Effects Of Dipeptidyl Peptidase-4 Inhibitors Research Articles

Glucagon-like peptide-1 (GLP-1) mediates the protective effects of dipeptidyl peptidase IV inhibition on pulmonary hypertension

BackgroundPulmonary hypertension (PH) is a progressive disease leading to death ultimately. Our recently published data demonstrated that inhibiting dipeptidyl peptidase IV (DPP-4) alleviated pulmonary vascular remodeling in experimental PH. However, whether glucagon-like peptide-1 (GLP-1) mediated the protective effect of DPP-4 inhibition (DPP-4i) on PH is unclear.ResultsIn the present study, GLP-1 receptor antagonist (exendin-3) abolished the protective effects of DPP-4 inhibitor (sitagliptin) on right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling (PVR) in monocrotaline (MCT, 60 mg/kg)-induced PH in rat. Notably, activation of GLP-1 receptor by GLP-1 analogue liraglutide directly attenuated RVSP and PVR in MCT-induced PH, as well as bleomycin- and chronic hypoxia-induced PH. Moreover, liraglutide potently inhibited MCT-induced inflammation and suppressed MCT-induced down-regulation of vascular endothelial marker (VE-cadherin and vWF) in lung. In vitro studies showed liraglutide reversed TGF-β1 (5 ng/ml) combining IL-1β (5 ng/ml) induced endothelial-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs), which could be abolished by GLP-1 receptor antagonist (exendin-3). Furtermore, liraglutide suppressed TGF-β1-IL-1β-induced phosphorylation of both Smad3 and ERK1/2.ConclusionsOur data suggest that GLP-1 mediated the protective effects of DPP-4i on pulmonary vascular and RV remodeling in experimental PH, which may be attributed to the inhibitory effect on EndMT.

Effect of Dipeptidyl Peptidase-4 Inhibitors on the Risk of Bone Fractures in a Korean Population.

BackgroundThere have been equivocal results in studies of the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i) on fractures. In this study, we analyzed the effect of DPP-4i on bone fracture risk in a Korean population.MethodsWe extracted subjects (n = 11,164) aged 50 years or older from the National Health Insurance Service–National Sample Cohort 2.0 from 2009 to 2014. Our control group included subjects without diabetes (n = 5,582), and our treatment groups with diabetes included DPP-4i users (n = 1,410) and DPP-4i non-users (n = 4,172). The primary endpoint was the incidence of a composite outcome consisting of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures. The secondary endpoint was the incidence of each individual component of the composite outcome. Survival analysis was performed with adjustment for age, gender, diabetes complications severity index, Charlson comorbidity index, hypertension medication, and dyslipidemia treatment.ResultsThe incidence of the composite outcome per 1,000 person-years was 0.089 in DPP-4i users, 0.099 in DPP-4i non-users, and 0.095 in controls. There was no significant difference in fracture risk between DPP-4i users and DPP-4i non-users or controls after the adjustments (P > 0.05). The incidences of osteoporosis diagnosis, osteoporotic fractures, vertebral fractures, non-vertebral fractures, and femoral fractures were not significantly different between DPP-4i users and non-users. The results of subgroup analyses by gender and age were consistent.ConclusionDPP-4i had no significant effect on the risk of fractures in a Korean population.

Dipeptidyl Peptidase-4 Inhibitors versus Other Antidiabetic Drugs Added to Metformin Monotherapy in Diabetic Retinopathy Progression: A Real World-Based Cohort Study.

BackgroundTo investigate the effects of dipeptidyl peptidase-4 inhibitor (DPP4i) as add-on medications to metformin on progression of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus, compared with sulfonylurea (SU) or thiazolidinedione (TZD).MethodsWe identified 4,447 patients with DPP4i, 6,136 with SU, and 617 with TZD in addition to metformin therapy from the database of Korean National Health Insurance Service between January 2013 and December 2015. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) for DR progression. The progression of DR was defined by the procedure code of panretinal photocoagulation, intravitreal injection or vitrectomy; or the addition of diagnostic code of vitreous hemorrhage, retinal detachment, or neovascular glaucoma.ResultsThe age and sex-adjusted HR of DR progression was 0.74 for DPP4i add-on group compared with SU add-on group (95% confidence interval [CI], 0.62 to 0.89). This lower risk of DR progression remained significant after additional adjustments for comorbidities, duration of metformin therapy, intravitreal injections and calendar index year (HR, 0.80; 95% CI, 0.66 to 0.97).ConclusionThis population-based cohort study showed that the use of DPP4i as add-on therapy to metformin did not increase the risk of DR progression compared to SU.

Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase-4 inhibitors: An analysis of Medicare claims data from 2007 to 2015

Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase-4 inhibitors: An analysis of Medicare claims data from 2007 to 2015

Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase-4 inhibitors: An analysis of Medicare claims data from 2007 to 2015.

To examine the outcomes of dipeptidyl peptidase-4 (DPP-4) inhibitor initiation with and without concurrent metformin treatment. We identified Medicare enrollees initiating a DPP-4 inhibitor, a sulphonylurea or a thiazolidinedione. Using propensity-score-weighted Poisson models, we evaluated 1-year cardiovascular (CV) outcome incidence among initiators of DPP-4 inhibitors versus comparators in subgroups with and without concurrent metformin use, and assessed the interaction between initiation drug and metformin. Outcomes included mortality, non-fatal myocardial infarction (MI), stroke, and a composite outcome. For the DPP-4 inhibitor (n = 13 391) versus sulphonylurea (n = 33 206) comparison, rate differences in composite outcome incidence favoured DPP-4 inhibitors: -2.0/100 person-years among metformin users (95% confidence interval [CI] -2.7 to -1.3) and - 1.0/100 person-years (95% CI -1.8 to -0.2) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-1.5/100 person-years [95% CI -2.1 to -0.9] and -0.7/100 person-years [95% CI -1.4 to 0.0]) and non-fatal MI (-0.5/100 person-years [95% CI -0.8, -0.3] and 0.1/100 person-years [95% CI -0.2 to 0.4]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for non-fatal MI (P = 0.008). For the DPP-4 inhibitor (n = 22 210) versus thiazolidinedione (n = 9517) comparison, rate differences in composite outcome incidence for DPP-4 inhibitor initiation were -0.6/100 person-years (95% CI -1.5 to 0.2) among metformin users and 1.0 (95% CI 0.0 to 2.0) among metformin non-users. Similar rate difference trends among metformin users and non-users were seen for mortality (-0.5/100 person-years [95% CI -1.3 to 0.1] and 0.8/100 person-years [95% CI -0.0 to 1.7]) and non-fatal MI (-0.1/100 person-years [95% CI -0.4 to 0.2] and 0.2/100 person-years [95% CI -0.1 to 0.6]). The interaction between DPP-4 inhibitor initiation and metformin was statistically significant for the composite outcome (P = 0.024) and mortality (P = 0.023). Incidence rate differences in multiple CV outcomes appeared more favourable when DPP-4 inhibitor initiation occurred in the presence of metformin, suggesting a possible interaction between DPP-4 inhibitors and metformin.

Efficacy of DPP‐4 inhibitors, GLP‐1 analogues, and SGLT2 inhibitors as add‐ons to metformin monotherapy in T2DM patients: a model‐based meta‐analysis

