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Aims: The aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes. Materials and methods: We conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and <9.0% and BMI ≥20 kg/m2 despite treatment with a drug naïve or other than DPP-4 inhibitors or SGLT2 inhibitors. A total of 103 subjects were randomly assigned to receive once daily oral luseogliflozin (L) or teneligliptin (T). The primary endpoint was the effect of L vs. T on the change in logarithmus naturalis (Ln) disposition index (DI) (DI 0-120min; combining measures of insulin secretion and sensitivity) from baseline to week 25-26 (post intervention), which was calculated by conducting an oral glucose tolerance test. Results: Ln DI 0-120min were improved in both groups: -0.46 ± 0.68 to -0.20 ± 0.59 (p =0.03) in L group and -0.26 ± 0.60 to -0.05 ± 0.62 (p =0.01) in T group. The change in Ln serum proinsulin/C-peptide ratio, a marker of β-cell dysfunction, was reduced in L group (1.63 ± 0.63 to 1.56 ± 0.68, p =0.16), but rather increased in T group (1.70 ± 0.75 to 1.90 ± 0.51, p =0.01), with significant difference between the two groups (-0.27; p =0.004). Conclusions: Improvement of disposition index in subjects with obese type 2 diabetes was comparable between luseogliflozin and teneligliptin. On the other hand, it is likely that alleviation of β-cell dysfunction is more effective with luseogliflozin compared to tenegliptin. Clinical trial registration: https://rctportal.niph.go.jp/en , identifier jRCTs061190008. [ABSTRACT FROM AUTHOR]

Background: Limited evidence exists to support any specific medication over others to prevent dementia in older patients with type 2 diabetes (T2D). We investigated whether treatment with sodium‐glucose cotransporter 2 (SGLT‐2) inhibitors is associated with a lower risk of incident dementia and all‐cause mortality, relative to dipeptidyl peptidase‐4 (DPP‐4) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA). Methods: In this retrospective, active‐comparator cohort study, we used data from the TriNetX electronic health records network. Our primary cohort comprised patients with T2D aged ≥50 years, registered between January 2012 and December 2022. Patients with a history of dementia were excluded. We used Kaplan–Meier survival analysis to estimate the incidence of dementia and all‐cause mortality in our cohort after they had used glucose‐lowering drugs for at least 12 months. Propensity score matching was performed to balance the SGLT‐2 inhibitor, DPP‐4 inhibitor and GLP‐1 RA cohorts. Subgroup analyses for sex and age were also conducted. Results: Our first cohort comprised 193 948 patients treated with metformin and SGLT‐2 inhibitors and an equal number of patients treated with metformin and DPP‐4 inhibitors. In this cohort, the risk of dementia and all‐cause mortality was lower in patients treated with SGLT‐2 inhibitors than in those treated with DPP‐4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59–0.65, for dementia; HR: 0.54, 95% CI: 0.52–0.56, for all‐cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT‐2 inhibitors and an equal number of patients treated with metformin and GLP‐1 RAs. In this cohort, the risk of dementia and all‐cause mortality was lower in those treated with SGLT‐2 inhibitors than in those treated with GLP‐1 RAs (HR: 0.92, 95% CI: 0.87–0.98, for dementia; HR: 0.88, 95% CI: 0.85–0.91, for all‐cause mortality). Conclusions: The use of SGLT‐2 inhibitor was associated with a lower risk of incident dementia and all‐cause mortality in older adults with T2D compared to DPP‐4 inhibitor and GLP‐1 RA. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the renal prognosis of dipeptidyl peptidase‐4 inhibitor (DPP‐4i) users and non‐users using real‐world Asian data. Methods: Using databases from DeSC Healthcare, Inc., patients aged 30 years or older who used antidiabetic drugs from 2014 to 2021 were identified. Propensity score matching analyses were used to compare renal prognosis between DPP‐4i users and non‐users. The primary outcomes were estimated glomerular filtration rate (eGFR) decline and end‐stage kidney disease (ESKD) development in the eGFR of 45 mL/min/1.73m2 or higher and eGFR of less than 45 mL/min/1.73m2 groups, respectively. Results: In total, 65 375 and 9866 patients were identified in the eGFR of 45 mL/min/1.73m2 or higher and eGFR of less than 45 mL/min/1.73m2 groups, respectively. In the eGFR of 45 mL/min/1.73m2 or higher group, propensity score matching created 16 002 pairs. A significant difference was observed in the primary outcome of eGFR decline between DPP‐4i users and non‐users at 2 years (−2.31 vs. −2.56 mL/min/1.73m2: difference, 0.25 mL/min/1.73m2; 95% confidence interval [CI], 0.06‐0.44) and 3 years (−2.75 vs. −3.41 mL/min/1.73m2: difference, 0.66 mL/min/1.73m2; 95% CI, 0.39‐0.93). In the eGFR less than 45 mL/min/1.73m2 group, propensity score matching created 2086 pairs. After a mean of 2.2 years of observation, ESKD development was 1.15% and 2.30% in users and non‐users, respectively, and Kaplan–Meier analysis revealed a significant difference (log rank P =.005). Conclusions: This retrospective real‐world study revealed that patients using DPP‐4is had a better renal prognosis than those not using DPP‐4is. [ABSTRACT FROM AUTHOR]

Prevalensi diabetes melitus tipe 2 (DMT2) meningkat, sehingga manajemen terapi yang efektif dan cost-effective sangat penting. Kombinasi metformin dengan dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) dan metformin dengan sulfonilurea (SU) merupakan terapi lini kedua pada pasien DMT2, masing-masing memiliki kelebihan dan kekurangan terkait biaya dan efektivitas. Review ini bertujuan untuk membandingkan hasil penelitian cost-effectiveness dari kedua kombinasi tersebut guna membantu praktisi kesehatan dalam membuat keputusan pemilihan terapi dalam pengelolaan DMT2. Review ini menganalisis temuan dari berbagai jurnal yang dipublikasikan secara online, menggunakan database SCOPUS dan PubMed serta mengikuti skema PRISMA dan PICO. Penelitian yang memenuhi kriteria pencarian adalah 75 studi, 35 di antaranya berasal dari Scopus dan 40 PubMed. Terdapat beberapa artikel dikecualikan dan didapatkan 5 studi yang memenuhi kriteria akhir kemudian dilakukan penilaian kualitas berdasarkan standar CHEERS 2022. Analisis menunjukkan bahwa kombinasi DPP-4 inhibitor dan metformin lebih efektif dibandingkan kombinasi sulfonilurea dan metformin dalam mengelola diabetes melitus tipe 2, temuan ini didukung oleh pemelitian dari berbagai negara, menunjukkan pengurangan risiko hipoglikemia dan peningkatan kualitas hidup pasien. Tinjauan sistematis ini menunjukkan bahwa kombinasi DPP-4 inhibitor dengan metformin adalah terapi lini kedua yang cost effective dibandingkan dengan kombinasi sulfonilurea dan metformin untuk penderita diabetes melitus tipe 2.

