sitagliptin-phosphate and Kidney-Diseases

Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.. To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.. A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023.. Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control.. Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat.. Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment.. In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control.. ClinicalTrials.gov Identifier: NCT01794143.

Topics: Adult; Albuminuria; Diabetes Mellitus, Type 2; Disease Progression; Female; Glomerular Filtration Rate; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin Glargine; Kidney; Kidney Diseases; Liraglutide; Male; Metformin; Middle Aged; Sitagliptin Phosphate

We conducted the multicenter, prospective, open-label study in type 2 diabetic (T2DM) patients with renal dysfunction, to clarify the efficacy and the safety in relation to renal function and glycemic control, and the economic effect when other dipeptidyl peptidase-4 (DPP-4) inhibitors were switched to a small dose of sitagliptin depending on their renal function.. Vildagliptin, alogliptin, or linagliptin received for more than 2 months were changed to sitagliptin at 25 or 12.5 mg/day depending on their renal function in 49 T2DMs. Renal function and glycemic control, and the drug cost were assessed during 6 months.. Estimated glomerular filtration rate was not changed in patients not on hemodialysis (n = 29). The HbA1c levels were not altered in all of the patients including those on hemodialysis (n = 20). The active glucagon-like peptide-1 levels or other renal parameters were not altered significantly. There were no adverse events to be related to the drugs. The daily drug expense was reduced by 88.1 yen per patient.. Switching to a small dose of sitagliptin according to the renal function in T2DM patients with renal dysfunction demonstrated the same efficacy and safety as those with other full-dose DPP-4 inhibitors, indicating a therapeutic option with a high cost performance.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Japan; Kidney Diseases; Male; Middle Aged; Prospective Studies; Sitagliptin Phosphate

There are limited data comparing dipeptidyl peptidase-4 (DPP-4) inhibitors directly. We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment (RI).. This study was a parallel-arm, randomised, multicentre, double-blind, 24 week study conducted in 87 centres across Brazil and the USA. Patients with type 2 diabetes, either drug naive or treated with any glucose-lowering agents, who had inadequate glycaemic control (HbA1c 6.5-10.0% [48-86 mmol/mol]) and an estimated GFR <30 ml min(-1) [1.73 m](-2) were randomised (via interactive voice response technology) to vildagliptin 50 mg once daily or sitagliptin 25 mg once daily. These doses are recommended in this patient population and considered maximally effective. Participants, investigators and the sponsor were blinded to group assignment. Efficacy endpoints included change in HbA1c and fasting plasma glucose (FPG) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events.. In total, 148 patients were randomised, 83 to vildagliptin and 65 to sitagliptin. All patients were analysed. After 24 weeks, the adjusted mean change in HbA1c was -0.54% (5.9 mmol/mol) from a baseline of 7.52% (59 mmol/mol) with vildagliptin and -0.56% (6.1 mmol/mol) from a baseline of 7.80% (62 mmol/mol) with sitagliptin (p = 0.874). FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin (p = 0.185). Both treatments were well tolerated with overall similar safety profiles.. At their recommended doses for severe RI, vildagliptin (50 mg once daily) compared with sitagliptin (25 mg once daily) demonstrated similar efficacy and both drugs were well tolerated. This study provides further support for the use of DPP-4 inhibitors in patients with severe RI.. ClinicalTrials.gov NCT00616811 (completed). This study was planned and conducted by Novartis.

Topics: Adamantane; Aged; Blood Glucose; Brazil; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Kidney Diseases; Male; Middle Aged; Nitriles; Pyrrolidines; Sitagliptin Phosphate; United States; Vildagliptin

Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM.. T2DM was induced in rats by 2 weeks of a high-fat diet followed by intravenous injection of streptozotocin. Metabolic disturbance and cardiac, vascular, and renal dysfunction were analyzed in the experimental groups.. Sitagliptin and LASSBio-2124 administration after T2DM induction reduced elevated glucose levels to 319.8 ± 13.2 and 279.7 ± 17.8 mg/dL, respectively (p < 0.05). LASSBio-2124 also lowered the cholesterol and triglyceride levels from 76.8 ± 8.0 to 42.7 ± 3.2 mg/dL and from 229.7 ± 25.4 to 100.7 ± 17.1 mg/dL, in diabetic rats. Sitagliptin and LASSBio-2124 reversed the reduction of the plasma insulin level. LASSBio-2124 recovered the increased urinary flow in diabetic animals and reduced 24-h proteinuria from 23.7 ± 1.5 to 13.3 ± 2.8 mg (p < 0.05). It also reduced systolic and diastolic left-ventricular dysfunction in hearts from diabetic rats.. The effects of LASSBio-2124 were superior to those of sitagliptin in the cardiovascular systems of T2DM rats. This new prototype showed promise for the avoidance of comorbidities in a T2DM experimental model, and thus may constitute an innovative therapeutic agent for the treatment of these conditions in the clinical field in future.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart; Kidney Diseases; Male; Rats; Rats, Wistar; Sitagliptin Phosphate; Streptozocin; Ventricular Dysfunction, Left

Recent studies demonstrated the reno-protective effects of two dipeptidyl peptidase-4 (DPP-4) inhibitors, saxagliptin and sitagliptin, against gentamycin-induced renal injury. However, none of these studies investigated whether renal DPP-4 contributes to the pathogenesis of this nephrotoxicity or not. This prompted us to test this hypothesis and to assess, for the first time, the potential reno-protective effect of linagliptin and whether this action is related or not to DPP-4 inhibition. Lingliptin was chosen since it is mainly excreted through a non-renal pathway and can therefore be used safely in individuals with renal injury.. Male Sprague-Dawley rats were administered gentamycin (100 mg/kg/day, ip for 10 days) alone or combined with linagliptin (3 mg/kg/day, orally for 14 days). Gentamycin was administered once daily during the last ten days of the linagliptin treatment.. Linagliptin administration ameliorated gentamycin-induced renal injury and restored renal functional, oxidative, inflammatory, apoptotic and histopathological changes. Furthermore, the current study highlighted the role of increased plasma and renal DPP-4 in the pathogenesis of gentamycin renal insults and showed that the potential reno-protective effect of linagliptin is partly, mediated via inhibition of DPP-4, in addition to other antioxidant, anti-inflammatory and anti-apoptotic actions.. Linagliptin may serve as a beneficial adjutant to reduce gentamycin-induced renal injury.

