OBJECTIVE: We evaluated the pharmacokinetics, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin/sitagliptin versus individual component (IC) tablets in healthy Western and Korean participants. The combination of these antihyperglycemic drugs provides efficient glucose control, and the use of FDC has generally been shown to improve medication adherence in individuals with type 2 diabetes mellitus (T2DM).
METHODS: Two randomized, open-label, two-period, two-treatment, single-dose, single-center, crossover bioequivalence studies conducted on healthy fasted German participants (aged 18-55 years; Western study) and South Korean participants (aged 19-55 years; Korean study) were included. In both studies, pharmacokinetic parameters (maximum [peak] plasma concentration [Cmax], area under the plasma concentration-time curve from zero to the last quantifiable concentration [AUClast], and area under the plasma concentration-time curve from zero to infinity [AUCinf]) were used to assess the bioequivalence of 10 mg dapagliflozin/100 mg sitagliptin FDC (Treatment A) with their ICs (Treatment B) under fasted conditions. Safety and tolerability were assessed throughout the study.
RESULTS: Forty-six healthy participants (male, 60.9%; mean age, 39.5 years; mean body mass index [BMI], 23.9 kg/m2) were randomized in the Western study, and 51 healthy participants (male, 100.0%; mean age, 24.6 years; mean BMI, 23.9 kg/m2) were randomized in the Korean study. In both studies, the participants were randomized 1:1 into treatment sequence AB and treatment sequence BA. Dapagliflozin/sitagliptin FDC was bioequivalent to IC tablets in both Western and Korean studies, as the 90% confidence interval of the FDC to IC ratios of the geometric least-squares means of the pharmacokinetic parameters for both dapagliflozin and sitagliptin was within the 0.8000-1.2500 bioequivalence criterion limit. The observed differences in pharmacokinetic parameters, such as Cmax, AUClast, and AUCinf, between the Western and Korean studies were not clinically meaningful. Dapagliflozin/sitagliptin FDC and their ICs were well tolerated, with no serious adverse events reported in any of the study populations.
CONCLUSIONS: The 10 mg dapagliflozin/100 mg sitagliptin FDC and IC formulations were bioequivalent in fasted healthy Western and Korean participants, with no new safety concerns identified, thus offering a useful alternative for patients currently receiving individual medications as part of their treatment regimen.
BACKGROUND: Western study (clinicaltrials.gov: NCT05266404) and Korean study (clinicaltrials.gov: NCT05453786).

BACKGROUND: The association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of urogenital infections remains controversial. This study aimed to investigate the association between SGLT2 inhibitors and the incidence of perineal soft tissue infections, including Fournier\'s gangrene (FG), genital bacterial infections, and urinary tract infections (UTIs), using administrative claims data in Japan.
METHODS: In this retrospective cohort study, we utilized the JMDC Claims Database. The study included patients aged 18 years or older diagnosed with type 2 diabetes mellitus, identified by a diagnostic code, who received new prescriptions for SGLT2 inhibitors or dipeptidyl peptidase 4 (DPP-4) inhibitors between April 2014 and August 2020. Using one-to-one propensity score (PS) matching, we compared the incidence of perineal soft tissue infections, including FG, genital bacterial infection, and UTIs between groups treated with SGLT2 and DPP-4 inhibitors. Hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using the Cox proportional hazards model.
RESULTS: We identified 34,897 patients in the SGLT2 inhibitor group and 135,311 patients in the DPP-4 inhibitor group. After one-to-one PS matching, 31,665 pairs were generated. The mean age of the patients was 51 years, with approximately 70% being male. The use of SGLT2 inhibitors was associated with a decreased risk of UTI (HR 0.90, 95% CI 0.83-0.98) and an increased risk of genital bacterial infection (HR 1.23, 95% CI 1.03-1.46) compared to DPP-4 inhibitors. However, no significant association was observed with perineal soft tissue infection (HR 1.05, 95% CI 0.61-1.81).
CONCLUSIONS: SGLT2 inhibitors were associated with a reduced risk of UTI and an increased risk of genital bacterial infection. They showed no significant association with perineal soft tissue infection when compared to DPP-4 inhibitors. Future research should explore broader demographics, focusing on the elderly and achieving gender balance, to gain a comprehensive understanding of infection risks.

UNASSIGNED: Antihyperglycemic drug utilization studies are conducted frequently and describe the uptake of new drug therapies across may jurisdictions. An increasingly important, yet often absent, aspect of these studies is the impact of rurality on drug utilization.
UNASSIGNED: The objective of this study was to explore the association between place of residence (rural, urban, metropolitan) and the use of dipeptidyl peptidase 4 inhibitors (DPP-4i) for first treatment intensification of type 2 diabetes.
UNASSIGNED: A retrospective cohort study was conducted from April 1, 2008 to March 31, 2019 of new metformin users. A multivariable logistic regression analysis was performed to determine the association between place of residence (using postal codes) and likelihood of DPP-4i dispensing.
UNASSIGNED: After adjusting for confounders, analysis revealed that rural-dwellers are less likely to have a DPP-4i dispensed, compared with metropolitan-dwellers (aOR:0.64; 95%CI:0.61-0.67) and over-time, the uptake in rural areas was slower.
UNASSIGNED: This study demonstrates that rurality can have an impact on drug therapy decisions at first treatment intensification, with respect to the utilization of new therapies.