The aim of the present study was to quantitate the hypoglycaemic effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1r) and sodium glucose cotransporter 2 inhibitors (SGLT2i) as add-on treatments to metformin monotherapy in patients with type 2 diabetes mellitus (T2DM) using a model-based meta-analysis (MBMA). A systematic literature search of public databases was conducted to develop models that describe the time courses of the fasting plasma glucose (FPG)- and haemoglobin A1c (HbA1c)-lowering effects of three antidiabetic classes using NONMEM 7.3.0. Seventy-six publications were eligible for this study, and 873 FPG and 1086 HbA1c values were collected. We developed a physiological indirect response model that described the time courses of FPG and HbA1c and simulated reductions in these values 90 days after the initiation of add-on treatments. FPG and HbA1c reductions with once weekly exenatide, liraglutide and dulaglutide were greater than those with other drugs. Mean changes from baseline FPG and HbA1c with these drugs were as follows: exenatide (-22.5 and -16.6%), liraglutide (-22.1 and -16.3%), and dulaglutide (-19.3 and -14.3%). The hypoglycaemic effects of DPP-4i and SGLT2i were similar. Once weekly exenatide, liraglutide and dulaglutide provided better hypoglycaemic effects among the antidiabetic drugs analysed. Long-acting GLP-1r appears to be more useful for T2DM patients inadequately controlled with metformin monotherapy.

Linagliptin-related pancreatitis in a diabetic patient with biliary calculus: A case report.

Rationale:Dipeptidyl peptidase-4 inhibitors are commonly used drugs for the treatment of type 2 diabetes mellitus. While acute pancreatitis cases induced by saxagliptin, sitagliptin, and vildagliptin (all of which are members of the dipeptidyl peptidase-4 group) have been reported, there is no clear evidence suggesting that linagliptin may cause pancreatitis, and information in this regard is limited to a few studies. Moreover, no pancreatitis cases have been reported that were directly associated with linagliptin.Patient concerns:We present a case of linagliptin-related pancreatitis in a 79-year-old male diabetic patient with biliary calculi. The patient, who was diagnosed with acute pancreatitis 4 months after initiating linagliptin 5 mg/d treatment, was admitted to our hospital.Diagnoses:The patient's pancreatic enzymes were high. Ultrasonography showed multiple biliary calculi, and abdominal computed tomography showed edematous pancreatitis.Interventions:Linagliptin was discontinued and clinical improvement was achieved with standard acute pancreatitis treatment.Outcomes:This is the 1st case report suggesting that linagliptin might be associated with the risk of pancreatitis and could be an etiologic cause of pancreatitis, similar to the other members of its group.Lessons:While the results of previous studies stated that there was no data to prove a causal relationship between dipeptidyl peptidase-4 inhibitors and pancreatitis, concerns regarding this subject have continued to arise. Therefore, new and comprehensive studies are needed to determine the long-term effects of dipeptidyl peptidase-4 inhibitors on type 2 diabetes mellitus patients and to shed light on the side effects of these medications.

The Effect of Linagliptin versus Metformin Treatment-Related Quality of Life in Patients with Type 2 Diabetes Mellitus.

IntroductionThere have been no studies directly comparing the effect of dipeptidyl peptidase-4 inhibitors with that of metformin on treatment-related quality of life (QOL) when used as first-line therapy in patients with type 2 diabetes mellitus (T2DM).MethodsThis study is a prospective, randomized, open-label, multicenter, parallel-group, comparative study. Forty-four participants who failed to achieve target glycemic control with diet and exercise therapy were randomly allocated to receive linagliptin or metformin therapy. We compared treatment-related QOL among the two groups using the Oral Hypoglycemic Agent Questionnaire, version 2 (OHA-Q version 2) and the self-administered Diabetes Therapy-Related QOL (DTR-QOL) questionnaire.ResultsAfter randomization, 21 patients in the linagliptin group and 22 patients in the metformin treatment group were included in the full analysis set. Biochemical parameters, incidence of adverse effects, and rate of adherence to medication were comparable between the two groups. Over the 24-week treatment period, no significant differences in overall OHA-Q scores between the groups were observed, although the subscale 1 (treatment convenience) score was significantly higher in the linagliptin group than in the metformin group. The overall DTR-QOL score did not differ between the two groups; however, the DTR-QOL scores significantly improved after 24 weeks of linagliptin treatment, but not after metformin treatment.ConclusionWe did not find significantly better treatment-related QOL with linagliptin among Japanese patients with T2DM. In terms of treatment convenience, our data showed that linagliptin was superior to metformin.FundingThis study was financially supported by Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly and Company. The journal’s article processing fees were covered by a research fund from Juntendo University.Clinical Trial RegistrationUMIN000022953.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-018-0539-5) contains supplementary material, which is available to authorized users.

