Dipeptidyl Peptidase-4 Inhibitor Group Research Articles

Meta-Analysis of 11 Heterogeneous Studies regarding Dipeptidyl Peptidase 4 Inhibitor Add-On Therapy for Type 2 Diabetes Mellitus Patients Treated with Insulin.

Background Several clinical trials have addressed the therapeutic strategy of adding dipeptidyl peptidase 4 (DPP-4) inhibitors to the treatment of type 2 diabetes mellitus (DM) inadequately controlled by insulin therapy. However, there is a high degree of heterogeneity in these studies, and the cause of which has not been identified. Methods We conducted a meta-analysis of randomized controlled trials, which compared the efficacy and safety of adding DPP-4 inhibitors or placebo to insulin therapy; the level of hemoglobin A1c (HbA1c) in the patients was >7.0%, and the duration of treatment was ≥8 weeks. We focused on the mean changes in HbA1c from the baseline (ΔHbA1c) and the incidence of hypoglycemia. We assumed that five baseline parameters (HbA1c, fasting blood glucose, body mass index (BMI), duration of type 2 DM, and duration of treatment) could affect ΔHbA1c. Regarding the incidence of hypoglycemia, we suspected that the heterogeneity was caused by differences in the definition of hypoglycemia among the studies. Results Data obtained from 11 studies (n = 4654 patients) were included in the analysis. The mean ΔHbA1c between the DPP-4 inhibitor and placebo groups was -0.61% (95% confidence interval (CI): -0.74 to -0.48, I2 = 73.4%). There was substantial heterogeneity among the 11 studies, but 74.1% of this variability was explained by the difference in BMI. The odds ratio for the incidence of hypoglycemia was 1.02 (95% CI: 0.74 to 1.42, I2 = 63.8%), with substantial heterogeneity due to differences in the definition of hypoglycemia among the studies. There was no apparent effect of publication bias. Conclusions The addition of DPP-4 inhibitors to insulin therapy for adult patients with type 2 DM can significantly reduce HbA1c levels without increasing the occurrence of hypoglycemia. BMI and hypoglycemia definition could explain the heterogeneity in the clinical trials. This trial is registered with PROSPERO #CRD42016035994.

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors

BackgroundSodium glucose cotransporter 2 inhibitor (SGLT2i) reduces the risk of hard cardiovascular endpoints in type 2 diabetes mellitus (T2DM) patients with/without established cardiovascular diseases. Whether SGLT2i is associated with a lower risk of new-onset atrial fibrillation (AF) in T2DM patients is unclear. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i compared to dipeptidyl peptidase-4 inhibitor (DPP4i) among a longitudinal cohort of diabetic patients.MethodsWe used medical data from a multi-center healthcare provider in Taiwan, which included a total of 15,606 and 12,383 patients treated with SGLT2i and DPP4i, respectively, from June 1, 2016 to December 31, 2018. We used propensity-score weighting to balance covariates across study groups. Patients were followed up from the drug index date until the occurrence of new-onset AF, discontinuation of the index drug, or the end of the study period, whichever occurred first.ResultsOverall, 55%, 45%, and 0% of the patients were treated with empagliflozin, dapagliflozin, and canagliflozin, respectively. Most patients in the DPP4i group were prescribed with linagliptin (51%), followed by sitagliptin (24%), saxagliptin (13%), vildagliptin (8%) and alogliptin (5%). The use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i after propensity-score weighting [hazard ratio: 0.61; 95% confidential interval: 0.50–0.73; P < 0.001]. Subgroup analysis revealed that the use of SGLT2i was associated with a lower risk of new-onset AF compared with DPP4i across several subgroups including old age, female in gender, the presence of cardiovascular disease, hemoglobin A1c ge 8%, and chronic kidney disease. The advantage of SGLT2i over DPP4i persisted with different SGLT2i (dapagliflozin or empagliflozin) and either low- or standard-dose SGLT2i.ConclusionsSGLT2i was associated with a lower risk of new-onset AF compared with DPP4i among T2DM patients in real-world practice.

Quality-of-Life Comparison of Dapagliflozin Versus Dipeptidyl Peptidase4 Inhibitors in Patients with Type2 Diabetes Mellitus: A Randomized Controlled Trial (J-BOND Study).

