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1. The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50μCi [14C] cetagliptin.2. The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and feces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.3. Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulfate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and feces at low levels, except that metabolite M640B was not detected in feces. All metabolites were observed with < 10% of parent compound systemic exposure after oral administration.

Aim: To determine the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on postprandial glomerular hyperfiltration compared with the sulphonylurea glimepiride in adults with type 2 diabetes (T2D). Materials and Methods: In this predefined substudy within a randomized, double-blind, parallel-group, intervention trial, overweight people with T2D without renal impairment were treated with once-daily linagliptin 5 mg (N = 10) or glimepiride 1 mg (N = 13) as an add-on to metformin for 8 weeks. After a standardized liquid protein-rich meal, the glomerular filtration rate (GFR) and effective renal plasma flow were determined by inulin and para-aminohippuric acid clearance, respectively, based on timed urine sampling. Intrarenal haemodynamics were estimated using the Gomez equations. Glucoregulatory/vasoactive hormones, urinary pH and fractional excretions (FE) of sodium, potassium and urea were measured. Results: Compared with glimepiride, linagliptin increased the postprandial filtration fraction (FF; mean difference 2.1%-point; P =.016) and estimated glomerular hydraulic pressure (mean difference 3.0 mmHg; P =.050), and tended to increase GFR (P =.08) and estimated efferent renal arteriolar resistance (RE; P =.08) from baseline to week 8. No differences in FE were noted. Glimepiride reduced HbA1c more than linagliptin (mean difference −0.40%; P =.004), without between-group differences in time-averaged postprandial glucose levels. In the linagliptin group, change in FF correlated with change in mean arterial pressure (R = 0.807; P =.009) and time-averaged mean glucagon (R = 0.782; P =.008), but not with changes in glucose, insulin, intact glucagon-like peptide-1, renin or FENa. Change in glucagon was associated with change in RE (R = 0.830; P =.003). Conclusions: In contrast to our hypothesis, compared with glimepiride, linagliptin does not reduce postprandial hyperfiltration, yet appears to increase FF after meal ingestion by increasing blood pressure or RE.

Cystic fibrosis-related diabetes (CFRD) affects 40-50% of adult patients with cystic fibrosis. Insulin therapy is recommended but there are therapeutic challenges, particularly risk of hypoglycemia and aversion of some patients to injectables. An oral incretin-based therapy using a DPP-4i (dipeptidyl peptidase-4 inhibitor), may be a reasonable option, especially in the early stage of the disease. The effect of chronic incretin-based therapy on CFRD is unknown. Here is a report of 3 cases of CFRD patients treated with sitagliptin and the response to therapy over a period of 5-10 years. An effective glycemic control was demonstrated in all the patients, at least during the first 5 years of sitagliptin treatment, and the benefit persisted for a decade in two of them. The secondary failure of the DPP-4i occurred in a CFRD patient with a phenotype resembling type 2 diabetes. A DPP-4i may have an important role in the management of CFRD.

Background and ObjectiveTo investigate whether dipeptidyl peptidase-4 inhibitors (DPP-4i) have beneficial effects on amyloid aggregation and longitudinal cognitive outcome in diabetic Alzheimer disease–related cognitive impairment (ADCI).MethodsWe retrospectively reviewed 282 patients with ADCI with positive 18F-florbetaben amyloid PET images. Patients were classified into 3 groups according to prior diagnosis of diabetes and DPP-4i use: diabetic patients being treated with (ADCI-DPP-4i+, n = 70) or without DPP-4i (ADCI-DPP-4i−, n = 71) and nondiabetic patients (n = 141). Multiple linear regression analyses were performed to determine intergroup differences in global and regional amyloid retention using standardized uptake value ratios calculated from cortical areas. We assessed longitudinal changes in Mini-Mental State Examination (MMSE) score using a linear mixed model.ResultsThe ADCI-DPP-4i+ group had lower global amyloid burden than the ADCI-DPP-4i− group (β = 0.075, SE = 0.024, p = 0.002) and the nondiabetic ADCI group (β = 0.054, SE = 0.021, p = 0.010) after adjusting for age, sex, education, cognitive status, and APOE ε4 carrier status. The ADCI-DPP-4i+ group had lower regional amyloid burden in temporo-parietal areas than either the ADCI-DPP-4i− group or the nondiabetic ADCI group. The ADCI-DPP-4i+ group showed a slower longitudinal decrease in MMSE score (β = 0.772, SE = 0.272, p = 0.005) and memory recall subscore (β = 0.291, SE = 0.116, p = 0.012) than the ADCI-DPP-4i− group.DiscussionThese findings suggest that DPP-4i use is associated with low amyloid burden and favorable long-term cognitive outcome in diabetic patients with ADCI.

Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

Aim: \ud To assess if sodium-glucose co-transporter-2 inhibitors (SGLT2is) reduce the risk of all-cause mortality, cardiovascular death and hospitalization for heart failure (HF) or chronic kidney disease (CKD) to a greater extent than dipeptidyl peptidase-4 inhibitors (DPP4is) in people with type 2 diabetes (T2D) with or without established cardiovascular and/or renal disease (CVRD).\ud \ud Methods: \ud This retrospective cohort study propensity-matched 24 438 patients receiving an SGLT2i 1:1 to a patient receiving a DDP4i, stratified based on the presence of CVRD. The primary outcomes were the time to each of the following: all-cause mortality, cardiovascular death or hospitalization for HF, myocardial infarction, stroke and CKD.\ud \ud Results: \ud Overall, SGLT2is were associated with reductions in all-cause mortality, cardiovascular mortality, hospitalization for HF and hospitalization for CKD compared with DPP4is. In patients with no CVRD history, SGLT2is were associated with reductions in all-cause mortality (HR 0.71, 95% CI 0.57-0.88; P = .002), hospitalization for HF (HR 0.76, 95% CI 0.59-0.98; P = .035) and hospitalization for CKD (HR 0.75, 95% CI 0.63-0.88; P < .001). In patients with established cardiovascular disease (CVD) or at high risk, SGLT2is were associated with reductions in all-cause mortality (HR 0.69, 95% CI 0.59-0.82; P < .001), cardiovascular mortality (HR 0.76, 95% CI 0.62-0.95; P = .014), hospitalization for HF (HR 0.73, 95% CI 0.63-0.85; P < .001), hospitalization for stroke (HR 0.75, 95% CI 0.59-0.94; P = .013) and hospitalization for CKD (HR 0.49, 95% CI 0.43-0.54; P < .001).\ud \ud Conclusion: \ud There was consistency across subgroups and sensitivity analyses. SGLT2is were associated with a reduced risk of all-cause mortality and hospitalization for HF and CKD compared with DPP4-is, highlighting the need to introduce SGLT2is early in the management of patients with T2D.

AIMS: To improve glycemic variability (GV) is crucial in the management of multiple daily insulin (MDI) treatment in diabetes. To evaluate the GV improvement in MDI treated type 2 diabetes (T2D) with low-dose metformin 750 mg/day (LMET), which was popular in the clinical practice in Japan, we compared the effect of adding vildagliptin 100 mg/day (LMET + DPP4i treatment) or increased metformin dose to 1500 mg/day (HMET treatment), in the setting of continuous glucose monitoring (CGM) analysis. MATERIALS AND METHODS: Single-center, open-label, 12 weeks—two period cross-over design. Twenty T2D with inadequately controlled (7.0%

Aims/Introduction This study investigated the impact of the dipeptidyl peptidase‐4 inhibitor, anagliptin, on hepatic insulin clearance (HIC) in Japanese type 2 diabetes patients and explored its relationship to glycemic status. Materials and Methods Data on 765 participants in anagliptin phase 2 and 3 studies were analyzed. Adjusted changes in variables during 12 weeks of anagliptin therapy were compared with a placebo. HIC was calculated as the ratio, C‐peptide area under the curve 0–120 min to insulin area under the curve 0–120 min, after a meal tolerance test. To explore the effects of baseline HIC levels on variables, participants receiving anagliptin were divided according to quartiles of baseline HIC. Furthermore, multivariate analysis investigated the association between baseline HIC levels and glycemic status. Results Anagliptin significantly reduced glycosylated hemoglobin levels (P, Anagliptin affected hepatic insulin clearance (HIC) levels according to HIC baseline levels. Anagliptin reduced HIC in the relatively higher HIC group (baseline HIC ≥median). Anagliptin increased HIC in the relatively lower HIC group (baseline HIC