Improvement in Mortality and End-Stage Renal Disease in Patients With Type 2 Diabetes After Acute Kidney Injury Who Are Prescribed Dipeptidyl Peptidase-4 Inhibitors

ObjectiveTo focus on the potential beneficial effects of the pleiotropic effects of dipeptidyl peptidase-4 inhibitors (DPP4is) on attenuating progression of diabetic kidney disease in reducing the long-term effect of the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Patients and MethodsData from the National Health Insurance Research Database from January 1, 1999, to July 31, 2011, were analyzed, and patients with diabetes weaning from dialysis-requiring AKI were identified. Cox proportional hazards models and inverse-weighted estimates of the probability of treatment were used to adjust for treatment selection bias. The outcomes were incident end-stage renal disease (ESRD) and mortality, major adverse cardiovascular events, and hospitalized heart failure. ResultsOf a total of 6165 patients with diabetes weaning from dialysis-requiring AKI identified, 5635 (91.4%) patients were DPP4i nonusers and 530 (8.6%) patients were DPP4i users. Compared with DPP4i nonusers, DPP4i users had a lower risk of ESRD (hazard ratio, 0.81; 95% CI, 0.70-0.94; P=.04) and all-cause mortality (hazard ratio, 0.28; 95% CI, 0.23-0.34; P<.001) after adjustments for CKD, advanced CKD, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use. In contrast, the risk of major adverse cardiovascular events and hospitalized heart failure did not differ significantly between groups. ConclusionDipeptidyl peptidase-4 inhibitor users had a lower risk of ESRD and mortality than did nonusers among patients with diabetes after weaning from dialysis-requiring AKI. Therefore, a prospective study of AKI to CKD transitions after episodes of AKI is needed to optimally target DPP4i interventions.

Differential effect of concomitant antidiabetic agents on carotid atherosclerosis: a subgroup analysis of the PROLOGUE study.

Accumulated evidence shows that some antidiabetic agents attenuate the progression of carotid atherosclerosis assessed as intima-media thickness (IMT). Although some studies have demonstrated an inhibitory effect of dipeptidyl peptidase-4 inhibitors on carotid IMT progression, in the PROLOGUE study sitagliptin failed to slow progression relative to conventional therapy for 24months. We hypothesized that differences in the concomitant antidiabetic agents between the groups have influenced the progression of carotid IMT. We performed a post hoc analysis of the PROLOGUE study using subgroups stratified by concomitant antidiabetic agents. Although no subgroup with any combination of agents in the overall patients showed a significant difference between sitagliptin group and conventional therapy group in the changes from baseline in mean common carotid artery (CCA)-IMT at 24months, a significant attenuation of mean CCA-IMT progression was observed in the sitagliptin group relative to conventional therapy group only in three combination subgroups aged < 70years, namely no thiazolidinedione; no thiazolidinedione or biguanide; and no thiazolidinedione, biguanide or α-glucosidase inhibitor, even after adjustment for multiple confounding factors. In the three subgroups, no significant difference between sitagliptin group and conventional therapy group in the changes from baseline in HbA1c at 24months was detected. Our data suggest that some concomitant agents, whose prescription frequencies were increased in the conventional therapy group, may have masked the inhibitory effect of sitagliptin on carotid IMT progression in the PROLOGUE study.

