Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data.

OBJECTIVE: To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice. DESIGN: Cohort study emulating a comparative effectiveness trial (target trial). SETTING: Linked primary care, hospital, and death data in England, 2015-21. PARTICIPANTS: 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin. MAIN OUTCOME MEASURES: Primary outcome was absolute change in glycated haemoglobin A1c (HbA1c) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures. RESULTS: 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA1c change between baseline and one year were -2.5 mmol/mol (95% confidence interval (CI) -3.7 to -1.3) for SGLT-2 inhibitors versus sulfonylureas and -3.2 mmol/mol (-4.6 to -1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking-the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43). CONCLUSIONS: This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA1c, BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure (v DPP-4 inhibitors) and kidney disease progression (v sulfonylureas), with no evidence of differences in other clinical endpoints.

Evaluating the efficacy and safety of empagliflozin addition to insulin and oral antidiabetic medication (OAD) regimen in poorly controlled type 2 diabetes and obese patients.

Insulin resistance complicates diabetes care. Its effectiveness and tolerability as an addition to metformin, DPP4 inhibitor and insulin treatment in type 2 diabetic patients will be examined in this research. Participants with type 2 diabetes from poor socio-economic backgrounds had HbA1c values ≥8.5% when using Insulin+Metformin+DPP-4 inhibitors. They received 10mg Empagliflozin daily for 12 weeks (n=143). The main outcome was change in HbA1c at 12th week from baseline. Secondary outcomes were baseline weight and week 12 FPG. Adjusted mean (SE) HbA1c increases at week 12 were: Mean ± SD 10.38 (6.8-17.0) vs. Mean±SD 9.05±1.77 (5.60-16.0) with empagliflozin 10mg. When added to the regimen, empagliflozin significantly reduced FPG, systolic and diastolic blood pressure. The mean (SE) BMI increases from baseline were 31.28±5.89 (16.0-66.0) and 29.73±5.47 (3.0-46.0) with 10mg empagliflozin. Two individuals experienced urinary tract infections as AEs, but no genital infections. Adding empagliflozin 10mg daily to metformin+DPP4 inhibitor+insulin improved glycemic control, body weight and blood pressure for 12 weeks. The intervention was well-tolerated, highlighting empagliflozin's therapeutic potential.

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test.

DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.

Concentration-QTc Modeling of the DPP-4 Inhibitor HSK7653 in a First-in-Human Study of Chinese Healthy Volunteers.

Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus with a twice-monthly dosing regimen. This study included 62 participants (48 without food effect, 14 with food effect) receiving single doses of HSK7653 (5, 10, 25, 50, 100, and 150 mg) or placebo. Pharmacokinetic samples were collected over 24 hours postdosing and sampling times are aligned with 12-lead electrocardiograms (ECGs) which were derived from continuous ECG recordings. For the concentration-QT interval corrected for heart rate (C-QTc) analysis, we used linear mixed-effects modeling to characterize the correlation between plasma concentrations of HSK7653 and the change from baseline in the QT interval which was corrected by Fridericia's formula (ΔQTcF). The result showed that a placebo-corrected Fridericia corrected QT interval (ΔΔQTcF) prolongation higher than 10 milliseconds is unlikely at the mean maximum observed concentration (Cmax) (411 ng/mL) associated with the recommended therapeutic doses (25 mg twice-monthly), even at the highest supratherapeutic concentration (2425 ng/mL). Thus, HSK7653 does not significantly affect QT prolongation at either recommended doses or the highest supratherapeutic concentration.

A short-term economic evaluation of early insulin therapy compared to oral anti-diabetic drugs in order to reduce the major adverse events in type 2 diabetes patients in Iran.

