Effects of Dipeptidyl Peptidase-4 Inhibitor and Angiotensin-Converting Enzyme Inhibitor on Experimental Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and worldwide. Proteinuria is a major marker of the severity of injury. Dipeptidyl peptidase-4 inhibitor (DPP-4I) increases incretin-related insulin production and is, therefore, used to treat diabetes. We investigated whether DPP4I could have direct effect on kidney independent of its hypoglycemic activity. We, therefore, tested the effects of DPP4I with or without angiotensin-converting enzyme inhibitor (ACEI) on the progression of diabetic nephropathy and albuminuria in a murine model of DKD. eNOS-/-db/db mice were randomized to the following groups at age 10 weeks and treated until sacrifice: baseline (sacrificed at week 10), untreated control, ACEI, DPP4I, and combination of DPP4I and ACEI (Combo, sacrificed at week 18). Systemic parameters and urine albumin-creatinine ratio were assessed at baseline, weeks 14, and 18. Kidney morphology, glomerular filtration rate (GFR), WT-1, a marker for differentiated podocytes, podoplanin, a marker of foot process integrity, glomerular collagen IV, and alpha-smooth muscle actin were assessed at the end of the study. All mice had hyperglycemia and proteinuria at study entry at week 10. Untreated control mice had increased albuminuria, progression of glomerular injury, and reduced GFR at week 18 compared with baseline. DPP4I alone reduced blood glucose and kidney DPP-4 activity but failed to protect against kidney injury compared with untreated control. ACEI alone and combination groups showed significantly reduced albuminuria and glomerular injury, and maintained GFR and WT-1+ cells. Only the combination group had significantly less glomerular collagen IV deposition and more podoplanin preservation than the untreated control. DPP-4I alone does not decrease the progression of kidney injury in the eNOS-/-db/db mouse model, suggesting that targeting only hyperglycemia is not an optimal treatment strategy for DKD. Combined DPP-4I with ACEI added more benefit to reducing the glomerular matrix.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

Dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor additively ameliorate hepatic steatosis through different mechanisms of action in high-fat diet-fed mice.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice. METHOD: C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated. RESULTS: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups. CONCLUSION: The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis.

Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial.

AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.

Acute and Chronic Exposure to Linagliptin, a Selective Inhibitor of Dipeptidyl Peptidase-4 (DPP-4), Has an Effect on Dopamine, Serotonin and Noradrenaline Level in the Striatum and Hippocampus of Rats.

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters-dopamine, serotonin and noradrenaline-and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices.

Incident and recurrent hypoglycaemia with linagliptin and glimepiride over a median of 6 years in the CAROLINA cardiovascular outcome trial.

AIM: The CAROLINA trial established non-inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre-specified and post-hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA. MATERIALS AND METHODS: Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1-4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator-reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored. RESULTS: Over 6.3 years median follow-up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [-0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (-1.54 kg, [-1.80, -1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator-reported hypoglycaemia were 0.21 (0.19-0.24) and 0.12 (0.10-0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient-years with linagliptin versus glimepiride. These differences occurred during night-time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation. CONCLUSIONS: Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk.

Efficacy and safety of cetagliptin as monotherapy in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled phase 3 trial.

AIM: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. MATERIALS AND METHODS: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. RESULTS: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported. CONCLUSIONS: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet.

A randomized, double-blind, placebo controlled, phase 3 trial to evaluate the efficacy and safety of cetagliptin added to ongoing metformin therapy in patients with uncontrolled type 2 diabetes with metformin monotherapy.

AIM: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. METHODS: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once-daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24-week double-blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open-label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all-patients-treated population using an analysis of co-variance. RESULTS: After 24 weeks, both add-on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were -1.17 ± 0.794%, -1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment ß-function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. CONCLUSIONS: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy.

Overall and inter-individual effect of four different drug classes on soluble urokinase plasminogen activator receptor in type 1 and type 2 diabetes.

AIM: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. METHODS: We conducted post hoc analyses of a randomized, open-label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin-creatinine ratio ≥30 and ≤500 mg/g assigned to 4-week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4-week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR-reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated-measures linear mixed-effects models were employed. RESULTS: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best-performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best-performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best-performing drug and the other three was -19.7% (95% CI -23.1, -16.3; P < 0.001). CONCLUSIONS: We demonstrated no overall effect of 4-week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels.