OBJECTIVE: Myocarditis is a potentially fatal disease, but curative treatments have not yet been established. Myocardial inflammation is an important pathogenesis of this disease, and immunosuppressants such as methylprednisolone and immunoglobulin have been used for treatment; however, the effectiveness needs to be improved. Thalidomide and dipeptidyl peptidase (DPP) 4 inhibitors were recently investigated regarding their immunomodulatory properties. This study aimed to test whether thalidomide or a DPP4 inhibitor (evogliptin) can improve the effectiveness of myocarditis treatment using a rat model of experimental autoimmune myocarditis (EAM).
METHODS: Rats with or without myocarditis were administered thalidomide at 100 mg/kg/day and DPP4 inhibitor at 10 mg/kg/day orally. Measurement of echocardiography, serum inflammatory cytokines, myocardial histopathological examination, and immunohistochemical staining for leukocytes, macrophages, CD4+ T cells, and cytoskeleton were performed after 3 weeks, and the fibrosis area was measured after 3 and 6 weeks.
RESULTS: Thalidomide and DPP4 inhibitor did not reduce the severity of myocarditis compared with the EAM without treatment rats by comparing the echocardiographic data, myocardial CD4+, macrophages, neutrophil infiltrations, and the heart weight/body weight ratio in 3 weeks. The levels of inflammatory cytokines were not lower in the thalidomide and DPP4 inhibitor-treated group than in the untreated group in 3 weeks. In 6 weeks, thalidomide and DPP4 inhibitors did not reduce the fibrosis area compared to untreated groups.
CONCLUSIONS: Although thalidomide and the DPP4 inhibitor had an immunomodulatory effect and are used against inflammatory diseases, they did not ameliorate myocardial inflammation and fibrosis in this rat model of EAM.

OBJECTIVE: To compare preconception use of sodium-glucose cotransporter-2 (SGLT2i) and dipeptidyl peptidase-4 (DPP4i) inhibitors to sulfonylurea agents, and associated peri-conceptional A1c concentration, and risk of pregnancy loss and congenital anomalies.
METHODS: This population-based cohort study used administrative datasets for all of Ontario, Canada, and included women eligible for free medication coverage and who achieved a recognized pregnancy from April 2007-November 2021. Exposure was a SGLT2i, DPP4i or sulfonylurea (referent) dispensed at least 90 days preconception. Study outcomes included differences in periconceptional A1c; miscarriage, induced abortion, or stillbirth; and any congenital anomaly - the latter two outcomes assessed using propensity score overlap weighting.
RESULTS: The mean (SD) periconceptional A1c was 8.1 % (2.0) among those prescribed any sulfonylurea, compared with 8.3 % (2.0) with a DPP4i and 7.8 % (1.6) with any SGLT2i. The risk of pregnancy loss was lowest among those exclusively prescribed a SGLT2i (relative risk [RR] 0.51, 95 % CI 0.22 to 0.91). Risk of a congenital anomaly at birth did not differ significantly comparing DPP4i or SGLT2i to sulfonylurea agents.
CONCLUSIONS: Neither SGLT2i nor DPP4i use before pregnancy was associated with a difference in A1c, or a higher risk of selective adverse outcomes, compared to sulfonylureas. Future larger studies are required, including assessment of medication use after conception, during the critical period of embryogenesis.

UNASSIGNED: Although not definitive, there is small increased risk of acute pancreatitis with the use of dipeptidyl peptidase 4 inhibitors (DPP4i). Hence, there is an interest in the elevation of pancreatic enzymes among type 2 diabetes mellitus (T2DM) patients using DPP4i. However, the studies regarding their association are limited and provide conflicting results. Moreover, there are no such studies among South Indian T2DM patients. Hence, we evaluated the prevalence of hyperamylasemia among South Indian T2DM patients and its association with DPP4i use.
UNASSIGNED: This cross-sectional study was conducted at a tertiary health care center from South India. Adult T2DM patients on stable doses of antidiabetic medications for at least previous 3 months were included in the study. Patients with other types of diabetes mellitus, gall stones, diabetic ketoacidosis, acute illness, chronic kidney disease and untreated hypothyroidism were excluded from the study. All participants were evaluated with glycemic parameters, serum creatinine and serum amylase. Hyperamylasemia was defined as serum amylase ≥220 U/L.
UNASSIGNED: A total of 200 participants were included in the study among whom 93 patients were not on DPP4i whereas 107 were on DPP4i including 41 (38.32%) each on teneligliptin and sitagliptin. Baseline characteristics including glycemic measures were comparable between DPP4i users and nonusers. A total of 14 patients (7%) had hyperamylasemia but the prevalence of hyperamylasemia did not differ between DPP4i users and nonuser (6/107 vs. 8/93, P = 0.42).
UNASSIGNED: Asymptomatic hyperamylasemia is not uncommon in South Indian T2DM patients but is not associated with the use of DPP4i.