OBJECTIVE: While there are some recommendations about early insulin therapy in newly diagnosed Type 2 Diabetes Mellitus (T2DM) patients, there is not sufficient evidence on this strategy's cost-effectiveness. This study compared early insulin therapy versus oral anti-diabetic drugs (OADs) for managing T2DMusing a cost-effectiveness analysis approach in Iran. METHODS: In this economic evaluation, a decision analytic model was designed. The target population was newly diagnosed type 2 diabetic patients, and the study was carried out from the perspective of Iran's healthcare system with a one-year time horizon. Basal insulin, Dipeptidyl peptidase-4 (DPP-4) inhibitors, and Thiazolidinediones (TZDs) were compared in this evaluation. The main outcome for assessing the effectiveness of each intervention was the reduction in the occurrence of diabetes complications. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and deterministic and probabilistic sensitivity analyses were carried out. RESULTS: The DPP-4 inhibitors strategy was the dominant strategy with the highest effectiveness and the lowest cost. Early insulin therapy was dominated (ICER: $-53,703.18), meaning that it was not cost-effective. The sensitivity analyses consistently affirmed the robustness of the base case findings. The probabilistic sensitivity analysis indicated probabilities of 77%, 22%, and 1% for DPP-4 inhibitors, TZDs strategies, and early insulin therapy, respectively, in terms of being cost-effective. CONCLUSION: In terms of cost-effectiveness, early insulin therapy was not cost-effective compared to OADs for managing newly diagnosed T2DM patients. Future studies in this regard, utilizing more comprehensive evidence, can yield more accurate results.

Low-Dose Sulfonylurea Plus DPP4 Inhibitor Lower Blood Glucose and Enhance Beta-Cell Function Without Hypoglycemia.

CONTEXT: Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. OBJECTIVE: To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. METHODS: Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. RESULTS: SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). CONCLUSION: Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.

Risk of genital and urinary tract infections associated with SGLT-2 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes mellitus: A retrospective cohort study in Korea.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are antidiabetic drugs with associated safety concerns regarding the risk of genital and urinary tract infections. This study assessed the risk of genital and urinary tract infections associated with prescription of SGLT-2 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes mellitus (T2DM) compared to dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylurea (SU), and thiazolidinedione (TZD). We conducted a retrospective cohort study using the NHIS-National Health Insurance-Database in Korea from 2014 to 2017. Patients aged ≥19 years and those diagnosed with T2DM prior to drug prescription were enrolled. The outcomes were genital and urinary tract infections. Analysis was performed using Cox's proportional hazard model following 1:1 propensity score matching to calculate the hazard ratio (HR) with a 95% confidence interval (CI). Among the 107 131 patients included in the study, a total of 7738, 7145, and 2175 patients were assigned to the DPP-4 inhibitors, SU, and TZD comparator groups, using the propensity score (PS) of each comparator based on 7741 people in the assessed drug SGLT-2 inhibitor group. SGLT-2 inhibitors were associated with a higher risk of genital infections than DPP-4 inhibitors (HR: 2.39, 95% CI: 2.07-2.76), SU (HR: 3.23, 95% CI: 2.73-3.81), and TZD (HR: 3.23, 95% CI: 2.35-4.44), as an add-on therapy to metformin. Similar results were observed for the risk of urinary tract infections. In conclusion, SGLT-2 inhibitors are significantly associated with a higher risk of genital and urinary tract infections compared to DPP-4 inhibitors, SU, and TZD.

Sitagliptin and Narrow-Band Ultraviolet-B for Moderate Psoriasis (DINUP): A Randomised Controlled Clinical Trial.

BACKGROUND: Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes mellitus (T2DM), has been reported to improve psoriasis. OBJECTIVE: We compared the effects of sitagliptin treatment, a DPP-4 inhibitor, in combination with narrow-band ultraviolet-B (NB-UVB) phototherapy compared to NB-UVB alone on psoriasis severity, quality of life, cardiovascular disease risk factors and immune parameters in people with moderate psoriasis without T2DM. METHODS: In this 39-week, single-centre, randomised controlled trial, people were allocated randomly to receive sitagliptin for 24 weeks with NB-UVB or NB-UVB alone. The primary endpoint was the change in Psoriasis Area and Severity Index (PASI) from baseline to 24 weeks. We estimated that 120 participants would be needed to have 80% power to find a significant difference between the groups. RESULTS: A total of 118 patients were randomised. The median (IQR) baseline PASI was 8.8 (7.5-11.6). At 24 weeks, the mean difference from baseline in PASI (-1.0 [95% CI -2.0 to 0.0]) was significantly larger in the sitagliptin/NB-UVB arm than in the NB-UVB-alone arm (p = 0.044). There were significant differences in the change in Hospital Anxiety and Depression Scale (-2.5 [95% CI -4.0 to -1.0]; p = 0.002) and EuroQol 5-item questionnaire (0.1 [95% CI 0.0-0.1]; p = 0.036) values from baseline to 24 weeks between the sitagliptin/NB-UVB and the NB-UVB-alone arm. There were no treatment-related serious adverse events. CONCLUSION: Sitagliptin therapy combined with NB-UVB phototherapy significantly improved psoriasis severity, albeit modestly, compared to NB-UVB phototherapy alone in patients with moderate psoriasis without T2DM.

Improved Erythrocyte Deformability Induced by Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetic Patients.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are antidiabetic drugs that improve cardiovascular outcomes. Hemoglobin and hematocrit values increase after SGLT-2 inhibitor administration. Although these factors increase blood viscosity and the risk of cardiovascular disease, SGLT-2 inhibitors have protective effects on the cardiovascular system. The mechanisms for this paradoxical phenomenon remain unclear, and the effect of SGLT-2 inhibitors on hemorheology has not been studied. METHODS: We evaluated the hemorheological parameters of 63 patients of whom 38 received metformin with a dipeptidyl peptidase 4 (DPP-4) inhibitor, while 25 received metformin with SGLT-2 inhibitor. Blood viscosity was measured using a cone-and-plate viscometer, erythrocyte aggregation was measured using a modified erythrocyte sedimentation rate method, and erythrocyte membrane fluctuation was measured as deformability, using a diffraction optical tomography. RESULTS: Both blood viscosity and erythrocyte aggregation increased in the SGLT-2 inhibitor group, although erythrocyte deformability was significantly improved compared with that of the DPP-4 inhibitor group (DPP-4 inhibitor 43.71 ± 5.13 nm; SGLT-2 inhibitor 53.88 ± 4.88 nm; p < 0.001). When the two groups were compared after propensity score matching, no differences in blood viscosity at high shear rates and erythrocyte aggregation were observed, although erythrocyte deformability was significantly improved in the SGLT-2 inhibitor group (DPP-4 inhibitor 45.01 ± 5.28 nm; SGLT-2 inhibitor 53.14 ± 4.72 nm; p = 0.001). CONCLUSION: This study demonstrates that erythrocyte deformability was improved in the SGLT-2 inhibitor group compared with that in the DPP-4 inhibitor group. This improvement in erythrocyte deformability is expected to have a protective effect on the cardiovascular system.

Hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea and Chlorella sorokiniana possess synergistic hypoglycemic activity through inhibiting α-glucosidase and dipeptidyl peptidase-4 activity.

BACKGROUND: The prevalence of diabetes mellitus worldwide has increased in recent decades. Maintaining the level of blood glucose is the most basic and important issue for diabetics. This study aimed to investigate the hypoglycemic activity of a combination of hypoglycemic peptide-enriched hydrolysates of Corbicula fluminea (ACH) and Chlorella sorokiniana (PCH). RESULTS: Combined supplementation of ACH and PCH synergistically inhibited α-glucosidase and DPP4 activities in vitro. After 4 weeks of treatment with ACH and/or PCH, the plasma glucose concentration and insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), total cholesterol (TC) and triglyceride (TG) levels significantly decreased. The hypoglycemic peptides in ACH and PCH were purified and assayed for α-glucosidase and DPP4 activity. The hypoglycemic peptides in ACH and PCH effectively decreased α-glucosidase and DPP4 activities. In silico assays showed that these two peptide types have different docking poses, which determined their inhibitory effect against α-glucosidase and DPP4 activity. CONCLUSION: Combined treatment with hypoglycemic peptide-enriched ACH and PCH could modulate blood glucose by synergistically inhibiting α-glucosidase and DPP4 activities. © 2021 Society of Chemical Industry.

Study on the Mechanism of the Blood-Glucose-Lowering Effect of Collagen Peptides from Sturgeon By-Products.

