sitagliptin-phosphate and Renal-Insufficiency--Chronic

As type 2 diabetes mellitus (T2DM) progresses, most patients will require insulin replacement therapy. Whether oral antidiabetic drug (OAD) therapy should be retained when initiating insulin is still debated. While the rationale to keep metformin with insulin is strong (mostly as an insulin-sparing agent to limit weight gain), the evidence is less clear for other OADs. In particular, the question now comes up what the expected benefit could be of combining the newer agents, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors with insulin. Additionally, when metformin is no longer a treatment option, as in the case of patients with severe renal impairment, insulin is often used as monotherapy, with little evidence of benefit in maintaining other OADs. In this specific situation, it is also of interest to evaluate the potential benefit of combined treatment with a DPP-4 inhibitor and insulin. Among the classic limitations of insulin therapy in patients with T2DM, hypoglycemia remains a major barrier to glycemic control, along with weight gain exacerbation. The oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and are weight neutral. In addition to the expected benefits associated with limiting insulin dose and regimen complexity, the specific advantages the DPP-4 inhibitor drug class on hypoglycemia and weight gain could justify combining DPP-4 inhibitors with insulin; additionally, a DPP-4 inhibitor may be of special value to decrease glycemic excursions that are not properly addressed by basal insulin therapy and metformin use, even after optimizing titration of the basal insulin. However, given the common original perception that treatment with DPP-4 inhibitors may be less beneficial with increasing disease progression because of the loss of β-cell function, the potential relevance of these agents in the setting of advanced T2DM treated with insulin was not necessarily anticipated. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have started to emerge. Our article provides a comprehensive overview of the currently available evidence from controlled randomized clinical trials and we discuss the potential role of DPP-4 inhibitors in the this setting. Further clinical experience will allow to fully assess the positioning of these agents in insulin-treated T2DM populations.

Topics: Adamantane; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Sitagliptin is the first dipeptidylpeptidase-4 inhibitor to be used in the management of type 2 diabetes. It is widely used as an add-on therapy to ongoing management or as monotherapy where it is deemed necessary. It has been found to be beneficial in improving β-cell function and glycemic control, and also is used in special circumstances like chronic kidney disease, with appropriate dose reductions. Overall, cardiovascular outcomes are no different from other oral hypoglycemic agents. In this review article we have summarized all the previous studies relevant to sitagliptin use in clinical practice and emphasized its use in various stages of chronic kidney disease.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Pyrazines; Renal Insufficiency, Chronic; Severity of Illness Index; Sitagliptin Phosphate; Triazoles

Chronic kidney disease (CKD) is a common complication of diabetes mellitus and the most common cause of end-stage renal disease (ESRD). As the worldwide prevalence of diabetes continues to increase, the number of patients with CKD will also increase. Therefore, it is essential that physicians know how to safely and effectively manage diabetes in the setting of CKD. Adequate glycaemic control in patients with diabetes is important to prevent ESRD and other complications and to decrease mortality. However, many glucose-lowering agents need to be dose-adjusted or should not be used in the setting of stage 3 CKD or higher (defined as an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), particularly in patients with stage 5 CKD (eGFR <15 ml/min/1.73 m(2)) and in those receiving dialysis. Insulin therapy is appropriate for patients undergoing dialysis; however, several orally administered glucose-lowering agents can also be used safely in these patients. In this Review, we provide an overview of the use of noninsulin glucose-lowering agents in the dialysis population.

Topics: Adamantane; Biguanides; Diabetic Nephropathies; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Glucagon-Like Peptides; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Meglumine; Metformin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Dialysis; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome; Triazoles; Uracil; Vildagliptin

To characterize the incidence of diabetes-associated complications and assess the safety of sitagliptin in participants with chronic kidney disease (CKD) in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).. For participants with baseline eGFR measurements (n = 14 528), baseline characteristics and safety outcomes were compared for the CKD cohort (eGFR < 60 mL/min per 1.73 m. CKD was present in 3324 (23%) participants at entry into TECOS. The mean (SD) age for this CKD cohort was 68.8 (7.9) years, mean diabetes duration was 13.7 (9.0) years, and 62% were men. Incidences of serious adverse events, malignancy, bone fracture, severe hypoglycaemia and most categories of diabetes complications were higher in the CKD cohort compared with those without CKD. Over ~2.8 median years of follow-up, CKD participants assigned to sitagliptin had rates of diabetic eye disease, diabetic neuropathy, renal failure, malignancy, bone fracture, pancreatitis and severe hypoglycaemia similar to those of placebo-assigned participants.. Participants in TECOS with CKD had higher incidences of serious adverse events and diabetes complications than those without CKD. Treatment with sitagliptin was generally well tolerated, with no meaningful differences in safety outcomes observed between those with CKD assigned to sitagliptin or placebo.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug-Related Side Effects and Adverse Reactions; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Placebos; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Treatment Outcome