Abstract Impaired function of the retinal neurovascular unit (NVU) is an early event in diabetic retinopathy (DR). It has been previously shown that topical delivery of the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin can protect against diabetes-mediated dysfunction of the retinal NVU in the db/db mouse. The aim of the present study was to examine whether sitagliptin could prevent the DR-like lesions within the NVU of the new non-diabetic model of DR, the Trpv2 knockout rat (Trpv2 +/−). For that purpose, at 3 months of age, Trpv2 +/− rats were topically treated twice daily for two weeks with sitagliptin or PBS-vehicle eyedrops. Trpv2 +/+ rats treated with vehicle served as the control group. Body weight and glycemia were monitored. Optical coherence tomography recordings, fundus images and retinal samples were obtained to evaluate sitagliptin effects. The results revealed that sitagliptin eye drops had no effect on body weight or glycemia. Vehicle-treated Trpv2 +/− rats exhibited retinal thinning and larger diameters of major retinal blood vessels, upregulation of inflammatory factors and oxidative markers, glial activation and formation of acellular capillaries. However, topical administration of sitagliptin significantly prevented all these abnormalities. In conclusion, sitagliptin eye drops exert a protective effect against DR-like lesions in Trpv2 +/− rats. Our results suggest that sitagliptin eye drops carry significant potential to treat not only early-stages of DR but also other diseases with impairment of the NVU unrelated to diabetes.

Aim: To evaluate the efficacy and safety of gemigliptin and dapagliflozin dual add‐on therapy (GEMI + DAPA) to metformin in type 2 diabetes (T2D) patients who had inadequate glycaemic control on metformin alone, compared with a single add‐on of either gemigliptin (GEMI) or dapagliflozin (DAPA) to metformin. Materials and Methods: In this randomized, double‐blind, double‐dummy, active‐controlled, parallel‐group, phase 3 study, 469 T2D patients treated with a stable dose of metformin for 8 weeks or longer were randomized to receive GEMI + DAPA (n = 157) and either GEMI (n = 156) or DAPA (n = 156). The primary endpoint was change in HbA1c levels from baseline at week 24. Results: Baseline characteristics including body mass index and T2D duration were similar among groups. At week 24, the least square mean changes in HbA1c from baseline were −1.34% with GEMI + DAPA, −0.90% with GEMI (difference between GEMI + DAPA vs. GEMI −0.44% [95% confidence interval {CI}: −0.58% to −0.31%], P <.01) and −0.78% with DAPA (difference between GEMI + DAPA vs. DAPA −0.56% [95% CI: −0.69% to −0.42%], P <.01). Both upper CIs were less than 0, demonstrating the superiority of GEMI + DAPA for lowering HbA1c. The rates of responders achieving HbA1c less than 7% and less than 6.5% were greater with GEMI + DAPA (84.9%, 56.6%) than with GEMI (55.3%, 32.2%) and DAPA (49.3%, 15.3%). The incidence rate of adverse events was similar across groups, with low incidence rates of hypoglycaemia, urinary tract infection and genital infection. Conclusions: These results suggest that the addition of GEMI + DAPA to metformin as triple combination therapy was effective, safe and well‐tolerated, especially for T2D patients who experienced poor glycaemic control on metformin alone. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add‐on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). Materials and Methods: This multicentre, randomized, 104‐week, open‐label trial randomized 105 patients with drug‐naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. Results: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was −2.56% in the TCT group vs. –2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P =.027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P <.001). TCT was well‐tolerated and had fewer adverse events than SAT. Conclusions: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients. [ABSTRACT FROM AUTHOR]

Background: Limited direct comparative studies exist in terms of the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) on the kidney outcomes in Japanese individuals with type 2 diabetes. Methods: This retrospective cohort study included 561 Japanese adults with type 2 diabetes, who were newly prescribed either an SGLT2i or a DPP4i and had an eGFR ≥ 30 mL/min/1.73 m2. The cohort comprised 207 women and 354 men, with a mean (± standard deviation) age of 63 (± 12) years. The exposure and outcome were SGLT2i or DPP4i initiation and eGFR slope during the overall follow-up period, restricted to participants who were followed for ≥2 years. We adopted the on-treatment analysis. Analysis of covariance was used to compare the adjusted eGFR slope between the two groups, incorporating 10 variables at baseline. Results: During the median follow-up period of 3.4 years, least square mean (95% CI) eGFR slopes were −1.91 (−2.15, −1.67) and −1.12 (−1.58, −0.67) mL/min/1.73 m2/year in individuals treated with a DPP4i (n = 460) and an SGLT2i (n = 101), respectively, demonstrating statistical significance (p = 0.002). The robustness of this finding was strengthened by sensitivity analyses. Conclusions: This study provides potential evidence of the superiority of SGLT2is over DPP4is in slowing kidney function decline in Japanese adults with type 2 diabetes and eGFR ≥ 30 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Purpose: The role of lower hemoglobin A1c (HbA1c) variability in the effect of sodium glucose cotransporter‐2 inhibitors (SGLT2i) on acute kidney injury (AKI) remains unclear. We compared AKI risk between SGLT2i and dipeptidyl peptidase 4 inhibitors (DPP4i) initiators. Additionally, we aimed to explore the extent to which SGLT2i's influence on AKI risk is mediated by reducing long‐term HbA1c variability. Methods: Using 2018–2022 year data in Yinzhou Regional Health Care Database, we included adult, type 2 diabetes patients who were new users of SGLT2i or DPP4i. The effect of SGLT2i versus DPP4i on AKI, HbA1c variability, and AKI through HbA1c variability was compared using inverse probability of treatment weighted Cox proportional hazards models, median regression models, and causal mediation analysis. Results: With a median follow‐up of 1.76 years, 19 717 adults (for SGLT2i, n = 6008; for DPP4i, n = 13 709) with type 2 diabetes were included. The adjusted hazard ratio for SGLT2i versus DPP4i was 0.79 (95% confidence interval [CI] 0.64–0.98) for AKI. The adjusted differences in median HbA1c variability score (HVS) and HbA1c reduction were −16.67% (95% CI: −27.71% to −5.62%) and −1.98% (95% CI: −14.34% to 10.38%), respectively. Furthermore, lower AKI risk associated with SGLT2i was moderately mediated (22.77%) through HVS. The results remained consistent across various subgroups and sensitivity analyses. Conclusions: Compared to DPP4i, lower AKI risk associated with SGLT2i is moderately mediated through HbA1c variability. These findings enhance our understanding of the effect of SGLT2i on AKI and underscore the importance of considering HbA1c variability in diabetes treatment and management. [ABSTRACT FROM AUTHOR]

AimsThe aim of this study is to directly compare the effects of SGLT2 inhibitors and DPP-4 inhibitors on β-cell function in patients with type 2 diabetes.Materials and methodsWe conducted a 26-week, randomized, open-label, parallel-group study, including a 1-2 week drug washout period, in patients with type 2 diabetes with HbA1c ≥7.0% and

Dipeptidyl peptidase-4 (DPP-4) inhibitors belong to a prominent group of pharmaceutical agents that are used in the governance of type 2 diabetes mellitus (T2DM). They exert their antidiabetic effects by inhibiting the incretin hormones like glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide which, play a pivotal role in the regulation of blood glucose homoeostasis in our body. DPP-4 inhibitors have emerged as an important class of oral antidiabetic drugs for the treatment of T2DM. Surprisingly, only a few 2D-QSAR studies have been reported on DPP-4 inhibitors. Here, fragment-based QSAR (Laplacian-modified Bayesian modelling and Recursive partitioning (RP) approaches have been utilized on a dataset of 108 DPP-4 inhibitors to achieve a deeper understanding of the association among their molecular structures. The Bayesian analysis demonstrated satisfactory ROC values for the training as well as the test sets. Meanwhile, the RP analysis resulted in decision tree 3 with 2 leaves (Tree 3: 2 leaves). This present study is an effort to get an insight into the pivotal fragments modulating DPP-4 inhibition. [ABSTRACT FROM AUTHOR]