Risk of Pancreatitis With Incretin Therapies Versus Thiazolidinediones in the Veterans Health Administration.

BACKGROUND: Incretin therapies, comprised of the dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been increasingly utilized for the treatment of type 2 diabetes (T2DM). Previous studies have conflicting results regarding risk of pancreatitis associated with these agents-some suggest an increased risk and others find no correlation. Adverse event reporting systems indicate that incretin therapies are some of the most common drugs associated with reports of pancreatitis. OBJECTIVES: This study aimed to compare the odds of developing pancreatitis in veterans with T2DM prescribed an incretin therapy versus thiazolidinediones (TZDs: pioglitazone and rosiglitazone) within the Veterans Health Administration (VHA). METHODS: This was a retrospective cohort study analyzing veterans with T2DM first prescribed an incretin therapy or a TZD between January 1, 2011, and December 31, 2021. A diagnosis of pancreatitis within 365 days of being prescribed either therapy was counted as a positive case. Data was collected and analyzed utilizing VA's Informatics and Computing Infrastructure (VINCI) and an adjusted odds ratio was calculated. RESULTS: The TZD cohort consisted of 42 912 patients compared with the incretin cohort of 304 811 patients. The TZD cohort had a pancreatitis incidence rate of 1.94 cases per 1000 patients. The incretin cohort had a incidence rate of 2.06 cases per 1000 patients. An adjusted odds ratio found no statistical difference of pancreatitis cases between the TZD and incretin cohorts (adjusted odds ratio [AOR] = 0.94, 95% CI [0.75, 1.18]). CONCLUSION AND RELEVANCE: This retrospective cohort study of national VHA data found a relatively low incidence of pancreatitis in both cohorts, and an adjusted odds ratio found no statistical difference of pancreatitis in patients prescribed an incretin therapy compared with a control group. This data adds to growing evidence that incretin therapies do not seem to be associated with an increased risk of developing pancreatitis.

Risk Assessment for Heart Failure in Patients with Type 2 Diabetes Mellitus Treated with Dipeptidyl Peptidase 4 Inhibitor Using a Large Claims Dataset.

Heart failure is a prevalent comorbidity in patients with diabetes mellitus (DM). However, it is unclear whether the risk factors for heart failure in DM patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are the same as those for the general population. In this study, we evaluated the factors of new-onset heart failure in working-age patients with diabetes who started DPP-4 inhibitor therapy. This study included 7938 working-age patients. The primary endpoint of the study was the proportion of patients developing heart failure within 12 months of starting DPP-4 inhibitor therapy, which was found to be 1.89% (n = 150). In these patients, risk factors of new-onset heart failure were aging, history of atrial fibrillation, and hypertension but not sex, smoking, high body mass index, weight gain of over 10 kg from 20 years of age, levels of low-density lipoprotein or glycated hemoglobin A1c (HbA1c), history of angina pectoris, myocardial infarction, and chronic kidney disease. We confirmed that cardiovascular comorbidities are risk factors for new-onset heart failure in patients with DM, while general risk factors are not. In conclusion, physicians and pharmacists need to carefully monitor working-age patients with cardiovascular history who start DPP-4 inhibitor therapy even if they do not exhibit general risk factors for heart failure.

SGLT2 Inhibitors and the Risk of Acute Kidney Injury in Older Adults With Type 2 Diabetes.

RATIONALE & OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been found to have many benefits for patients with type 2 diabetes. However, whether SGLT2 inhibitors increase the risk of acute kidney injury (AKI) remains unknown. We examined the association of AKI hospitalization with prior initiation of an SGLT2 inhibitor compared with initiation of a dipeptidyl peptidase 4 (DPP-4) inhibitor or a glucagon-like peptide 1 receptor agonist (GLP-1RA) among older adults with type 2 diabetes in routine practice. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: Older adults aged at least 66 years with type 2 diabetes enrolled in Medicare fee-for-service and who were new users of SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1RA agents in the interval from March 2013 to December 2017. EXPOSURES: New use of an SGLT2 inhibitor versus new use of a DPP-4 inhibitor or GLP-1RA. OUTCOME: The primary outcome was hospitalization for AKI, defined as a discharge diagnosis of AKI in the primary or secondary position. ANALYTICAL APPROACH: New users of SGLT2 inhibitors were matched at a 1:1 ratio to new users of DPP-4 inhibitors or GLP-1RAs using propensity scores in 2 pairwise comparisons. Cox proportional hazards regression models generated hazard ratios (HRs) with 95% CIs in propensity score-matched groups. RESULTS: Totals of 68,130 and 71,477 new users of SGLT2 inhibitors were matched to new users of DPP-4 inhibitors or GLP-1RAs, respectively. Overall, the mean age of study participants was 72 years. The risk of AKI was lower in the SGLT2 inhibitor group than in the DPP-4 inhibitor group (HR, 0.71 [95% CI, 0.65-0.76]) or the GLP-1RA group (HR, 0.81 [95% CI, 0.75-0.87]). LIMITATIONS: Residual confounding and lack of laboratory data. CONCLUSIONS: Among older adults with type 2 diabetes, initiation of an SGLT2 inhibitor was associated with a reduced risk of AKI compared with initiation of a DPP-4 inhibitor or a GLP-1RA.

The risk of incident atrial fibrillation in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors: a nationwide cohort study.

BACKGROUND: Although a few meta-analyses were conducted to compare the risk of incident atrial fibrillation (AF) between sodium-glucose cotransporter-2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and other anti-hyperglycemic agents using indirect or direct comparison, the above analyses showed conflicting results with each other. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i, GLP-1RA, and dipeptidyl peptidase-4 inhibitor (DPP4i) among a large longitudinal cohort of diabetic patients. METHODS: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, a total of 344,893, 44,370, and 393,100 consecutive patients with type 2 diabetes without preexisting AF receiving GLP-1RA, SGLT2i, and DPP4i, respectively, were enrolled from May 1, 2016, to December 31, 2019. We used 1:1 propensity score matching (PSM) to balance covariates across paired study groups. Patients were followed from the drug index date until the occurrence of AF, death, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. RESULTS: After PSM, there were 245,442, 43,682, and 39,190 paired cohorts of SGLT2i-DPP4i, SGLT2i-GLP-1RA, and GLP-1RA-DPP4i, respectively. SGLT2i treatment was associated with lower risk of new-onset AF in participants with type 2 diabetes compared with either DPP4i [hazard ratio (HR):0.90; 95% confidential interval (CI) 0.84-0.96; P = 0.0028] or GLP-1RA [HR 0.74; 95% CI 0.63-0.88; P = 0.0007] treatment after PSM. There was no difference in the risk of incident AF between GLP-1RA and DPP4i users [HR 1.01; 95% CI 0.86-1.19; P = 0.8980]. The above findings persisted among several important subgroups. Dapagliflozin was specifically associated with a lower risk of new-onset AF compared with DPP4i (P interaction = 0.02). CONCLUSIONS: Compared with DPP4i, SGLT2i but not GLP-1RA was associated with a lower risk of incident AF in patients with type 2 diabetes.

The impact of oral hypoglycemics and statins on outcomes in myelodysplastic syndromes.

Observational studies suggest an anti-neoplastic effect associated with statins, metformin, and dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. We linked the Ontario subset of a prospective Canadian myelodysplastic syndromes (MDS) registry with provincial administrative databases. We assessed the impact of statin/oral hypoglycemic medication exposure on overall survival (OS) using Cox regression analysis, controlling for comorbidities and sociodemographic factors. Five hundred thirty-three patients aged ≥ 66 years were included: 49.3% used statins, 18.9% used metformin, 9.0% used sulfonylureas, and 6.4% used DPP4i. Three hundred ninety-five patients were lower-risk based on the International Prognostic Scoring System. On univariate analysis, we identified a marginal improvement in OS in the lower-risk group using DPP4i (HR 0.98, 95% CI 0.95-1.00, P = 0.05), while there was no impact on mortality for higher-risk DPP4i users (HR 1.03, CI 0.99-1.07, P = 0.21). There was no mortality difference for statins (HR 1.00, CI 1.00-1.01, P = 0.93), metformin (HR 1.00, CI 0.99-1.01, P = 0.81), or sulfonylureas (HR 1.00, CI 0.99-1.02, P = 0.43) in the entire cohort, as well as when stratified into lower/higher-risk groups. On multivariable analysis in the lower-risk group, there was no association between DPP4i and OS (HR 0.98, CI 0.95-1.00, P = 0.06). Prospective studies with larger cohorts of patients and longer follow-up are required to further study the impact of DPP4i in MDS.