In a previous study, we found that the collagen peptides prepared from the by-products of Bester sturgeon had an inhibitory effect on elevated blood glucose levels in a glucose tolerance test with ICR mice. In the present study, we examine the mechanism of the effect of sturgeon collagen peptides (SCPs) in detail. When glucose was orally administered to mice along with the SCPs, it was found that the glucose remained in the stomach for a longer time. In the above tests, the amount of glucose excreted in the feces of mice also increased. On the contrary, it was revealed that the SCPs have a dipeptidyl-peptidase-IV (DPP-IV) inhibitory ability in an in vitro test. In subsequent oral and intravenous glucose administration tests, glucagon-like peptide-1 (GLP-1) and insulin levels in the blood of mice were maintained at high levels. These results suggested the following three mechanisms: SCPs slow the rate of transportation of glucose from the stomach into the small intestine, resulting in delayed glucose absorption; SCPs suppress the absorption of glucose in the small intestine and excrete it from the body; SCPs inhibit DPP-IV in the blood and maintain a high GLP-1 level in blood, which in turn stimulates insulin secretion.

Effects of dipeptidyl peptidase-4 inhibition on portal hypertensive and cirrhotic rats.

BACKGROUND: Portal hypertension is a pathophysiological abnormality with distinct vascular derangements associated with liver cirrhosis. Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetic agents which exert pleiotropic vascular effects, but their relevant impact on portal hypertension and liver cirrhosis remains unclear. This study aims to clarify this issue. METHODS: Rats receiving partial portal vein ligation (PVL) and common bile duct ligation (BDL) served as experimental models for portal hypertension and cirrhosis, respectively. After linagliptin (a DPP-4 inhibitor) treatment, the survival rate, hemodynamics, biochemistry parameters and liver histopathology were evaluated. In addition, the collateral vascular responsiveness and severity of portal-systemic shunting were examined. mRNA and protein expression in the vasculature and liver were also examined. RESULTS: Linagliptin significantly reduced portal pressure (control vs linagliptin: 12.9 ± 1.2 vs 9.1 ± 2.0 mmHg, p = 0.001) and upregulated nitric oxide synthase expression in the collateral vessel, superior mesentery artery, and liver of PVL rats. However, the portal hypotensive effect was insignificant in BDL rats. Glucose plasma levels, liver and renal biochemistry parameters were not significantly altered by linagliptin. The degree of portal-systemic shunting and collateral vascular responsiveness were also not significantly altered by linagliptin treatment. Linagliptin did not improve liver fibrosis and hepatic inflammation in BDL rats. CONCLUSION: DPP-4 inhibition by linagliptin reduced portal pressure in portal hypertensive rats but not in cirrhotic rats. It may act by decreasing intrahepatic resistance via upregulation of hepatic nitric oxide synthase in portal hypertensive rats.

Cost-Effectiveness of Dipeptidylpeptidase-4 Inhibitors Added to Metformin in Patients With Type 2 Diabetes in China.

Purpose: Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context. Materials and Methods: In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters. Results: Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022 versus linagliptin 5 mg, saxagliptin 5 mg, sitagliptin 100 mg and vildagliptin50 mg, respectively. The sitagliptin 100 mg strategy was the cheapest option. The ICER of alogliptin 25 mg against sitagliptin 100 mg strategy was $6,952 per additional QALY gained, and the rest of the strategies were dominated or extended dominated. The most influential parameters were the cost of DPP-4 inhibitors and their treatment efficacy. Conclusions: These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.

Association of Dipeptidyl Peptidase-4 Inhibitor Use and Amyloid Burden in Patients With Diabetes and AD-Related Cognitive Impairment.

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

Identification and structure-activity relationship exploration of uracil-based benzoic acid and ester derivatives as novel dipeptidyl Peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Our previously reported carboxyl-containing DPP-4 inhibitors were highly potent but were poorly bioavailable. Esters of the carboxyl analogs exhibited a significant DPP-4 potency loss albeit with enhanced oral absorption. Herein, we described identification and structure-activity relationship (SAR) exploration of a novel series of benzoic acid and ester derivatives as low single-digit nanomolar DPP-4 inhibitors. Importantly, the esters displayed comparable activities to the acids counterparts. Molecular simulation revealed that ester adopts a similar binding mode to acid. Moreover, the selected esters and acids demonstrated high selectivity and low cytotoxicity, as well as good metabolic stability. And more importantly, the esters possessed excellent pharmacokinetic profiles for oral administration. The best compound ester 19b demonstrated long DPP-4 inhibition in vivo, and robustly improved the glucose tolerance in normal and db/db mice while ensuring glucose-lowering potency in chronic treatment. Our results supported that the compound 19b can be served as a potential candidate for the treatment of type 2 diabetes.