Background Incretins are a group of glucose-lowering drugs with favourable cardiovascular (CV) effects against neoatherosclerosis. Incretins' potential effect in stent failure is unknown. The aim of this study is to determine if incretin treatment decreases the risk of stent-thrombosis (ST), and/or in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) with implanted drug-eluting stents (DES). Methods Observational study including all diabetes patients who underwent PCI with DES in Sweden from 2007 to 2017. By merging 5 national registers, the information on patient characteristics, outcomes and drug dispenses was retrieved. Cox regression analysis with estimated hazard ratios (HRs) adjusted for confounders with 95% confidence intervals (CIs) was used to analyse for the occurrence of ST/ISR, and major adverse cardiovascular events (MACE). A subgroup analysis for the type of incretin treatment was performed. Results In total 18,505 diabetes patients (30% women) underwent PCI, and 32,463 DES were implanted. Of those, 10% (3449 DES in 1943 patients) were treated with incretins. Median follow-up time was 995 days (Control Group) vs. 771 days (Incretin Group). No significant difference in the risk of ST/ISR was found neither for the main study group (HR:0.98 95% CI:0.80–1.19) nor for the subgroups. No reduction of the risk of MACE (HR:0.96 95% CI:0.88–1.06) was observed. There was a 26% lower risk for CV death in favour of incretin treated patients (HR:0.74 95% CI:0.57–0.95). Conclusion In diabetes patients who underwent PCI incretin treatment was not associated with lower risk of stent failure, but with lower risk of CV death.

Background and aims This study aims to synthesize evidence on dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in COVID-19 patients and factors affecting it. Methods We performed a systematic literature search from PubMed, Scopus, and Embase databases from inception of databases up until 7 March 2021. Studies that met all of the following criteria were included: 1) observational studies or randomized controlled trials that report COVID-19 patients, 2) reporting DPP-4 inhibitor use, 3) mortality, and 4) mortality based on DPP-4 inhibitor use. The exposure was DPP-4 inhibitor, defined as DPP-4 inhibitor use that started prior to COVID-19 hospitalization. The control group was patients with no exposure to DPP-4 inhibitor. The outcome was mortality. The pooled effect estimate was reported as risk ratio (RR). Results There were 4,477 patients from 9 studies in this systematic review and meta-analysis. 31% of (15%, 46%) the patients use DPP-4 inhibitor. Mortality occurs in 23% (15%, 31%) of the patients. DPP-4 inhibitor was associated with lower mortality in patients with COVID-19 (RR 0.76 [0.60, 0.97], p = 0.030, I2: 44.5%, p = 0.072). Meta-regression analysis showed that the association between DPP-4 inhibitor and mortality was significantly affected by metformin (RR 1.02 [1.00, 1.04], p = 0.048) and angiotensin converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) use (RR 1.04 [1.01, 1.07], p = 0.006), but not age (p = 0.759), sex (reference: male, p = 0.148), and hypertension (p = 0.218). Conclusion DPP-4 inhibitor use was associated with lower mortality in COVID-19 patients, and the association was weaker in patients who were also taking metformin and/or ACE inhibitors.

Objectives Wolfram syndrome (WS) is a rarely seen autosomal recessive multisystem neurodegenerative disorder caused by mutations in the WFS1 gene. Case Presentation Three sisters with WS had diabetes mellitus (DM) at 4 years of age and optic atrophy. In addition, the first case had hearing impairment, and the second case had diabetes insipidus and urinary incontinence. Linagliptin was administered to the first case as add-on therapy to intensive insulin treatment 15 years after the onset of DM, and her insulin need showed a dramatic decrease. The third case had a remission phase one month after the onset of DM. Conclusions Even in cases with the same mutation, symptoms and findings may widely vary in WS. Remission of diabetes has rarely been reported in WS. Also, this report describes the first trial of a dipeptidyl peptidase-4 inhibitor in a patient with WS which provided a decrease in exogenous insulin need.

Background: No meta-analysis has holistically analysed and summarised the efficacy and safety of gemigliptin in type 2 diabetes. The meta-analysis addresses this knowledge gap.Methods: Electronic databases were searched for randomised controlled trials (RCTs) involving diabetes patients receiving gemigliptin in the intervention arm and placebo/active comparator in the control arm. The primary outcome was change in haemoglobin A1c (HbA1c). The secondary outcomes were alterations in glucose, glycaemic targets, lipids, insulin resistance, and adverse events.Results: Data from 10 RCTs involving 1,792 patients were analysed. Four had an active control group (ACG), with metformin/dapagliflozin/sitagliptin/glimepiride as the active comparator; six had a passive control group (PCG), with placebo/rosuvastatin as controls. HbA1c reduction by gemigliptin at 24 weeks was comparable to ACG (mean difference [MD], 0.09%; 95% confidence interval [CI], –0.06 to 0.23; P=0.24; I2=0%; moderate certainty of evidence [MCE]), but superior to PCG (MD, –0.91%; 95% CI, –1.18 to –0.63); PI2=89%; high certainty of evidence [HCE]). Gemigliptin was superior to PCG regarding achieving HbA1c P=0.02; I2=74%; 24 weeks: OR, 4.48; 95% CI, 2.09 to 9.60; PI2=69%; HCE). Gemigliptin was comparable to ACG regarding achieving HbA1c P=0.77; I2=66%; MCE). Adverse events were similar between the gemigliptin and control groups (risk ratio [RR], 1.06; 95% CI, 0.82 to 1.36; P=0.66; I2=35%; HCE). The gemigliptin group did not have increased hypoglycaemia (RR, 1.19; 95% CI, 0.62 to 2.28; P=0.61; I2=19%; HCE).Conclusion: Gemigliptin has good glycaemic efficacy and is well-tolerated over 6 months of use.

Clinical trials are often performed to investigate the effects of various types of cardiometabolic therapies on cardiovascular surrogate markers, including vascular function and biomarkers. This study platform has the potential to provide information on the suspected actions of drugs and mechanistic insights into their prognostic impact. However, despite using the same class of drugs and similar study designs we are often faced with inconsistent and even conflicting results, possibly leading to some confusion in the clinical setting. When interpreting these results, it is important to investigate what caused the differences and carefully assess the information, taking into account the research situation and the patient population investigated. Using this approach, assessment of the impact on cardiovascular surrogate markers observed in clinical studies from multiple perspectives should help to better understand the potential cardiovascular effects. In this commentary we discuss how we should interpret the effects of cardiometabolic therapeutics on vascular surrogate markers, based on viewpoints learned from the results of clinical trials on dipeptidyl peptidase-4 inhibitors. This learning strategy could also be helpful for appropriate selection of drugs for evidence-based, patient-centric, tailored medication.

