Serum thrombospondin-2 level changes with liver stiffness improvement in patients with type 2 diabetes.

OBJECTIVE: Baseline circulating thrombospondin-2 (TSP2) level was identified as a potential novel hepatic fibrosis biomarker that associates with development and progression of hepatic fibrosis in patients with nonalcoholic fatty liver disease and type 2 diabetes. Here, we investigated whether circulating TSP2 levels changed with improvement in liver stiffness (LS), which reflects liver fibrosis on transient elastography. DESIGN: Serum TSP2 levels were measured in participants from a randomized, open-label intervention study, at baseline and after 24-weeks treatment of either dapagliflozin 10 mg (N = 30) or sitagliptin 100 mg daily (N = 30). Vibration-controlled transient elastography was performed to evaluate the severity of hepatic fibrosis and steatosis using LS and controlled attenuation parameter (CAP), respectively. PATIENTS AND MEASUREMENTS: Among all 60 participants with similar clinical characteristics at baseline (mean HbA1c 8.9%, CAP 289 dB/m and LS 5.8 kPa), despite similar HbA1c lowering, treatment with dapagliflozin, but not sitagliptin, led to significant improvements in body weight (BW) (p = .012), CAP (p = .015) and LS (p = .011) after 24 weeks. RESULTS: Serum TSP2 level decreased significantly from baseline in dapagliflozin-treated participants (p = .035), whereas no significant change was observed with sitagliptin. In correlation analysis, change in serum TSP2 levels only positively correlated with change in LS (r = .487, p = .006), but not with changes in BW, CAP or HbA1c after dapagliflozin treatment. CONCLUSIONS: Serum TSP2 level decreased with LS after dapagliflozin treatment, and was independent of improvements in BW, glycemic control and hepatic steatosis, further supporting the potential of serum TSP2 level as a novel hepatic fibrosis biomarker in type 2 diabetes.

Early treatment with dipeptidyl-peptidase 4 inhibitors reduces glycaemic variability and delays insulin initiation in type 2 diabetes: A propensity score-matched cohort study.

AIMS: To examine whether early treatment intensification using dipeptidyl-peptidase 4 inhibitors (DPP4i) delays insulin initiation in Chinese patients diagnosed with type 2 diabetes for less than 5 years. MATERIALS AND METHODS: In a territory-wide prospective cohort study, patients with type 2 diabetes initiating DPP4i at diabetes duration <2 years (early intensification) and 3-5 years (late intensification) were matched using 1:1 propensity-score matching (n = 908 in each arm). We used Cox regression to compare the risk of insulin initiation between the two groups. We explored the interactive and mediation effects of glycated haemoglobin (HbA1c) variability score (HVS), defined as the percentage of HbA1c varying by ≥0.5% compared with preceding values. RESULTS: Of 1816 patients (60.7% men, mean age 54.4 ± 11.9 years), 92.4% and 71.9% were treated with metformin and sulphonylureas respectively at DPP4i initiation. Early DPP4i intensification [hazard ratio (HR) 0.71, (95% CI 0.58-0.68)] and low HVS (<50%) (HR = 0.40, 0.33-0.50) were associated with delayed insulin initiation during a median 4.08 years of follow-up. Early intensification with low HVS had the lowest risk versus late intensification with high HVS (HR = 0.30, 0.22-0.40) (pinteraction  = 0.013). HVS mediated 19.5% of the total effect of early DPP4i intensification on delaying insulin initiation. The late and early intensification groups had similar HbA1c at month 0 (8.4 ± 1.3% vs. 8.4 ± 1.5%) and month 3 (7.6 ± 1.2% vs. 7.6 ± 1.3%) after DPP4i initiation. By month 12, HbA1c in the late intensification group deteriorated (7.9 ± 1.4%) but remained stable in the early intensification group (7.6 ± 1.4%, p = 0.001) with persistent between-group difference over 72 months (8.2 ± 1.7% vs. 7.7 ± 1.6%, p = 0.001). CONCLUSIONS: In type 2 diabetes, early DPP4i intensification delayed insulin initiation, partially explained by reduced glycaemic variability.

A model-informed approach to accelerate the clinical development of cofrogliptin (HSK7653), a novel ultralong-acting dipeptidyl peptidase-4 inhibitor.

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.

Comparison of renal prognosis between dipeptidyl peptidase-4 inhibitor users and non-users.