Evidence from cardiovascular outcome trials (CVOTs) for newer antidiabetic drugs is increasingly influencing revised recommendations for second-line therapy in type 2 diabetes (T2D). This systematic review aimed to compare the cost-effectiveness of newer antidiabetic drugs specified as sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), and dipeptidyl peptidase 4 inhibitor (DPP-4i) for T2D in a second-line setting.
A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, and all relevant published studies were searched comprehensively in electronic databases, including PubMed, Embase, Web of Science, and International Health Technology Assessment database published from April 2023. The quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 reporting checklists.
We included 28 studies that met the inclusion criteria. Overall reporting of the identified studies largely met CHEERS 2022 recommendations. The CORE and Cardiff models were the most frequently utilized for pharmacoeconomic evaluation in T2D. Four studies consistently discovered that SGLT2i was more cost-effective than GLP-1RA in T2D who were not adequately controlled by metformin monotherapy. Four studies compared GLP-1RA with DPP-4i, sufonylurea (SU), or insulin. Except for one that demonstrated SU was cost-effective, all were GLP-1RA. Five studies revealed that SGLT2i was more cost-effective than DPP-4i or SU. Eleven studies indicated that DPP-4i was more cost-effective than traditional antidiabetic drugs. Four additional studies explored the cost-effectiveness of various antidiabetic drugs as second-line options, indicating that SU, SGLT2i, or meglitinides were more economically advantageous. The most common driven factors were the cost of new antidiabetic drugs.
Newer antidiabetic drugs as second line are the cost-effective option for T2D from the cost-effectiveness perspective, especially SGLT2i.

OBJECTIVE: Sodium load increases endogenous glucagon-like peptide-1 (GLP-1) levels in humans. Therefore, patients with an increased amount of dietary sodium intake are supposed to have higher endogenous GLP-1 levels compared to those with less dietary sodium intake. Therefore, it can be hypothesized that patients with type 2 diabetes mellitus (T2DM) with more dietary sodium intake show better dipeptidyl peptidase-4 inhibitor (DPP-4i) effect on glycemic control because of the expected higher GLP-1 level. Thus, we performed a single-center cohort study to explore this idea.
METHODS: Medical records of patients with T2DM prescribed DPP-4i in the last 11 years were investigated. Dietary sodium intake was measured before the DPP-4i prescription with Tanaka\'s formula using casual spot urine samples. The effect of DPP-4i on glycemic control was estimated by the subtraction of glycated hemoglobin (HbA1c) before DPP-4i initiation from HbA1c 1 year after DPP-4i administration. We analyzed 50 patients.
RESULTS: DPP-4i improved HbA1c by -0.41% ± 0.66%. The effect of DPP-4i on glycemic control was significantly negatively correlated with the dietary sodium intake (r = -0.400). Thus, the more dietary sodium intake, the better the glycemic control by DPP-4i.
CONCLUSIONS: Thus, patients can expect better plasma glucose control by DPP-4is if patients are taking increased dietary sodium intake.

Acute kidney injury (AKI) is a prevalent medical condition accompanied by mutual affection of other organs, including the liver resulting in complicated multiorgan malfunction. Macrophages play a vital role during tissue injury and healing; they are categorized into \"classically activated macrophages\" (M1) and \"alternatively activated macrophages\" (M2). The present study investigated and compared the conventional fluid therapy vs Dipeptidyl peptidase 4 inhibitor (DPP-4i) vildagliptin on the liver injury induced by AKI and evaluated the possible molecular mechanisms. Thirty rats comprised five groups (n = 6 rats/group): control, AKI, AKI+saline (received 1.5 mL of normal saline subcutaneous injection), AKI+vildagliptin (treated with oral vildagliptin 10 mg/kg), AKI+saline+vildagliptin. AKI was induced by intramuscular (i.m) injection of 50% glycerol (5 ml/kg). At the end of the work, we collected serum and liver samples for measurements of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrotic factor-α (TNF-α), and interleukin-10 (IL-10). Liver samples were processed for assessment of inducible nitric oxide synthase (iNOS) as a marker for M1, arginase 1 (Arg-1) as an M2 marker, c-fos, c-Jun, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and high-mobility-group-box1 (HMGB1) protein. The difference was insignificant regarding the relative expression of AP-1, c-Jun, c-fos, MAPK, and HMGB between the AKI+saline group and the AKI+Vildagliptin group. The difference between the same two groups concerning the hepatic content of the M1 marker (iNOS) and the M2 marker Arg-1 was insignificant. However, combined therapy produced more pronounced changes in these markers, as the difference in their relative expression between the AKI+saline+Vildagliptin group and both the AKI+saline group and the AKI+Vildagliptin group was significant. Accordingly, we suggest that the combined saline and vildagliptin hepatoprotective effect involves the downregulation of the MAPK/AP-1 signaling pathway.

Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP.