scholarly journals Renal Effects of DPP-4 Inhibitors: A Focus on Microalbuminuria

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Martin Haluzík ◽  
Jan Frolík ◽  
Ivan Rychlík
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Cardiovascular Complications ◽  
Special Focus ◽  
Renal Effects ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Increased Risk ◽  
Glucagon Like Peptide 1

Incretin-based therapies represent one of the most promising options in type 2 diabetes treatment owing to their good effectiveness with low risk of hypoglycemia and no weight gain. Other numerous potential beneficial effects of incretin-based therapies have been suggested based mostly on experimental and small clinical studies including its beta-cell- and vasculo-protective actions. One of the recently emerged interesting features of dipeptidyl peptidase-4 (DPP-4) inhibitors is its possible protective effect on the diabetic kidney disease. Here, we review the renal effects of DPP-4 inhibitors with special focus on its influence on the onset and progression of microalbuminuria, as presence of microalbuminuria represents an important early sign of kidney damage and is also associated with increased risk of hypoglycemia and cardiovascular complications. Mechanisms underlying possible nephroprotective properties of DPP-4 inhibitors include reduction of oxidative stress and inflammation and improvement of endothelial dysfunction. Effects of DPP-4 inhibitors may be both glucagon-like peptide-1 (GLP-1) dependent and independent. Ongoing prospective studies focused on the nephroprotective effects of DPP-4 inhibitors will further clarify its possible role in the prevention/attenuation of diabetic kidney disease beyond its glucose lowering properties.

scholarly journals Role of incretin based therapies in the treatment of diabetic kidney disease

2018 ◽  
Vol 21 (5) ◽  
pp. 395-398 ◽  
Author(s):  
Paola Fioretto ◽  
Andrea Frascati
Keyword(s):  
Diabetes Mellitus ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
The Metabolic Syndrome ◽  
Cardiovascular Morbidity And Mortality ◽  
Increased Risk ◽  
Glucagon Like Peptide 1 ◽  
Stage Renal Disease

Diabetic kidney disease (DKD), a serious microvascular complication of diabetes mellitus is a leading cause of end-stage renal disease and is associated with an increased risk of cardiovascular morbidity and mortality. Despite advancements in blood glucose and blood pressure (BP) control, ~20% to 40% of patients with diabetes mellitus develop DKD. Intensive glycaemic and BP control positively influence decline in estimated glomerular filtration rate and albuminuria, thereby delaying the onset and progression of diabetic nephropathy. Incretin based therapies namely glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used glucose lowering agents and have shown favorable renal outcomes in DKD. This article discusses the extra-glycaemic properties of incretin based therapies and their renoprotective effects on components of the metabolic syndrome, including obesity, hypertension and dyslipidaemia; reduction in oxidative stress and inflammation; and increase in natriuresis.

scholarly journals Sitagliptin ameliorates ER stress in diabetic kidney disease through upregulation of SIRT1

2021 ◽  
Vol 1 (1) ◽  
pp. 33-41
Author(s):  
Qunzi Zhang ◽  
Junjie Jia ◽  
Li He ◽  
Ying Fan ◽  
Niansong Wang
Keyword(s):  
Kidney Disease ◽  
Er Stress ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Er Homeostasis

Abstract Objectives Endoplasmic reticulum (ER) stress plays a significant role in the progression of diabetic kidney disease (DKD), and dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemic agents, exerting renal beneficial effects in DKD. Here, we investigated the role of DPP4 inhibitor Sitagliptin (Sita) in ER homeostasis in the kidneys of diabetic DBA2/J (D2) mice and in albumin-stimulated HK-2 cells. Methods and Results ER stress was observed both in vivo and in vitro, as reflected by notably increased glucose-regulated protein of 78 kDa (GRP78), CHOP, high phosphorylation of PERK (p-PERK), and cleaved caspase3 (c-CASP3), whereas Sita effectively attenuated these disorders. Meanwhile, Sita increased the expression of SIRT1 both in vivo and in vitro. To further validate the potential effects of SIRT1 in regulating ER stress, we regulated SIRT1 by siRNA and overexpressed plasmids in albumin-overloaded HK-2 cells. Elevated SIRT1 alleviated albumin-induced ER stress, while decreased SIRT1 further aggravated ER stress in albumin-treated HK-2 cells. Conclusion The results suggest that a novel mechanism links the DPP4 enzyme to ER stress during tubular injury in DKD and highlight that SIRT1 may be a potential target for managing DKD.

scholarly journals Incretins in the Therapy of Diabetic Kidney Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12312
Author(s):  
Agnieszka Przezak ◽  
Weronika Bielka ◽  
Andrzej Pawlik
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Oral Glucose ◽  
Antidiabetic Drug ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Drug Classes ◽  
Increased Risk ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Patients With Diabetes

Diabetic kidney disease is a microvascular complication that occurs in patients with diabetes. It is strongly associated with increased risk of kidney replacement therapy and all-cause mortality. Incretins are peptide hormones derived from the gastrointestinal tract, that besides causing enhancement of insulin secretion after oral glucose intake, participate in many other metabolic processes. Antidiabetic drug classes, such as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide receptor agonists, which way of action is based on incretins facility, not only show glucose-lowering properties but also have nephroprotective functions. The aim of this article is to present the latest information about incretin-based therapy and its influence on diabetic kidney disease appearance and progression, point its potential mechanisms of kidney protection and focus on future therapeutic possibilities bound with these two antidiabetic drug classes.

scholarly journals Insulin Withdrawal in Diabetic Kidney Disease: What Are We Waiting for?

