| 1. |
- Ahrén, Bo, et al.
(författare)
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Clinical evidence and mechanistic basis for vildagliptin's action when added to metformin.
- 2011
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 13:3, s. 193-203
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Tidskriftsartikel (refereegranskat)abstract
- Several new oral antidiabetic agents, known as 'gliptins' or 'enzyme dipeptidyl peptidase-IV (DPP-4) inhibitors', have been developed for the treatment of type 2 diabetes and a key clinical use of the gliptins is in combination with metformin. There are important differences in the kinetics of the interaction of different gliptins with the catalytic site of DPP-4, which may lead to varying pharmacokinetics, pharmacodynamics and dosing regimens. Therefore, individual gliptins need to be characterized and here we discuss the extensively studied DPP-4 inhibitor vildagliptin, which has binding characteristics that ensure inhibition of the enzyme beyond the presence of detectable drug levels in plasma. As vildagliptin has been used most often at doses of 50 mg once or twice daily, in combination with metformin, this review focuses on these dose regimens. All clinical trials employing vildagliptin (50 mg once or twice daily) as an add-on therapy to metformin (identified by MEDLINE search using keywords vildagliptin and metformin or known by authors to be in press) are reviewed, as is current knowledge of the mechanism of action of vildagliptin. Vildagliptin added to a stable dose of metformin elicits a dose-related decrease in both HbA1c and fasting plasma glucose. The additional efficacy seen with 50 mg twice daily [ΔHbA1c ∼- 1.1% (-12.1 mmol/mol)] relative to 50 mg once daily [ΔHbA1c ∼- 0.7% (-7.7 mmol/mol)] is attributable to an overnight effect of the evening dose of vildagliptin, with prolonged DPP-4 inhibition and elevated fasting levels of the intact and insulinotropic form of glucagon-like peptide-1 (GLP-1). Vildagliptin's therapeutic actions are primarily mediated by GLP-1 and metformin enhances vildagliptin's effect to raise plasma levels of intact GLP-1. Vildagliptin is weight-neutral and has a very low hypoglycaemic potential, explained by its remarkable ability to enhance both α-cell and β-cell sensitivity to glucose. Therefore, vildagliptin offers a clinically important outcome when added to metformin with a twice daily dose regimen, taking advantage of its tight binding and slow dissociation characteristics that lead to a sustained overnight effect.
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| 2. |
- Ahrén, Bo, et al.
(författare)
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Improved meal-related insulin processing contributes to the enhancement of B-Cell function by the DPP-4 inhibitor vildagliptin in patients with type 2 diabetes
- 2007
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Ingår i: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 1439-4286 .- 0018-5043. ; 39:11, s. 826-829
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the contribution of insulin processing to the improved meal-related B-cell function previously shown with the DPP-4 inhibitor vildagliptin. Fifty-five patients with type 2 diabetes (56.5 +/- 1.5 years; BMI=29.6 +/- 0.5kg/m(2); FPG = 9.9 +/- 0.2 mmol/l; HbA1c=7.7 +/- 0.1 %) were studied: 29 pateients were treated with vildagliptin and 26 patients with placebo, both added to an ongoing metformin regimen (1.5-3.0g/day). A standardized breakfast was given at baseline and after 52 weeks of treatment, and proinsulin related to insulin secretion was measured with C-peptide in the fasting and postprandial (over 4h post-meal) states to evaluate B-cell function. The between-treatment difference (vildaglip-tin-placebo) in mean change from baseline in fasting proinsulin to C-peptide ratio (fastP/C) was -0.007 +/- 0.009 (p=0.052). Following the standard breakfast, 52 weeks of treatment with vildagliptin significantly decreased the dynamic proinsulin to C-peptide ratio (dynP/C) relative to placebo by 0.010 +/- 0.008 (p = 0.037). Importantly, when the P/C was expressed in relation to the glucose stimulus (i.e., the fasting glucose and glucose AUC(0-240min), respectively), the P/C relative to glucose was significantly reduced with vildagliptin vs. placebo, both in the fasting state (p = 0.023) and postprandially (p = 0.004). In conclusion, a more efficient B-cell insulin processing provides further evidence that vildagliptin treatment ameliorates abnormal B-cell function in patients with type 2 diabetes.