To evaluate chronic kidney disease (CKD) and cardiovascular outcomes in TECOS (Clinical trial reg. no. NCT00790205, clinicaltrials.gov) participants with type 2 diabetes and cardiovascular disease treated with sitagliptin, a dipeptidyl peptidase 4 inhibitor, according to baseline estimated glomerular filtration rate (eGFR).. We used data from 14,671 TECOS participants assigned in a double-blind design to receive sitagliptin or placebo added to existing therapy, while aiming for glycemic equipoise between groups. Cardiovascular and CKD outcomes were evaluated over a median period of 3 years, with participants categorized at baseline into eGFR stages 1, 2, 3a, and 3b (≥90, 60-89, 45-59, or 30-44 mL/min/1.73 m. Participants with eGFR stage 3b were older, were more often female, and had a longer duration of diabetes. Four-point major adverse cardiovascular event rates increased with lower baseline eGFR (3.52, 3.55, 5.74, and 7.34 events/100 patient-years for stages 1-3b, respectively). Corresponding adjusted hazard ratios for stages 2, 3a, and 3b versus stage 1 were 0.93 (95% CI 0.82-1.06), 1.28 (1.10-1.49), and 1.39 (1.13-1.72), respectively. Sitagliptin therapy was not associated with cardiovascular outcomes for any eGFR stage (interaction P values were all >0.44). Kidney function declined at the same rate in both treatment groups, with a marginally lower but constant eGFR difference (-1.3 mL/min/1.73 m. Impaired kidney function is associated with worse cardiovascular outcomes. Sitagliptin has no clinically significant impact on cardiovascular or CKD outcomes, irrespective of baseline eGFR.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Kidney; Male; Middle Aged; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Treatment Outcome

Patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease have an increased risk of micro- and macrovascular disease, but limited options for antihyperglycemic therapy. We compared the efficacy and safety of sitagliptin with glipizide in patients with T2DM and moderate-to-severe chronic renal insufficiency and inadequate glycemic control.. Patients (n = 426) were randomized 1:1 to sitagliptin (50 mg every day [q.d.] for moderate renal insufficiency and 25 mg q.d. for severe renal insufficiency) or glipizide (2.5 mg q.d., adjusted based on glycemic control to a 10-mg twice a day maximum dose). Randomization was stratified by: 1) renal status (moderate or severe renal insufficiency); 2) history of cardiovascular disease; and 3) history of heart failure.. At week 54, treatment with sitagliptin was noninferior to treatment with glipizide in A1C change from baseline (-0.8 vs. -0.6%; between-group difference -0.11%; 95% CI -0.29 to 0.06) because the upper bound of the 95% CI was less than the prespecified noninferiority margin of 0.4%. There was a lower incidence of symptomatic hypoglycemia adverse events (AEs) with sitagliptin versus glipizide (6.2 and 17.0%, respectively; P = 0.001) and a decrease in body weight with sitagliptin (-0.6 kg) versus an increase (1.2 kg) with glipizide (difference, -1.8 kg; P < 0.001). The incidence of gastrointestinal AEs was low with both treatments.. In patients with T2DM and chronic renal insufficiency, sitagliptin and glipizide provided similar A1C-lowering efficacy. Sitagliptin was generally well-tolerated, with a lower risk of hypoglycemia and weight loss versus weight gain, relative to glipizide.

Topics: Body Weight; Diabetes Mellitus, Type 2; Female; Glipizide; Humans; Hypoglycemic Agents; Male; Pyrazines; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Triazoles