Abstract P328: Effect of Sitagliptin on the Hemodynamic and Metabolic Response to a Mixed Meal in Individuals With Type 2 Diabetes and Hypertension

Dipeptidyl peptidase IV (DPP4) inhibitors such as sitagliptin are anti-diabetes drugs that may also have cardiovascular effects. We tested the hypothesis that there is an interactive effect between sitagliptin and angiotensin-converting enzyme (ACE) inhibition on blood pressure (SBP, DBP, MAP) and heart rate (HR) after a meal. We enrolled 52 type 2 diabetics (T2DM) with hypertension. The mean age was 56.1±10.2 years. 58.5% were men, 28.3% were black and 67.9% were white. Individuals were randomized to one of three BP agents: ramipril 10mg/d, valsartan 320mg/d [a renin-angiotensin-aldosterone system (RAAS) inhibiting drug without enzyme activity], and amlodipine 10mg/d (a RAAS-independent control) for 15 weeks. On the 5 th , 10 th , and 15 th week of anti-hypertensive therapy each participant underwent one-week crossover treatment with sitagliptin 100 mg/d + placebo, placebo + placebo, and sitagliptin + aprepitant 80 mg/d (a substance P receptor blocker, as DPP4 and ACE degrade substance P). On the last day of each treatment, participants were given a mixed meal (712 calories: 45% from fat, 33% carbohydrate, 22% protein). There was no difference in pre-prandial BP among the three crossover treatments. Following the meal, SBP (p=0.002) and MAP (p&lt;0.001) were significantly decreased during either DPP4 inhibitor crossover treatment compared to placebo. In particular, in patients treated with an ACE inhibitor, post-prandial SBP (0.015) and MAP (p=0.021) were lower during DPP4 inhibition. This was true after controlling for significant effects of race (p=0.002) and gender (p=0.0007). Post-prandial HR was not affected by DPP4 inhibition during ACE inhibition. The effect of DPP4 inhibition on fasting glucose but not on postprandial glucose differed among anti-hypertensive treatment groups. DPP4 inhibition decreased the formation of PYY3-36 from PYY following the meal. There is an interactive effect between DPP4 inhibition and anti-hypertensive therapy on post-prandial BP and metabolic parameters.

DPP-4 inhibitors promote proliferation and migration of rat brain microvascular endothelial cells under hypoxic/high-glucose conditions, potentially through the SIRT1/HIF-1/VEGF pathway.

Vascular disease in diabetes, for example, stroke, presents a significant public health burden. Recently, the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin has been found to counteract stroke among diabetic patients, showing great promise in drug repurposing and indication expansion. However, the molecular basis of this protection mechanism remains unknown. The expression and localization of DPP-4 in rat brain microvascular endothelial cells (rBMVECs) were assessed with immunofluorescent staining and Western blotting. The effects of DPP-4 inhibitors on cell proliferation and migration of rBMVECs were determined using MTT and transwell assays, separately. The influence of DPP-4 inhibition on the expression of molecular markers (eg, VEGF, eNOS, HIF-1α. SIRT1) was examined at both mRNA and protein levels with qRT-PCR and Western blotting, individually. DPP-4 inhibitors (40nmol/L linagliptin, 30μmol/L berberine) offer protection from hypoxia/high glucose induced impairments in the proliferation and migration of rBMVECs. Treatment with DPP-4 inhibitors counteracted the attenuating effects of hypoxic/high-glucose conditions on the expression of VEGF, eNOS, HIF-1α, and SIRT1, which can be completely eliminated by the inhibition of SIRT1 with 1mmol/L nicotinamide. The protection of rBMVECs from hypoxia/high-glucose induced impairment by DPP-4 inhibitors may be mediated by the SIRT1/HIF-1α/VEGF pathway.