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| 3. |
- Ahrén, Bo, et al.
(författare)
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Mechanisms of Action of the DPP-4 Inhibitor Vildagliptin in Man.
- 2011
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 13:9, s. 775-783
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Forskningsöversikt (refereegranskat)abstract
- Inhibition of dipeptidyl peptidase-4 (DPP-4) by vildagliptin prevents degradation of glucagon-like peptide-1 (GLP-1) and reduces glycemia in type 2 diabetes, with low risk for hypoglycemia and no weight gain. Vildagliptin binds covalently to the catalytic site of DPP-4, eliciting prolonged enzyme inhibition. This raises intact GLP-1 levels, both after meal ingestion and in the fasting state. Vildagliptin has been shown to stimulate insulin secretion and to inhibit glucagon secretion in a glucose-dependent manner. At hypoglycemic levels, the counterregulatory glucagon response is enhanced relative to baseline by vildagliptin. Vildagliptin also inhibits hepatic glucose production, mainly through changes in islet hormone secretion, and improves insulin sensitivity, as determined with a variety of methods. These effects underlie the improved glycemia with low risk for hypoglycemia. Vildagliptin also suppresses postprandial triglyceride-rich lipoprotein levels after ingestion of a fat-rich meal and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced triglyceride stores in non-fat tissues. The large body of knowledge on vildagliptin regarding enzyme binding, incretin and islet hormone secretion and glucose and lipid metabolism is summarized, with discussion of the integrated mechanisms and comparison with other DPP-4 inhibitors and GLP-1 receptor activators, where appropriate.
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| 4. |
- Ahrén, Bo, et al.
(författare)
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The islet enhancer vildagliptin: mechanisms of improved glucose metabolism.
- 2008
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Ingår i: International journal of clinical practice. Supplement. - : Hindawi Limited. - 1368-504X .- 1368-5031. ; 62, s. 8-14
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Tidskriftsartikel (refereegranskat)abstract
- Vildagliptin is a potent, selective and reversible inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for rapid inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). GLP-1 and GIP are important for the maintenance of normal glucose homeostasis as they enhance the sensitivity of insulin (beta-cell) and glucagon (alpha-cell) secretion to glucose. The delicate balance that is achieved by the incretin hormones is disturbed in type 2 diabetes mellitus (T2DM). Mechanistic studies of vildagliptin performed to characterise the effects of DPP-4 inhibition on pancreatic islet function and glucose metabolism have found that vildagliptin produces dose-dependent reductions in DPP-4; these result in persistent levels of active GLP-1 and GIP in the circulation leading to improved beta-cell sensitivity to glucose and glucose-dependent insulin secretion, and improved alpha-cell sensitivity to glucose and reduction in inappropriate glucagon secretion. These islet effects in turn lead to a reduction of the inappropriate endogenous glucose production and glucose utilisation during meals, resulting in improved glucose tolerance, and to a reduction of the inappropriate endogenous glucose production during the postabsorptive period that contributes to a reduced fasting hyperglycaemia. These islet effects are associated with improved insulin sensitivity and reduced meal-related hypertriglyceridaemia. In contrast, the GLP-1 effect of significantly delaying gastric emptying was not evident with vildagliptin treatment. The metabolic benefits of vildagliptin observed in T2DM are also evident in subjects with impaired glucose tolerance. Hence, vildagliptin improves glucose metabolism mainly by improving islet function.
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| 5. |
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| 6. |
- Dunning, B E, et al.
(författare)
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Alpha cell function in health and disease: influence of glucagon-like peptide-1
- 2005
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 48:9, s. 1700-1713
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Forskningsöversikt (refereegranskat)abstract
- Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.