To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) > or =30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end-stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed.. In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated haemoglobin A(1c) (HbA(1c)) values of 6.5-10% were allocated (2:1) to sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve plasma concentrations similar to those observed in patients with normal renal function treated with 100 mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50 mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day.. Patients (N = 91) with a mean baseline HbA(1c) value of 7.7% (range: 6.2-10.3%) were randomized to sitagliptin (n = 65) or placebo (n = 26). After 12 weeks, the mean change [95% confidence interval (CI)] from baseline in HbA(1c) was -0.6% (-0.8, -0.4) in the sitagliptin group compared with -0.2% (-0.4, 0.1) in the placebo group [between-group difference (95% CI) = -0.4% (-0.7, -0.1)]. At 54 weeks, patients continuously treated with sitagliptin had a mean change (95% CI) from baseline in HbA(1c) of -0.7% (-0.9, -0.4). The overall incidence of adverse experiences was generally similar between groups. Between-group differences in incidences of specific clinical adverse experiences were generally small; however, the proportion of patients for whom hypoglycaemia was reported was lower in the sitagliptin group (4.6%) compared with the placebo/glipizide group (23.1%). Consistent with the high mortality risk in this patient population, there were six deaths during this 54-week study [5 of 65 patients (7.7%) in the sitagliptin group and 1 of 26 patients (3.8%) in the placebo/glipizide group]; no death was considered by the investigator to be drug related. The overall incidences of drug-related and serious adverse experiences and discontinuations because of adverse experiences were generally similar between groups.. In this study, sitagliptin was generally well tolerated and provided effective glycaemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.

Topics: Aged; Blood Glucose; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glipizide; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Lipids; Male; Middle Aged; Placebos; Pyrazines; Renal Insufficiency, Chronic; Severity of Illness Index; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Limited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk.. To evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD).. This retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score-matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score-matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2.. Empagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2).. Primary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching.. Among 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, -17.6 [95% CI, -24.9 to -10.4]; HHF: RD, -16.7 [95% CI, -21.7 to -11.9]), HF (modified MACE: RD, -41.1 [95% CI, -59.9 to -22.6]; HHF: RD, -50.4 [95% CI, -67.5 to -33.9]), or CKD (modified MACE: RD, -26.7 [95% CI, -41.3 to -12.3]; HHF: RD, -31.9 [95% CI, -43.5 to -20.8]).. In this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.

Topics: Aged; Atherosclerosis; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucose; Heart Failure; Humans; Hypoglycemic Agents; Liraglutide; Male; Medicare; Myocardial Infarction; Renal Insufficiency, Chronic; Retrospective Studies; Sitagliptin Phosphate; United States

This study investigated the molecular mechanisms underlying the antiproteinuric effect of DPP4 inhibition in 5/6 renal ablation rats and tested the hypothesis that the urinary activity of DPP4 correlates with chronic kidney disease (CKD) progression. Experiments were conducted in male Wistar rats who underwent 5/6 nephrectomy (Nx) or sham operation followed by 8 wk of treatment with the DPP4 inhibitor (DPP4i) sitagliptin or vehicle. Proteinuria increased progressively in Nx rats throughout the observation period. This increase was remarkably mitigated by sitagliptin. Higher levels of proteinuria in Nx rats compared to control rats were accompanied by higher urinary excretion of retinol-binding protein 4, a marker of tubular proteinuria, as well as higher urinary levels of podocin, a marker of glomerular proteinuria. Retinol-binding protein 4 and podocin were not detected in the urine of Nx + DPP4i rats. Tubular and glomerular proteinuria was associated with the reduced expression of megalin and podocin in the renal cortex of Nx rats. Sitagliptin treatment partially prevented this decrease. Besides, the angiotensin II renal content was significantly reduced in the Nx rats that received sitagliptin compared to vehicle-treated Nx rats. Interestingly, both urinary DPP4 activity and abundance increased progressively in Nx rats. Additionally, urinary DPP4 activity correlated positively with serum creatinine levels, proteinuria, and blood pressure. Collectively, these results suggest that DPP4 inhibition ameliorated both tubular and glomerular proteinuria and prevented the reduction of megalin and podocin expression in CKD rats. Furthermore, these findings suggest that urinary DPP4 activity may serve as a biomarker of renal disease and progression.

Topics: Angiotensin II; Animals; Biomarkers; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Fibrosis; Intracellular Signaling Peptides and Proteins; Kidney; Low Density Lipoprotein Receptor-Related Protein-2; Male; Membrane Proteins; Proteinuria; Rats, Wistar; Renal Insufficiency, Chronic; Retinol-Binding Proteins, Plasma; Signal Transduction; Sitagliptin Phosphate

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is commonly prescribed to patients with type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses. We compare the 1-year risk of death or hospitalization with congestive heart failure in patients with CKD newly prescribed sitagliptin at >50 versus ≤50 mg/d.. This population-based cohort study included older adults (>66 years) with type 2 diabetes and an eGFR<45 ml/min per 1.73 m. Of 9215 patients, 6518 started sitagliptin at >50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at >50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, -0.12%; 95% confidence interval, -0.19 to -0.06) and a lower risk of all-cause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98).. The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at >50 versus ≤50 mg/d.. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_25_CJN08310520_final.mp3.

