (SD) CKD-EPI eGFR was 81.2 (20.6) ml/min/1.73m(2) for liraglutide and 81.6 (20.3) ml/min/1.73m(2) for comparator. For liraglutide, BW changed -1.9 (95% CI (-2.0; -1.8)) kg, for comparator BW changed 0.2 (95% CI (0.03; 0.3)) kg. Using regression modelling, a 10% BW decrease yielded no change in creatinine, MDRD eGFR or CKD-EPI eGFR for both liraglutide and comparator, but was associated with a 10.2% (-11.3%; -9.1%) decrease in CG eGFR for liraglutide, and a 10.6% (-12.0%; -9.1%) decrease for comparator.
A liraglutide-induced weight reduction of 1.9kg was not associated with change in creatinine. Accordingly, there was no change in weight-independent estimates of GFR, whereas weight-dependent estimates were changed. The MDRD and CKD-EPI equations can be used in patients experiencing pharmaceutically induced weight reductions.
Available from: Kristy Heppner
- " remains in circulation ( Knudsen et al . , 2000 ) . The half - life for liraglutide is about 10 – 14 h in humans ( Agerso et al . , 2002 ) and is recommended for once - daily administration . Both exenatide ( DeFronzo et al . , 2005 ; Heine et al . , 2005 ; Moretto et al . , 2008 ; Norris et al . , 2009 ) and liraglutide ( Astrup et al . , 2009 ; Garber et al . , 2009 ; Niswender et al . , 2013 ; Lean et al . , 2014 ) significantly improve glycemic control and cause a significant body weight loss in T2DM patients . Gastrointestinal side effects including nau - sea and vomiting have been reported with both exenatide and liraglutide treatment although these side effects are often tran - sient and occur"
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ABSTRACT: Glucagon-like peptide-1 (GLP-1) enhances meal-related insulin secretion, which lowers blood glucose excursions. In addition to its incretin action, GLP-1 acts on the GLP-1 receptor (GLP-1R) in the brain to suppress feeding. These combined actions of GLP-1R signaling cause improvements in glycemic control as well as weight loss in type II diabetes (T2DM) patients treated with GLP-1R agonists. This is a superior advantage of GLP-1R pharmaceuticals as many other drugs used to treat T2DM are weight neutral or actual cause weight gain. This review summarizes GLP-1R action on energy and glucose metabolism, the effectiveness of current GLP-1R agonists on weight loss in T2DM patients, as well as GLP-1R combination therapies.
Available from: Edward Emery
- "Gut hormones play essential roles in a wide range of metabolic functions such as the regulation of food absorption, appetite, and glucose homeostasis . As a consequence, drugs that enhance GLP-1 action are now widely used in the treatment of T2DM (Garber et al., 2009; Nauck et al., 2009; Zinman et al., 2009) and are under investigation for the treatment of obesity (Marre et al., 2009). Attention is also turning toward the enteroendocrine L cells themselves and whether they could be targeted for the treatment of obesity and diabetes. "
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ABSTRACT: It has long been speculated that metabolites, produced by gut microbiota, influence host metabolism in health and diseases. Here, we reveal that indole, a metabolite produced from the dissimilation of tryptophan, is able to modulate the secretion of glucagon-like peptide-1 (GLP-1) from immortalized and primary mouse colonic L cells. Indole increased GLP-1 release during short exposures, but it reduced secretion over longer periods. These effects were attributed to the ability of indole to affect two key molecular mechanisms in L cells. On the one hand, indole inhibited voltage-gated K+ channels, increased the temporal width of action potentials fired by L cells, and led to enhanced Ca2+ entry, thereby acutely stimulating GLP-1 secretion. On the other hand, indole slowed ATP production by blocking NADH dehydrogenase, thus leading to a prolonged reduction of GLP-1 secretion. Our results identify indole as a signaling molecule by which gut microbiota communicate with L cells and influence host metabolism
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