Administration Of Dipeptidyl Peptidase-4 Inhibitor Research Articles

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.

Comparison of Adverse Events Occurred During Administration of Dipeptidyl Peptidase-4 Inhibitor in Patients with Diabetes Using FDA Adverse Event Reporting System.

Various dipeptidyl peptidase-4 (DPP-4) inhibitors have been approved for the treatment of diabetes. The frequencies of known serious side effects might differ among DPP-4 inhibitors, therefore a large sample size is needed to study them in prospective clinical trials. We examined the adverse events that occurred during the administration of a DPP-4 inhibitor in patients with diabetes using FDA Adverse Event Reporting System (FAERS) data. We used FAERS data reported between January 2013 and March 2022 in patients with diabetes who received a DPP-4 inhibitor. Statistical analyses were conducted to calculate reporting odds ratio (ROR) and adjusted ROR (aROR) controlling for differences in patient background. The 9 target DPP-4 inhibitors were sitagliptin (N = 26,843), vildagliptin (N = 4767), alogliptin (N = 2085), linagliptin (N = 7969), saxagliptin (N = 3334), teneligliptin (N = 461), anagliptin (N = 102), trelagliptin (N = 17), and omarigliptin (N = 12). Compared with sitagliptin, aROR of acute kidney injury was significantly < 1.000 for alogliptin (0.247 [95% confidence interval (CI) 0.150-0.408], p < 0.001) but aROR of pemphigoid was significantly > 1.000 for alogliptin (3.082 [95% CI 2.156-4.406], p < 0.001). Similar statistical analyses were conducted for other adverse events and the types of adverse events with aROR of significantly < 1.000 or > 1.000 differed depending on the type of DPP-4 inhibitor. Although it is impossible to select a DPP-4 inhibitor with aROR of < 1.000 of all occurrences of adverse events, these results may be used for drug selection when the patient has adverse events that need to be avoided. We provided the sample code of software R that can reproduce the results.

Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor.

Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

Oral antidiabetes agents for the management of inpatient hyperglycaemia: so far, yet so close.

Hyperglycaemia is an ongoing challenge in hospital settings and is associated with poor outcomes. Current recommendations for the management of inpatient hyperglycaemia suggest insulin as the main glucose-lowering treatment choice and limit the administration of oral antidiabetes agents to a small proportion of cases because of safety concerns. To present and critically appraise the available evidence on the use of oral antidiabetes agents in the hospital setting and the risk-benefit balance of such an approach in the era of cardiovascular outcomes trials. PubMed, Embase and Google Scholar databases were searched to identify relevant published work. Available evidence on the efficacy and the safety profile of oral agents in the context of their use in hospitalized individuals are summarized and discussed in this narrative review. There is no robust evidence to suggest the use of metformin,thiazolidinediones, sulfonylureas and sodium-glucose co-transporter-2 inhibitors in the hospital setting, although some of their effects on acute outcomes deserve further evaluation in future studies. However, the use of dipeptidyl peptidase-4 inhibitors in inpatients with type 2 diabetes is supported by a few, well-designed, randomized controlled trials.These trials have demonstrated good safety and tolerability profiles, comparable to insulin glucose-lowering efficacy, and a reduction in insulin dose when dipeptidyl peptidase-4 inhibitors are co-administered with insulin, in individualswith mild to moderate hyperglycaemia and a stable clinical condition. The administration of dipeptidyl peptidase-4 inhibitors to specific groups of inpatients might be a safe and effective alternative to insulin.

1815-P: Dipeptidyl Peptidase-4 Inhibitor Improves Steatohepatitis by Targeting Trail Receptor-Mediated Apoptosis Under Modulation of Dipeptidyl Peptidase-4 Expression