IntroductionNo study has compared the effects of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) on patients’ quality-of-life (QOL).MethodsWe enrolled 253 drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM), randomly assigned them into a dapagliflozin (SGLT2i) group or DPP4i group in approximately 1:1 ratio, and monitored them for 24 weeks. The primary endpoint was the proportion of subjects indicating improvement in the “overall quality of life” domain of SHIELD-WQ-9 at week 24. Secondary endpoints included other domains of SHIELD-WQ-9, DTR-QOL, EQ-5D-5L, medication preference, medication adherence, diet therapy adherence, body weight, body mass index (BMI), abdominal circumference, HbA1c, and frequency of adverse events.ResultsThe proportion of subjects indicating improvement in the “overall quality of life” domain of SHIELD-WQ-9 at week 24 was higher in the dapagliflozin group (28.4%) than in the DPP4i group (18.6%) (p = 0.08). The proportion of subjects indicating improvement in the “physical health” domain of SHIELD-WQ-9 at week 24 was significantly higher in the dapagliflozin group (42.2%) than in the DPP4i group (23.7%) (p = 0.004). Total scores and domain 1 scores of DTR-QOL showed greater improvement in the dapagliflozin group (14.3 ± 15.6 and 15.5 ± 20.8, respectively) than in the DPP4i group (10.2 ± 15.6 and 10.3 ± 19.5, respectively) (both p = 0.05). EQ-5D-5L scores had significantly improved in the DPP4i group (0.023 ± 0.088) (p = 0.005); the intergroup difference was not significant (p = 0.14). Body weight (p < 0.001), BMI (p < 0.001), and abdominal circumference (p = 0.019) had significantly decreased in the dapagliflozin group compared with the corresponding values in the DPP4i group.ConclusionDapagliflozin showed a comparable or more favorable benefit on Japanese patients’ QOL compared with DPP4is. Dapagliflozin was well tolerated. It significantly reduced body weight, which was significantly correlated with improvement in the patients’ QOL. This study demonstrates that dapagliflozin can be used as a first-line drug for T2DM in Japan with a beneficial impact on patients’ QOL.Trial RegistrationUniversity Hospital Medical Information Network Clinical Trial Registry (UMIN000030514); Japan Registry of Clinical Trials (jRCTs051180165).Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-020-00941-8) contains supplementary material, which is available to authorized users.

Comparative effectiveness of glucagon-like peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors on noninvasive indices of hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus

Background and aimsNonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM). There is currently no approved treatment for NAFLD. The main aim was the evaluation of the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RA) vs. dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment on noninvasive indices of hepatic steatosis and fibrosis in patients with T2DM. MethodsIn this retrospective study, three noninvasive indices of hepatic steatosis [HSI, NAFLD ridge score, and triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio] and five of fibrosis (APRI, FIB-4, NAFLD fibrosis score, BAAT and BARD) were calculated before and after (6–18 months) the addition of a DPP-4i (n = 152) or a GLP-1 RA (n = 37) in patients with T2DM. ResultsRegarding steatosis indices, NAFLD ridge score was significantly decreased in the GLP-1 RA group (baseline: 0.90 ± 0.34, follow-up: 0.67 ± 0.24; p = 0.001), but not in the DPP-4i group (p = 0.25); the difference for group∗time interaction was significant (p = 0.02). HSI showed a trend between groups, being significantly different at baseline and follow-up (p < 0.001) with no significant difference in group∗time interaction. Indices of fibrosis were not essentially changed within or between groups. ConclusionsNAFLD ridge score was significantly decreased after the addition of GLP-1 RA in patients with T2DM. This study warrants further prospective clinical trials.