Background: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) and dipeptidyl peptidase 4 inhibitor (DPP4i) are oral hypoglycemic agents. Although SGLT2i has been shown having the beneficial effects on heart failure in basic and clinical studies, the combined effects of SGLT2i and DPP4i have not been established well. We investigated the effects of SGLT2i and DPP4i against diabetes mice model of myocardial ischemia-reperfusion injury. Methods: Streptozotocin-induced diabetic C57BL/6J mice were divided into control (vehicle), empagliflozin (30 mg/kg/day), linagliptin (3 mg/kg/day) and combination (30 mg/kg/day and 3 mg/kg/day, respectively) groups. After 7 days of drug administration, 30 min of myocardial ischemia was performed. We investigated body weight, heart weight, blood glucose, and cardiac functions by pressure-volume Millar catheter followed by 28 days of additional drug administration. Results: Blood glucose levels, body weight, and heart weight were not significantly different between the groups. In Millar catheter analysis, left ventricular volume at the peak left ventricular ejection rate which is one of the cardiac systolic parameters in combination group was significantly preserved than that in control (P = 0.036). The cardiac index in the combination group tended to be preserved compared to that in the control (P = 0.06). The pathological fibrotic area in the left ventricle in the combination group also tended to be smaller (P = 0.08). Conclusions: Combination therapy with linagliptin and empagliflozin preserved cardiac systolic function on the diabetes mice model of myocardial ischemia-reperfusion injury independent of blood glucose levels. Cardiol Res. 2021;12(2):91-97 doi: https://doi.org/10.14740/cr1194

In this study, we compared the efficacy of a dipeptidyl peptidase-4 inhibitor (DPP4i) to improve glucose control in patients with type 2 diabetes mellitus (T2DM) with or without Hashimoto's thyroiditis (HT). First, we compared the change in glycated hemoglobin (HbA1c) between the hypothyroid condition (before levothyroxine sodium hydrate [LT4] treatment) and euthyroid condition (after LT4 treatment when patients had achieved euthyroidism for at least six months) in patients with T2DM and HT. Next, we compared the change in HbA1c levels before and six months of DPP4i treatment in patients with T2DM with and without HT. In hypothyroid condition the change in HbA1c after six months of DPP4i treatment was 0.13% ± 0.86%. The change in HbA1c levels from when patients first achieved euthyroidism to after six months in the euthyroid condition was 0.26% ± 0.90%. DPP4i efficacy in patients with T2DM and HT was reduced compared to patients with T2DM but without HT (-0.40 ± 0.90 vs. -0.99 ± 0.5, p = 0.0032). These data suggest that hypothyroidism does not impact on DPP4i efficacy. However, the effect of DPP4i in patients with T2DM and HT was reduced compared to that in T2DM patients without HT. An estimation of thyroid function before prescribing DPP4i may be useful tool for predicting the efficacy of DPP4i, allowing the ruling out complications from HT.

Introduction: Dipeptidyl peptidase-4 (DPP-4) has been hypothesized to improve responsiveness to erythropoiesis-stimulating agent (ESA). We aimed to describe the trend in DPP-4 inhibitor prescription patterns and assess the association between DPP-4 inhibitor prescription and ESA hyporesponsiveness (eHypo) in Japanese hemodialysis (HD) patients with diabetes mellitus (DM). Methods: We analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study phase 4–6 (2009–2017) on patients with DM who underwent HD thrice per week for at least 4 months. The primary exposure of interest was having a DPP-4 inhibitor prescription. The primary analysis outcomes were a binary indicator of eHypo (mean hemoglobin 6,000 units/week over 4 months) and the natural log-transformed ESA resistance index (ERI). We used conditional logistic regression to compare within-patient changes in eHypo before and after initial DPP-4 inhibitor prescription. We used linear generalized estimating equation models to compare continuous ERI outcomes while accounting for within-patient repeated measurements with an exchangeable correlation structure. Results: There was a monotonic increase in DPP-4 inhibitor prescription according to study year up to 20% in 2017. Moreover, 12.8% of patients with a DPP-4 inhibitor prescription were ESA hyporesponsive before the initial DPP-4 inhibitor prescription. After DPP-4 inhibitor prescription, the odds of eHypo and mean log-ERI remained unchanged in the whole cohort of our study. The interaction analysis of DPP-4 inhibitor and sideropenia showed that DPP-4 inhibitors attenuated eHypo in the patients without iron deficiency. Conclusion: Our findings indicate a recent increase in DPP-4 inhibitor prescription among Japanese HD patients with DM. DPP-4 inhibitors could improve ERI in patients undergoing HD without iron deficiency.

Background and aims Case reports have described occurrence of rheumatoid arthritis (RA) after initiation of Dipeptidyl Peptidase-4 Inhibitors (DPP4i), suggesting a possible adverse effect of the medications. However, the findings from subsequent cohort studies suggest the opposite as they indicate that T2DM patients who used DPP4i tended to have a lower risk of RA. We aimed to investigate the association between use of DPP4i and incident RA in patients with type 2 diabetes mellitus (T2DM) using systematic review and meta-analysis. Methods Potentially eligible studies were identified from Medline and EMBASE databases from inception to May 2020 using search strategy that comprised of terms for “Dipeptidyl peptidase-4 inhibitor” and “Rheumatoid arthritis”. Eligible study must be cohort study consisting of one cohort of patients with T2DM who were DPP4i users and another cohort of comparators with T2DM who did not receive DPP4i. Then, the study must report effect estimates with 95% confidence intervals (95% CIs) comparing incident RA between DPP4i users versus comparators. Point estimates with standard errors retrieved from each study were combined together using the generic inverse variance method. Results A total of 709 articles were identified. After systematic review, four retrospective cohort studies met the eligibility criteria and were included into the meta-analysis. DPP4i users had a significantly lower risk of incident RA compared with comparators with the pooled hazard ratio of 0.72 (95% CI, 0.54–0.96; I2 75%). Conclusion This systematic review and meta-analysis found a significant association between DPP4i use and a lower risk of incident RA.

Aim To examine the real‐world cardiovascular effectiveness and safety associated with sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor compared with dipeptidyl peptidase‐4 (DPP‐4) inhibitor treatment in older adults with type 2 diabetes. Materials and Methods In this retrospective cohort study, older adults with type 2 diabetes (aged ≥65 years) were identified in the Korean National Health Insurance Service database from September 2014 to December 2016. In total, 408 506 new users of an SGLT2 inhibitor or DPP‐4 inhibitor were propensity score matched. Cox regression was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for outcomes of interest: hospitalization for heart failure (HHF), all‐cause death, myocardial infarction, stroke, diabetic ketoacidosis (DKA), bone fracture, severe hypoglycaemia, genital infection and urinary tract infection (UTI). Results Compared with DPP‐4 inhibitors, new users of SGLT2 inhibitors had a lower risk of HHF (HR 0.86; 95% CI 0.76‐0.97), all‐cause death (HR 0.85; 95% CI 0.75‐0.98) and stroke (HR 0.86; 95% CI 0.77‐0.97), but a similar risk of myocardial infarction (HR 0.95; 95% CI 0.77‐1.19). The risks of DKA, bone fracture and severe hypoglycaemia were similar between both groups, although genital infection (HR 2.44; 95% CI 2.22‐2.67) and UTI (HR 1.05; 95% CI 1.00‐21.11) were more frequent among new users of SGLT2 inhibitors compared with DPP‐4 inhibitors. Conclusion Our findings suggest that initiation of SGLT2 inhibitors offers cardiovascular disease protection and can be used safely in older adults with type 2 diabetes.

Diabetes, obesity and metabolism 23(2), 569-580 (2021). doi:10.1111/dom.14254, Published by Wiley-Blackwell, Oxford [u.a.]

Aim: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. Methods: PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin ( n =122) or sitagliptin ( n =128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. Results: Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P =0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P =0.07). Conclusions: PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.

Background. Several clinical trials have addressed the therapeutic strategy of adding dipeptidyl peptidase 4 (DPP-4) inhibitors to the treatment of type 2 diabetes mellitus (DM) inadequately controlled by insulin therapy. However, there is a high degree of heterogeneity in these studies, and the cause of which has not been identified. Methods. We conducted a meta-analysis of randomized controlled trials, which compared the efficacy and safety of adding DPP-4 inhibitors or placebo to insulin therapy; the level of hemoglobin A1c (HbA1c) in the patients was >7.0%, and the duration of treatment was ≥8 weeks. We focused on the mean changes in HbA1c from the baseline (ΔHbA1c) and the incidence of hypoglycemia. We assumed that five baseline parameters (HbA1c, fasting blood glucose, body mass index (BMI), duration of type 2 DM, and duration of treatment) could affect ΔHbA1c. Regarding the incidence of hypoglycemia, we suspected that the heterogeneity was caused by differences in the definition of hypoglycemia among the studies. Results. Data obtained from 11 studies ( n = 4654 patients) were included in the analysis. The mean ΔHbA1c between the DPP-4 inhibitor and placebo groups was -0.61% (95% confidence interval (CI): -0.74 to -0.48, I 2 = 73.4 % ). There was substantial heterogeneity among the 11 studies, but 74.1% of this variability was explained by the difference in BMI. The odds ratio for the incidence of hypoglycemia was 1.02 (95% CI: 0.74 to 1.42, I 2 = 63.8 % ), with substantial heterogeneity due to differences in the definition of hypoglycemia among the studies. There was no apparent effect of publication bias. Conclusions. The addition of DPP-4 inhibitors to insulin therapy for adult patients with type 2 DM can significantly reduce HbA1c levels without increasing the occurrence of hypoglycemia. BMI and hypoglycemia definition could explain the heterogeneity in the clinical trials. This trial is registered with PROSPERO #CRD42016035994.