DPP-4 Inhibitors and Increased Reporting Odds of Bullous Pemphigoid: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS) from 2006 to 2020.

BACKGROUND: In recent years, an association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid has been detected in pharmacovigilance studies in European and Asian countries; however, no pharmacovigilance data have been published yet in the USA. OBJECTIVE: The objective of this study was to examine the relationship between bullous pemphigoid and DPP-4 inhibitors and other oral diabetes mellitus medications in the FDA Adverse Event Reporting System (FAERS). METHODS: Case/non-case analyses were performed in the FAERS using data from 2006 to 2020 to examine the reporting odds ratio (ROR) signal for bullous pemphigoid for all classes of oral diabetes medications. These analyses were performed under multiple conditions to control for bias: (1) comparison to all other drugs in the FAERS; (2) comparison to other diabetes medications; and (3) comparison to all other diabetes medications where only a single agent was implicated. RESULTS: A statistically significant ROR for bullous pemphigoid was found for DPP-4 inhibitors under all conditions: (1) 109.79 (95% confidence interval [CI] 101.61-118.62); (2) 74.46 (95% CI 60.58-91.52); and (3) 35.94 (95% CI 27.91-46.28). A larger signal was seen for non-US Food and Drug Administration (FDA)-approved (anagliptin, vildagliptin, teneligliptin) vs FDA-approved DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin), likely because of an overestimation of the ROR for non-FDA-approved drugs. The largest signal was seen under conditions 1 and 2 with vildagliptin (1) 1022.83 (95% CI 909.45-1150.35) and (2) 158.84 (95% CI 127.01-198.66) followed by anagliptin (1) 628.63 (95% CI 221.36-1785.24) and (2) 60.64 (95% CI 20.98-175.26), alogliptin, teneligliptin, linagliptin, sitagliptin, and saxagliptin. Under condition 3, the largest signal was seen with linagliptin 122.25 (95% CI 93.96-159.07). Both metformin and the sulfonylureas had a significant ROR under condition 2 [3.42 (95% CI 3.01-3.89) and 2.07 (95% CI 1.66-2.57) respectively]; however, this association was not present under condition 3 as only confounded cases occurred, and a large majority of reported cases had concurrent exposure to a DPP-4 inhibitor. CONCLUSIONS: Our findings support an association between DPP-4 inhibitors and bullous pemphigoid. This association was maintained under controls to limit bias and falsely elevated signal, including controlling for disease state and cases with multiple drug exposures. Non-FDA-approved DPP-4 inhibitors had a larger ROR compared with FDA-approved DPP-4 inhibitors, likely owing to fewer reported adverse effects overall for non-FDA-approved drugs in FAERS.

Effect of one-week administration of dipeptidyl peptidase-IV inhibitory peptides from chum salmon milt on postprandial blood glucose level: a randomised, placebo-controlled, double-blind, crossover, pilot clinical trial.

Salmon milt peptide (SMP), an unused fish processing byproduct, exhibits strong inhibitory activity against dipeptidyl peptidase-IV (DPP-IV) and a suppressive effect on postprandial hyperglycaemia in Sprague-Dawley rats. Herein, we conducted a randomised, placebo-controlled, double-blind, crossover study of healthy Japanese subjects to investigate the effect of glucose loading on postprandial blood glucose levels after one week of administering continuous or single dose of 500 mg of SMP. The primary and secondary outcomes of reduced blood glucose and insulin levels were not met in the 14 subjects included in the analysis. This may be due to the ineffectiveness of SMP in insulin resistance due to its DPP-IV inhibitory activity. Therefore, we conducted a SMP subgroup analysis based on the homeostasis model assessment of insulin resistance (HOMA-IR); the group with normal HOMA-IR (<1.6) had a significantly lower area under the curve and blood glucose at 60 min after glucose loading than the group with HOMA-IR ≥1.6. These results suggest that SMP is effective in subjects without insulin resistance. There were no adverse events associated with the test food, and SMP was considered safe. This report is the first to investigate the effect of a food ingredient with DPP-IV inhibitory activity in a clinical trial.

