Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension

Chaykovska, Lyubov; Alter, Markus; Websky, Karoline von; Hohmann, M; Tsuprykov, Oleg; Reichetzeder, Christoph; Kutil, Barbara; Kraft, Robin; Klein, Thomas; Hocher, Berthold

doi:10.1097/hjh.0b013e3283649b4d

Cited by 37 publications

(37 citation statements)

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“…To address this concern, a recent study tested whether linagliptin affected BP when used in combination with the angiotensin receptor blocker (ARB) telmisartan in a model of renal hypertension. In contrast to the previous studies showing that DPP-4i therapy countered the BP-lowering effects of ACEi (86,87,121), the BP-lowering effects of telmisartan were not countered by linagliptin and tended to further improve BP in a rat model of renovascular hypertension (33). This study suggests the possibility that hypertension, renal function, and glycemic control may be more effectively managed in patients with T2DM treated with a combination of ARB/DPP-4i as opposed to ACEi/DPP-4i.…”

Section: Dpp-4i and Vasculoprotectioncontrasting

confidence: 83%

Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

Aroor

Sowers

Jia

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

103

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Dipeptidylpeptidase-4 (DPP-4) is a ubiquitously expressed transmembrane protein that removes NH2-terminal dipeptides from various substrate hormones, chemokines, neuropeptides, and growth factors. Two known substrates of DPP-4 include the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide, which are secreted by enteroendocrine cells in response to postprandial hyperglycemia and account for 60–70% of postprandial insulin secretion. DPP-4 inhibitors (DPP-4i) block degradation of GLP-1 and gastric inhibitory peptide, extend their insulinotropic effect, and improve glycemia. Since 2006, several DPP-4i have become available for treatment of type 2 diabetes mellitus. Clinical trials confirm that DPP-4i raises GLP-1 levels in plasma and improves glycemia with very low risk for hypoglycemia and other side effects. Recent studies also suggest that DPP-4i confers cardiovascular and kidney protection, beyond glycemic control, which may reduce the risk for further development of the multiple comorbidities associated with obesity/type 2 diabetes mellitus, including hypertension and cardiovascular disease (CVD) and kidney disease. The notion that DPP-4i may improve CVD outcomes by mechanisms beyond glycemic control is due to both GLP-1-dependent and GLP-1-independent effects. The CVD protective effects by DPP-4i result from multiple factors including insulin resistance, oxidative stress, dyslipidemia, adipose tissue dysfunction, dysfunctional immunity, and antiapoptotic properties of these agents in the heart and vasculature. This review focuses on cellular and molecular mechanisms mediating the CVD protective effects of DPP-4i beyond favorable effects on glycemic control.

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Section: Dpp-4i and Vasculoprotectioncontrasting

confidence: 83%

Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

Aroor

Sowers

Jia

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

103

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“…DPP-4 inhibitors were found to have renal beneficial effects in animal models of non-diabetic nephropathy such as 5/6 nephrectomy (Tsuprykov et al 2016) Streptozotocin-induced diabetic CD-1 mice Linagliptin -Reduced plasma cystatin C levels and UACR -Ameliorated kidney fibrosis, glomerular size and mesangial area Kanasaki et al (2014), Shi et al (2015) Diabetic db/db mice Gemigliptin -Suppressed albuminuria -Decreased mesangial expansion -Suppressed podocyte apoptosis -Reduced oxidative damage Jung et al (2015), Moon et al (2016) Glp1r 2-kidney-1-clip hypertension (Chaykovska et al 2013), tacrolimus-induced kidney injury (Lim et al 2015), rat Thy-1 glomerulonephritis model (Higashijima et al 2015) and unilateral ureteral obstruction (Min et al 2014).…”

Section: Dpp-4 Inhibition In Animal Models Of Diabetic Nephropathymentioning

confidence: 99%

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

Hasan

Hocher

2017

Journal of Molecular Endocrinology

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Diabetic nephropathy is one of the most frequent, devastating and costly complications of diabetes. The available therapeutic approaches are limited. Dipeptidyl peptidase type 4 (DPP-4) inhibitors represent a new class of glucose-lowering drugs that might also have reno-protective properties. DPP-4 exists in two forms: a plasma membranebound form and a soluble form, and can exert many biological actions mainly through its peptidase activity and interaction with extracellular matrix components. The kidneys have the highest DPP-4 expression level in mammalians. DPP-4 expression and urinary activity are up-regulated in diabetic nephropathy, highlighting its role as a potential target to manage diabetic nephropathy. Preclinical animal studies and some clinical data suggest that DPP-4 inhibitors decrease the progression of diabetic nephropathy in a blood pressure-and glucose-independent manner. Many studies reported that these reno-protective effects could be due to increased half-life of DPP-4 substrates such as glucagon-like peptide-1 (GLP-1) and stromal derived factor-1 alpha (SDF-1a). However, the underlying mechanisms are far from being completely understood and clearly need further investigations.

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“…Of note, a small clinical study suggested that DPP-4 inhibitor treatment with sitagliptin attenuated the hypotensive effect of maximal angiotensin-converting enzyme inhibition via the activation of the sympathetic nervous system 56. A preclinical study in male Wistar rats with hypertension induced by stenosis of the renal artery was undertaken to examine the effects of linagliptin, administered alone and with angiotensin receptor blocker therapy, on blood pressure, renal function, and oxidative stress 57. Results demonstrated that linagliptin administered in combination with telmisartan-normalized blood pressure and reduced oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

Linagliptin: from bench to bedside

Doupis¹

2014

DDDT

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PurposeThe nature of biomedical research affords a broad range of investigational topics at the preclinical stage, not all of which may be explored in subsequent clinical studies. To provide a comprehensive perspective on the physiologic effects of the dipeptidyl peptidase-4 inhibitor linagliptin, this review will discuss the results of both preclinical and clinical research, summarizing data describing outcomes associated with its use.SummaryClinical studies demonstrate an overall favorable safety profile, low risk for hypoglycemia, weight neutrality, primarily nonrenal clearance, and efficacy for glycosylated hemoglobin reduction, typically ranging from 0.6% to 0.8% depending on baseline levels. In addition to these characteristics, preclinical research on linagliptin has yielded several interesting findings such as improved wound healing, reduced hepatic fat content, decreased infarct size following myocardial infarction or intracranial stroke, and improved vascular function with decreased oxidative stress. In accordance with its preclinical profile, linagliptin is unique among available dipeptidyl peptidase-4 compounds because it does not require dose adjustment when used in patients with renal dysfunction. Reduction of albuminuria with linagliptin on top of inhibitors of the renin–angiotensin–aldosterone system in both preclinical and post hoc clinical analysis serves as the foundation for ongoing clinical trials.ConclusionIn addition to its efficacy for glycemic control, current literature points to other potential opportunities associated with linagliptin therapy. These results warrant further investigation and underscore the importance of translational study based on findings from preclinical research. Moving forward, we can expect that future research on linagliptin and other incretin-based therapies will continue to expand their applications beyond the maintenance of glycemic control in patients with type 2 diabetes.

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Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension

Abstract: Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent.

Cited by 37 publications

References 50 publications

Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

Pleiotropic effects of the dipeptidylpeptidase-4 inhibitors on the cardiovascular system

Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy

Linagliptin: from bench to bedside

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