Ethnobotanically in Indonesia, Diospyros celebica Bakh is recognized as having antidiabetic activity. This study aimed to isolate antidiabetic compounds from the leaves of Eboni (Diospyros celebica). D. celebica leaves were dried and extracted with 96% ethanol, then fractionated and purified guided by antioxidant activity test, a-glucosidase inhibitory test, and dipeptidyl peptidase-4 (DPP-4) inhibitory test until bioactive isolates were obtained. The isolates were identified and their structures were determined based on NMR 1H, 13C, 2D, and LCMS/MS spectroscopic data. Extracts and fractions have potential antioxidant (DPPH), glucosidase inhibitor, and DPP-4 inhibitor activities as well as containing flavonoids and polyphenols. From the ethyl acetate fraction, isolate 26a-2 namely 3,5-digalloyl-(-)- epiafzelechin was obtained which was active as a DPPH scavenger, glucosidase inhibitor, and DPP4 inhibitor. The extracts, fractions, and flavonoid compounds in D. celebica leaves have the potential for antidiabetic drug candidates. [ABSTRACT FROM AUTHOR]

Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies. [ABSTRACT FROM AUTHOR]

The worldwide incidence of type 2 diabetes mellitus (T2DM), a chronic metabolic disorder, is increasing rapidly. A newer category of oral hypoglycemic medications called dipeptidyl peptidases-4 (DPP-4) inhibitors has come into existence for the management of T2DM. DPP-4 inhibitors, i.e., linagliptin, saxagliptin, and sitagliptin, belong to BCS class III, while alogliptin belongs to BCS class I. These drugs have high aqueous solubility and, therefore, short elimination half-life which necessitates the need for multiple daily dosing. Furthermore, the unrestrained drug release from conventional tablets can cause elevation in systemic drug concentrations which might instigate gastrointestinal side effects. The poor membrane permeability of BCS class III drugs also results in their poor oral bioavailability. Therefore, clinical compliance and therapeutic efficacy of DPP-4 inhibitors can be enhanced by nanotechnology-based techniques. This research paper has described various risk factors and pathophysiology of T2DM and also explained about the mode of action of DPP-4 inhibitors. The main objectives and rationale of this review include the exploration of preclinical pharmacological investigations and the summarization of developed nanoformulations of DPP-4 inhibitors researched in previous decades. The nanoformulations which has been synthesized for DPP-4 inhibitors in the past few decades for the management of T2DM include polymeric nanoparticle, solid lipid nanoparticle, transferosomes, niosomes, mucoadhesive nanoparticle, and self-microemulsifying drug delivery systems. [ABSTRACT FROM AUTHOR]

Aim: To employ a model‐informed drug development approach in facilitating decision making and expediting the clinical progress of cofrogliptin (HSK7653), a novel ultralong‐acting dipeptidyl peptidase‐4 (DPP‐4) inhibitor, for the treatment of type 2 diabetes (T2D) via a biweekly dosing regimen. Methods: Firstly, a population pharmacokinetics and pharmacodynamics (PopPKPD) model was developed using PK and PD data from a single ascending dose study to simulate the PK and PD time profiles of HSK7653 after multiple doses. Secondly, model‐based meta‐analysis (MBMA) was performed on published clinical studies of Eastern Asian subjects for all DPP‐4 inhibitors. We hypothesized a consistent relationship between PK and DPP‐4 inhibition in both healthy individuals and in those with T2D, establishing a quantitative correlation between DPP‐4 inhibition and HbA1c. Finally, the predicted PK/DPP‐4 inhibition/HbA1c profiles were validated by T2D patients in late clinical trials. Results: The PK/DPP‐4 inhibition/HbA1c profiles of T2D patients treated with HSK7653 matched the modelled data. Our PopPKPD and MBMA models predict multiple ascending dosing PK and PD characteristics from single ascending dosing data, as well as the long‐term efficacy in T2D patients, based on healthy subjects. Conclusions: Successful waiver approval for the phase 2b dose‐finding study was achieved through model‐informed recommendations, facilitating the clinical development of HSK7653 and other DPP‐4 inhibitors. [ABSTRACT FROM AUTHOR]

Introduction: This study assessed the safety, tolerability, and PK/PD of HSK7653 tablets in Chinese patients with type 2 diabetes mellitus (T2DM). Methods: This was a Phase IIa, multicenter, randomized, double-blind, placebo-controlled, and dose-increasing study with 48 Chinese diabetes patients. Subjects were randomly assigned to placebo and 10/25/50 mg dose groups, and they received oral administration once every two weeks for a total of six times. Safety and tolerability were assessed throughout this study, and PK/PD parameters were analyzed using non-compartment model with WinNonlin. Results: The three doses of HSK7653 were well tolerated, and the incidence of TEAE and ADR was not significantly increased compared with the placebo group. Cmax increased linearly with the increasing dose, and the mean t1/2 was 64.0–87.0 h. The first dose and last dose PK parameters were similar. After oral administration of 10–50 mg HSK7653 every two weeks, the average Rac_Cmax and Rac_AUC were 0.9–1.0 and 1.0–1.1 respectively; therefore, HSK7653 was not accumulated in vivo. All three doses significantly inhibited DPP-4 activity and increased plasma GLP-1 level and serum insulin levels. When the plasma concentration of HSK7653 was ≥ 20.0 ng/mL, the DPP-4 inhibition rate in all subjects was maintained at > 80.0%. In 10 and 25 mg dose groups, the HbA1c levels maintained a downward trend compared with the placebo group. Discussion: HSK7653 showed desirable pharmacokinetic and pharmacodynamic properties with good safety and tolerability in Chinese T2DM patients. DPP-4 inhibition rate and plasma GLP-1 levels were higher in each dose group than in placebo group. Trial Registration Number: CTR20182505 (Drug Clinical Trial Registration and Information Disclosure Platform, www.chinadrugtrials.org.cn). [ABSTRACT FROM AUTHOR]

Abstract Small animal models have shown improved cardiac function with DPP‐4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP‐4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post‐op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non‐ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p