Topics: Adamantane; Animals; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Gentamicins; Kidney; Kidney Diseases; Linagliptin; Male; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

This study aimed at investigating the possible ameliorative effects of sitagliptin in mice with gentamicin (GEN) nephrotoxicity. Sitagliptin was given to the animals at an oral dose of 10mgkg

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Creatinine; Cystatin C; Cytokines; Dipeptidyl-Peptidase IV Inhibitors; Female; Gentamicins; Injections, Intraperitoneal; Kidney; Kidney Cortex; Kidney Diseases; Mice; Oxidative Stress; Sitagliptin Phosphate; Urea

Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear.. Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks.. A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91phox, p47phox, and p67phox in rat kidneys with doxorubicin nephropathy.. NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.

Topics: Animals; Anti-Inflammatory Agents; Dipeptidyl-Peptidase IV Inhibitors; Doxorubicin; Inflammasomes; Kidney Diseases; Linagliptin; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

This study aimed to investigate the potential protective effect of sitagliptin on gentamicin-induced nephrotoxicity and to elucidate the underlying mechanism.. Wistar rats were allocated as follows: Gentamicin group: received gentamicin intraperitoneally (100 mg/kg/day); Gentamicin plus sitagliptin group: received simultaneous gentamicin and sitagliptin (30 mg/kg/day orally); Sitagliptin group: received only sitagliptin; and. received saline. Blood urea nitrogen (BUN), serum creatinine, urine protein levels and histopathology of kidney tissues were evaluated. The activity of mitochondrial enzyme complexes reflects the mitochondrial function. Oxidative stress biomarkers and immunohistochemical studies for apoptotic markers caspase-3 and bax were evaluated.. Gentamicin causes significant elevation of BUN, serum creatinine and urine proteins. Oxidative stress was revealed by decreased superoxide dismutase activity and catalase activity, glutathione depletion and increased malondialdehyde. Significant decrease in mitochondrial NADH dehydrogenase, succinate dehydrogenase, cytochrome c oxidase and mitochondrial redox activity indicates mitochondrial dysfunction, along with significant elevation in renal caspase-3 and bax. The aforementioned markers and the histological injury in renal tubules were significantly reversed upon sitagliptin treatment.. These findings suggest that sitagliptin treatment attenuates renal dysfunction and structural damage through the reduction of oxidative stress, mitochondrial dysfunction and apoptosis in the kidney.

Topics: Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers; Blood Glucose; Blood Urea Nitrogen; Creatinine; Cytoprotection; Disease Models, Animal; Electron Transport; Energy Metabolism; Gentamicins; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Mitochondria; Oxidative Stress; Proteinuria; Rats, Wistar; Sitagliptin Phosphate

Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury.

Topics: Adamantane; Albuminuria; Animals; Blood Glucose; Blood Pressure; Cytoprotection; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension; Kidney Diseases; Kidney Glomerulus; Male; Rats, Inbred Dahl; Sitagliptin Phosphate

This study was designed to investigate the possible effect of sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in diabetic rats. T2DM in rats was induced by the administration of nicotinamide (230 mg/kg, i.p.), 15 min prior to a single dose of streptozotocin (65 mg/kg, i.v.). In vivo renal I/R was performed in both T2DM and normal rats. Each protocol comprised ischemia for 30 min followed by reperfusion for 24h and a treatment period of 14 days before induction of ischemia. Sitagliptin treated diabetic rats that underwent renal I/R demonstrated significant decrease in the serum concentrations of aspartate aminotransferase (p < 0.01), urea nitrogen (p < 0.01) and creatinine (p < 0.001) compared to renal I/R in diabetic rats. Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in renal tissue were significantly (p < 0.05, p < 0.001, p < 0.01, p < 0.05 respectively) decreased after renal I/R in sitagliptin treated rats compared to diabetic rats. Antioxidant enzymes like glutathione (p < 0.05), glutathione peroxidase (p < 0.001), superoxide dismutase (p < 0.05) and catalase (p < 0.001) were significantly increased after renal I/R in sitagliptin treated diabetic rats compared to non treated diabetic rats. The typical DNA laddering was observed when renal I/R performed in diabetic rats, which indicates cell apoptosis. Sitagliptin treated rats demonstrated a decrease in DNA fragmentation and apoptosis. Furthermore, renal histopathology preserved in sitagliptin treated rats verified protection against renal I/R in diabetes. The results of present investigation established sitagliptin treatment attenuated renal damage induced by renal I/R in diabetic rats.

Topics: Animals; Apoptosis; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; DNA Fragmentation; Female; Glutathione; Glutathione Peroxidase; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Oxidative Stress; Peroxidase; Pyrazines; Rats; Rats, Wistar; Reperfusion Injury; Sitagliptin Phosphate; Superoxide Dismutase; Triazoles; Xanthine Oxidase