Introduction Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed for type 2 diabetes (T2D) and their glycemic control effects are well studied. However, information regarding the effects of switching DPP-4 inhibitors is limited, especially in older patients. Research Design and Methods We investigated whether switching from linagliptin to teneligliptin decreases blood glucose in older (≥65 years) T2D patients. In total, 164 patients with T2D who switched from linagliptin to teneligliptin for >12 weeks were included and the primary outcome was glycemic changes. Results Switching from linagliptin to teneligliptin ameliorated fasting blood glucose (148.1 ± 47.1 to 139.6 ± 43.4 mg/dL), glycated hemoglobin (HbA1c; 7.9 ± 1.3 to 7.5 ± 1.2%), and postprandial blood glucose (224.8 ± 77.4 to 205.8 ± 70.8 mg/dL) levels (all P 8.0%) and chronic kidney disease (estimated glomerular filtration rate

Introduction No study has compared the effects of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) on patients’ quality-of-life (QOL). Methods We enrolled 253 drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM), randomly assigned them into a dapagliflozin (SGLT2i) group or DPP4i group in approximately 1:1 ratio, and monitored them for 24 weeks. The primary endpoint was the proportion of subjects indicating improvement in the “overall quality of life” domain of SHIELD-WQ-9 at week 24. Secondary endpoints included other domains of SHIELD-WQ-9, DTR-QOL, EQ-5D-5L, medication preference, medication adherence, diet therapy adherence, body weight, body mass index (BMI), abdominal circumference, HbA1c, and frequency of adverse events. Results The proportion of subjects indicating improvement in the “overall quality of life” domain of SHIELD-WQ-9 at week 24 was higher in the dapagliflozin group (28.4%) than in the DPP4i group (18.6%) (p = 0.08). The proportion of subjects indicating improvement in the “physical health” domain of SHIELD-WQ-9 at week 24 was significantly higher in the dapagliflozin group (42.2%) than in the DPP4i group (23.7%) (p = 0.004). Total scores and domain 1 scores of DTR-QOL showed greater improvement in the dapagliflozin group (14.3 ± 15.6 and 15.5 ± 20.8, respectively) than in the DPP4i group (10.2 ± 15.6 and 10.3 ± 19.5, respectively) (both p = 0.05). EQ-5D-5L scores had significantly improved in the DPP4i group (0.023 ± 0.088) (p = 0.005); the intergroup difference was not significant (p = 0.14). Body weight (p

The use of dipeptidyl peptidase-4 inhibitors (DPP4i) appears to be associated with a small but significantly elevated risk of bullous pemphigoid (BP). Although the pathogenic mechanism of DPP4i-associated BP remains unclear, this adverse event is reported with multiple gliptins, suggesting a class effect. However, previous studies from various countries showed that vildagliptin had been implicated in most cases. The aim of this study was to illustrate a case series of DPP4i-associated BP in Thai patients. We conducted a retrospective study from consecutive cases of BP in people with type 2 diabetes mellitus (T2DM) from January 2008, the year in which the first DPP4i was introduced in Thailand, until December 2019. During the study period, 10 BP patients with T2DM were identified. A total of 5 DPP4i-associated BP (3 on vildagliptin, 1 on linagliptin, and 1 on sitagliptin) were found. All patients were male with a mean age at BP development of 80.4 years (73–86 years). All patients had a long-standing duration of diabetes (median duration 34 years), and mean A1C was 7.5 ± 1.4%. The median time to BP development after the introduction of DPP4i was 64 months (range 20–128 months). The severity of BP was classified as mild in 2 cases. In all cases, the association between the drug intake and BP onset was classified as “possible” according to the Naranjo causality scale. All of the patients continued taking DPP4i after BP diagnosis, and one patient died of lung cancer 18 months after BP diagnosis. Only 2 patients could achieve complete remission at least 2 months after stopping DPP4i. Our case series demonstrated a potential link between DPP4i and the development of BP, which mainly occurred in very elderly male patients. The latency period from an introduction of DPP-4i could be several years, and the clinical course after DPP4i discontinuation varied. Clinicians prescribing DPP4i should be aware of this association and consider stopping this medication before a refractory disease course ensues.

Aim To determine the glucose‐independent effect of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor linagliptin versus the sulphonylurea glimepiride on systemic haemodynamics in the fasting and postprandial state in patients with type 2 diabetes (T2D). Materials and Methods In this prespecified secondary analysis of a phase IV, double‐blind trial, 46 metformin‐treated, overweight patients with T2D were included and randomly assigned (1:1) to once‐daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. In a sub‐study involving 26 patients, systemic haemodynamics were also assessed following a standardized liquid meal (Nutridrink Yoghurt style). Systemic haemodynamics (oscillometric device and finger photoplethysmography), arterial stiffness (applanation tonometry) and cardiac sympathovagal balance (heart rate variability [HRV]) were measured in the fasting state and repetitively following the meal. Ewing tests were performed in the fasting state. Results From baseline to week 8, linagliptin compared with glimepiride did not affect systemic haemodynamics, arterial stiffness or HRV in the fasting state. Linagliptin increased parasympathetic nervous activity, as measured by the Valsalva manoeuvre (P = .021) and deep breathing test (P = .027) compared with glimepiride. Postprandially, systolic blood pressure (SBP) dropped an average of 7.6 ± 1.6 mmHg. Linagliptin reduced this decrease to 0.7 ± 2.3 mmHg, which was significant to glimepiride (P = .010). Conclusions When compared with glimepiride, linagliptin does not affect fasting blood pressure. However, linagliptin blunted the postprandial drop in SBP, which could benefit patients with postprandial hypotension.

Background and aim Non-alcoholic fatty liver disease (NAFLD) represents a broad spectrum of chronic liver disease characterized by aberrant accumulation of triglycerides (TG) in hepatocytes without excessive alcohol consumption. Hepatic lipotoxicity derived from overaccumulation of free fatty acids is considered as one of the typical hallmarks of NAFLD. Insulin resistance (IR) and chronic inflammation are widely recognized as the key etiological factors associated with NAFLD. Dipeptidyl peptidase 4 inhibitor (DPP4i) is a novel pharmacological agent extensively applied in the treatment of Type 2 Diabetes Mellitus (T2DM) for decades which also have a liver protective effect. Methods In order to invest the therapeutic efficiency and underlying mechanism of DPP4i saxagliptin, we used high-fat diet (HFD) and streptozotocin-induced NAFLD treated with saxagliptin. Biochemical, histomorphological, genetic and protein expression of related pathways were investigated. Results Fasting blood glucose (FBG), TG, total cholesterol (TC), and low-density lipoprotein cholesterin significantly increased in NAFLD group, which also exhibited severe steatosis. Other remarkable findings were hyperinsulinemia, increased DPP4, PTP-1B and TNF-α level and decreased GLP-1, ACOX-1, CPT-1A expression, concomitant with liver DPP4 expression enhancement and serum DPP4 elevation. These undesirable consequences were alleviated by saxagliptin to a certain degree. Conclusion DPP4i saxagliptin improves NAFLD by ameliorating IR, inflammation, downregulation of hepatic DPP4 and sDPP4, as well as subsequent steatosis. The elevation of hepatic DPP4 and sDPP4 and succedent post-treatment decrease suggested that DPP4 may involve in the development of NAFLD. The anti-lipotoxic effect of DPP4i may involve the activation of CPT1A and ACOX1 related β-oxidation signaling pathway suppression of TNF-α mediated inflammatory and PTP-1B. The results covered in this article showed that saxagliptin affects many aspects of the pathological characteristics of NAFLD, suggesting that DPP4i saxagliptin may offer a novel therapeutic option for NAFLD.