Long-term clinical outcomes of oral antidiabetic drugs as fixed-dose combinations: A nationwide retrospective cohort study.

AIM: To compare treatment patterns and clinical outcomes of single-pill fixed-dose combination (FDC) and two-pill combination (TPC) therapies using real-world data. METHODS: We conducted a nationwide retrospective cohort study using South Korea's healthcare database (2002-2015). We identified two cohorts of incident patients with type 2 diabetes who initiated FDC or TPC therapy within 4 months of their first prescription for metformin or sulphonylurea. We examined persistence and adherence patterns and the clinical outcome of a composite endpoint of death or hospitalization for acute myocardial infarction, heart failure or stroke and compared the differences in treatment patterns and clinical outcomes using Cox models. RESULTS: Of 5143 and 10 973 patients who initiated FDC and TPC therapy, respectively, we identified 5143 patient pairs after propensity score matching. The FDC group exhibited greater median time to treatment discontinuation (163 vs. 146 days), and proportion of days covered at 12 months (mean 0.60 vs. 0.57, P < .0001) and at 24 months (0.53 vs. 0.51, P = .014) than the TPC group. The FDC group, compared with the TPC group, had reduced risks of the composite clinical outcome (hazard ratio 0.86, 95% confidence intervals 0.77-0.97) and hospitalization for stroke (0.80, 0.67-0.96). CONCLUSION: FDC therapy may provide favourable cardiovascular benefits, especially reducing the risk of hospitalization for stroke, and has better medication adherence among patients with type 2 diabetes.

Revisiting 'intensive' blood glucose control: A causal directed acyclic graph-guided systematic review of randomized controlled trials.

AIM: To clarify the importance of HbA1c reduction and antidiabetic drug use in preventing major adverse cardiovascular events (MACE) for patients with type 2 diabetes (T2D). MATERIALS AND METHODS: We conducted an updated systematic review of contemporary large randomized controlled trials assessing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk in adult T2D patients. Mixed-effects meta-regression was performed to examine the associations of HbA1c reduction with subsequent risk of macrovascular and microvascular events. We evaluated the potential mediating role of HbA1c reduction in the relationship between antidiabetic drugs and MACE. RESULTS: Eighteen placebo-controlled trials comprising 155 610 participants were included. The effects of treatment differed among antidiabetic drug classes for most adverse outcomes with high heterogeneity (I2 : 63.7%-95.8%). Mean HbA1c reduction was lowest with dipeptidyl peptidase-4 inhibitors (0.30%), followed by sodium-glucose co-transporter-2 inhibitors (0.46%), and was highest with glucagon-like peptide-1 receptor agonists (0.58%) and thiazolidinediones (0.60%). Lower relative risks of MACE were significantly associated with larger reductions in achieved HbA1c (ß -0.3182; 95% CI: -0.5366 to -0.0998; P = .0043), even after adjusting for drug classes. When considering HbA1c lowering as a mediator to be controlled, beneficial effects owing to specific antidiabetic treatment for MACE were not observed (χ2  = 1.4494; P = .6940). The proportion mediated by HbA1c reduction was 50.0%-63.5% for these antidiabetic agents. CONCLUSIONS: The main benefits of antidiabetic agents might result from the reduction in blood sugar levels and are generally independent of drugs used. Risk reduction in MACE was proportional to the magnitude of HbA1c decrease conferred by antidiabetic agents with less hypoglycaemic hazard.

A randomized clinical trial of the efficacy and safety of sitagliptin as initial oral therapy in youth with type 2 diabetes.