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.

Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add-on therapy in drug-naïve patients with type 2 diabetes (TRIPLE-AXEL study): A multicentre, randomized, 104-week, open-label, active-controlled trial.

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.

Dual add-on therapy of gemigliptin and dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin alone: The SOLUTION 2 study.

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.

Comparative effectiveness of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors on liver function in patients with type 2 diabetes in Japan: A real-world data analysis.

AIM: To compare the effects of sodium-glucose co-transporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) on liver function in patients with type 2 diabetes (T2D) in Japan. MATERIALS AND METHODS: This was a Japanese retrospective cohort study using the RWD Database (1 January 2015 to 24 September 2021). Patients newly treated with an SGLT2i or a DPP4i were matched 1:4 (SGLT2i:DPP4i) using propensity score. The primary endpoint was the change from baseline to 1 year after the index date in alanine aminotransferase (ALT). Secondary endpoints included change from baseline in various laboratory test results, including the Fibrosis-4 (FIB-4) index, aspartate aminotransferase, gamma-glutamyl transpeptidase (GGT), albumin and HbA1c. Endpoints were compared between treatment groups using Welch's t-test in the full population and in subgroups stratified by baseline characteristics. RESULTS: Baseline characteristics of 955 and 3063 matched patients newly treated with an SGLT2i and a DPP4i, respectively, were well balanced. Patients receiving an SGLT2i had significantly greater reductions in ALT, FIB-4 index and GGT and a significantly greater increase in albumin than patients receiving a DPP4i. A significantly greater change from baseline in ALT was observed in the SGLT2i group than in the DPP4i group among subgroups with lower baseline FIB-4 index and HbA1c. CONCLUSIONS: In this study, improvements in various measures, including ALT, the FIB-4 index, GGT and albumin, were observed with SGLT2is compared with DPP4is, suggesting that SGLT2is may provide hepatoprotective benefits, including the prevention of liver fibrosis, in patients with T2D in Japan.

Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks.

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.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability.

AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

Association between sodium-glucose cotransporter-2 inhibitors and arrhythmic outcomes in patients with diabetes and pre-existing atrial fibrillation.

AIMS: Prior studies suggest that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may decrease the incidence of atrial fibrillation (AF). However, it is unknown whether SGLT2i can attenuate the disease course of AF among patients with pre-existing AF and Type II diabetes mellitus (DM). In this study, our objective was to examine the association between SGLT2i prescription and arrhythmic outcomes among patients with DM and pre-existing AF. METHODS AND RESULTS: We conducted a population-based cohort study of adults with DM and AF between 2014 and 2019. Using a prevalent new-user design, individuals prescribed SGLT2i were matched 1:1 to those prescribed dipeptidyl peptidase-4 inhibitors (DPP4is) based on time-conditional propensity scores. The primary endpoint was a composite of AF-related healthcare utilization (i.e. hospitalization, emergency department visits, electrical cardioversion, or catheter ablation). Secondary outcome measures included all-cause mortality, heart failure (HF) hospitalization, and ischaemic stroke or transient ischaemic attack (TIA). Cox proportional hazard models were used to examine the association of SGLT2i with the study endpoint. Among 2242 patients with DM and AF followed for an average of 3.0 years, the primary endpoint occurred in 8.7% (n = 97) of patients in the SGLT2i group vs. 10.0% (n = 112) of patients in the DPP4i group [adjusted hazard ratio 0.73 (95% confidence interval 0.55-0.96; P = 0.03)]. Sodium-glucose cotransporter-2 inhibitors were associated with significant reductions in all-cause mortality and HF hospitalization, but there was no difference in the risk of ischaemic stroke/TIA. CONCLUSION: Among patients with DM and pre-existing AF, SGLT2is are associated with decreased AF-related health resource utilization and improved arrhythmic outcomes compared with DPP4is.

The Effect of Sodium Glucose Cotransporter-2 Inhibitors on Hemoglobin A1c Variability and Acute Kidney Injury: A Causal Mediation Analysis.

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.

Linagliptin Mitigates TGF-ß1 Mediated Epithelial-Mesenchymal Transition in Tacrolimus-Induced Renal Interstitial Fibrosis via Smad/ERK/P38 and HIF-1α/LOXL2 Signaling Pathways.