Aims: To assess post‐initiation predictors of discontinuation of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors compared to dipeptidyl‐peptidase‐4 (DPP‐4) inhibitors in the United Kingdom. Materials and Methods: We conducted a comparative population‐based retrospective cohort study using primary care data from the UK Clinical Practice Research Datalink (CPRD) with linked data to hospital and death records. We included new metformin users who initiated either SGLT2 inhibitors or DPP‐4 inhibitors between January 2013 and October 2019. The main outcome was treatment discontinuation, defined as the first 90‐day gap after the estimated treatment end date. We used a series of extended Cox models to assess which time‐dependent predictors were associated with treatment discontinuation. To test if the hazard ratio of discontinuation for each predictor was statistically different between SGLT2 and DPP‐4 inhibitors, an exposure‐predictor interaction term was added to each model. Results: There were 2550 new users of SGLT2 inhibitors and 8195 new users of DPP‐4 inhibitors. Approximately 69% of SGLT2 inhibitor and 74% of DPP‐4 inhibitor users had discontinued treatment by the end of follow‐up. Occurrence of fractures after treatment initiation was a significant predictor of discontinuation of SGLT2 inhibitors (hazard ratio [HR] 4.13, 95% confidence interval [CI] 2.12‐8.06) but not DPP‐4 inhibitors (HR 0.93, 95% CI 0.79‐1.11). The rate of treatment discontinuation was significantly higher for those with low estimated glomerular filtration rate and minimal contact with the healthcare system. Efficacy endpoints, such as heart failure and glycated haemoglobin level, were not associated with treatment discontinuation. Conclusions: Our findings reflect some discrepancy between the available evidence and prescribing behaviour for SGLT2 inhibitors. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether sodium‐glucose cotransporter‐2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase‐4 (DPP‐4) inhibitor use as add‐on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). Methods: A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first‐ever prescription for a DPP‐4 inhibitor or an SGLT2 inhibitor as add‐on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP‐4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP‐4 inhibitor use. Results: A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP‐4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP‐4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91‐1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64‐1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. Conclusion: Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP‐4 inhibitor use. [ABSTRACT FROM AUTHOR]

The aim of this study is to reveal the effects of the use of linagliptin, a DPP‐4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT‐PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p‐JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims/Introduction Although the association between dipeptidyl peptidase‐4 (DPP‐4) inhibitors and bullous pemphigoid (BP) has begun to be established, some studies have suggested there are risk differences among DPP‐4 inhibitors. We conducted a population‐based cohort study to examine the risk differences. Materials and Methods Using the claims databases of the Fukuoka Prefecture Wide‐Area Association of Latter‐Stage Elderly Healthcare between April 1, 2013 and March 31, 2017, we conducted a retrospective cohort study to compare patients receiving one DPP‐4 inhibitor with those who were prescribed another antidiabetic drug. The primary outcome was an adjusted hazard ratio (HR) of the development of bullous pemphigoid during a 3‐year follow‐up. The secondary outcome was the development of BP requiring systemic steroids immediately after the diagnosis. These were estimated using Cox proportional hazards regression models. Results The study comprised 33,241 patients, of which 0.26% (n = 88) developed bullous pemphigoid during follow‐up. The percentages of patients with bullous pemphigoid who required immediate systemic steroid treatment was 0.11% (n = 37). We analyzed four DPP‐4 inhibitors: sitagliptin, vildagliptin, alogliptin, and linagliptin. Vildagliptin and linagliptin raised the risk of BP significantly (primary outcome, vildagliptin, HR 2.411 [95% confidence interval (CI) 1.325–4.387], linagliptin, HR 2.550 [95% CI 1.266–5.136], secondary outcome, vildagliptin HR 3.616 [95% CI 1.495–8.745], linagliptin HR 3.556 [95% CI 1.262–10.024]). A statistically significant risk elevation was not observed with sitagliptin and alogliptin (primary outcome, sitagliptin, HR 0.911 [95% CI 0.508–1.635], alogliptin, HR 1.600 [95% CI 0.714–3.584], secondary outcome, sitagliptin, HR 1.192 [95% CI 0.475–2.992], alogliptin, HR 2.007 [95% CI 0.571–7.053]). Conclusions Not all the DPP‐4 inhibitors could induce bullous pemphigoid significantly. Therefore, the association warrants further investigations before generalization.

Naoyuki Akashi,1 Tomio Umemoto,1 Hodaka Yamada,2 Takayuki Fujiwara,3 Kei Yamamoto,1 Yousuke Taniguchi,1 Kenichi Sakakura,1 Hiroshi Wada,1 Shin-ichi Momomura,1 Hideo Fujita1 1Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan; 2Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, Saitama, Japan; 3Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, JapanCorrespondence: Tomio Umemoto, Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan, Tel +81-48-647-2111, Fax +81-48-648-5188, Email to-ume@omiya.jichi.ac.jpPurpose: Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endothelial progenitor cells (EPCs) in peripheral blood circulation. However, the underlying mechanisms and effects on vascular endothelial function remain unclear. We evaluated whether the DPP-4 inhibitor teneligliptin increases circulating EPCs by inhibiting stromal-derived factor-1α (SDF-1α) and improves flow-mediated vascular dilatation (FMD) in type 2 diabetes mellitus patients with acute coronary syndrome (ACS) or its risk factors.Patients and Methods: This single-center, open-label, prospective, randomized controlled trial evaluated 17 patients (hemoglobin A1c ≤ 7.5% and peak creatinine phosphokinase < 2000 IU/mL) with ACS or a history of ACS or multiple cardiovascular risk factors. Metabolic variables of glucose and lipids, circulating EPCs, plasma DPP-4 activity, and SDF-1α levels, and FMD were evaluated at baseline and 28 ± 4 weeks after enrollment. Patients were randomly assigned to either the teneligliptin (n = 8) or control (n = 9) groups.Results: The DPP-4 activity (∆− 509.5 ± 105.7 vs ∆32.8 ± 53.4 μU/mL) and SDF-1α levels (∆− 695.6 ± 443.2 vs ∆11.1 ± 193.7 pg/mL) were significantly decreased after 28 weeks in the teneligliptin group than those in the control group. The number of EPCs showed an increasing trend in the teneligliptin treated group; albeit this did not reach statistical significance. Glucose and lipid levels were not significantly different between the groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group when compared to the control group (∆3.8% ± 2.1% vs ∆− 0.3% ± 2.9%, P=0.006).Conclusion: Teneligliptin improved FMD through a mechanism other than increasing the number of circulating EPCs.Keywords: endothelial progenitor cell, teneligliptin, DPP-4 inhibitor, flow-mediated dilation, type 2 diabetes mellitus

Purpose: To report a rare Ocular Cicatricial Pemphigoid (OCP) case in a patient taking a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), a medication used for the management of type 2 diabetes, for at least six years. Observations: A 64-year-old male presented with refractory bilateral conjunctival inflammation and ocular discharge that had persisted for two months, despite multiple prior therapies for presumed bacterial conjunctivitis. Upon initial examination, clinical findings strongly suggested OCP, and he had elevated levels of anti-BP180 antibodies. Despite receiving systemic treatments such as steroid pulse therapy and therapeutic plasma exchange after discontinuing DPP-4 inhibitors, his condition progressively worsened, with manifestations such as forniceal shortening in his left eye. Consequently, the patient required keratoepithelioplasty, amniotic membrane transplantation in his left eye, and bilateral eyelid entropion surgery. His condition initially worsened for a time after discontinuing the DPP-4 inhibitor, but it gradually improved over time, and ocular surface surgical intervention was not required in the right eye. Conclusions and Importance: The findings in this study demonstrate that severe refractory OCP may occur while taking the DPP-4 inhibitor, thus indicating that a detailed interview regarding medications is essential for patients with ocular pemphigoid, especially those with type 2 diabetes.

Objective: Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. Methods: Expression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. Results: Autophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet–fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. Conclusions: Collectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy.

