Impact Of Dipeptidyl Peptidase-4 Inhibitors Research Articles

Impact of DPP-4 Inhibitors in Patients with Diabetes Mellitus and Heart Failure: An In-Depth Review

The increasing prevalence of both type 2 diabetes mellitus and heart failure has underscored the urgent need for optimized therapeutic strategies that address the complex interplay between these conditions. Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as a popular class of glucose-lowering agents due to their favorable glycemic effects, safety profile, and potential cardiovascular benefits. However, the impact of DPP-4 inhibitors on heart failure outcomes in patients with diabetes remains contentious, with conflicting evidence from clinical trials and observational studies. This review critically examines current evidence on the use of DPP-4 inhibitors in patients with coexisting diabetes and heart failure, focusing on pharmacodynamics, safety, and efficacy outcomes. We explore the physiological mechanisms by which DPP-4 inhibitors may influence heart failure risk, including modulation of inflammation, oxidative stress, and myocardial fibrosis. Clinical trials such as SAVOR-TIMI 53, EXAMINE, and TECOS are evaluated to provide a comprehensive analysis of DPP-4 inhibitors’ effects on hospitalization for heart failure, mortality, and cardiovascular events in diabetic patients. While some trials suggest an increased risk of HF hospitalizations with specific DPP-4 inhibitors (e.g., saxagliptin), others report neutral effects, raising questions about the class effects versus individual drug characteristics within this group. Additionally, we address discrepancies in outcomes related to patient demographics, HF phenotype, and comorbid conditions that may influence DPP-4 inhibitors’ risk–benefit profile. Comparative insights into alternative glucose-lowering therapies such as SGLT2 inhibitors and GLP-1 receptor agonists are also provided, highlighting potential implications for treatment selection in this high-risk population. In summary, this review synthesizes available evidence on DPP-4 inhibitors’ impact in diabetic patients with heart failure, aiming to guide clinicians in making informed therapeutic decisions. While DPP-4 inhibitors remain a viable option in diabetes management, caution is warranted in patients with advanced heart failure, and future research is essential to refine patient-specific guidelines.

Updating and calibrating the Real-World Progression In Diabetes (RAPIDS) model in a non-Veterans Affairs population.

To present the Real-World Progression In Diabetes (RAPIDS) 2.0 Risk Engine, the only simulation model to study the long-term trajectories of outcomes arising from dynamic sequences of glucose-lowering treatments in type 2 diabetes (T2DM). The RAPIDS model's risk equations were re-estimated using a Least Absolute Shrinkage and Selection Operator (LASSO)-based regularization of features that spanned baseline data from the last two quarters of current time and interactions with age. These equations were supplemented with estimates for the impact of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitor classes of drugs as monotherapies and their combinations with metformin based on newer trial data and comprehensive meta-analyses. The probabilistic RAPIDS 2.0 model was calibrated (N = 25 000) and validated (N = 263 816) using electronic medical records (EMR) data between 2008 and 2021 from a national network of US healthcare organizations. The EMR-based cohort had a mean age of 61 years at baseline, with 50% women, 70% non-Hispanic White individuals and 20% non-Hispanic Black individuals, and was followed for 17.5 quarters (range: 3-50). The final RAPIDS 2.0 risk engine accurately predicted the long-term trajectories of all nine biomarkers and nine outcomes in the hold-out validation sample. Similar accuracies in predictions were observed in each of the 14 subgroups studied. The RAPIDS 2.0 model demonstrated valid long-term predictions of outcomes in individuals with T2DM in the United States as a function of dynamic sequences of treatment use patterns. This highlights its potential to project long-term comparative effectiveness between alternative sequences of glucose-lowering treatment uses in the United States.

Effect of DPP-4i inhibitors on renal function in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials

AimsAbout 20–40% patients with type 2 diabetes mellitus (T2DM) had an increased risk of developing diabetic nephropathy (DN). Dipeptidyl peptidase-4 inhibitors (DPP-4i) were recommended for treatment of T2DM, while the impact of DPP-4i on renal function remained unclear. This study aimed to explore the effect of DPP-4i on renal parameter of estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR) in T2DM.MethodsA systematic search was performed across PubMed, Embase and Cochrane Library. A fixed or random-effects model was used for quantitative synthesis according to the heterogeneity, which was assessed with I2 index. Sensitivity analysis and publication bias were performed with standard methods, respectively.ResultsA total of 17 randomized controlled trials were identified. Administration of DPP-4i produced no significant effect on eGFR (WMD, -0.92 mL/min/1.73m2, 95% CI, -2.04 to 0.19) in diabetic condition. DPP-4i produced a favorable effect on attenuating ACR (WMD, -2.76 mg/g, 95% CI, -5.23 to -0.29) in patients with T2DM. The pooled estimate was stable based on the sensitivity test. No publication bias was observed according to Begg’s and Egger’s tests.ConclusionsTreatment with DPP-4i preserved the renal parameter of eGFR in diabetic condition. Available evidences suggested that administration of DPP-4i produced a favorable effect on attenuating ACR in patients with T2DM.International Prospective Register for Systematic Review (PROSPERO) numberCRD.42020144642.