Aims Recent studies indicated that sodium glucose cotransporter‐2 inhibitors (SGLT2i) reduced heart failure hospitalization in patients with type 2 diabetes mellitus (T2DM). However, whether SGTL2i can improve left ventricular (LV) systolic and diastolic function remained unclear. This study aimed to compare the change in echocardiographic parameters in T2DM patients receiving SGLT2i with a different baseline LV ejection fraction (LVEF). The change in echocardiographic parameters was also compared between T2DM patients treated with SGLT2i and those treated with dipeptidyl peptidase‐4 inhibitor (DPP4i). Methods and results This multicentre cohort study consecutively enrolled 665, 119, and 132 T2DM patients treated with SGLT2i with a preserved (≥50%), moderately reduced (40–50%), and reduced baseline LVEF (

Type 2 diabetes mellitus (T2DM) is highly prevalent in the general population and especially in patients with heart failure (HF). It is not only a risk factor for incident HF, but is also associated with worse outcomes in prevalent HF. Therefore, antihyperglycaemic management in patients at risk of or with established HF is of importance to reduce morbidity/mortality. Following revision of the drug approval process in 2008 by the Food and Drug Administration and European Medicines Agency, several cardiovascular outcome trials on antihyperglycaemic drugs have recently investigated HF endpoints. Signals of harm in terms of increased risk of HF have been identified for thiazolidinediones and the dipeptidyl peptidase 4 inhibitor saxagliptin, and therefore, these drugs are not currently recommended in HF. Sulfonylureas also have an unfavourable safety profile and should be avoided in patients at increased risk of/with HF. Observational studies have assessed the use of metformin in patients with HF, showing potential safety and potential survival/morbidity benefits. Overall use of glucagon‐like peptide 1 receptor agonists has not been linked with any clear benefit in terms of HF outcomes. Sodium–glucose cotransporter protein 2 inhibitors (SGLT2i) have consistently shown to reduce risk of HF‐related outcomes in T2DM with and without HF and are thus currently recommended to lower risk of HF hospitalization in T2DM. Recent findings from the DAPA‐HF trial support the use of dapagliflozin in patients with HF with reduced ejection fraction and, should ongoing trials with empagliflozin, sotagliflozin, and canagliflozin prove efficacy, will pave the way for SGLT2i as HF treatment regardless of T2DM.

Introduction To evaluate the efficacy and safety of dipeptidyl peptidase 4 inhibitors (DPP4i) used in combination with insulin in patients with type 2 diabetes mellitus (T2DM). Methods We searched the MEDLINE, Embase, and Cochrane library databases for randomized controlled trials (RCTs) published through June 2018. Studies with at least a 12-week treatment period were included to compare the addition of DPP4i to insulin with insulin control therapy. Meanwhile, groups on a stable insulin dosage (insulin-stable subgroup) or titrating insulin dosage (insulin-flexible subgroup) were analyzed separately. Results Twenty-one RCTs with 3697 patients randomized to a DPP4i/insulin treatment arm and 3538 to an insulin control arm were included. DPP4i, when added to insulin therapy, led to a significantly greater reduction in HbA1c (− 0.57%, 95% CI − 0.66, − 0.48) and provided significantly greater odds of achieving the HbA1c target

Background To investigate the association of dipeptidyl peptidase-4 inhibitors (DPP4is) treatment doses and tuberculosis (TB) in patients with diabetes. Methods We allocated participants into DPP4i users and non-users from the Longitudinal Health Insurance Database. A chi-square test and Wilcoxon's rank-sum test were used to analyze the baseline discrete variables and continuous variable, respectively. The incidence rate was calculated in 1,000 personyears. The hazard ratios (HRs) were adjusted using a multivariate Cox regression model. The effect of DDP4i dosage on TB was analyzed. The Kaplan-Meier method was used to assess the cumulative incidence curves with a log-rank test. Results We identified 6,399 DPP4i users and 6,399 non-users. The incidence rate of TB in DPP4i users and non-users was 22.2 and 16.2 per 1,000 person-years, respectively. The HR of TB for DPP4i users relative to non-users was 1.04 (P=0.89). Most of the analysis of factors such as the incidence rate, gender and diabetic comorbidities in our study were non-significant. The risk of developing TB in patients with over 20 average defined daily doses (DDDs) per year was increased by 2.19 times (P=0.048). Conclusions In our long-term nationwide population-based cohort study, higher doses of DPP4i (20 average DDDs) could increase TB infection risk in patients with diabetes. To pay more attention to this kind of diabetic patients with DPP4i treatment will be more important for the public health issue of TB prevention.

OBJECTIVE Poor outcomes have been reported in patients with type 2 diabetes and coronavirus disease 2019 (COVID-19); thus, it is mandatory to explore novel therapeutic approaches for this population. RESEARCH DESIGN AND METHODS In a multicenter, case-control, retrospective, observational study, sitagliptin, an oral and highly selective dipeptidyl peptidase 4 inhibitor, was added to standard of care (e.g., insulin administration) at the time of hospitalization in patients with type 2 diabetes who were hospitalized with COVID-19. Every center also recruited at a 1:1 ratio untreated control subjects matched for age and sex. All patients had pneumonia and exhibited oxygen saturation RESULTS Of the 338 consecutive patients with type 2 diabetes and COVID-19 admitted in Northern Italy hospitals included in this study, 169 were on sitagliptin, while 169 were on standard of care. Treatment with sitagliptin at the time of hospitalization was associated with reduced mortality (18% vs. 37% of deceased patients; hazard ratio 0.44 [95% CI 0.29–0.66]; P = 0.0001), with an improvement in clinical outcomes (60% vs. 38% of improved patients; P = 0.0001) and with a greater number of hospital discharges (120 vs. 89 of discharged patients; P = 0.0008) compared with patients receiving standard of care, respectively. CONCLUSIONS In this multicenter, case-control, retrospective, observational study of patients with type 2 diabetes admitted to the hospital for COVID-19, sitagliptin treatment at the time of hospitalization was associated with reduced mortality and improved clinical outcomes as compared with standard-of-care treatment. The effects of sitagliptin in patients with type 2 diabetes and COVID-19 should be confirmed in an ongoing randomized, placebo-controlled trial.

Background Dipeptidyl peptidase-4 (DPP-4) rapidly inactivates incretin hormones and several chemokines, thus influencing chemokine function. There have recently been several reports that DPP-4 inhibitor therapy is associated with an increased risk of bullous pemphigoid (BP), an autoimmune skin disease. Previous studies have demonstrated an increase of CCL11/Eotaxin, a DPP-4 substrate, in serum and blister fluid from patients with BP. Serum levels of CCL22/macrophage-derived chemokine (MDC) and CXCL10/IP-10, other DPP-4 substrates, are also elevated in BP patients. Materials and Methods In patients with type 2 diabetes, we investigated the effect of treatment with teneligliptin (a DPP-4 inhibitor) for 24 weeks on plasma levels of CCL11/Eotaxin, CCL22/MDC and CXCL10/IP-10 during a meal test. Ten consecutive patients with type 2 diabetes who showed inadequate glycemic control by metformin and/or sulfonylureas were recruited. A standard meal test was performed at baseline and after 24 weeks of treatment with teneligliptin at 20 mg/day. Blood samples were collected at 0, 30, 60 and 120 minutes after ingestion of the meal. In addition to plasma levels of the 3 chemokine, plasma DPP-4 enzyme activity and soluble DPP-4 antigen were measured. Results Treatment with teneligliptin decreased hemoglobin A1c and reduced fasting plasma DPP-4 activity by 90.1% compared with baseline. Unexpectedly, plasma levels of all 3 chemokines (including CCL11/Eotaxin) were not increased after teneligliptin treatment, and instead were significantly lower at every point during the meal test. Conclusions Teneligliptin reduced the plasma concentrations of 3 chemokines (DPP-4 substrates) that may be related to the occurrence of DPP4 inhibitor-associated BP (UMIN000012508).