The association between immunoregulatory cytokines, such as interleukin (IL)‐10 or IL‐35, and dipeptidyl peptidase‐4 inhibitor (DPP4i)‐related bullous pemphigoid (BP) has not been evaluated. Serum IL‐10 and IL‐35 levels were measured in 39 patients with BP (24 males and 15 females; 6 DPP4i‐related and 33 DPP4i‐unrelated BP patients) and 10 healthy controls. The number of CD26+ cells in the dermis around bulla on sections was counted immunohistochemically for 12 patients (six patients with DPP4i‐related BP and six randomly sampled patients with DPP4i‐unrelated BP). Patients with DPP4i‐related BP had lower levels of serum eosinophils (DPP4i‐related vs. DPP4i‐unrelated BP: 476.1 ± 234.0 vs. 911.3 ± 948.8/μL; p = 0.537) and a higher rate of infiltrating CD26+ cells (32.9 ± 7.1% vs. 15.7 ± 4.4%; p = 0.01). There were no significant differences in serum IL‐10 (6.77 ± 0.24 vs. 6.84 ± 0.20 pg/mL), serum IL‐35 (2.63 ± 0.17 vs. 2.63 ± 0.21 pg/mL), serum anti‐BP180NC16a antibodies (67.31 ± 37.4 vs. 76.18 ± 54.59 U/mL) and Bullous Pemphigoid Disease Area Index before treatment in this study. Serum IL‐10 and IL‐35 levels do not increase in patients with BP and may not be a candidate for a therapeutic target for BP. An increase in CD26+ cells might be associated with DPP4i‐related BP. [ABSTRACT FROM AUTHOR]

The differences in baseline could be explained by the differences in pathophysiology as type 1 diabetes is primarily characterized as an autoimmune disease, whereas type 2 diabetes is characterized by chronic inflammation. *p < 0.05; **p < 0.01 gl CONCLUSIONS Previous studies have established the anti-inflammatory effects of ARBs, DPP-4 inhibitors, SGLT2 inhibitors and baricitinib in individuals with type 1 diabetes or type 2 diabetes. Keywords: ARB; baricitinib; DPP-4 inhibitor; empagliflozin; inflammation; inflammatory markers; JAK-STAT inhibitor; linagliptin; SGLT2 inhibitor; telmisartan EN ARB baricitinib DPP-4 inhibitor empagliflozin inflammation inflammatory markers JAK-STAT inhibitor linagliptin SGLT2 inhibitor telmisartan 2413 2418 6 07/04/23 20230801 NES 230801 BACKGROUND Inflammation plays an important role in the initiation and progression of kidney function decline in individuals with diabetes.[1] In experimental models of diabetes and chronic kidney disease (CKD), interventions with drugs commonly used to treat cardiovascular and kidney complications have shown anti-inflammatory effects, including angiotensin receptor blockers (ARBs),[[2], [4]] sodium-glucose co-transporter-2 (SGLT2) inhibitors,[[5], [7]] dipeptidyl peptidase-4 (DPP-4) inhibitors,[[8], [10]] and Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors.[[11]] In clinical studies, treatment with renin-angiotensin-aldosterone-system inhibitors, SGLT2 inhibitors, DPP-4 inhibitors and JAK-STAT inhibitors has also been shown to exert anti-inflammatory effects.[[5], [11], [13], [15]] The follow-up of most previous studies was more than 6 months. Overall, the concentrations of the inflammation markers were lower in participants with type 1 diabetes compared with those with type 2 diabetes (Table 1). 1 TABLE Baseline characteristics of the total, ROTATE-1 and ROTATE-2 participants. [Extracted from the article]

Aim: To investigate the effects of gemigliptin on cardiac function and compare the effects of gemigliptin and glimepiride in patients with type 2 diabetes (T2D). Materials and Methods: Sixty T2D patients being treated with metformin were assigned to a gemigliptin group (50 mg daily) or a glimepiride group (2 mg daily) for 24 weeks. The preadjudicated extension period was up to 52 weeks. Glucose metabolism variables and cardiac biomarkers were measured. Echocardiography was used to evaluate cardiac functions. Results: The HbA1c levels decreased significantly from 8.1% ± 0.6% to 6.8% ± 0.6% in the gemigliptin group and from 8.1% ± 0.6% to 7.0% ± 0.7% in the glimepiride group, without a between‐group difference. Gemigliptin reduced insulin resistance, high sensitivity C‐reactive protein and low‐density lipoprotein cholesterol levels, and blood pressure, and increased adiponectin level compared with glimepiride therapy. Gemigliptin induced favourable changes in body composition. Left ventricular end‐diastolic volume decreased in the gemigliptin group but increased in the glimepiride group, with a borderline between‐group difference. Cardiac biomarkers did not change significantly in either group. At 52 weeks, the HbA1c levels in both groups increased slightly; 7.3% ± 0.8% in the gemigliptin group versus 7.7% ± 1.3% in the glimepiride group, without a between‐group difference. Conclusions: Gemigliptin had a comparable glucose‐lowering efficacy without deleterious effects on cardiac functions or on biomarkers reflective of myocardial injury or heart failure during the 24‐week observation period. However, larger, longer‐term studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Aims: The purpose of this study is to investigate the regulation of adipose tissue insulin resistance with DPP-4 inhibitors in treatment-naive subjects with T2DM and to examine its relation to other diabetic parameters. Subjects and methods: A total of 147 subjects were treated with alogliptin 12.5–25 mg/day (n = 55), sitagliptin 25–50 mg/day (n = 49), or teneligliptin 10–20 mg/day (n = 43) monotherapy for 3 months. Changes in adipo-IR, a mathematical model used to evaluate adipose tissue insulin resistance, and various diabetic parameters were analyzed in this prospective, non-randomized observational study. Results: Among these three drugs, only alogliptin significantly reduced adipo-IR (−25.9%, p < 0.004) and some lipid parameters, such as LDL-C, T-C/HDL-C, log(TG)/HDL-C, non-HDL-C/HDL-C, and LDL-C/HDL-C. Subjects in the alogliptin group were divided into two groups with distinct changes in adipo-IR. Group A had a significant decrease in adipo-IR (−56.5%, p < 0.00001, n = 28), whereas group B had an insignificant increase (19.1%, p = 0.055, n = 27). Significant reductions in FBG or HbA1c were observed in groups A and B, respectively. Group A also showed significant reductions in HOMA-R, T-C/HDL-C, TG, log(TG)/HDL-C, non-HDL-C/HDL-C, LDL-C/HDL-C, and FFA, as well as increases in QUICKI or HDL-C. In contrast, group B showed significant reductions in QUICKI or LDL-C, and increases in HOMA-R, insulin, HOMA-B, C-peptide, or CPR-index. Conclusions: In contrast to other tested DPP-4 inhibitors, alogliptin demonstrated the ability to down-regulate insulin resistance in adipose tissue, as well as certain atherogenic lipids. This study provides the initial evidence of a DPP-4 inhibitor's potential to regulate adipose tissue insulin resistance. Furthermore, adipo-IR is associated with non-LDL-C lipid parameters instead of glycemic control in those receiving alogliptin. [ABSTRACT FROM AUTHOR]