Topics: Age Factors; Aged; Aged, 80 and over; Blood Glucose; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Heart Failure; Hospitalization; Humans; Kidney; Male; Ontario; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Sitagliptin Phosphate; Time Factors; Treatment Outcome

We assessed the effect of treatment with the dipeptidyl peptidase-4 inhibitor, sitagliptin, on adenine-induced chronic kidney disease (CKD). Six equal groups of rats were given either normal food or food mixed with adenine (0.25% w/w for five weeks) to induce CKD. Some of these groups were also simultaneously treated with sitagliptin (2.5 and 10 mg/kg/day, by gavage). Rats given adenine showed elevation of blood pressure, decreased body weight and increased relative kidney weight. Adenine also significantly increased plasma urea, creatinine, cystatin C, liver-type fatty acid-binding protein concentrations and neutrophil gelatinase-associated lipocalin activity by 404%, 354%, 667%, 91% and 281% respectively and reduced plasma α-Klotho by 50%. In addition, adenine significantly increased albumin/creatinine ratio and N-acetyl-β-d-glucosaminidase activity by 3553% and 400% respectively and reduced creatinine clearance by 91%. Adenine feeding also significantly elevated the plasma concentration of inflammatory cytokines (plasma tumor necrosis factor-alpha, interleukin-1beta and transforming growth factor beta-1) and significantly reduced antioxidant indices (catalase, glutathione reductase and superoxide dismutase). Histopathologically, adenine caused renal fibrosis, inflammation and atrophy. When given concomitantly with adenine, sitagliptin ameliorated all the measured adenine-induced physiological and biochemical changes but not the histopathological changes. Sitagliptin (10 mg/kg/day) reduced plasma urea and creatinine by 32% and 25% respectively and increased creatinine clearance by 248%. These findings suggest a renoprotective action of sitagliptin on adenine-induced CKD.

Topics: Adenine; Animals; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Protective Agents; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sitagliptin Phosphate

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.

Topics: Angiotensin I; Angiotensin II; Animals; Anti-Inflammatory Agents; Antioxidants; Blood Pressure; Body Weight; Cardiotonic Agents; Diastole; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Kidney; Kidney Function Tests; Male; Myocardium; Peptide Fragments; Peptidyl-Dipeptidase A; Rats, Wistar; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sitagliptin Phosphate; Up-Regulation; Ventricular Remodeling

To estimate the proportion of patients with moderate to severe chronic kidney disease (CKD) whose initial dipeptidyl-peptidase-4 inhibitor (DPP4-i) dosage was concordant with prescribing information (label) recommendations in the United States.. Adult patients with type 2 diabetes mellitus (T2DM) who initiated a DPP4-i (linagliptin, sitagliptin, saxagliptin) between 1 January 2011 and 30 June 2014 were identified using electronic medical records and administrative claims, with index date being the date of first observed DPP4-i treatment. Patients were required to have chronic kidney disease (CKD) stage 3b, 4 or 5 (estimated Glomerular Filtration Rate [eGFR] value <45 ml/min/1.73 m. Of the 492 patients (323 sitagliptin, 57 saxagliptin, 112 linagliptin), 36.2% were prescribed doses that were not concordant with label recommendations (44.9% for sitagliptin, 57.9% for saxagliptin and 0% for linagliptin [which does not require dosage adjustment]). Concordant patients were slightly older (mean age 71 years vs. 68, p = .01) but had similar gender distribution (55% vs. 60% female, p = .31) compared to those who were not concordant. They had lower general health status (Charlson Comorbidity Score 2.6 vs. 2.2, p = .03), and had similar pre-index all-cause total costs ($25,245 vs. $21,972, p = .68) and lower pre-index T2DM-related costs ($1618 vs. $1922, p = .05).. More than a third of DPP4-i patients with CKD stage 3b or higher were prescribed doses not concordant with DPP4-i label dosage recommendations.