AIMS To investigate the effect of anagliptin (Ana), a dipeptidyl peptidase-4 (DPP-4) inhibitor, on acute ischemia-induced bladder dysfunction in rats. METHODS Eight-week-old female Wistar-ST rats were randomly assigned into four groups: (a) sham; (b) ligation (Lig); (c) Lig + Ana; and (d) Lig + Liraglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist; Lira). Rats in the Lig, Lig + Ana, and Lig + Lira groups underwent ligature of the bilateral internal iliac arteries. Ana was orally administered mixed with the CE-2 diet. Lira was subcutaneously administered once a day. Blood glucose levels, plasma dipeptidyl peptidase 4 (DPP-4) activity, GLP-1 levels, and bladder function were measured in all groups. Bladder blood flow was measured in the sham, Lig, and Lig + Ana groups, 4 weeks postsurgery. RESULTS No differences in blood glucose levels among the groups were observed. DPP-4 activity decreased in the Lig + Ana group (P

To investigate the effect of dipeptidyl peptidase-4 inhibitor (DPP4i) for Klebsiella pneumoniae (KP) pneumonia in patients with diabetes. Patients newly diagnosed with type 2 diabetes from 2009 to ...

OBJECTIVE: Linagliptin, a dipeptidyl peptidase-4 inhibitor, recently demonstrated cardiovascular (CV) safety versus placebo in Asians with advanced type 2 diabetes mellitus (T2DM) in the CARMELINA(®) trial. We assessed its CV safety compared with the sulfonylurea glimepiride in Asians with relatively early T2DM in the CAROLINA(®) trial. METHODS: Based on prespecified and post hoc subgroup analyses of the multinational CAROLINA(®) trial in which adults with relatively early T2DM and elevated CV risk were randomized to linagliptin or glimepiride added to usual care, we analyzed data for participants from Asian countries. This included the primary outcome defined as time to first CV death, non-fatal myocardial infarction, or non-fatal stroke [three-point major adverse cardiovascular events (3P-MACE)]. RESULTS: Of the 6033 participants, 933 (15.5%) were from Asia. During a median follow-up of 6.2 years, 3P-MACE occurred in 9.5% and 11.1% of the linagliptin and glimepiride groups, respectively (hazard ratio [HR] 0.85; 95% confidence interval [CI] 0.57–1.26]), consistent with the overall population (HR 0.98; 95% CI 0.84–1.13; P = 0.17 for treatment by region interaction). Similarly, there were no significant differences between groups for other outcomes, including CV death (HR 0.73; 95% CI 0.38–1.38), non-CV mortality (HR 0.76; 95% CI 0.37–1.57) and hospitalization for heart failure (HR 0.89; 95% CI 0.36–2.19). Hypoglycemia adverse events occurred in 13.1% of linagliptin patients versus 42.1% of glimepiride patients (HR 0.25; 95% CI 0.19–0.33; P

The interplay between obesity and type 2 diabetes (T2D) in poststroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically used T2D drugs: the dipeptidyl peptidase 4 inhibitor linagliptin and the sulfonylurea glimepiride. We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet [HFD]) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the poststroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks. We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis, and atrophy of parvalbumin-positive (PV+) interneurons were quantified by immunohistochemistry. T2D/obesity impaired poststroke neurological recovery in association with hyperglycemia, neuroinflammation, and atrophy of PV+ interneurons. Both drugs counteracted these effects. In nondiabetic mice, only linagliptin accelerated recovery. These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies that are based on efficacious glycemia regulation, even if initiated days after stroke.

Alogliptin, a dipeptidylpeptidase-4 inhibitor, is an oral hypoglycemic agent approved in many countries for the treatment of patients with type 2 diabetes, including the United States, Europe, and Japan. The drug is effective both as a monotherapy, and as an additional or combined treatment of type 2 diabetes. Alogliptin is well tolerated by patients, including the elderly, as well as those suffering from kidney and / or liver failure or having a high risk of cardiovascular events. The low risk of hypoglycemia, weight gain, acute pancreatitis, and side gastrointestinal events. During treatment with alogliptin has been demonstrated in both long-term (up to 4.5 years) studies and in actual clinical practice. Alogliptin increases postprandial levels of the glucagon-like peptide-1, which leads to insulin secretion and normalization of glucose homeostasis. Treatment with alogliptin is associated not only with improved glucose metabolism, but also with a decrease in blood pressure and arterial rigidity in patients with arterial hypertension and diabetes, as well as normalizing the lipid profile. In patients with diabetes mellitus who have recently undergone acute coronary syndrome and received alogliptin, the frequency of serious adverse cardiovascular events does not increase. Experimental data show that alogliptin reduces ventricular hypertrophy, interstitial fibrosis, and diastolic dysfunction. Alogliptin has a number of unique properties. It is assumed that it can increase the number of circulating endothelial progenitor cells that play an important role in endothelial repair and neovascularization. Alogliptin preserves the functionality and structure of the mitochondria of cardiomyocytes. The drug may be a potential treatment for patients with MODY1 diabetes at an early stage of the disease, when residual insulin secretion is preserved. Treatment with a fixed combination of Alogliptin + Metformin results in better glycemic control than monotherapy and is well tolerated. There is evidence that treatment with alogliptin is not associated with an increased risk of pancreatitis or pancreatic cancer.

Introduction Metformin is the recommended initial treatment in type 2 diabetes mellitus (T2DM), but when this does not give adequate glucose control the choice of which second-line drug to use is uncertain as none have been found to have a better overall glycaemic response. In this real-world study dipeptidyl peptidase 4 inhibitors (DPP4i), sulphonylureas (SU), thiazolidinediones (TZD) and sodium glucose co-transporter 2 inhibitors (SGLT2i) were compared for their effectiveness in lowering glycated haemoglobin (HbA1c) levels for a particular individual based on their clinical characteristics. Methods A retrospective analysis was undertaken of electronic health records of people with T2DM prescribed metformin alongside a DPP4i, SU, TZD or SGLT2i at second-line. Regression modelling was used to model the changes in HbA1c from baseline at month 6 and month 12 for the individual therapies, adjusting for demographic and clinical characteristics. Results There were 7170 people included in the study. Treatment at second-line with SUs, DPP4i, TZDs and SGLT2i resulted in similar percentages of people achieving the recommended HbA1c target of

Background and aims Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for ASCVD, the aim of this study was to investigate the effects of a dipeptidyl peptidase-4 inhibitor, sitagliptin, on prevention of progression of coronary atherosclerosis assessed by three-dimensional quantitative coronary angiography (3D-QCA) in T2DM patients with coronary artery disease (CAD). Methods This was a prospective, randomized, double-center, open-label, blinded end point, controlled 18-month study in patients with CAD and T2DM. A total of 149 patients, who had at least 1 atherosclerotic plaque with 20%–80% luminal narrowing in a coronary artery, and had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention, were randomized to sitagliptin group (n = 74) or control group (n = 75). Atherosclerosis progression was measured by repeat 3D-QCA examination in 88 patients at study completion. The primary outcome was changes in percent atheroma volume (PAV) from baseline to study completion measured by 3D-QCA. Secondary outcomes included change in 3D-QCA-derived total atheroma volume (TAV) and late lumen loss (LLL). Results The primary outcome of PAV increased of 1.69% (95%CL, −0.8%–4.2%) with sitagliptin and 5.12% (95%CL, 3.49%–6.74%) with the conventional treatment (p = 0.023). The secondary outcome of change in TAV in patients treated with sitagliptin increased of 6.45 mm3 (95%CL,-2.46 to 6.36 mm3) and 9.45 mm3 (95%CL,-4.52 to 10.14 mm3) with conventional treatment (p = 0.023), however, no significant difference between groups was observed (p = 0.175). Patients treated with sitagliptin had similar LLL as compared with conventional antidiabetics (−0.06, 95%CL, −0.22 to 0.03 vs. −0.08, −0.23 to −0.03 mm, p = 0.689). Conclusions In patients with type 2 diabetes and coronary artery disease, treatment with sitagliptin resulted in a significantly lower rate of progression of coronary atherosclerosis compared with conventional treatment.