Linagliptin inhibits lipopolysaccharide-induced inflammation in human U937 monocytes

BackgroundAtherosclerosis and inflammation are more common in patients with diabetes than in patients without diabetes, and atherosclerosis progression contributes to inflammation. Therefore, anti-inflammatory therapy is important for the prognosis of patients with diabetes. Linagliptin is the only bile-excreted, anti-diabetic oral dipeptidyl peptidase-4 (DPP-4) inhibitor. Although the anti-inflammatory effects of DPP-4 inhibitors in vivo and in vitro have been reported, few in vitro studies have examined the effects of linagliptin using monocytes, which play a central role in arteriosclerosis-related inflammation. Herein, we assessed the anti-inflammatory effects of linagliptin in human U937 monocytes.MethodsU937 cells at densities of 1 × 106 cells/mL were cultured in Roswell Park Memorial Institute medium supplied with 10% fetal bovine serum and treated with 100 nM phorbol myristate acetate for 48 h for differentiation into macrophages. The media were replaced, and the cells were pretreated with 1, 5, 10, 50, and 100 nM linagliptin for 1 h or were left untreated. The media were then replaced again, and the cells were treated with 1 μg/mL lipopolysaccharide (LPS) or 10 nM interleukin (IL)-1β only, in combination with 1, 5, 10, 50, and 100 nM linagliptin or were left untreated. The extracted media were used to measure IL-6 and tumor necrosis factor (TNF)-α levels using enzyme-linked immunosorbent assay kits.ResultsLPS alone significantly increased IL-6 and TNF-α production compared with the control treatment. The treatment of cells with linagliptin at all concentrations significantly inhibited the LPS-stimulated IL-6 and TNF-α production. Meanwhile, IL-1β alone significantly increased IL-6 production compared with the control treatment. No significant difference in IL-6 production was noted between the cells treated with IL-1β and simultaneous treatment with IL-1β and linagliptin.ConclusionsLinagliptin inhibited LPS-induced inflammation in human monocytic U937 cells.

Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Dipeptidyl Peptidase-4 Inhibition

Type 2 diabetes is characterized by absolute or relative hypoinsulinemia and hyperglucagonemia. Dipeptidyl peptidase 4 inhibitors (DPP-4i) augment insulin secretion and decrease glucagon secretion, but if glucagon is removed from the metabolic equation, the effect of DPP-4i is unknown. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, patients with type 2 diabetes (n=12, age [mean (SD)]: 60.9 (7.8) years, BMI 34.6 (7.1) kg/m2; HbA1c 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration of 1) placebo, 2) DPP-4i (5 mg linagliptin) 2 hours before the meal, 3) glucagon receptor antagonist (GRA) (300 mg LY2409021) 12 hours before the meal, and 4) GRA + DPP-4i. Compared to placebo, fasting plasma glucose (FPG) was lowered by GRA but not DPP-4i. Adding DPP-4i to GRA did not lower FPG further. Compared to placebo, DPP-4i increased insulin responses to the meal (C-peptide AUC) (P&amp;lt;0.01), but did not result in a difference in plasma glucose excursions (Figure). GRA alone lowered glucose AUC, and the combination of GRA and DPP-4i lowered glucose AUC further. In conclusion, the combination of DPP-4i and GRA has additive effects on postprandial glucose excursions. This seems to be driven by the efficient reduction in FPG by GRA combined with additional reduction in postprandial glucose excursions by DPP-4i. Disclosure S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. E. Nielsen-Hannerup: None. H. Maagensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

A Real-World Evaluation of the Association between Cardiovascular Outcomes and T2D Therapy

Data from placebo controlled, randomized clinical trials (RCTs) have demonstrated cardio-protective effects of certain diabetes therapy classes, including sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon receptor agonists (GLP-1RA). However, the majority of these trials made comparisons to placebo and there is limited data on head to head comparisons between specific classes. We performed an observational cohort study using the Truven Health MarketScan® Research Databases (2013-2016) to compare the risk of cardiovascular events between patients initiating treatment with SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP-4is) and GLP-1-RAs vs. sulfonylureas (SUs) in a real-world setting. Propensity score weighting and doubly robust methods (boosting and Poisson regression) were used to control for differences in baseline characteristics. The primary study outcomes were hospitalization for congestive heart failure, acute myocardial infarction, stroke and a composite of all three. Lower extremity amputations were also examined. The relative risks of events in the 12 months before and after treatment initiation were compared to generate relative risk ratios. Protective effects of SGLT2is compared to SUs were observed (Table). Interestingly, there was also a protective effect of DPP-4is on individual outcomes compared to SUs in contrast to DPP-4i vs. placebo in RCTs. Disclosure E. Thiel: None. W.D. Marder: Employee; Self; IBM. W.T. Cefalu: None. T. Darsow: None. M. Petersen: None. L. Latts: Other Relationship; Self; Medtronic, Novo Nordisk Inc., Sanofi.