OBJECTIVE: To assess the efficacy and safety of DPP-4 inhibition with sitagliptin in youth with type 2 diabetes (T2D). STUDY DESIGN: This was a 54-week, double-blind, randomized, controlled clinical trial evaluating the safety and efficacy of DPP-4 inhibition with sitagliptin 100 mg once daily as initial oral therapy in youth with T2D. The 190 participants, aged 10-17 years, had HbA1c 6.5%-10% (7.0%-10% if on insulin). All were negative for pancreatic autoantibodies and overweight/obese at screening or diagnosis. The trial was placebo controlled for the first 20 weeks, after which metformin replaced placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean ± SD HbA1c = 7.5% ± 1.0, BMI percentile = 97.1% ± 6.8, age = 14.0 years ± 2.0 [57.4% <15], 60.5% female). At Week 20, least squares mean changes from baseline in HbA1c were -0.01% (sitagliptin) and 0.18% (placebo); between-group difference (95% CI) = -0.19% (-0.68, 0.30), p = 0.448. At Week 54, the changes in HbA1c were 0.45% (sitagliptin) and -0.11 (placebo/metformin). There were no notable between-group differences in the adverse event profiles through Week 54. CONCLUSIONS: DPP-4 inhibition with sitagliptin did not provide significant improvement in glycemic control. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01485614; EudraCT: 2011-002528-42).

Efficacy and safety of the addition of sitagliptin to treatment of youth with type 2 diabetes and inadequate glycemic control on metformin without or with insulin.

OBJECTIVE: To assess the efficacy and safety of sitagliptin in youth with type 2 diabetes (T2D) inadequately controlled with metformin ± insulin. STUDY DESIGN: Data were pooled from two 54-week, double-blind, randomized, placebo-controlled studies of sitagliptin 100 mg daily or placebo added onto treatment of 10- to 17-year-old youth with T2D and inadequate glycemic control on metformin ± insulin. Participants (N = 220 randomized and treated) had HbA1c 6.5%-10% (7.0%-10% if on insulin), were overweight/obese at screening or diagnosis and negative for pancreatic autoantibodies. The primary endpoint was change from baseline in HbA1c at Week 20. RESULTS: Treatment groups were well balanced at baseline (mean HbA1c = 8.0%, BMI = 30.9 kg/m2 , age = 14.4 years [44.5% <15], 65.9% female). The dose of background metformin was >1500 mg/day for 71.8% of participants; 15.0% of participants were on insulin therapy. At Week 20, LS mean changes from baseline (95% CI) in HbA1c for sitagliptin/metformin and placebo/metformin were -0.58% (-0.94, -0.22) and -0.09% (-0.43, 0.26), respectively; difference = -0.49% (-0.90, -0.09), p = 0.018; at Week 54 the LS mean (95% CI) changes were 0.35% (-0.48, 1.19) and 0.73% (-0.08, 1.54), respectively. No meaningful differences between the adverse event profiles of the treatment groups emerged through Week 54. CONCLUSIONS: These results do not suggest that addition of sitagliptin to metformin provides durable improvement in glycemic control in youth with T2D. In this study, sitagliptin was generally well tolerated with a safety profile similar to that reported in adults. (ClinicalTrials.gov: NCT01472367, NCT01760447; EudraCT: 2011-002529-23/2014-003583-20, 2012-004035-23).

Disposition study of the novel dipeptidyl peptidase 4 inhibitor cetagliptin in rats.

Dipeptidyl peptidase-4 (DPP-4) inhibitor is a class of oral antihyperglycemic agents and therapeutic approach for type 2 diabetes. Cetagliptin is a novel oral and selective DPP-4 inhibitor and developed as a promising candidate for treatment of type 2 diabetes mellitus.This study aimed to evaluate the metabolism and excretion of cetagliptin in Sprague-Dawley (SD) rats, and to detect and identify metabolites of cetagliptin.The SD rats were administered with a single oral dose of 6 mg/kg with approximately 100 µCi of [14C] cetagliptin. The mean total recovery of radioactivity was 90.20% within 168h in SD rats excreta. Cetagliptin was the major radioactive component in SD rats plasma, urine and eliminated primarily by faecal excretion. The recovery of cetagliptin in urine and feces was 25.15% and 13.85% of the dose, respectively. Cetagliptin was well absorbed after oral administration in SD rats based on the total recovery of radioactivity in BDC SD rats bile and urine.Six major metabolites were observed and identified in SD rats, comprising 0.20 to 4.53% of total plasma AUC. These major metabolites were the hydroxylated, N-sulphate and N-carbamoyl glucuronic acid conjugates of the cetagliptin, two metabolites formed by glucuronide of a hydroxylated metabolite.

The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model.

The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1ß (IL-1ß) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)-dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.