BACKGROUND Hypertrophic scars and keloids, which are abnormalities of fibrosis, often occur in surgical wounds; however, their exact cause and preventive measures are unknown. The administration of dipeptidyl peptidase-4 inhibitors to humans is expected to suppress fibrosis in wounds and minimize hypertrophic scar and keloid formation. METHODS This study aimed to verify the suppressive effect of dipeptidyl peptidase-4 inhibitors on the formation of hypertrophic scars or keloids using real world data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. It is a retrospective cohort study, and data were extracted from the National Database between April of 2013 and March of 2015. Patients who underwent median sternotomy were included in the study based on their claimed surgical codes. Subjects who were prescribed dipeptidyl peptidase-4 inhibitors constituted the treatment group; subjects who were not prescribed or administered dipeptidyl peptidase-4 inhibitors during that period constituted the nontreatment group. RESULTS Subjects included 5430 patients throughout Japan (3509 men and 1921 women). Of the 446 subjects who were treated with dipeptidyl peptidase-4 inhibitors within 1 year before the procedure, fewer than 10 (

BACKGROUND AND OBJECTIVE: To evaluate impact of baseline systemic dipeptidyl peptidase-4 (DPP-4) inhibitor use in diabetic macular edema (DME). PATIENTS AND METHODS: This was a post hoc exploratory analysis of previously completed randomized, controlled clinical trials (VISTA and VIVID) in patients with DME evaluating intravitreal aflibercept injection (IAI) every 4 weeks (2q4) or every 8 weeks (2q8) or macular laser photocoagulation. RESULTS: Overall, a small number of patients (12.2% [n = 35], 9.7% [n = 28], and 15.4% [n = 44]) in the laser control, 2q4, and 2q8 groups reported baseline DPP-4 inhibitor use. There were no differences in changes from baseline in best-corrected visual acuity, central subfield thickness, or rates of 2-or-greater-step improvement in Diabetic Retinopathy Severity Scale score based on DPP-4 inhibitor use within each treatment group. CONCLUSION: DPP-4 inhibitor use at baseline did not influence the magnitude of visual and anatomic benefit in patients with DME being treated with IAI or laser. [ Ophthalmic Surg Lasers Imaging Retina. 2020;51:226–234.]

Introduction Teneligliptin, a dipeptidyl peptidase 4 inhibitor, was approved for the treatment of type 2 diabetes mellitus (T2DM) in Japan in 2012. However, clinical trials of teneligliptin involved limited numbers of elderly patients. Therefore, we investigated the safety and efficacy of teneligliptin in elderly patients with T2DM. Methods This 3-year follow-up RUBY surveillance registered patients with T2DM who started treatment with teneligliptin between May 2013 and February 2015 in Japan. Collected data included demographics, treatments, adverse drug reactions (ADRs), and laboratory variables. Data were analysed for patients in three age subgroups (, Plain Language Summary Teneligliptin is an oral drug taken once daily to manage blood glucose levels in people with type 2 diabetes. A number of studies of teneligliptin have investigated its safety and efficacy, but these studies included limited numbers of elderly people, aged 75 years or older. Following the approval of teneligliptin in Japan, post-marketing surveillance was started to monitor its safety and efficacy when prescribed by doctors to people in actual clinical practice. We analysed data from the surveillance to check if the safety and efficacy of teneligliptin differ in younger and older people separately. We found that there was no clear difference in the number of adverse drug reactions among three age subgroups

Angiogenic T (Tang) cells are mediators of vascular repair, and are characterized by surface expression of CXCR4. This receptor for stromal cell-derived factor-1α (SDF-1α) is cleaved by dipeptidyl peptidase-4 (DPP-4). Tang cell levels were investigated in people with type 2 diabetes mellitus (T2DM) compared with matched healthy controls and after treatment with the DPP-4 inhibitor Linagliptin. People with T2DM were randomized to 5 mg/day Linagliptin (n = 20) or placebo (n = 21) for 26 weeks. Tang cell frequency was identified in peripheral blood mononuclear cells (CD3+CD31+CXCR4+) and levels of endothelial progenitor cells (EPCs) (CD34+CD133+KDR+) were also assessed in whole blood. Circulating Tang cell levels were significantly lower in people with T2DM compared with the healthy control group. SDF-1α levels increased significantly in Linagliptin-treated people with T2DM compared to placebo, and a trend was observed in change of Tang cell levels, while EPC count did not change. In conclusion, circulating Tang cell levels were considerably lower in people with T2DM, while a trend was observed in recruitment of Tang cells after 26 weeks of treatment with Linagliptin. These data suggest that DPP-4 inhibitors may potentially exert beneficial effects on bone marrow-driven vascular repair.

Renal fibrosis is considered to be the final common outcome of chronic kidney disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors have demonstrated protective effects against diabetic kidney disease. However, the anti-fibrotic effect of evogliptin, a DPP-4 inhibitor, has not been studied. Here, we report the beneficial effects of evogliptin on unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice. Evogliptin attenuated UUO-induced renal atrophy and tubulointerstitial fibrosis. Immunohistochemistry and Western blotting demonstrated that evogliptin treatment inhibits pro-fibrotic gene expressions and extracellular matrix production. In vitro findings showed that the beneficial effects of evogliptin on renal fibrosis are mediated by inhibition of the transforming growth factor-β/Smad3 signaling pathway. The present study demonstrates that evogliptin is protective against UUO-induced renal fibrosis, suggesting that its clinical applications could extend to the treatment of kidney disease of non-diabetic origin.

Objectives: In different studies, it has been shown that the use of dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4 inh) does not increase the risk of pancreatitis or pancreatic cancer. Although the number of studies involving clinical pancreatitis clinics is sufficient, the number of studies involving clinical non-pancreatitis hyperamylasemia is rare. The aim of the study was to investigate the relationship between DPP-4 inh usage and amylase and lipase increment without clinical pancreatitis symptoms. Materials and Methods: Eighty-seven patients who met the inclusion criteria were enrolled. The patients were divided into 3 groups according to their use of saxagliptin, sitagliptin, or vildagliptin. All patients included in the study were receiving metformin at a dose of 2 g/day. Fasting blood glucose, postprandial blood glucose, HbA1C, serum creatinine, ALT, amylase, and lipase results were recorded at the beginning of treatment and at the end of 3 months. Results: There was an increase in all groups in terms of amylase and lipase values but there was no significant difference between the groups in terms of increase (p>0.05) There was no statistically significant increase in the saxagliptin and vildagliptin groups (p>0.05) when the baseline and 3-month values of lipase and amylase increase were examined. However, there was a statistically significant increase in amylase and lipase in the sitagliptin group (p

Background: There are several reports of seasonal variation in hemoglobin A1c (HbA1c) in patients with type 2 diabetes (T2DM), but no reports of seasonal variation in the effect of add-on drugs on blood glucose control in insulin-treated patients. Methods: Using data collected from 630 patients in a multicenter study, we compared the amount of change in HbA1c after 1, 3, 6, 9, and 12 months of add-on administration of sitagliptin in insulin-treated patients divided into four groups based on the month when sitagliptin was started. Results: A significantly larger decrease in HbA1c at 6 months from baseline was observed in the group that started add-on sitagliptin in February to April than in the other three groups. However, the amount of change in HbA1c at 12 months did not differ among the groups. Conclusions: The consideration of seasonal variation enables more accurate evaluation of a drug’s short-term effect on blood glucose control. J Clin Med Res. 2020;12(3):200-208 doi: https://doi.org/10.14740/jocmr4103