Cost Effectiveness of DPP-4i and SGLT2i Combination Therapy for the Treatment of Type 2 Diabetes in the U.S.

Management of type 2 diabetes (T2D) needs different treatment strategies to achieve the individualized glycemic goal. This study evaluated the long-term cost effectiveness of strategies involving pathway 1: metformin followed by intensification with dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and insulin vs. pathway 2: metformin followed by intensification with sulfonylurea (SU) and insulin in the U.S. Cost-effectiveness analysis was performed using the validated QuintilesIMS CORE Diabetes Model from a U.S. payer perspective. Clinical and economic outcomes were modeled over a lifetime for a cohort of T2D patients who fail to achieve glycemic goal on metformin monotherapy. Clinical data were obtained from clinical trials. Direct medical costs [e.g., medications (whole sale acquisition costs), diabetes management, adverse events, and complications] were obtained from published sources. Despite higher direct medical costs for pathway 1 compared to pathway 2 ($117,779 vs. $93,196 respectively); pathway 1 improved total quality-adjusted life years (QALY) by 0.28 vs. pathway 2. Pathway 1 also led to cost offsets from fewer diabetes-related complications and delayed initiation of insulin. The incremental cost-effectiveness ratio (ICER) was favorable for pathway 1 at $89,038/QALY. Most of the scenario analysis (changes in treatment effect, hypoglycemia, and cardiovascular protective effects of SGLT2is) resulted in ICERs under $100,000/QALY except for the population with baseline HbA1c of 7%, and older age (65+ years). Negotiated discounts on branded medications resulted in significant improvement in ICERs (ICER of $69,554/QALY for 15% discount and $0/QALY for 75% discount). Among patients failing metformin monotherapy in the U.S, additional intensification with DPP-4i followed by SGLT2i may be considered more cost effective compared to intensification with SU followed by insulin. Disclosure M. Pawaskar: Employee; Self; Merck &amp; Co., Inc. S. Bilir: Consultant; Self; Merck &amp; Co., Inc.. A. Graber-Naidich: None. C.D. Gonzalez: Employee; Self; Merck &amp; Co., Inc. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc. G.M. Davies: Employee; Self; Merck &amp; Co., Inc..

Meta-analysis of HbA1c-Lowering Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Combination with Insulin in T2DM Patients

Randomized controlled trials (RCTs) have evaluated the efficacy of dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to insulin compared to insulin alone in T2DM patients, while there have been differences in the magnitude of the outcome effect across studies. This updated systematic review and meta-analysis aimed to evaluate the effect of DPP-4i in combination with insulin on HbA1c in T2DM patients. MEDLINE, EMBASE, and Cochrane databases were searched for RCTs that compared DPP-4i plus insulin to insulin alone for T2DM patients, with or without background therapy with other oral agents. The primary endpoint was the absolute change of HbA1c from baseline. Weighted mean difference (WMD) with 95% confidence intervals (CI) was calculated using a random effect model. The methodological quality of included RCTs was evaluated using the Cochrane risk of bias tool. Eighteen RCTs involving 6,493 patients with average follow-up of 32 weeks were identified and analyzed. DPP-4i plus insulin showed greater reduction in HbA1c than insulin alone (WMD -0.52%, 95% CI -0.61 to -0.43; P&amp;lt;0.0001) (Figure 1). In conclusion, compared with use of insulin alone, DPP-4i in combination with insulin can significantly lower HbA1c levels in T2DM patients. Further analysis is needed to better understand effects of this combination therapy on other outcomes, such as hypoglycemia and insulin. Disclosure J. Yang: None. Q. Tian: None. Y. Tang: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; GlaxoSmithKline plc.. Stock/Shareholder; Spouse/Partner; GlaxoSmithKline plc. A.K. Shah: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; Merck &amp; Co., Inc. R. Zhang: Employee; Self; Merck Sharp &amp; Dohme Corp. G. Chen: Employee; Self; Merck Sharp &amp; Dohme Corp.. Y. Zhang: None. S. Rajpathak: Employee; Self; Merck &amp; Co., Inc. T. Hong: Advisory Panel; Self; Novo Nordisk A/S, AstraZeneca.