Topics: Adamantane; Aged; Aged, 80 and over; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sitagliptin Phosphate

Chronic kidney diseases are characterized by renal fibrosis with excessive matrix deposition, leading to a progressive loss of functional renal parenchyma and, eventually, renal failure. Renal microcirculation lesions, including the phenotypic conversion of vascular cells, contribute to renal fibrosis. Here, renal microcirculation lesions were established with monocrotaline (MCT, 60 mg/kg). Sitagliptin (40 mg/kg/d), a classical dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the renal microcirculation lesions by inhibiting glomerular tuft hypertrophy, glomerular mesangial expansion, and microvascular thrombosis. These effects of sitagliptin were mediated by glucagon-like peptide-1 receptor (GLP-1R), since they were blocked by the GLP-1R antagonist exendin-3 (Ex-3, 40 ug/kg/d). The GLP-1R agonist liraglutide showed a similar renal protective effect in a dose-independent manner. In addition, sitagliptin, as well as liraglutide, alleviated the MCT-induced apoptosis of renal cells by increasing the expression of survival factor glucose-regulated protein 78 (GRP78), which was abolished by the GLP-1R antagonist Ex-3. Sitagliptin and liraglutide also effectively ameliorated the conversion of vascular smooth muscle cells (SMCs) from a synthetic phenotype to contractile phenotype. Moreover, sitagliptin and liraglutide inhibited endothelial-mesenchymal transition (EndMT) via downregulating transforming growth factor-

Topics: Animals; Dipeptidyl-Peptidase IV Inhibitors; Fibrosis; Glomerular Mesangium; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Microcirculation; Monocrotaline; Rats; Rats, Sprague-Dawley; Renal Insufficiency, Chronic; Sitagliptin Phosphate

Limited data are available about the cardiovascular (CV) safety and efficacy of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in ischemic stroke patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Ischemic stroke patients with T2DM and CKD were selected from the Taiwan National Health Insurance Research Database (NHIRD) from March 1, 2009 to December 31, 2011. A total of 1375 patients were divided into 2 age- and gender-matched groups: patients who received sitagliptin (n = 275; 20%) and those who did not (n = 1,100). Primary major adverse cardiac and cerebrovascular events (MACCE), including ischemic stroke, hemorrhagic stroke, myocardial infarction (MI), or CV death, were evaluated. During a mean 1.07-year follow-up period, 45 patients (16.4%) in the sitagliptin group and 165 patients (15.0%) in the comparison group developed MACCEs (Hazard ratio [HR] 1.05; 95% confidence interval [CI], 0.75-1.45). Compared to the non-sitagliptin group, the sitagliptin group had a similar risk of ischemic stroke (HR 0.82; 95% CI, 0.51-1.32.), hemorrhagic stroke (HR 1.50; 95% CI, 0.58-3.82), MI (HR 1.14; 95% CI, 0.49-2.65), and CV mortality (HR 1.06; 95% CI, 0.61-1.85). The use of sitagliptin in recent ischemic stroke patients with T2DM and CKD was not associated with increased or decreased risk of adverse CV events.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Renal Insufficiency, Chronic; Risk Factors; Sitagliptin Phosphate; Stroke; Taiwan

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Myocardial Infarction; Renal Insufficiency, Chronic; Sitagliptin Phosphate

The cardiovascular safety and efficacy of sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, in type 2 diabetic patients with chronic kidney disease (CKD) after acute myocardial infarction (AMI) are unclear.. We analyzed data from the Taiwan National Health Insurance Research Database between March 1st, 2009 and December 31st, 2011. A total of 1025 AMI patients with diabetes with chronic kidney disease were selected as the study cohort. The study evaluated the cardiovascular safety and efficacy of sitagliptin by comparing 205 subjects (20%) who use sitagliptin to 820 matched subjects (80%) who do not. The primary outcomes included myocardial infarction, ischemic stroke or cardiovascular death.. Primary composite outcomes occurred in 54 patients in the sitagliptin group (26.3%) and in 164 patients in the comparison group (20.0%) (HR, 1.32; 95% CI, 0.97-1.79; P=0.079) during the mean follow-up of 1.02years (SD=0.71years). The sitagliptin group had similar risks of ischemic stroke, all-cause mortality or hospitalization for heart failure (HF) compared to the non-sitagliptin group (P=0.938, 0.523 and 0.795 respectively). However, sitagliptin use was associated with increased risks of recurrent myocardial infarction (HR, 1.73; 95% CI, 1.15-2.58; P=0.008) and percutaneous coronary revascularization (HR, 1.43; 95% CI, 1.04-1.95; P=0.026).. Among type 2 diabetic patients with CKD after AMI, the use of sitagliptin was not associated with an increased risk of cardiovascular death, ischemic stroke or hospitalization for HF but was associated with increased risks of recurrent MI and percutaneous coronary revascularization.

Topics: Aged; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Male; Middle Aged; Myocardial Infarction; Patient Discharge; Population Surveillance; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Taiwan; Treatment Outcome