Dipeptidyl peptidase-4 inhibitors alleviate cognitive dysfunction in type 2 diabetes mellitus

BackgroundPatients with type 2 diabetes mellitus (T2DM) are commonly at high risk for developing cognitive dysfunction. Antidiabetic agents might be repurposed for targeting cognitive dysfunction in addition to modulation on glucose homeostasis. This study aimed to evaluate the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on cognitive function in T2DM.MethodsPubMed, Embase, Cochrane Library and Web of Science were systematically searched from inception to September 30, 2023. Weighted mean differences were calculated using the Mantel-Haenszel (M-H) fixed or random effects model based on the degree of heterogeneity among studies. Heterogeneity was evaluated using a Chi-squared test and quantified with Higgins I2. Sensitivity analysis was performed with the leave-one-out method, and publication bias was evaluated according to Begg’s and Egger’s tests.ResultsSix clinical trials involving 5,178 participants were included in the pooled analysis. Administration of DPP-4i generally correlated with an increase of Mini-Mental State Examination (MMSE) scores (1.09, 95% CI: 0.22 to 1.96). DPP-4i alleviated cognitive impairment in the copying skill subdomain of MMSE (0.26, 95% CI: 0.12 to 0.40). Treatment with DPP-4i also resulted in an increase of Instrumental Activities of Daily Living (IADL) scores (0.82, 95% CI: 0.30 to 1.34). However, DPP-4i produced no significant effects on Barthel Activities of Daily Living (BADL) scores (0.37, 95% CI: -1.26 to 1.99) or other test scores.ConclusionsDPP-4i treatment favourably improved cognitive function in patients with T2DM. Further trials with larger samples should be performed to confirm these estimates and investigate the association of different DPP-4i with cognitive function among diabetic patients.Trial registration in PROSPEROCRD42023430873.

Dipeptidyl peptidase-4 inhibitors reduced long-term cardiovascular risk in diabetic patients after percutaneous coronary intervention via insulin-like growth factor-1 axis

Dipeptidyl-peptidase-4 inhibitors (DPP4i) have been the most used antidiabetic medications worldwide due to their good safety profiles and tolerability with a low risk of hypoglycemia, however, large cardiovascular outcome trials (CVOTs) have not shown any significant the prognostic superiority. On the contrary, since observational studies have suggested the effects of DPP4i are enhanced some populations, such as Asians and those who without overweight, their prognostic benefit is still under debate. The aim of this study was thus to assess the prognostic impact of DPP4i in patients with both diabetes and coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) through the insulin-like growth factor-1 (IGF-1) axis, a substrate of DPP4. This single-center analysis involved consecutive Japanese diabetic patients who underwent PCI for the first time between 2008 and 2018 (n = 885). Primary and secondary endpoints were set as cardiovascular (CV) death and the composite of CV death, non-fatal myocardial infarction and ischemic stroke (3P-MACE). Serum levels of IGF-1 and its main binding protein (insulin-like growth factor binding protein-3: IGFBP-3) were measured. In consequences, unadjusted Kaplan–Meier analyses revealed reduced incidences of CV-death and 3P-MACE by DPP4i, which was particularly enhanced in patients who were not overweight (BMI ≤ 25). Multivariate Cox hazard analyses consistently indicated reduced risks of CV death by DPP4i at PCI (hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.16–0.82, p = 0.01) and 3P-MACE (HR 0.47, 95% CI 0.25–0.84, p = 0.01), respectively. Moreover, elevated IGF-1 activity indicated by the IGF-1/IGFBP-3 ratio was associated with decreased risks of both endpoints and it was significantly higher in patients with DPP4i (p < 0.0001). In conclusion, the findings of the present study indicate beneficial effects of DPP4i to improve outcomes in Japanese diabetic patients following PCI, which might be mediated by DPP4–IGF-1 axis.

The impact of oral hypoglycemics and statins on outcomes in myelodysplastic syndromes.

Observational studies suggest an anti-neoplastic effect associated with statins, metformin, and dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. We linked the Ontario subset of a prospective Canadian myelodysplastic syndromes (MDS) registry with provincial administrative databases. We assessed the impact of statin/oral hypoglycemic medication exposure on overall survival (OS) using Cox regression analysis, controlling for comorbidities and sociodemographic factors. Five hundred thirty-three patients aged ≥ 66years were included: 49.3% used statins, 18.9% used metformin, 9.0% used sulfonylureas, and 6.4% used DPP4i. Three hundred ninety-five patients were lower-risk based on the International Prognostic Scoring System. On univariate analysis, we identified a marginal improvement in OS in the lower-risk group using DPP4i (HR 0.98, 95% CI 0.95-1.00, P = 0.05), while there was no impact on mortality for higher-risk DPP4i users (HR 1.03, CI 0.99-1.07, P = 0.21). There was no mortality difference for statins (HR 1.00, CI 1.00-1.01, P = 0.93), metformin (HR 1.00, CI 0.99-1.01, P = 0.81), or sulfonylureas (HR 1.00, CI 0.99-1.02, P = 0.43) in the entire cohort, as well as when stratified into lower/higher-risk groups. On multivariable analysis in the lower-risk group, there was no association between DPP4i and OS (HR 0.98, CI 0.95-1.00, P = 0.06). Prospective studies with larger cohorts of patients and longer follow-up are required to further study the impact of DPP4i in MDS.

Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials.

BACKGROUNDDipeptidyl peptidase-4 (DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus (T2DM). Recently, a series of large, randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published. AIMTo pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias. METHODSWe searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following “hard” efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia.RESULTSWe pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio (RR) = 1.02, 95%CI: 0.94-1.11, I2 = 0%], hospitalization for heart failure (RR = 1.09, 95%CI: 0.92-1.29, I2 = 65%) and cardiovascular death (RR = 1.02, 95%CI: 0.93-1.11, I2 = 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke (RR = 0.96, 95%CI: 0.85-1.08, I2 = 0%) and coronary revascularization (RR = 0.99, 95%CI: 0.90-1.09, I2 = 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR = 1.00, 95%CI: 0.85-1.18, I2 = 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation (RR = 0.95, 95%CI: 0.78-1.17, I2 = 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52% (RR = 1.52, 95%CI: 1.03-2.24, I2 = 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias. CONCLUSIONDPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.

The Effect of DPP-4i on Endothelial Function and Arterial Stiffness in Patients with Type 2 Diabetes: A Systematic Review of Randomized Placebo-controlled Trials.

We systematically reviewed the literature regarding the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on vascular function, including endothelial function and arterial stiffness, as predictors of atherosclerosis progression and cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). We searched PubMed in order to identify clinical trials that investigated the effect of DPP-4i on vascular function in patients with T2DM when compared with placebo. Although 168 articles were initially found, only 6 studies (total 324 patients) investigated the effect of DPP-4i in comparison with placebo, specifically linagliptin and sitagliptin, and satisfied the inclusion criteria. There are scarce data to indicate that linagliptin may enhance endothelial function and exert a slight beneficial effect on arterial wall properties. Sitagliptin seems to have a neutral effect on these variables. Further trials are needed to elucidate the topic. The standards of reporting were in accordance with the PRISMA guidelines.

Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: Potential impact of dipeptidyl peptidase-4 inhibitors.

Dipeptidyl peptidase-4 (DPP-4), glycyl-prolyl-naphthylamidase, is a serine protease that catalyzes the hydrolysis of various proline-containing polypeptides. It is involved in the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF-1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific α-chemokine receptor (CXCR4) and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. DPP-4 inhibition has received considerable attention because of its significant therapeutic benefits in the regulation of insulin secretion and tissue insulin sensitivity, the regulation of tumor growth and metastasis, angiogenesis, tissue repair, especially after myocardial infarction, and regulation of endocrine function. Inhibition of circulating proteases appears to maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. In the present article, we present an overview of some basic facts about the role of DPP-4 in glucose homeostasis, the mechanism of its inhibition, and a brief summary of available DPP-4 inhibitors. Furthermore, since protection against the overactivity of proteases is important for restorating cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1.

PCV1 - Impact of Dipeptidyl Peptidase-4 Inhibitors on The Risk of Cardiovacular-Related Hsopitalizations

PCV1 - Impact of Dipeptidyl Peptidase-4 Inhibitors on The Risk of Cardiovacular-Related Hsopitalizations

The impact of diabetes and diabetes medications on bone health.

Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fragility fractures despite increased body weight and normal or higher bone mineral density. The mechanisms by which T2DM increases skeletal fragility are unclear. It is likely that a combination of factors, including a greater risk of falling, regional osteopenia, and impaired bone quality, contributes to the increased fracture risk. Drugs for the treatment of T2DM may also impact on the risk for fractures. For example, thiazolidinediones accelerate bone loss and increase the risk of fractures, particularly in older women. In contrast, metformin and sulfonylureas do not appear to have a negative effect on bone health and may, in fact, protect against fragility fracture. Animal models indicate a potential role for incretin hormones in bone metabolism, but there are only limited data on the impact of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 agonists on bone health in humans. Animal models also have demonstrated a role for amylin in bone metabolism, but clinical trials in patients with type 1 diabetes with an amylin analog (pramlintide) have not shown a significant impact on bone metabolism. The effects of insulin treatment on fracture risk are inconsistent with some studies showing an increased risk and others showing no effect. Finally, although there is limited information on the latest class of medications for the treatment of T2DM, the sodium-glucose co-transporter-2 inhibitors, these drugs do not seem to increase fracture risk. Because diabetes is an increasingly common chronic condition that can affect patients for many decades, further research into the effects of agents for the treatment of T2DM on bone metabolism is warranted. In this review, the physiological mechanisms and clinical impact of diabetes treatments on bone health and fracture risk in patients with T2DM are described.