Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment

Guedes, Erika Paniago; Hohl, Alexandre; Melo, Thaís Gomes de; Lauand, Felipe

doi:10.1186/1758-5996-5-25

Cited by 32 publications

(16 citation statements)

References 36 publications

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“…Glycemic control achieved by metformin was also able to prevent and reverse vascular remodeling on both vascular beds (15; 22) and decreased plasma and tissue ET-1 levels. Given that glycemic control remains to be a key treatment strategy for the management of vascular complications of diabetes and most patients come to the clinic after onset of these complications, we were interested in testing whether linagliptin, a DPP-IV inhibitor class of oral hypoglycemic that is increasingly used for treatment of diabetes, modulates the ET system after vascular disease is established (16). The results of this study demonstrate that linagliptin partially restores the structure of MCAs while reducing ET-1 levels without any change in blood glucose levels, which led us to further investigate the regulation of ET receptors by linagliptin in an in vitro model.…”

Section: Discussionmentioning

confidence: 99%

“…It is also possible that metformin has a direct effect. Recent evidence suggest that DPP-IV inhibitors, a new class of oral glucose lowering agents that is increasingly used in the management of type 2 diabetes (16), also improve endothelial dysfunction and reduce pro-oxidative and pro-inflammatory conditions independent of its glucose lowering effects (17). However, the effect of DPP-IV inhibitors on the ET system remained unknown.…”

Section: Introductionmentioning

confidence: 99%

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Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system

2016

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Introduction Endothelin-1 (ET-1) mediates cerebrovascular remodeling in vascular smooth muscle layer of the middle cerebral arteries (MCA) in type-2 diabetic Goto-Kakizaki (GK) rats. While metformin, oral glucose lowering agent, prevent/restores vascular remodeling and reduce systemic and local ET-1 levels whether this effect was specific to metformin remained unknown. Our working hypotheses were 1) linagliptin, a DPP-IV inhibitor, can reverse diabetes-mediated cerebrovascular remodeling and this is associated with decreased ET-1, and 2) linagliptin prevents the high glucose induced increase in ET-1 and ET receptors in brain vascular smooth muscle cells (bVSMCs). Methods Diabetic and non-diabetic GK rats were treated with linagliptin (4 weeks). MCAs were fixed in buffered 4% paraformaldehyde and used for morphometry. Human bVSMCs incubated in normal glucose (5.5mM)/high glucose (25 mM) conditions were treated with the linagliptin (100nM; 24 hours). ET-1 secretion and ET receptors were measured in media and cell lysate respectively. Immunostaining was performed for ETA and ET-B receptor. ET receptors were also measured in cells treated with ET-1 (100nM) and linagliptin. Results Linagliptin treatment regressed vascular remodeling of MCAs in diabetic animals but had no effect on blood glucose. bVSMCs in normal/high glucose condition did not show any significant difference in ET-1 secretion or ET-A and ET-B receptor expression. ET-1 treatment in high glucose condition significantly increased the ET-A receptors and this effect was inhibited by linagliptin. Conclusions Linagliptin is effective in reversing established pathological cerebrovascular remodeling associated with diabetes. Attenuation of the ET system could be a pleiotropic effect of linagliptin that provides vascular protection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system

2016

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“…Several inhibitors are available, and they differ in their pharmacokinetic characteristics. With the exception of linagliptin, which is excreted unchanged via the bile route [283], DPP-4 inhibitors are excreted via the renal route [284]. Sitagliptin and saxagliptin are also substrates of CYP3A4 [285], which is highly expressed in women [20], suggesting a possible interaction with oral contraceptives [285].…”

Section: Dpp-4 Inhibitorsmentioning

confidence: 99%

Sex and gender influences on pharmacological response: an overview

Franconi

Campesi

2014

Expert Review of Clinical Pharmacology

106

107

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Research on the specific effects of sex and gender on pharmacokinetics and pharmacodynamics, as well as safety profile tolerability and drug efficacy, of medications remain meager because female animals and women have only recently been included in the pharmacological domain. To date, the influence of sex and gender on access to care and emotional factors, including patients and care provider dyads, the placebo effect, adherence, and safety profiles, are discussed. Furthermore, differences in drug responses, mainly for antidiabetic drugs, have been described. However, further studies are needed to explore the impact of sex and gender on reaching the most appropriate and tailored prescription for each patient, regardless of sex and gender.

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“…Linagliptin is a highly specific, potent inhibitor of DPP4 that is currently indicated for the treatment of type 2 diabetes (T2D). In clinical studies, linagliptin effectively reduced glycated hemoglobin (HbA1c) levels in patients with T2D and exhibited a placebo-like safety and tolerability profile[13]. Linagliptin has an interesting pharmacokinetic profile in terms of its predominantly non-renal elimination.…”

Section: Introductionmentioning

confidence: 99%

Linagliptin alleviates fatty liver disease in diabetic db/db mice

Мичурина¹,

Ishenko²,

Климонтов³

et al. 2016

WJD

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AIMTo study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) in db/db mice.METHODSMale diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin (10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was assessed by immunohistochemistry.RESULTSIn 18-wk-old diabetic mice, liver steatosis (predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets (92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets (20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels.CONCLUSIONThe DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.

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Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment

Cited by 32 publications

References 36 publications

Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system

Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system

Sex and gender influences on pharmacological response: an overview

Linagliptin alleviates fatty liver disease in diabetic db/db mice

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