Effect of the dipeptidyl peptidase-4 inhibitor linagliptin on atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbits: iMap-IVUS and pathological analysis.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have potential as a treatment for atherosclerosis. However, it is unclear whether DPP-4 inhibitors stabilize atherosclerotic plaque or alter the composition of complex plaque. Sixteen Watanabe heritable hyperlipidemic rabbits aged 10-12weeks with atherosclerotic plaque in the brachiocephalic artery detected by iMap™ intravascular ultrasound (IVUS) were divided into a DPP-4 inhibitor group and a control group. Linagliptin was administered to the DPP-4 inhibitor group via nasogastric tube at a dose of 10mg/kg/day for 16weeks, and control rabbits received the same volume of 0.5% hydroxyethylcellulose. After evaluation by IVUS at 16weeks, the brachiocephalic arteries were harvested for pathological examination. IVUS revealed that linagliptin significantly reduced the plaque volume and vessel volume (control group vs. DPP-4 inhibitor group: ∆plaque volume, 1.02 ± 0.96mm3 vs. - 3.59 ± 0.92 mm3, P = 0.004; ∆vessel volume, - 1.22 ± 2.36mm3 vs. - 8.66 ± 2.33 mm3, P = 0.04; %change in plaque volume, 6.90 ± 5.62% vs. - 15.06 ± 3.29%, P = 0.005). With regard to plaque composition, linagliptin significantly reduced the volume of fibrotic, lipidic, and necrotic plaque (control group vs. DPP-4 inhibitor group: ∆fibrotic volume, 0.56 ± 1.27mm3 vs. - 5.57 ± 1.46mm3, P = 0.04; ∆lipidic volume, 0.24 ± 0.24mm3 vs. - 0.42 ± 0.16mm3 P = 0.04; ∆necrotic volume, 0.76 ± 0.54mm3 vs. - 0.84 ± 0.25mm3, P = 0.02). Pathological examination did not show any significant differences in the %smooth muscle cell area or %fibrotic area, but infiltration of macrophages into plaque was reduced by linagliptin treatment (%macrophage area: 12.03% ± 1.51% vs. 7.21 ± 1.65%, P < 0.05). These findings indicate that linagliptin inhibited plaque growth and stabilized plaque in Watanabe heritable hyperlipidemic rabbits.

The plasma levels of atrial natriuretic peptide and brain natriuretic peptide in type 2 diabetes treated with sodium-glucose cotransporter-2 inhibitor

PurposeThe aim of this study was to determine the levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) after treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitor or dipeptidyl peptidase-4 (DPP4) inhibitor in patients with type-2 diabetes inadequately controlled by insulin, and to determine whether variation in ANP levels can explain favorable cardiovascular outcome. MethodsWe enrolled 56 patients, aged 18–80years, with type-2 diabetes inadequately controlled by insulin: i.e., HbA1c level 7.5–10.5% despite at least 8weeks’ injectable insulin at a stable mean dose of 20–150IU daily, with or without no more than two oral antidiabetic agents. FindingsThe 56 patients were randomized between 3 treatment groups: SGLT2 inhibitor (n=18), DPP4 inhibitor (n=19) and placebo (n=19). Patients who received SGLT2 inhibitor or DPP4 inhibitor treatment all showed significantly lower HbA1c levels, fasting blood glucose (FBG) levels and systolic blood pressure at 24weeks than controls. SGLT2 inhibitor treatment decreased ANP levels, BNP levels, systolic blood pressure and weight compared with placebo. Compared to those receiving DPP4 inhibitor, patients receiving SGLT2 inhibitor showed lower HbA1c levels (7.01 vs. 7.58%; P=0.03), ANP levels (28.41 vs. 43.03 pg/mL; P=0.00) and weight (66.14 vs. 71.76 kg; P=0.04) at 24weeks after adjusting for baseline values. The SGLT2 inhibitor group showed higher sodium concentrations than the placebo and DPP4 inhibitor groups (145.89 vs. 143.89 and 144.79 mmol/L, respectively; P=0.00 and P=0.04) at 24 weeks. ANP and BNP levels did not significantly correlate with HbA1c and blood glucose levels. ImplicationsThese results indicated that SGLT2 inhibitors may be superior to DPP4 inhibitors in reducing risk of cardiovascular disease in diabetic patients. The major study limitation was the small number of patients per group, which should be enlarged in further research.

Livedoid and Purpuric Skin Eruptions Associated With Coagulopathy in Severe COVID-19

Importance Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase–4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited. Objective To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. Design, Setting, and Participants This cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation sulfonylurea were included. Main Outcomes and Measures The primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis. Results A total of 1 664 880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43). Conclusions and Relevance This study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.

Evaluation of Risk of Bullous Pemphigoid With Initiation of Dipeptidyl Peptidase–4 Inhibitor vs Second-generation Sulfonylurea

Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited. To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas. This cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation sulfonylurea were included. The primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis. A total of 1 664 880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43). This study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.

Comparison of heart failure risk and medical costs between patients with type 2 diabetes mellitus treated with dapagliflozin and dipeptidyl peptidase-4 inhibitors: a nationwide population-based cohort study

BackgroundDapagliflozin is one of the novel glucose-lowering agents, which has recently been reported to reduce the risk of hospitalization for heart failure (hHF). The present study aimed to compare the differences between the risk of hHF after using dapagliflozin and dipeptidyl peptidase-4 inhibitors (DPP-4i) as second-line drugs for the treatment of type 2 diabetes mellitus using the latest nationwide population data in Korea. Additionally, we aimed to examine the impact of clinical outcomes on direct medical costs in the two groups.MethodsThe present population-based, retrospective cohort study was conducted using the nationwide claims data between September 01, 2014 and June 30, 2018. New users of dapagliflozin and DPP-4i were identified from the database and the differences in patients’ characteristics between the two groups were analyzed using propensity score-weighted analysis. Cox proportional hazards regression analysis was used to estimate the risk of hHF. A simple model was used for the estimation of direct medical costs for 3 years.ResultsIn total, 23,147 patients in the dapagliflozin group and 237,187 patients in the DPP-4i group were selected for the analysis. The incidence rates of hHF were 3.86 and 6.79 per 1000 person-years in the dapagliflozin and DPP-4i groups, respectively. In the entire study population, the hazard ratio for hHF in the dapagliflozin group compared to the DPP-4i group was 0.58 (95% confidence interval 0.46–0.74), with 0.55 (95% confidence interval 0.41–0.74) among patients with underlying cardiovascular disease and 0.66 (95% confidence interval 0.46–0.95) among patients without underlying cardiovascular disease. The direct medical costs were $57,787 lower in the dapagliflozin group than in the DPP-4i group for 3 years.ConclusionsThis study showed that dapagliflozin lowers the risk for hHF and subsequently reduces direct medical costs compared to DPP-4i. The protective effect against hHF was more evident among patients with underlying cardiovascular disease.

P1014INCRETIN BASED THERAPIES IN DIABETIC KIDNEY TRANSPLANT RECIPIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and Aims Diabetes mellitus (DM) is the major cause of ESRD. New-onset DM after transplantation (NODAT) frequently occurs and increases the risk of infection and mortality. Kidney transplant recipients (KTR) with pre-existing risk factors for DMt2 are more prone to develop NODAT. An intriguing novel concept is the use of the incretin-based therapies including dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1-RAs) and Sodium-glucose co-transporter-2 inhibitors (SGLT2i) in solid organ transplantation. This class of antidiabetic therapy is not yet established in KTR. Our aim was to examine the efficacy and safety of incretin-based therapies in DM or NODAT in KTR. Method We searched without language restrictions for all publications on Kidney/Renal Transplantation and DPP-4i, GLP-1-RAs and SGLT-2i using electronic databases including Medline, Embase, Cochrane, PubMed. We hand-search the reference lists of every relevant study for additional publications. Further searches were done by reviewing abstract and review articles. We included every study (retrospective/prospective) that used these classes of antidiabetics as treatment of NODAT or DMt2 in KTR. All the primary and secondary outcomes were calculated as mean ± sd. Heterogeneity was assessed with Cochrane’s Q statistics and quantified using the I stat, which indicated the proportion of variability across studies that was due to heterogeneity. We used the DerSimonian-Laird estimator for tau^2. Meta-regression was used to assess the effect of different antidiabetics on the primary and secondary outcomes. We assumed a priori the presence of heterogeneity and we used the model of random effects in all analyses. We assessed publication bias using the Begg-Mazumdar test and to nullify the estimated bias the trim-and-fill method, where it was necessary. A p-value &amp;lt; 0.05 was considered statistical significant. Results On the 1512 references screened, 16 studies were included in the final analysis. In total, 310 individuals were analyzed with a mean age of 55.98 ± 8.81 years, similar between studies. In 10 of them, participants were diagnosed with NODAT, whereas in all other trials were DMt2 or NODAT. In 8 studies participants received DPP-4i, in 6 SGLT-2i i and in rest 2 GLP-1-RAs. All included KTR were stable and transplanted over 6 months. The mean follow-up of all trials included was 22,03±14.95 weeks. Glycemic control reduces HbA1c (10 studies, MD=-0.38 %, I=45%). The MD of HbA1c for the DPP-4i group was -0.3741 and for the SGLT-2i group was -0.4596 mg/dl. Within every group of each different category of drugs, there was homogeneity (QM, p-value&amp;gt;0.05) and it was explained the most of the variance of the previous meta-analysis (QE= 15.76). The Begg-Mazumdar test showed that publication bias was not present (p&amp;gt; 0.05). Nine trials reported the difference of FPG and 5 of PPG before and after the administration of antidiabetics. The common MD estimator with a random effect model was – 25.76 for FPG and – 6.61 for PPG with a high grade of heterogeneity for both. Seven trials reported the change of body mass index (BMI) and body weight (BW) before and after the administration of this class of antidiabetics. The BW reduction, where reported, was significant in KTR on SGLT1i or DPP-4i whereas BMI wasn’t significantly reduced in this group, possible due to statistical artifact. The majority of the studies showed that GFR and hepatic biochemical parameters, didn’t change during therapy (DPP-4i, GLP-1-RAs, SGLT-2i). Conclusion Evidence concerning the efficacy of incretins in diabetes on KTR is limited. SGLT2i and DPP-4i are efficacious for glucose-lowering. The safety profile based on renal and hepatic function is indicative for the use of this class of antidiabetics in this population. More high-quality studies are required to help guide therapeutic choice for antidiabetics in KTR.

Vildagliptin vs. insulin treatment alone in diabetic acute coronary syndrome patients.

Vildagliptin, an oral antidiabetic of the dipeptidyl peptidase-4 (DPP-4) inhibitor drugs, exhibits an overall low risk of hypoglycemia with less frequent hypoglycemic events in type 2 diabetes mellitus (T2DM) patients than other antidiabetic drugs. We hypothesized that among hospitalized acute coronary syndrome (ACS) patients, the addition of vildagliptin to subcutaneous insulin therapy would reduce the risk of hypoglycemic events. One hundred ACS T2DM adult patients naive to DPP-4 inhibitors were enrolled during admission to the ICCU. Patients were divided into two randomized controlled groups: a subcutaneous rapid-acting insulin-only therapy group and an oral vildagliptin plus subcutaneous insulin group. The trial was open label with no placebo arm. Mean glucose values, insulin values given for correction per hospitalization, and the number of hypoglycemic events (glucose < 70 mg/dL) were documented. Eight hypoglycemia events occurred in the insulin-only group and none in the insulin plus DPP-4 inhibitor group (P < 0.001). Patients with acute myocardial infarction experienced a higher number of hypoglycemic events compared with unstable angina diagnosed patients. No significant differences were found regarding glucose level (P = 0.462) and administered insulin units (P = 0.639). In T2DM patients, the addition of DPP-4 inhibitors to routine subcutaneous insulin therapy may significantly reduce hypoglycemic events while maintaining acceptable recommended ranges of glucose. Further studies on a larger scale are required to verify these results and to support that DPP-4 inhibitors added to today's standard insulin-only treatment in hospitalized diabetic ACS patients may improve overall glycemic control and provide a potential treatment option in this challenging clinical setting.

The association between clinical and laboratory findings of bullous pemphigoid and dipeptidyl peptidase-4 inhibitors in the elderly: a retrospective study

AimTo evaluate the association between the use of dipeptidyl peptidase-4 inhibitors (DPP4I) and clinical and laboratory findings of bullous pemphigoid (BP) in patients treated at the European Reference Network – Skin Reference Centre in Croatia.MethodsThis retrospective study enrolled 82 patients treated for BP at the Department of Dermatovenereology, University Hospital Center Zagreb from January 2015 to December 2019. Clinical features of BP, presence of comorbidities, and laboratory findings of anti-BP antibodies and eosinophilia were analyzed in three groups of BP patients: 1) diabetes mellitus (DM) type II patients treated with DPP4I, 2) DM type II patients not treated with DPP4I, and 3) non-DM type II patients.ResultsThe average age and anti-BP180 titer were similar in all three groups. DPP4I group had a slightly lower eosinophil level in both peripheral blood (4.89%) and biopsy specimens (87.5%), but the difference was not significant. The prevalence of inflammatory BP in DPP4I group was 76.5%. DPP4I group had significantly higher percentage of patients with chronic renal failure and dementia (52.9% and 11.8%, respectively) compared with non-DPP4I DM (14.3% and 0%, respectively) and non-DM type II patients (15.7% and 0%, respectively).ConclusionBP patients treated with DPP4I and those not treated with DPP4Is did not significantly differ in laboratory findings. However, DPP4I treatment was associated with an inflammatory subtype of BP and a higher prevalence of dementia and chronic renal failure. These findings warrant further research into the association of BP and DM with dementia and chronic renal failure.