Objective: In patients with type 2 diabetes who were inadequately controlled with metformin and sulphonylurea, we compared the glucose‐lowering efficacy, cardiometabolic parameters and safety of two drugs, ipragliflozin, a sodium‐glucose cotransporter‐2 inhibitor, and sitagliptin, a dipeptidyl peptidase‐4 inhibitor. Materials and Methods: Patients with 7.5%‐9.0% glycated haemoglobin treated with metformin and sulphonylurea were randomly assigned to ipragliflozin (50 mg, n = 70) or sitagliptin (100 mg, n = 70) therapy for 24 weeks. Measures of glycaemic control, fatty liver indices, other metabolic parameters and subclinical atherosclerosis were compared by a paired t‐test before and after 24 weeks of treatment. Results: Mean glycated haemoglobin levels decreased from 8.5% to 7.5% in the ipragliflozin group and from 8.5% to 7.8% in the sitagliptin group, resulting in a 0.34% between‐group difference (95% confidence interval, 0.10%‐0.43%, p =.088). Fasting and postprandial 2‐h glucose levels also showed a similar trend, with a greater reduction with ipragliflozin therapy. An increase of over 70% in ketone levels and a decrease in whole body and abdominal fat masses were observed with ipragliflozin treatment. Fatty liver indices also improved with ipragliflozin treatment. Despite no difference in carotid intima‐media thickness and ankle‐brachial index, ipragliflozin therapy improved flow‐mediated vasodilation, reflecting endothelial function, while sitagliptin did not. The safety profile did not differ between the two groups. Conclusions: Ipragliflozin add‐on therapy can be a viable option for better glycaemic control with multiple vascular and metabolic benefits in patients with type 2 diabetes who are inadequately controlled with metformin and sulphonylurea. [ABSTRACT FROM AUTHOR]

Yesong Shin,1 Chungam Choi,2 Eun Sil Oh,2,3 Choon Ok Kim,2 Kyungsoo Park,1 Min Soo Park2– 4 1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea; 2Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, Yonsei University Health System, Seoul, Korea; 3Department of Pharmaceutical Medicine and Regulatory Science, Graduate Inter Program, Yonsei University College of Medicine, Seoul, Korea; 4Department of Pediatrics, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Min Soo Park, Department of Clinical Pharmacology, Severance Hospital, Yonsei University Health System, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea, Tel +82-2-2228-0400, Fax +82-31-787-4045, Email minspark@yuhs.acPurpose: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics.Patients and Methods: An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference.Results: Maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC0-96h) of evogliptin with and without co-administration of rifampicin were compared. Reference and test Cmax and AUC0-96h values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration.Conclusion: Rifampicin decreased the AUC0-96h of evogliptin by 61.8% without significantly affecting Cmax. The mechanism underlying the decrease in AUC0-96h is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.Keywords: drug–drug interaction, DPP-4 inhibitor, CYP3A inducer, evogliptin, rifampicin

The role of gut-kidney crosstalk in the progression of diabetic nephropathy (DN) is receiving increasing concern. On one hand, the decline in renal function increases circulating uremic toxins and affects the composition and function of gut microbiota. On the other hand, intestinal dysbiosis destroys the epithelial barrier, leading to increased exposure to endotoxins, thereby exacerbating kidney damage by inducing systemic inflammation. Dietary inventions, such as higher fiber intake, prebiotics, probiotics, postbiotics, fecal microbial transplantation (FMT), and engineering bacteria and phages, are potential microbiota-based therapies for DN. Furthermore, novel diabetic agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, may affect the progression of DN partly through gut microbiota. In the current review, we mainly summarize the evidence concerning the gut-kidney axis in the advancement of DN and discuss therapies targeting the gut microbiota, expecting to provide new insight into the clinical treatment of DN.

Introduction: Chronic kidney disease (CKD) poses a financial burden on most patients from low/middle income countries. Glycaemic control with affordable hypoglycemic agents may influence on the prognosis of diabetic nephropathy. Objectives: We aimed to compare the rates of CKD progression and proteinuria in the type 2 diabetic population in response to the use of various hypoglycemic agents. Patients and Methods: A retrospective cross-sectional study of a total of 250 patients of Afro-Caribbean descent at the University hospital of the West Indies between 2018 and 2019 was conducted. The use of hypoglycaemic agents and changes in albuminuria were calculated as odds ratios with a 95% confidence interval (CI). A P value<0.05 was considered statistically significant. Results: Of 250 patients with diabetic nephropathy, the number of rapid CKD progression was highest in patients on insulin (26.3%). In comparison, number of rapid progressions in patients receiving metformin, dipeptidyl peptidase 4 (DPP-4 inhibitors), sulfonylurea and pioglitazone were 19.1%, 22.2%, 21.9% and 20%, respectively. After eliminating confounding factors, comparison within the group analysis on DPP-4 inhibitors (n= 171) demonstrated 62.6% significant improvement in quantitative proteinuria with reduction of mean spot urine albumin creatinine ratio (ACR) from 362.1 ± 338.9 mg/g to 303 ± 300.1 mg/g (ORs, 0.77; 95% CI 0.41 to 0.97; P = 0.03). Conclusion: Type 2 diabetic patients requiring insulin were found to have progression of CKD than patients on oral hypoglycaemic agents. Among the affordable oral hypoglycaemic agents, DPP-4 inhibitors had an association with reduction in albuminuria. [ABSTRACT FROM AUTHOR]

Aim: To investigate the possible effect of haemodialysis (HD) on the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of evogliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor. Methods: A single‐dose, open‐label, parallel‐group study of eight end‐stage renal disease (ESRD) patients and eight matched healthy subjects was conducted. ESRD patients received a single oral dose of evogliptin 5 mg after and before HD with a 2‐week washout between each dose, and healthy subjects received a single oral dose of evogliptin 5 mg. Serial blood, dialysate, and urine samples were collected to assess the PK and PD profiles of evogliptin. To compare PK parameters before and after HD, geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were calculated. Results: The GMRs for the maximum concentration and area under the concentration‐time curve from time 0 to the last measurable timepoint (AUClast) of evogliptin when administered before HD compared with after HD were 0.7293 (90% CI 0.6171‐0.8620) and 0.9480 (90% CI 0.8162‐1.1010), respectively. The maximum DPP‐4 inhibitory effect, area under the DPP‐4 inhibitory effect‐time curve, and time duration of more than 80% DPP‐4 inhibition were comparable when evogliptin was administered before and after HD. Compared with healthy subjects, the mean AUClast of evogliptin was approximately 1.4‐fold greater in ESRD patients, but the difference is unlikely to affect the safety and efficacy of evogliptin. Conclusion: The effect of HD on the PK and PD characteristics of evogliptin was not clinically significant; therefore, dose adjustment according to HD status is not necessary. [ABSTRACT FROM AUTHOR]