2021 ◽  
Vol 18 (10) ◽  
pp. 5388
Author(s):  
Carlos Morillas ◽  
Luis D’Marco ◽  
María Jesús Puchades ◽  
Eva Solá-Izquierdo ◽  
Carmen Gorriz-Zambrano ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Insulin Therapy ◽  
Diabetic Kidney Disease ◽  
High Morbidity ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Good Glycaemic Control ◽  
Dipeptidyl Peptidase 4 Inhibitors ◽  
Glucagon Like Peptide 1 ◽  
New Guidelines

The prevalence of type 2 diabetes mellitus worldwide stands at nearly 9.3% and it is estimated that 20–40% of these patients will develop diabetic kidney disease (DKD). DKD is the leading cause of chronic kidney disease (CKD), and these patients often present high morbidity and mortality rates, particularly in those patients with poorly controlled risk factors. Furthermore, many are overweight or obese, due primarily to insulin compensation resulting from insulin resistance. In the last decade, treatment with sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to be beneficial in renal and cardiovascular targets; however, in patients with CKD, the previous guidelines recommended the use of drugs such as repaglinide or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors), plus insulin therapy. However, new guidelines have paved the way for new treatments, such as SGLT2i or GLP1-RA in patients with CKD. Currently, the new evidence supports the use of GLP1-RA in patients with an estimated glomerular filtration rate (eGFR) of up to 15 mL/min/1.73 m2 and an SGLT2i should be started with an eGFR > 60 mL/min/1.73 m2. Regarding those patients in advanced stages of CKD, the usual approach is to switch to insulin. Thus, the add-on of GLP1-RA and/or SGLT2i to insulin therapy can reduce the dose of insulin, or even allow for its withdrawal, as well as achieve a good glycaemic control with no weight gain and reduced risk of hypoglycaemia, with the added advantage of cardiorenal benefits.

scholarly journals New hypoglycemic agents and the kidney: what do the major trials tell us?

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1844 ◽  
Author(s):  
Brendan Smyth ◽  
Vlado Perkovic
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Sglt2 Inhibitors ◽  
Hypoglycemic Agents ◽  
New Agents ◽  
Diabetic Kidney ◽  
Dipeptidyl Peptidase 4 ◽  
Patient Groups ◽  
Glucagon Like Peptide 1 ◽  
The Impact

As the burden of diabetic kidney disease continues to expand, new therapies to preserve renal function or prevent diabetic nephropathy are urgently needed. In the past decade, a number of new hypoglycemic classes have emerged, each with a unique profile of action and benefits. Here we review the impact of glycemic control on renal outcomes and the results of the major clinical trials of glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium–glucose co-transporter 2 (SGLT2) inhibitors. Both GLP-1 agonists and SGLT2 inhibitors consistently demonstrate renal benefits. Further studies of these new agents in different patient groups and in comparison to (or in combination with) other treatments are required to better define their role in combating the burden of diabetic kidney disease.

scholarly journals Bardoxolone methyl: drug development for diabetic kidney disease

2020 ◽  
Vol 24 (10) ◽  
pp. 857-864 ◽  
Author(s):  
Hironori Kanda ◽  
Kengo Yamawaki
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Estimated Glomerular Filtration Rate ◽  
Defense Responses ◽  
Priority Review ◽  
Phase 3 ◽  
Diabetic Kidney ◽  
Increased Risk ◽  
Phase 2 Study ◽  
First Time

Abstract Bardoxolone methyl activates the Keap1/Nrf2 system that plays an important role in defense responses against oxidative stress. Importantly, bardoxolone methyl has demonstrated increases in estimated glomerular filtration rate (eGFR) in patients with diabetic kidney disease (DKD) in clinical studies. However, an overseas Phase 3 study of bardoxolone methyl in patients with stage G4 DKD was prematurely terminated due to an increased risk for heart failure, which was considered to have been caused by early-onset fluid overload. Subsequently, a Japanese Phase 2 study demonstrated, for the first time, that bardoxolone methyl directly improves GFR, which is a true indicator of kidney function, using the inulin clearance method. In Japan, bardoxolone methyl was designated for the treatment of DKD under the Priority Review and Designation (SAKIGAKE Designation) System established by the Ministry of Health, Labour and Welfare. A Japanese Phase 3 study, with endpoints such as a ≥ 30% decrease in eGFR, is currently ongoing to assess the efficacy and safety of bardoxolone methyl in more than 1,000 patients with stages G3 and G4 DKD who have no identified risk factors.

scholarly journals GLP-1 receptor agonists in diabetic kidney disease: from the patient-side to the bench-side

2018 ◽  
Vol 315 (6) ◽  
pp. F1519-F1525 ◽  
Author(s):  
Brad P. Dieter ◽  
Radica Z. Alicic ◽  
Katherine R. Tuttle
Keyword(s):  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Microvascular Complications ◽  
Renin Angiotensin System ◽  
Diabetic Kidney ◽  
Receptor Agonists ◽  
Patients With Diabetes ◽  
Glucagon Like Peptide 1 ◽  
Patient Side ◽  
End Stage

Diabetic kidney disease (DKD), one of the most common and severe microvascular complications of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Since the development of renin-angiotensin system inhibition nearly three decades ago, no new therapeutic agents have received regulatory approval for treatment of DKD. Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of newer antihyperglycemic agents, have shown promise for prevention of DKD onset and progression. This perspective summarizes clinical and experimental observations to give insight into biological mechanisms beyond glycemic control, such as natriuresis and anti-inflammatory actions, for preservation of kidney function in patients with diabetes.

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