Clinical outcomes of basal insulin and oral antidiabetic agents as an add-on to dual therapy in patients with type 2 diabetes mellitus

While basal insulin remains the most effective antidiabetic agent and substantially reduces the risk of hypoglycemia, few studies have examined the comparative effect of basal insulin in the real-world setting. This study aimed to assess the outcomes of adding basal insulin compared with thiazolidinediones (TZDs) or dipeptidyl peptidase-4 inhibitors (DPP-4is) as a third antidiabetic agent in patients with type 2 diabetes mellitus (T2DM). A retrospective cohort study involving T2DM was conducted with health administrative data in Taiwan. Patients starting a third antidiabetic agent after receiving a metformin-containing dual combination were identified. The study endpoints included composite major adverse cardiovascular events (MACEs), all-cause mortality, and hypoglycemia. Propensity score matching and Cox modeling were used for analysis. After matching, the basal insulin and TZD groups contained 6,101 and 11,823 patients, respectively, and the basal insulin and DPP-4i groups contained 6,051 and 11,900 patients, respectively. TZDs and DPP-4is were both associated with similar risks of MACEs and hypoglycemia but a lower risk of all-cause mortality than basal insulin (TZDs: HR 0.55, 95% CI 0.38–0.81; DPP-4is: HR 0.56, 95% CI 0.39–0.82). Further studies are needed to elucidate the findings of increased all-cause mortality risk in patients receiving basal insulin, especially those with advanced diabetes.

CD26/DPP4 Inhibitor: A Novel Prophylactic Drug for Chronic Allograft Dysfunction after Clinical Lung Transplantation

Prevention of chronic lung allograft dysfunction (CLAD) is still an issue. In mouse/rat lung transplantation (LTx) models, we have shown the efficacy of dipeptidyl peptidase 4 inhibitors (DPP4i), drugs for diabetes mellitus (DM). We assumed that the key mechanism might be stromal cell-derived factor-1 (SDF-1). This is a chemokine for regenerative stem cells to repair injured tissue, regarded as a direct injury marker. It is also induced by DPP4i to reinforce tissue repair. This study aims to elucidate the efficacy of DPP4i in clinical LTx, and to search for a new biomarker for CLAD or overall survival (OS). The patients who underwent cadaveric or living-donor LTx in our institution between 2002 and 2018 were retrospectively reviewed. Patients with DM were extracted and divided into two groups regarding the usage of DPP4i in perioperative periods. DPP4i therapy was based on the guideline for DM. SDF-1 and IL-10 in the serum samples in the 3rd and the 6th month after LTx were measured by ELISA. Patients' characteristics, postoperative outcomes, and the ELISA data were analyzed. Finally, we performed risk analyses for CLAD and OS. In a total of 95 LTx recipients with DM, 29 were treated with DPP4i, while 66 were not. 5-year CLAD-free survivals were 63% in the DPP4i group and 41% in the non-DPP4i group (p=0.044) (Figure). Other surgical outcomes were comparable. In three of four patients, SDF-1 levels increased after the initiation of DPP4i between the 3rd and the 6th month. In the evaluation of all, there was a positive correlation between IL-10 in the 6th month and SDF-1 in the 3rd month. According to the Cox regression model, the ratio of SDF-1 in the 6th month to the 3rd month was identified as the adverse prognostic factor for CLAD and OS. DPP4i may be a novel prophylactic drug for CLAD by inducing anti-inflammatory cytokine in LTx recipients with DM. The ratio of SDF-1 level in the 6th to the 3rd month may predict CLAD and OS. We will extend the research for non-DM patients as well.

Association between the Use of Dipeptidyl Peptidase 4 Inhibitors and the Risk of Dementia among Patients with Type 2 Diabetes in Taiwan.

Study Objectives: Diabetes mellitus per se and its related therapy have been frequently associated with an increased risk of developing dementia. However, studies that explored the risk of dementia from the use of the novel oral antidiabetic medication dipeptidyl peptidase 4 inhibitor (DPP-4i) have been limited, especially in Asian populations. The present study aimed to determine the effect of DPP-4i on the subsequent risk of dementia among patients with type 2 diabetes (T2D) in Taiwan. Methods: This study utilized data from the Longitudinal Health Insurance Database between 2008 and 2015. We enrolled 2903 patients aged ≥50 years, who were on DPP-4i for a diagnosis of T2D and had no dementia. A total of 11,612 subjects were included and compared with a propensity score-matched control group who did not use DPP-4i (non-DPP-4i group). Survival analysis was performed to estimate and compare the risk of dementia—including Alzheimer’s disease, vascular dementia, and other dementia types—between the two groups. Results: Both groups had a mean age of 68 years, had a preponderance of women (61.8%), and were followed up for a mean duration of 7 years. The risk of all-cause dementia was significantly lower in the DPP-4i group than in the non-DPP-4i group (hazard ratio (HR) 0.798; 95% confidence interval (CI) 0.681–0.883; p < 0.001), with a class effect. This trend was particularly observed for vascular dementia (HR 0.575; 95% CI 0.404–0.681; p < 0.001), but not in Alzheimer’s disease (HR 0.891; 95% CI 0.712–1.265; p = 0.297). The Kaplan–Meier analysis showed that the preventive effect on dementia was positively correlated with the cumulative dose of DPP-4i. Conclusions: DPP-4i decreased the risk of dementia with a class effect, especially vascular dementia, but not in Alzheimer’s disease. Our results provide important information on the drug choice when managing patients with T2D in clinical practice.

