linagliptin and Kidney-Failure--Chronic

Patients with diabetic kidney disease (DKD) are at increased risk to develop post-contrast acute kidney injury (AKI). Diabetic patients under dipeptidyl peptidase 4 inhibitors (DPP4Is) experience a lower propensity to develop AKI. We speculated that linagliptin as a single agent or in combination with allopurinol may reduce the incidence of post-contrast AKI in stage 3-5 chronic kidney disease (CKD) patients with underlying DKD.. Out of 951 DKD patients eligible for this study, 800 accepted to sign informed consent. They were randomly allocated to 4 equal groups that received their prophylaxis for 2 days before and after radiocontrast. The first control group received N-acetyl cysteine and saline, the 2. 20, 19, 14, and 8 patients developed post-contrast AKI in groups 1 through 4, respectively. Neither linagliptin nor allopurinol was superior to N-acetyl cysteine and saline alone. However, the combination of the two agents provided statistically significant renal protection: post-contrast AKI in group 4 was significantly lower than in groups 1 and 2 (. Linagliptin and allopurinol in combination may offer protection against post-contrast AKI in DKD exposed to radiocontrast. Further studies are needed to support this view.. NCT03470454.

Topics: Acetylcysteine; Acute Kidney Injury; Allopurinol; Chemoprevention; Contrast Media; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Kidney Failure, Chronic; Linagliptin; Prospective Studies; Protective Agents; Renal Insufficiency, Chronic; Saline Solution

Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m. Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA. A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m. Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA

Topics: Aged; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Incidence; Kidney; Kidney Failure, Chronic; Linagliptin; Male; Middle Aged; Mortality; Prognosis; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome

Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease.. To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events.. Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018.. Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines.. Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline.. Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis.. Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years.. ClinicalTrials.gov Identifier: NCT01897532.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Kidney Failure, Chronic; Linagliptin; Male; Middle Aged; Proportional Hazards Models; Risk Factors

Inflammation and glycemic control are important prognosis-related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti-inflammatory effects of monotherapy with linagliptin-a dipeptidase-4 inhibitor-in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), high-sensitivity C-reactive protein, GA, blood glucose, and active glucagon-like peptide-1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low-density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL-6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL-6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon-like peptide-1 levels increased 2.5-fold during the treatment. Over the 6-month treatment period, body weight and levels of high-sensitivity C-reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti-inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.

Topics: Aged; Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Linagliptin; Male; Purines; Quinazolines; Renal Dialysis

Hyperglycemia is associated with increased mortality and morbidity in patients with type 2 diabetes mellitus (T2DM) who are undergoing dialysis. Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been widely used in end-stage renal disease (ESRD) patients with T2DM, there are few studies on their efficacy in this population. We studied the effect of 3 different DPP-4 inhibitors on metabolic parameters in ESRD patients with T2DM.Two hundred ESRD patients with T2DM who were treated with DPP-4 inhibitors (sitagliptin, vildagliptin, or linagliptin) were enrolled and analyzed retrospectively. The changes in glycated hemoglobin (HbA1c), fasting plasma glucose, and lipid profiles were assessed before and after 3 months of treatment with DPP-4 inhibitors. Subgroup analysis was done for each hemodialysis (HD) and peritoneal dialysis (PD) group.There was no significant difference in the decrease in the HbA1c level among sitagliptin, vildagliptin, and linagliptin treatment groups (-0.74 ± 1.57, -0.39 ± 1.45, and -0.08 ± 1.40, respectively, P = 0.076). The changes in fasting blood glucose and lipid profiles were also not significantly different. In HD patients (n = 115), there was no difference in the HbA1c level among the 3 groups. In contrast, in PD patients (n = 85), HbA1c was reduced more after 3 months of treatment with sitagliptin compared with vildagliptin and linagliptin (-1.58 ± 0.95, -0.46 ± 0.98, -0.04 ± 1.22, respectively, P = 0.001).There was no significant difference in the glucose-lowering effect between the different DPP-4 inhibitors tested in ESRD patients. In PD patients, sitagliptin tends to lower the HbA1c level more than the other inhibitors. The glucose-lowering efficacy of the 3 DPP-4 inhibitors was comparable.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Linagliptin; Lipids; Male; Middle Aged; Nitriles; Peritoneal Dialysis; Pyrrolidines; Renal Dialysis; Retrospective Studies; Sitagliptin Phosphate; Treatment Outcome; Vildagliptin

This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily non-renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM).. Linagliptin pharmacokinetics was studied under single-dose and steady-state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end-stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM).. Renal excretion of unchanged linagliptin was <7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration-time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20-60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and C(max) values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from 14-15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r(2) = 0.18) was seen between creatinine clearance and steady-state exposure.. Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.

Topics: Analysis of Variance; Area Under Curve; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Kidney Failure, Chronic; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome

Uremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).. In a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.. DPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

Topics: Animals; Area Under Curve; Cardiomyopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Gene Expression Regulation; Glomerular Filtration Rate; Glucagon-Like Peptide 1; Heart; Humans; Kidney Failure, Chronic; Linagliptin; Myocardium; Natriuretic Peptide, Brain; Nephrectomy; Piperidines; Purines; Pyrazines; Quinazolines; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sitagliptin Phosphate; Triazoles; Uracil; Uremia