The dipeptidyl peptidase-4 (DPP-4) inhibitors, a novel anti-diabetic medication family, are renoprotective in diabetes, but a comparable benefit in chronic non-diabetic kidney diseases is still under investigation. This study aimed to elucidate the molecular mechanisms of linagliptin's (Lina) protective role in a rat model of chronic kidney injury caused by tacrolimus (TAC) independent of blood glucose levels. Thirty-two adult male Sprague Dawley rats were equally randomized into four groups and treated daily for 28 d as follows: The control group; received olive oil (1 mL/kg/d, subcutaneously), group 2; received Lina (5 mg/kg/d, orally), group 3; received TAC (1.5 mg/kg/d, subcutaneously), group 4; received TAC plus Lina concomitantly in doses as the same previous groups. Blood and urine samples were collected to investigate renal function indices and tubular injury markers. Additionally, signaling molecules, epithelial-mesenchymal transition (EMT), and fibrotic-related proteins in kidney tissue were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, immunohistochemical and histological examinations. Tacrolimus markedly induced renal injury and fibrosis as indicated by renal dysfunction, histological damage, and deposition of extracellular matrix (ECM) proteins. It also increased transforming growth factor ß1 (TGF-ß1), Smad4, p-extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P38/P38 mitogen-activated protein kinase (MAPK) protein levels. These alterations were markedly attenuated by the Lina administration. Moreover, Lina significantly inhibited EMT, evidenced by inhibiting Vimentin and α-smooth muscle actin (α-SMA) and elevating E-cadherin. Furthermore, Lina diminished hypoxia-related protein levels with a subsequent reduction in Snail and Twist expressions. We concluded that Lina may protect against TAC-induced interstitial fibrosis by modulating TGF-ß1 mediated EMT via Smad-dependent and independent signaling pathways.

Combination of spironolactone and sitagliptin improves clinical outcomes of outpatients with COVID-19: a prospective cohort study.

BACKGROUND: There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. In this observational study on acutely symptomatic outpatient COVID-19 cases, we investigated the effects of spironolactone and sitagliptin on the outcomes of the disease. METHODS: This is a prospective, naturally randomized cohort study. We followed mild to moderate symptomatic COVID-19 patients, who were treated with either combination (spironolactone 100 mg daily and sitagliptin 100 mg daily) or standard (steroid, antiviral and/or supportive care) therapy up to 30 days. The primary outcome was hospitalization rate. The secondary outcomes included ER visit, duration of disease, and complications, such as hypoglycemia, low blood pressure or altered mental status. RESULTS: Of the 206 patients referred to clinics randomly, 103 received standard therapy and 103 treated with combination therapy. There were no significant differences in baseline characteristics, except for slightly higher clinical score in control group (6.92 ± 4.01 control, 4.87 ± 2.92 combination; P < 0.0001). Treatment with combination therapy was associated with lower admission rate (5.8% combination, 22.3% control; P = 0.0011), ER visits (7.8% combination, 23.3% control; P = 0.0021) and average duration of symptoms (6.67 ± 2.30 days combination, 18.71 ± 6.49 days control; P ≤ 0.0001). CONCLUSIONS: The combination of sitagliptin and spironolactone reduced duration of COVID infection and hospital visits better than standard therapeutic approaches in outpatients with COVID-19. The effects of combination of sitagliptin and spironolactone in COVID-19 patients should be further verified in a double-blind, randomized, placebo-controlled trial.

Comparative effects of sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors on kidney function decline in Japanese individuals with type 2 diabetes.

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.

Analysis of IL-10 and IL-35 in dipeptidyl peptidase-4 inhibitor-related bullous pemphigoid.

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.

Post-initiation predictors of discontinuation of the sodium-glucose cotransporter-2 inhibitors: A comparative cohort study from the United Kingdom.

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.

Effect of haemodialysis on the pharmacokinetics and pharmacodynamics of evogliptin.

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.

Comparison of the effects of gemigliptin versus glimepiride on cardiac function in patients with type 2 diabetes uncontrolled with metformin: The gemi-heart study.

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.

Vascular and metabolic effects of ipragliflozin versus sitagliptin (IVS) in type 2 diabetes treated with sulphonylurea and metformin: IVS study.

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.

The associations of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as add-on to metformin with fracture risk in patients with type 2 diabetes mellitus.

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.