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are useful antidiabetic medications that prevent cleavage of incretin hormones by dipeptidyl peptidase-4 (DPP-4). As DPP-4 targets diverse substrates besides incretin, DPP-4i may exert nonglycemic pleiotropic effects. Recent studies have reported that hepatic DPP-4 expression is upregulated under nonalcoholic steatohepatitis (NASH) condition in animals and humans. We investigated whether DPP-4i could ameliorate the pathological phenotype of NASH and evaluated the underlying mechanisms in a mouse model. Mice were randomly assigned to one of three groups: Group 1, chow-fed mice with vehicle treatment for 20 weeks; group 2, high-fat, high-fructose, and high-cholesterol AMLN diet-fed mice with vehicle treatment for 20 weeks; group 3, AMLN diet-fed mice with vehicle treatment for 10 weeks followed by DPP-4i (teneligliptin 20 mg/kg/day by oral gavage) treatment for 10 weeks. Serum and liver tissues were analyzed. Administration of DPP-4i significantly reduced the body weight, liver to body weight ratio, and serum liver enzyme levels in AMLN diet-induced NASH model. DPP-4i-treated AMMN diet-fed mice revealed a marked alleviation in liver steatosis and fibrosis compared with vehicle-treated AMLN-fed mice. NASH alleviation in vivo significantly correlated with the suppression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated apoptosis and decreased DPP-4 expression in the liver. In vitro assay of palmitate-treated hepatocytes, treatment with DPP-4i significantly attenuated the hallmarks of TRAIL receptor-mediated lipoapoptosis, suppressing DPP-4 expression. DPP-4i may efficiently attenuate the pathogenesis of AMLN diet-induced NASH in mice by suppressing lipotoxicity-induced apoptosis, possibly through the modulation of hepatic DPP-4 expression. Disclosure S. Lee: None. M. Lee: None. E. Shin: None. Y. Kim: None. E. Kang: None. B. Cha: None. Funding Handok Inc. (2017-31-0006)

Dipeptidyl Peptidase-4 Inhibitor Reduces the Risk of Developing Hypertrophic Scars and Keloids following Median Sternotomy in Diabetic Patients: A Nationwide Retrospective Cohort Study Using the National Database of Health Insurance Claims of Japan.

Hypertrophic scars and keloids, which are abnormalities of fibrosis, often occur in surgical wounds; however, their exact cause and preventive measures are unknown. The administration of dipeptidyl peptidase-4 inhibitors to humans is expected to suppress fibrosis in wounds and minimize hypertrophic scar and keloid formation. This study aimed to verify the suppressive effect of dipeptidyl peptidase-4 inhibitors on the formation of hypertrophic scars or keloids using real world data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. It is a retrospective cohort study, and data were extracted from the National Database between April of 2013 and March of 2015. Patients who underwent median sternotomy were included in the study based on their claimed surgical codes. Subjects who were prescribed dipeptidyl peptidase-4 inhibitors constituted the treatment group; subjects who were not prescribed or administered dipeptidyl peptidase-4 inhibitors during that period constituted the nontreatment group. Subjects included 5430 patients throughout Japan (3509 men and 1921 women). Of the 446 subjects who were treated with dipeptidyl peptidase-4 inhibitors within 1 year before the procedure, fewer than 10 (<2 percent) developed either hypertrophic scars or keloids. Of the 4984 subjects who were not treated, 152 (3.05 percent) were at significantly lower risk for hypertrophic scars and keloids (p = 0.04). A logistic regression analysis was performed to adjust for confounding factors, with history of hypertrophic scar formation as the explained variable. This study revealed that dipeptidyl peptidase-4 inhibitors suppress the onset of hypertrophic scars or keloids after surgery in humans. Therapeutic, III.

Is Dipeptidyl Peptidase-4 Inhibitor a Risk Factor to Develop Permanent Hypothyroidism in Subacute Thyroiditis in Patients with Type 2 Diabetes Mellitus?