Glucose-lowering Drugs and Hospitalization for Heart Failure: A Systematic Review and Additive-effects Network Meta-analysis With More Than 500 000 Patient-years.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2is) prevent hospitalization resulting from heart failure (HHF). However, patients with type 2 diabetes mellitus use multiple antihyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations, the risk of HHF is unpredictable and so is the parallel effect of glucose-lowering. PURPOSE: To examine the impact of antihyperglycemic drugs and their association on HHF. DATA SOURCES: Forty randomized controlled trials (RCTs) reporting HHF. STUDY SELECTION: Published RCTs were the data source. DATA EXTRACTION: Incidence rates of HHF. DATA SYNTHESIS: Random additive-effects network meta-analysis showed that metformin (P = 0.55), sulfonylureas (P = 0.51), glucagon-like peptide-1 receptor-agonist (P = 0.16), and dipeptidyl peptidase 4 inhibitors (DPP4is; P = 0.54) were neutral on the risk of HHF. SGLT2is and SGLT2is + DPP4is reduced the risk of HHF with a hazard ratio (HR) of 0.68 (95% CI, 0.60-0.76; P < 0.0001) and 0.70 (95% CI, 0.60-0.81; P < 0.0001), respectively. Increased risk of HHF was associated with thiazolidinediones (TZDs) as monotherapy or in combination with DPP4is (HR: 1.45; 95% CI, 1.18-1.78; P = 0.0004) and 1.49 (95% CI, 1.18-1.88; P = 0.0008), respectively. Regardless of the therapy, a 1% reduction in HbA1c reduced the risk of HHF by 31.3% (95% CI, 9-48; P = 0.009). LIMITATIONS: There are no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes. CONCLUSIONS: The risk of HHF is reduced by SGLT2is as monotherapy or in combination with DPP4is and increased by TZDs as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.

[A case of dropped head syndrome suspected due to Dipeptidyl peptidase (DPP)-4 inhibitor use].

There have been a few reports on Dipeptidyl peptidase (DPP)-4 inhibitor-induced dropped head syndrome. However, there has been no known report on temporal changes in MRI findings. The patient described here was a 63-year-old man who was prescribed oral sitagliptin (50 mg/day) in February 2019. He experienced a dropped head from mid-January 2020, and in early April that year, he was admitted to our hospital for further evaluation. Weakness of the cervical extensor muscles (MMT 3) was noted, and MRI findings showed that the posterior cervical muscle group was hyperintense on short inversion time inversion recovery (STIR). We suspected sitagliptin to be the cause of his dropped head and discontinued it. On the 10th day of admission, his posture improved to the median position. One month after discontinuation of sitagliptin, MRI findings showed an improvement in the STIR hyperintensity of the posterior cervical muscle. In conclusion, if the initiation of a DPP-4 inhibitor results in dropped head syndrome, discontinuation of the drug should be considered.

GPR119 agonists for the treatment of type 2 diabetes: an updated patent review (2014-present).

Introduction: Type 2 diabetes is a rapid-growing complex chronic metabolic disease characterized by hyperglycemia due to lessened insulin secretion, insulin resistance and hepatic glucose overproduction. GPR119 is a class A of G protein-coupled receptor, expressed on certain enteroendocrine L and K cells in the small intestine and by ß-cells within the islets of Langerhans of the pancreas. Activation of GPR119 stimulates the secretion of glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose-dependent release of insulin in pancreatic ß-cells.Area covered: This review summarized the reported patents on GPR119 agonists from 2014 to present. The authors described the structural features of these novel synthetic molecules and compared their biological activities (including in vitro and in vivo) as potent GPR119 agonists for the treatment of diabetes.Expert opinion: GPR119 agonists remain the advantage of stimulating both insulin and incretin release in a glucose-dependent manner over other hypoglycemic agents, although some GPR119 agonist clinical candidates have been discontinued in Phase І or Phase II. GPR119 agonists will succeed to be developed as anti-diabetic drugs after accumulated scaffolds of agonists are discovered and the crystallographic structure of GPR119 is elucidated. The synergic effect of GPR119 agonist and DPP-4 inhibitor will also elicit a benefit for the new therapeutic of diabetes.