The pleiotropic cardiovascular effects of dipeptidyl peptidase-4 inhibitors.

Patients with Type 2 diabetes have an excess risk for cardiovascular disease. One of the several approaches, included in the guidelines for the management of Type 2 diabetes, is based on dipeptidyl peptidase 4 (DPP-4; also termed CD26) inhibitors, also called gliptins. Gliptins inhibit the degradation of glucagon-like peptide-1 (GLP-1): this effect is associated with increased circulating insulin-to-glucagon ratio, and a consequent reduction of HbA1c. In addition to incretin hormones, there are several proteins that may be affected by DPP-4 and its inhibition: among these some are relevant for the cardiovascular system homeostasis such as SDF-1α and its receptor CXCR4, brain natriuretic peptides, neuropeptide Y and peptide YY. In this review, we will discuss the pathophysiological relevance of gliptin pleiotropism and its translational potential.

Effect of Sitagliptin on Coronary Flow Reserve Assessed by Magnetic Resonance Imaging in Type 2 Diabetic Patients With Coronary Artery Disease.

The present study was conducted to assess the cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP4i) on coronary flow reserve (CFR), left ventricular (LV) function and endothelial function of the peripheral artery by comparison with those of α-glucosidase inhibitors (αGI) in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).Methods and Results:We randomly assigned 30 patients with T2DM and CAD to receive either sitagliptin or voglibose, and 28 patients (age 69±9 years, 75% male, hemoglobin A1c [HbA1c] 6.62±0.48%) completed the study (14 in each group). CFR and LV function, assessed by cardiac magnetic resonance imaging, and endothelial function, assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT), were measured at baseline and 24 weeks after treatment. Clinical and laboratory parameters, including HbA1c level, plasma active glucagon-like peptide-1 concentrations, and biomarkers of inflammation, were unchanged in both groups after 24 weeks of treatment. CFR were unchanged in both the αGI group (3.01±0.98 at baseline and 3.06±0.8 after treatment, P=NS) and the DPP4i group (4.29±2.04 at baseline and 3.63±1.31 after treatment, P=NS), with no interaction effect. LV functional parameters and the reactive hyperemia index also remained unchanged after the 24-week treatment. DPP4i did not improve CFR, LV function or endothelial function of the peripheral artery in patients with relatively well-controlled T2DM and CAD.

The MARLINA-T2D trial: putting the results into clinical perspective

ABSTRACTChronic kidney disease (CKD) and type 2 diabetes mellitus (T2D) frequently coexist and are associated with poor clinical outcomes. Dipeptidyl peptidase-4 (DPP-4) inhibitors can be used for patients with T2D and CKD, and preclinical evidence suggests these agents may slow the progression of kidney disease in T2D. Although clinical evidence of the renal effects of DPP-4 inhibitors is limited, the recent publication of the MARLINA-T2D study provided important new data. In MARLINA-T2D, linagliptin was associated with significant improvements in glycemic control with a non-significant reduction in albuminuria and no evidence of renal adverse effects in a high-risk population of patients with T2D and early diabetic kidney disease. Although there was no conclusive evidence of renoprotective effects, previous research suggests that clinically apparent renal benefits might develop with longer term treatment. The results of ongoing trials with primary renal endpoints are awaited with interest.