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| 7. |
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| 8. |
- Matthews, D. R., et al.
(författare)
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Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study
- 2010
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 12:9, s. 780-789
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Tidskriftsartikel (refereegranskat)abstract
- Methods: A randomized, double-blind, active-comparator study of patients with type 2 diabetes mellitus inadequately controlled (HbA1c 6.5-8.5%) by metformin monotherapy. Patients received vildagliptin (50 mg twice daily) or glimepiride (up to 6 mg/day) added to metformin. Results: In all, 3118 patients were randomized (vildagliptin, n = 1562; glimepiride, n = 1556). From similar baseline values (7.3%), after 2 years adjusted mean (s.e.) change in HbA1c was comparable between vildagliptin and glimepiride treatment: -0.1% (0.0%) and -0.1% (0.0%), respectively. The primary objective of non-inferiority was met. A similar proportion of patients reached HbA1c < 7% (36.9 and 38.3%, respectively), but with vildagliptin more patients reached this target without hypoglycaemia (36.0% vs. 28.8%; p = 0.004). The initial response (IR) was sustained for a mean (s.d.) of 309 (244) days with vildagliptin versus 270 (223) days for glimepiride (p < 0.001) (IR = nadir HbA1c where change from baseline >= 0.5% or HbA1c < 6.5% within the first six months of treatment. After IR was detected, sustained response = time between nadir and an increase of > 0.3% above IR). Independent of disease duration, age was a predictor of effect sustainability. Fewer patients experienced hypoglycaemia with vildagliptin (2.3% vs. 18.2% with glimepiride) with a 14-fold difference in the number of hypoglycaemic events (59 vs. 838). Vildagliptin had a beneficial effect on body weight [mean (s.e.) change from baseline -0.3 (0.1) kg; between-group difference -1.5 kg; p < 0.001]. Overall, both treatments were well tolerated and displayed similar safety profiles. Conclusions: Vildagliptin add-on has similar efficacy to glimepiride after 2 years' treatment, with markedly reduced hypoglycaemia risk and no weight gain.
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| 9. |
- Omar, Bilal, et al.
(författare)
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Enhanced beta cell function and anti-inflammatory effect after chronic treatment with the dipeptidyl peptidase-4 inhibitor vildagliptin in an advanced-aged diet-induced obesity mouse model
- 2013
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 56:8, s. 1752-1760
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Studies have shown that dipeptidyl peptidase-4 (DPP4) inhibitors stimulate insulin secretion and increase beta cell mass in rodents. However, in these models hyperglycaemia has been induced early on in life and the treatment periods have been short. To explore the long-term effects of DPP4 inhibition on insulin secretion and beta cell mass, we have generated a high-fat diet (HFD)-induced-obesity model in mice of advanced age (10 months old). METHODS: After 1 month of HFD alone, the mice were given the DPP4 inhibitor vildagliptin for a further 11 months. At multiple time points throughout the study, OGTTs were performed and beta cell area and long-term survival were evaluated. RESULTS: Beta cell function and glucose tolerance were significantly improved by vildagliptin with both diets. In contrast, in spite of the long treatment period, beta cell area was not significantly different between vildagliptin-treated mice and controls. Mice of advanced age chronically fed an HFD displayed clear and extensive pancreatic inflammation and peri-insulitis, mainly formed by CD3-positive T cells, which were completely prevented by vildagliptin treatment. Chronic vildagliptin treatment also improved survival rates for HFD-fed mice. CONCLUSIONS/INTERPRETATION: In a unique advanced-aged HFD-induced-obesity mouse model, insulin secretion was improved and the extensive peri-insulitis prevented by chronic DPP4 inhibition. The improved survival rates for obese mice chronically treated with vildagliptin suggest that chronic DPP4 inhibition potentially results in additional quality-adjusted life-years for individuals with type 2 diabetes, which is the primary goal of any diabetes therapy.
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