The observational, cross-sectional study of drug utilization 90% and use of dipeptidyl peptidase-4 inhibitor in the patients with type 2 diabetes mellitus

Background: Diabetes is a chronic metabolic disease which affects the quality of life. It leads to multiple complications due to metabolic involvement. Out of multiple drugs used to treat diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors are comparatively new drugs used for type-2-diabetes mellitus (DM) treatment. This study aimed to find out the drug utilization (DU) 90% and use of DPP-4 inhibitors in patients with type-2-DM.Methods: A prospective, cross-sectional, observational study was conducted at a private healthcare clinic of an endocrinologist in Nashik. Type-2-DM patients of both sexes were selected and a total of 199 patients were enrolled in the study. The consented patients were interviewed and prescription copies were collected. After studying them; statistical analysis was done and results and conclusions were drawn.Results: Out of total prescribed drugs, 58.77% of drugs were anti-diabetics. It was observed that the biguanides were most frequently (25.32%) prescribed while the least prescribed drugs were meglitinide analogues (0.08%). Most commonly utilized anti-diabetic found to be metformin. Vildagliptin 50 mg is the most commonly prescribed drug from DPP-4 inhibitors. Most of the drugs from the DPP-4 inhibitor group came under DU90%.Conclusions:DPP-4 inhibitors are showing wide acceptability by endocrinologists for type-2-DM management, according to this study. Performing repetitive drug utilization pattern study and circulation of standard treatment guidelines to practising physicians can be required. To emphasize the point on generic prescription, more awareness should be created. So that these can responses to further cost-effective and rational prescribing practices.

Dipeptidyl peptidase-4 inhibitor treatment could decrease chronic rhinosinusitis in diabetic patients.

To evaluate the relationship between dipeptidyl peptidase-4 inhibitor (DPP4i) treatment and chronic rhinosinusitis (CRS) in diabetic patients. We used the Longitudinal Health Insurance Database for this population-based and population-matched cohort design study. Chi-square and Wilcoxon rank-sum tests were used to evaluate the association between categorical and continuous variables, respectively. The Kaplan-Meier method with the log-rank test was used to estimate the risk of CRS and DPP4i users. A total of 6198 diabetic patients were included in this cohort study. DPP4i users had a lower risk of developing CRS. The risk of CRS was significantly lower in women, patients with a Diabetes Complications Severity Index score higher than 4, patients with comorbidities, and patients with higher cumulative defined daily dose in the DPP4i group. The results of our study demonstrate that the use of DPP4i treatment could decrease CRS risk in diabetic patients in Taiwan.

DPP4 inhibitor reinforces cell junction proteins in mouse model of short bowel syndrome.

Bacterial overgrowth commonly occurs and favors bacterial translocation in short bowel syndrome (SBS). Glucagon-like peptide-2 (GLP-2) is effective for treating SBS, but is rapidly inactivated by dipeptidyl peptidase IV (DPP4). DPP4 inhibitor (DPP4I) is known to be effective for treating SBS. Here, we investigated cell junction protein function following DPP4I administration in a mouse model of SBS. Mice were divided into four groups: naïve (n = 5), naïve + DPP4I (n = 6), control (n = 6), and DPP4I (n = 5). All control and DPP4I mice had 50% of their proximal small bowel resected. DPP4I or normal saline was administered orally twice daily from days 1-7 postoperatively. The functions of cell junction proteins were assessed by RT-PCR and immunohistochemistry. Body weights and blood glucose levels were recorded. E-Cadherin was significantly higher in the DPP4I group than in the control group. E-Cadherin, occludin, and claudin-4 were significantly higher in the naïve group than in the control group. Positive staining for E-cadherin and occludin varied widely between the control and DPP4I groups. Up-regulation of E-cadherin and occludin by DPP4I may be correlated with the anti-inflammatory action of DPP4I. Therefore, DPP4I may reduce bacterial translocation in SBS.