Background: We previously reported the effect of sitagliptin or glimepiride treatment for 24 weeks on body composition in Japanese overweight and obese patients with type 2 diabetes. Although the degree of HbA1c reduction was similar between the two groups, significant reduction of intrahepatic lipid (IHL), determined by proton magnetic resonance spectroscopy ( 1 H-MRCP), and fat mass (FM), determined by dual-energy X-ray absorptiometry (DXA), was observed in the sitagliptin group but not in the glimepiride group. As both IHL and FM are known as associating factors of insulin resistance, these reductions may lead to improvement of insulin sensitivity, which in turn may contribute to sitagliptin-induced amelioration of glycemic control. On the other hand, muscle and muscle/fat ratio were also reported to be positively correlated with insulin sensitivity, but we did not evaluate these factors. Methods: DXA separates the whole body into three major components, bone mass (BM), FM and fat and bone-free mass (FBFM), and measures the weight of each component. FBFM is normally used as a good marker of muscle mass; therefore, in this post-hoc analysis, we investigated whether sitagliptin treatment for 24 weeks influenced the FBFM and FBFM/FM ratio. Results: After 24 weeks, the FBFM and FBFM/FM ratio significantly increased in the sitagliptin group (47.6 ± 10.3 to 48.8 ± 11.0 kg, P < 0.05 and 2.0 ± 0.8 to 2.1 ± 0.8, P < 0.05), but not in the glimepiride group (49.7 ± 10.6 to 49.3 ± 9.9, P = 0.655 and 2.1 ± 0.9 to 2.0 ± 0.7, P = 0.855). The mean change of FBFM and FBFM/FM ratio from baseline to 24 weeks in the sitagliptin and glimepiride groups was 1.24 ± 2.01 (sitagliptin group) vs. -0.34 ± 2.63 kg (glimepiride group) (P = 0.074) and 0.13 ± 0.17 (sitagliptin group) vs. -0.11 ± 0.30 (glimepiride group) (P < 0.05), respectively. Conclusions: Sitagliptin 24-week treatment demonstrated not only reduction of body fat and liver fat but also an increase of muscle and muscle/fat ratio. These changes may partly explain the mechanism underlining sitagliptin-induced improvement of glycemic control. J Clin Med Res. 2020;12(2):122-126 doi: https://doi.org/10.14740/jocmr4078

ObjectivesTo compare the rates of major cardiovascular adverse events in sodium-glucose cotransporter-2 inhibitors (SGLT2I) and dipeptidyl-peptidase-4 inhibitors (DPP4I) users in a Chinese population.BackgroundSGLT2I and DPP4I are increasingly prescribed for type 2 diabetes mellitus patients. However, few population-based studies are comparing their effects on incident heart failure or myocardial infarction.MethodsThis was a population-based retrospective cohort study using the electronic health record database in Hong Kong, including type 2 diabetes mellitus patients receiving either SGLT2I or DPP4I between January 1st, 2015, to December 31st, 2020. Propensity-score matching was performed in a 1:1 ratio based on demographics, past comorbidities, non-SGLT2I/DPP4I medications with nearest-neighbor matching (caliper=0.1). Univariable and multivariable Cox models were used to identify significant predictors for new onset heart failure, new onset myocardial infarction, cardiovascular mortality, and all-cause mortality. Sensitivity analyses with competing risk models and multiple propensity score matching approaches were conducted. Subgroup age and gender analyses were presented.ResultsA total of 41994 patients (58.89% males, median admission age at 58 years old, interquartile rage [IQR]: 51.2-65.3) were included in the study cohorts with a median follow-up duration of 5.6 years (IQR: 5.32-5.82). After adjusting for significant demographics, past comorbidities, medication prescriptions and biochemical results, SGLT2I users have a significantly lower risk for myocardial infarction (hazard ratio [HR]: 0.34, 95% confidence interval [CI]: [0.28, 0.41], P < 0.0001), cardiovascular mortality (HR: 0.53, 95% CI: [0.38, 0.74], P = 0.0002) and all-cause mortality (HR: 0.21, 95% CI: [0.18, 0.25], P= 0.0001) under multivariable Cox regression. However, the risk for heart failure is comparable (HR: 0.87, 95% CI: [0.73, 1.04], P= 0.1343).ConclusionsSGLT2 inhibitors are protective against adverse cardiovascular events compared to DPP4I. The prescription of SGLT2I is preferred especially for males and patients aged 65 or older to prevent cardiovascular risks.

Objectives Investigating whether dipeptidyl peptidase-4 (DPP-4) inhibitors could influence clinical outcomes in intramural hematoma (IMH) patients with diabetes mellitus (DM). Methods IMH patients who received a "wait and watch strategy" were included. Cox proportional hazard models were constructed to identify potential risk factors. A Kaplan–Meier survival analysis was used to estimate all-cause and aorta-related mortality during the follow-up period. Results From January 2000 to December 2020, 1094 IMH patients were divided into group A (n=572, IMH patients without DM), group B (n=191, IMH patients with DM and receiving oral antidiabetic drugs [without admission of DDP-4 inhibitors]) and group C (n=331, IMH patients with DM and receiving oral antidiabetic drugs [including admission of DDP-4 inhibitors]). Group C had the lowest rate of aorta-related adverse events (6.4%), aorta-related mortality (1.2%) and reintervention (5.2%). Cox proportional hazard models revealed that lower eosinophil count (per 0.1, hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.73, P< 0.001) and thicker hematoma thickness (HR, 1.22; 95% CI, 1.06-1.39, P

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is associated with worse outcomes for patients with COVID-19. Commonly used glucose-lowering medications, metformin, dipeptidyl peptidase-4 inhibitor (DPP4i), or insulin, were found to impact the level of inflammatory and cytokine, therefore potentially influence the clinical outcomes in SARS-CoV-2 infected patients. Concerns remain on the early in-hospital use of these medications. This territory-wide retrospective observational study evaluated clinical improvement, virality, acidosis, hypoglycemia, hyperinflammation status, composite clinical outcomes associated with use of metformin, DPP4i, or insulin for hospitalized T2DM patients with COVID-19 infection. METHODS: Baseline covariate between the two groups were balanced by multiple imputation followed by inverse probability of treatment weighting for propensity score. Multivariable cox proportional hazard models were performed to estimate hazard ratios (HR) and their 95% confidence intervals (CI) of time-to-event outcomes. Exposure was defined as receiving glucose-lowering drug class within 3 days of admission. RESULTS: After propensity-score weighting, baseline characteristics were generally balanced. Metformin users (n = 609) were associated with quicker time to clinical improvement (HR = 1.41, 95%CI 1.19 to 1.65, P < 0.001), hospital discharge (HR = 1.43, 95%CI 1.20 to 1.69, P < 0.001) and recovery (HR = 2.09, 95%CI 1.42 to 3.06, P < 0.001), shorter hospital length of stay among survivors (-6.45 days, 95%CI -8.34 to -4.56, P < 0.001), reduced costs from 30-days onward, lower risk of composite outcome (HR = 0.41, 95%CI 0.23 to 0.74, P = 0.003) and macrophage activation (HR = 0.64, 95%CI 0.47 to 0.87, P < 0.004) when compared to non-metformin users. Shorter hospital length of stay was also observed in DPP4i users (n = 144) compared with non-DPP4i users (-5.32 days, 95%CI to 7.30 to -3.34, P < 0.001). Insulin users (n = 414) have greater risk of hypoglycemia during admission (HR = 2.61, 95%CI 1.23 to 5.53, P = 0.013) when compared to non-insulin users. CONCLUSION: Metformin and DPP4i have exhibited association with improved clinical outcomes while insulin has proved to be associated with increased risk of hypoglycemia for in hospitalized T2DM patients with COVID-19.