Aim: To determine whether the twice‐daily (BID) regimen is superior to the once‐daily (QD) regimen for managing glycaemic variability by comparing the effects of anagliptin 100 mg BID versus sitagliptin 100 mg QD. Materials and Methods: A double‐blinded, randomized, multicentre study was performed in 89 patients with type 2 diabetes treated with metformin alone (6.5% < HbA1c < 8.5%). Subjects were randomly assigned to anagliptin 100 mg BID or sitagliptin 100 mg QD in a 1:1 ratio for 12 weeks. Continuous glucose monitoring was used to measure the mean amplitude of glycaemic excursion (MAGE) and postprandial time in range (TIR) before and after dipeptidyl peptidase‐4 (DPP‐4) inhibitor treatment to compare glycaemic variability. Results: The decrease from baseline in MAGE at 12 weeks after DPP‐4 inhibitor treatment was significantly greater in the anagliptin BID group than in the sitagliptin QD group (P <.05); −30.4 ± 25.6 mg/dl (P <.001) in the anagliptin group versus −9.5 ± 38.0 mg/dl (P =.215) in the sitagliptin group. The TIR after dinner increased by 33.0% ± 22.0% (P <.001) in the anagliptin group and by 14.6% ± 28.2% (P =.014) in the sitagliptin group, with a statistically significant difference (P =.009). No statistically significant differences were observed between the groups in the changes in HbA1c and fasting plasma glucose (FPG). Conclusions: The anagliptin BID regimen for the treatment of type 2 diabetes was superior in blood glucose control after dinner to improve glycaemic variability, as indicated by MAGE and TIR, but was equivalent to the QD regimen in terms of HbA1c and FPG. [ABSTRACT FROM AUTHOR]

Metabolic diseases, particularly diabetes mellitus (DM), are significant global public health concerns. Despite the widespread use of standard-of-care therapies, cardiovascular disease (CVD) remains the leading cause of death among diabetic patients. Early and evidence-based interventions to reduce CVD are urgently needed. Large clinical trials have recently shown that sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) ameliorate adverse cardiorenal outcomes in patients with type 2 DM. These quite unexpected positive results represent a paradigm shift in type 2 DM management, from the sole importance of glycemic control to the simultaneous improvement of cardiovascular outcomes. Moreover, SGLT2i is also found to be cardio- and nephroprotective in non-diabetic patients. Several mechanisms, which may be potentially independent or at least separate from the reduction in blood glucose levels, have already been identified behind the beneficial effect of these drugs. However, there is still much to be understood regarding the exact pathomechanisms. This review provides an overview of the current literature and sheds light on the modes of action of novel antidiabetic drugs, focusing on inflammation, oxidative stress, and fibrosis. [ABSTRACT FROM AUTHOR]

A 57-year-old Japanese man with type 2 diabetes presented with bilateral pitting edema and pain of the hands and feet two months after being initiated on a dipeptidyl peptidase-4 (DPP-4) inhibitor, alogliptin. Laboratory tests showed elevated levels of C-reactive protein, matrix metalloproteinase-3 and vascular endothelial growth factor, and a negative rheumatoid factor. The computed tomography scan showed swelling in the dominant right wrist joint, and joint ultrasonography showed synovial swelling. He was diagnosed with remitting seronegative symmetrical synovitis and pitting edema (RS3PE) syndrome. Alogliptin was discontinued and prednisolone was initiated, thereafter, his symptoms quickly improved. As for his glycemic control, his hemoglobin A1c (HbA1c) went from an initial 9.1% to 8.3% once alogliptin was initiated. However, after being diagnosed with RS3PE syndrome, his treatment was changed from alogliptin to metformin, and his HbA1c remained between 6% and 7%. The diagnosis of RS3PE syndrome should be considered if pitting edema and arthralgia in the extremities are observed after initiating patients with type 2 diabetes on DPP-4 inhibitors.

ABSTRACT Objective: The occurrence of partial remission (honeymoon phase) in type 1 diabetes (T1D) has been associated with a reduced risk of chronic microvascular complications of diabetes. We have published case reports showing that a combination therapy with the DPP-4 inhibitor sitagliptin plus vitamin D3 (VIDPP-4i) can prolong the honeymoon phase in patients with new-onset T1D. In the present case-control study, we investigated the frequency of occurrence of clinical remission (CR) in patients with new-onset T1D after VIDPP-4i treatment. Subjects and methods: In this case-control study, we collected data spanning 10 years from medical records of 46 patients (23 females) recently diagnosed with T1D. Overall, 27 participants with CR (insulin dose-adjusted glycated hemoglobin [IDAA1c] ≤ 9) at 12 or 24 months composed the case group, and 19 participants without CR served as the control group. Chi-square with Yates correction was used to analyze the association between VIDPP-4i use and CR, and odds ratio (OR) was used to determine the chance of CR due to VIDPP-4i treatment exposure. Results: In all, 37 patients (80.4%) experienced CR at some time over 24 months. The mean CR duration was 13.15 ± 9.91 months. Treatment with VIDPP-4i was significantly associated with CR. At 24 months, the OR of CR after VIDPP-4i exposure was 9.0 (95% confidence interval [CI] 2.21-30.18, p = 0.0036). Additionally, 9 (33.6%) and 4 (14.8%) patients in the VIDPP-4i group experienced insulin-free CR at 12 and 24 months, respectively. Conclusion: Therapy with VIDPP-4i was associated with a higher frequency and duration of the honeymoon phase. Randomized controlled trials are needed to confirm these findings.

Empagliflozin has a demonstrated cardiovascular benefit. It is co-prescribed as a glucose-lowering medication in patients with type II diabetes mellitus. Herein, we discuss dual-emergency side-effects, Fournier's gangrene (FG) and diabetic ketoacidosis with lower-than-anticipated glucose levels in a patient on Empagliflozin, a sodium-glucose transport protein 2 inhibitor (SGLT-2i). The pathophysiologic mechanism of FG in correlation with SGLT-2i is not yet elucidated. SGLT-2i increase predisposition to genital mycotic and urinary infections, a mechanism favouring FG. A patient with type II diabetes mellitus on SGLT-2i presented with acute necrotic infection of the scrotum and simultaneous diabetic ketoacidosis with lower-than-anticipated glucose levels. This dual emergency was managed with debridement and medical treatment on lines of diabetes ketoacidosis, respectively. A re-look at this group of glucose-lowering medications from bedside towards benchtop research may help to prod into any other mechanistic basis of these life-threatening clinical occurrences. [ABSTRACT FROM AUTHOR]

Cholesterol efflux is a major atheroprotective function of high-density lipoproteins (HDLs) which removes cholesterol from the foam cells of lipid-rich plaques in Type 2 diabetes. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin phosphate increases plasma glucagon-like peptide-1 (GLP-1) concentrations and is used to treat Type 2 diabetes. GLP-1 plays an important role in regulating insulin secretion and expression via the GLP-1 receptor (GLP-1R), which is expressed in pancreatic islets as well as freshly isolated human monocytes and THP-1 cells. Here, we identified a direct role of GLP-1 and DPP-4 inhibition in HDL function. Cholesterol efflux was measured in cultivated phorbol 12-myristate 13-acetate-treated THP-1 cells radiolabeled with 3H-cholesterol and stimulated with liver X receptor/retinoid X receptor agonists. Contrary to vildagliptin, sitagliptin phosphate together with GLP-1 significantly (p < 0.01) elevated apolipoprotein (apo)A1-mediated cholesterol efflux in a dose-dependent manner. The sitagliptin-induced increase in cholesterol efflux did not occur in the absence of GLP-1. In contrast, adenosine triphosphate-binding cassette transporter A1 (ABCA1) mRNA and protein expressions in the whole cell fraction were not changed by sitagliptin in the presence of GLP-1, although sitagliptin treatment significantly increased ABCA1 protein expression in the membrane fraction. Furthermore, the sitagliptin-induced, elevated efflux in the presence of GLP-1 was significantly decreased by a GLP-1R antagonist, an effect that was not observed with a protein kinase A inhibitor. To our knowledge, the present study reports for the first time that sitagliptin elevates cholesterol efflux in cultivated macrophages and may exert anti-atherosclerotic actions that are independent of improvements in glucose metabolism. Our results suggest that sitagliptin enhances HDL function by inducing a de novo HDL synthesis via cholesterol efflux. [ABSTRACT FROM AUTHOR]