Incident cancer risk in dipeptidyl peptidase-4 inhibitor-treated patients with type 2 diabetes mellitus.

ObjectiveIt is known that patients with diabetes are susceptible to cancer development due to long-standing diabetic conditions. This study aimed to investigate new-onset cancer risk associated with dipeptidyl peptidase-4 (DPP-4) inhibitors as compared to metformin, the first-line antidiabetic agent with promising anticancer activity, in patients with type 2 diabetes mellitus (T2DM).MethodsA retrospective cohort study of adult T2DM patients was performed at a tertiary care hospital in Korea. Patients who received comparison therapies during 2008–2017 were propensity score (PS)-matched in a 1:1 ratio either to the DPP-4 inhibitors group or to the metformin group in accordance with their primary antidiabetic therapy.ResultsA total of 1538 patients (769 in each group) were found eligible for study entry. Although the rate of newly diagnosed malignancy, irrespective of specific sites or types, was numerically less frequent in the DPP-4 inhibitors group, the difference in overall cancer risk between groups was not statistically significant (HR=1.00, 95% CI=0.56–1.80, P=0.998). The PS-matched patients were further stratified by relevant patient factors and diabetes severity. No signal of increased risk of malignant complications among DPP-4 inhibitor-receiving diabetic patients was detected in any of the individual strata, nor in the subgroup patients where insulin-exposed patients were excluded from study analyses in consideration of its carcinogenic properties. Patient death or incident pancreatitis events were seldom encountered in both treatment groups; hence such risks were assessed as negligible with the use of either antidiabetic therapy.ConclusionThis PS-matched cohort study demonstrated no elevated risk of malignant complications with DPP-4 inhibitor treatment relative to metformin treatment among T2DM patients, irrespective of patient sex, age, comorbid conditions, and diabetes severity status. Similar results were confirmed in the subgroup analyses where a potential confounding effect due to the between-group disparity in insulin co-therapy was eliminated by excluding insulin-exposed patients from risk assessments.

Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections: A Population-Based Cohort Study.

Prior studies evaluating risk for severe urinary tract infections (UTIs) with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have reported conflicting findings. To assess whether patients initiating use of SGLT-2 inhibitors were at increased risk for severe UTI events compared with those initiating use of dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor (GLP-1) agonists. Population-based cohort study. 2 large, U.S.-based databases of commercial claims (March 2013 to September 2015). Within each database, 2 cohorts were created and matched 1:1 on propensity score. Patients were aged 18 years or older, had type 2 diabetes mellitus, and were initiating use of SGLT-2 inhibitors versus DPP-4 inhibitors (cohort 1) or GLP-1 agonists (cohort 2). The primary outcome was a severe UTI event, defined as a hospitalization for primary UTI, sepsis with UTI, or pyelonephritis; the secondary outcome was outpatient UTI treated with antibiotics. Hazard ratios (HRs) were estimated in each propensity score-matched cohort, with adjustment for more than 90 baseline characteristics. After 1:1 matching on propensity score, 123752 patients were identified in cohort 1 and 111978 in cohort 2 in the 2 databases. In cohort 1, persons newly receiving SGLT-2 inhibitors had 61 severe UTI events (incidence rate [IR] per 1000 person-years, 1.76), compared with 57 events in the DPP-4 inhibitor group (IR, 1.77) (HR, 0.98 [95% CI, 0.68 to 1.41]). In cohort 2, those receiving SGLT-2 inhibitors had 73 events (IR, 2.15), compared with 87 events in the GLP-1 agonist group (IR, 2.96) (HR, 0.72 [CI, 0.53 to 0.99]). Findings were robust across sensitivity analyses; within several subgroups of age, sex, and frailty; and for canagliflozin and dapagliflozin individually. In addition, SGLT-2 inhibitors were not associated with increased risk for outpatient UTIs (cohort 1: HR, 0.96 [CI, 0.89 to 1.04]; cohort 2: HR, 0.91 [CI, 0.84 to 0.99]). Generalizability of the study findings may be limited to patients with commercial insurance. In a large cohort of patients seen in routine clinical practice, risk for severe and nonsevere UTI events among those initiating SGLT-2 inhibitor therapy was similar to that among patients initiating treatment with other second-line antidiabetic medications. Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.