Abstract Introduction: Permanent hypothyroidism rationale is presented in 5 - 26% of the subacute thyroiditis patients. In the last decade, three cases of Subacute Thyroiditis (SAT) were treated with Dipeptidyl Peptidase-4 Inhibitor (DPP-4i) in patients with Type 2 Diabetes Mellitus (T2DM). Case Presentation: Case 1:52-year-old woman presented with T2DM on tolbutamide and sitagliptin. She was diagnosed with SAT and managed with loxoprofen sodium hydrate while maintaining her antidiabetic agents. Three months later, the thyroid function returned to euthyroid condition. Case 2: 74-year-old man T2DM patient on metformin, glimepiride, and sitagliptin. He was diagnosed with SAT and managed with loxoprofen sodium hydrate while maintaining ongoing antidiabetic management. One month later, his thyroid function deteriorated to hypothyroidism and further nine months later, the thyroid returned to euthyroid function. Case 3: 69-year-old-man T2DM patient on vildagliptin. He was diagnosed with SAT and managed with prednisolone (10mg/ day) with cessation of vildagliptin and introduction of insulin therapy. One month later, the thyroid function returned to euthyroid function. Conclusions: We experienced SAT during the administration of DPP-4i in three T2DM patients. Although one of them experienced transient hypothyroidism, none developed permanent hypothyroidism. DPP-4i may not be a risk factor of permanent hypothyroidism in SAT patients with T2DM. Keywords DPP4 inhibitors; Subacute thyroiditis; Type 2 diabetes mellitus Abbreviations DPP-4i: Dipeptidyl Peptidase-4 Inhibitor; TSH: Thyroid Stimulating Hormone; FT3: Free Triiodothyronine; FT4: Free Thyroxine; Tg: Thyroglobulin; CRP: C-Reactive Protein; Trab: TSH Receptor Antibody; Anti-Tg-Ab: Anti-Thyroglobulin Antibody

Dipeptidyl peptidase-4 inhibitors are associated with improved left ventricular diastolic function after acute myocardial infarction in diabetic patients.

Dipeptidyl peptidase-4 (DPP4) is an integral membrane glycoprotein that modulates the pathological state of diabetes mellitus (DM), and DPP4 inhibitors are a new class of anti-type-2 DM drugs. Recent preclinical studies have associated DPP4 inhibition with improved myocardial systolic and diastolic function. Based on preclinical findings, we investigated associations between the administration of DPP4 inhibitors and cardiac function after acute myocardial infarction (AMI) in a clinical setting. We enrolled 34 patients with diabetes who were treated for acute myocardial infarction at our hospital between January 2010 and December 2012. We retrospectively compared changes in cardiac parameters determined by trans-thoracic echocardiography between patients treated with (DPP4-I group; n=13) or without (non-DPP4-I group; n=21) a DPP4 inhibitor during follow-up. The values of E/e' and of e'/a' significantly decreased and increased, respectively, in the DPP4-I, compared with the non-DPP4-I group (-2.53±5.53 vs. 2.58±5.68, p=0.038 and 0.08±0.23 vs. -0.12±0.21, p=0.036, respectively). We concluded that DPP4 inhibitors could improve E/e' and e'/a' in patients with DM and AMI and thus might be effective for treating left ventricular diastolic failure.

Incretin-based Therapies for Type 2 Diabetes

There is a growing interest in developing therapeutic strategies for type 2 diabetes based on the actions of the hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones are the major incretins released from the intestine in response to nutrient ingestion, and they stimulate insulin secretion in a glucosedependent manner. Both peptides are degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), thus terminating their actions. Studies in animal models of diabetes have shown that the incretins also exert a number of additional actions that improve glucose disposal. GLP-1 reduces food intake and gastric emptying, as well as inhibiting glucagon secretion. Injectable formulations of DPP-4-resistant GLP-1-related peptides (incretin mimetics) that are now in clinical use (exenatide) or undergoing trials (e.g. liraglutide) have been shown to reduce fasting and postprandial glucose and glycosylated hemoglobin (A1C) levels and induce weight loss. Oral administration of DPP-4 inhibitors potentiates the actions of incretins released during a meal. Clinical trials have demonstrated that DPP-4 inhibitors are weight-neutral drugs that also effectively reduce plasma glucose and A1C levels. One inhibitor, sitagliptin, is now available in Canada and the United States, and another, vildagliptin, has recently been approved by the European Union. Other inhibitors are under development. Preclinical studies indicate that treatment with incretin mimetics or DPP-4 inhibitors also preserves beta cell mass by exerting mitogenetic and prosurvival effects. It is not known whether similar effects occur in humans.