We aimed to evaluate patient preferences towards three oral antihyperglycaemic therapies using conjoint analysis to determine which attributes may influence use. We used an online survey, completed by 553 US respondents with type 2 diabetes mellitus (T2DM; mean age 64 ± 9 years; 55% had cardiovascular [CV] risk; 27% had CV disease), to present hypothetical, blinded, pairwise, drug profile comparison choices, between different benefit/risk attributes and effect ranges. Attributes were derived from phase 3 trials for empagliflozin 25 mg (SGLT2 inhibitor), oral semaglutide 14 mg (GLP-1 receptor agonist) and sitagliptin 100 mg (DPP-4 inhibitor). Predicted therapy preference outcomes and relative importance of each attribute were calculated (presented as a percentage). Preference score was highest for the profile matching empagliflozin (56%), versus sitagliptin (38%; z-test, P < 0.001) and oral semaglutide (6%, z-test, P < 0.001). Results were overall consistent in subgroup analyses. Genital infection risk was the most important attribute (relative score: 19% [z-test, P = 0.077 ]). Other important attributes were fasting requirements (15%), weight reduction (15%), risk of vomiting (14%), CV benefit (12%), and risk of nausea (11%). HbA1c reduction (8%) and ability to take medication with other drugs (6%) were considered less important. While blinded to drug name/dose, respondents chose a drug profile similar to empagliflozin (41%) versus sitagliptin (31%), oral semaglutide (11%), or 'none of the options' (17%). While the drug profile comparable to empagliflozin was preferred, CV benefit was not the top patient priority. A shared physician-patient decision model and increased patient education are needed to ensure optimal use of guideline-directed T2DM therapies. • Novel research measuring patient preferences for new oral anti-diabetic treatment options (80/85 characters) • Patients seem to prefer a drug comparable to empagliflozin over sitagliptin or oral semaglutide (83/85 characters) • Increasing patient awareness of cardiovascular benefits of newer oral therapies is needed (79/85 characters) [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-4 (DPP-4) inhibitors have gained recognition as effective agents for lowering blood sugar levels, significantly improving glycemic control for individuals with type 2 diabetes mellitus (T2DM). Emodin, an anthraquinone derived from the traditional herbs rhubarb (Rheum officinale) and Polygonum cuspidatum , has been identified as an important component in the development of new treatments for diabetes. In the present work, we explored the DPP-4 inhibitory activity of emodin derivatives. This study focused on the design, synthesis, and evaluation of emodin derivatives for their in vitro DPP-4 inhibitory activity. Molecular docking studies indicated that 3- o -toluoyl emodin (OTEM) had the lowest docking score (−134.073) against the DPP-4 protein among the tested compounds. OTEM also achieved the highest drug-likeness score of 0.56 and demonstrated DPP-4 inhibitory activity, with an IC 50 value of 0.77 μM. Furthermore, structure-activity relationship (SAR) analysis suggested that the addition of an ortho-toluoyl group at the C-3 position could enhance DPP-4 inhibition. Additionally, quantitative structure-activity relationship (QSAR) model assessments revealed that log P was the only descriptor significantly influencing DPP-4 inhibitory activity. Therefore, the current study indicates that OTEM could serve as a promising lead compound to address the demand for antidiabetic agents. • Four emodin derivatives were designed and synthesized as DPP-IV inhibitors. • A molecular docking study showed that 3-ortho-toluoyl emodin exhibited the lowest docking score against the DPP-IV protein. • 3-ortho-toluoyl emodin could be considered as promising DPP-IV inhibitor drug candidate. • QSAR model showed that log P was affecting DPP-4 inhibitory activity. [ABSTRACT FROM AUTHOR]

Diabetes mellitus and associated chronic hyperglycemia enhance the risk of acute ischemic stroke and lead to worsened clinical outcome and increased mortality. However, post-stroke hyperglycemia is also present in a number of non-diabetic patients after acute ischemic stroke, presumably as a stress response. The aim of this review is to summarize the main effects of hyperglycemia when associated to ischemic injury in acute stroke patients, highlighting the clinical and neurological outcomes in these conditions and after the administration of the currently approved pharmacological treatment, i.e. insulin. The disappointing results of the clinical trials on insulin (including the hypoglycemic events) demand a change of strategy based on more focused therapies. Starting from the comprehensive evaluation of the physiopathological alterations occurring in the ischemic brain during hyperglycemic conditions, the effects of various classes of glucose-lowering drugs are reviewed, such as glucose-like peptide-1 receptor agonists, DPP-4 inhibitors and sodium glucose cotransporter 2 inhibitors, in the perspective of overcoming the up-to-date limitations and of evaluating the effectiveness of new potential therapeutic strategies.

Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta- Ins2 Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD. • Dual SGLT2 and DPP-4 inhibition exerts an additive effect on promoting natriuresis. • Enhanced natriuresis increases an afferent arteriolar vasoconstrictor release. • Enhanced natriuresis reduces an afferent arteriolar vasodilator secretion. • Such renal alterations attenuate intraglomerular hypertension in DKD. • Dual SGLT2 and DPP-4 inhibition offers higher renal benefits than SGLT2 inhibition. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of DBPR108 (prusogliptin), a novel dipeptidyl peptidase‐4 (DPP‐4) inhibitor, as an add‐on therapy in patients with type 2 diabetes (T2D) that is inadequately controlled with metformin. Materials and Methods: In this 24‐week, multi‐centre, randomized, double‐blind, placebo‐controlled, superiority, phase III study, adult T2D patients with HbA1c levels ranging from 7.0% to 9.5% on stable metformin were enrolled and randomized (2:1) into the DBPR108 + metformin and placebo + metformin groups. The primary endpoint was the change from baseline in HbA1c at week 24 of DBPR108 versus placebo as an add‐on therapy to metformin. Results: At week 24, the least‐square mean (standard error) change from baseline in HbA1c was significantly greater in the DBPR108 group (−0.70% [0.09%]) than in the placebo group (−0.07% [0.11%]) (P <.001), with a treatment difference of −0.63% (95% confidence interval: −0.87%, −0.39%) on the full analysis set. A higher proportion of patients achieved an HbA1c of 6.5% or less (19.7% vs. 8.5%) and an HbA1c of 7.0% or less (50.0% vs. 21.1%) at week 24 in the DBPR108 + metformin group. Furthermore, add‐on DBPR108 produced greater reductions from baseline in fasting plasma glucose and 2‐hour postprandial plasma glucose without causing weight gain. The overall frequency of adverse events was similar between the two groups. Conclusions: DBPR108 as add‐on therapy to metformin offered a significant improvement in glycaemic control, was superior to metformin monotherapy (placebo) and was safe and well‐tolerated in patients with T2D that is inadequately controlled with metformin. [ABSTRACT FROM AUTHOR]