Dipeptidyl Peptidase-4 Inhibitors Research Articles

Inhibition of sodium-glucose cotransporter-2 and liver-related complications in individuals with diabetes: a Mendelian randomization and population-based cohort study.

No medication has been found to reduce liver-related events. We evaluated the effect of sodium-glucose cotransporter-2 inhibitor (SGLT2i) on liver-related outcomes. Single nucleotide polymorphisms associated with SGLT2 inhibition were identified, and a genetic risk score (GRS) was computed using the UK Biobank data (n=337,138). Two-sample Mendelian randomization (MR) was conducted using the FinnGen (n=218,792) database and the UK Biobank data. In parallel, a nationwide population-based study using the Korean National Health Insurance Service (NHIS) database was conducted. The development of liver-related complications (ie, hepatic decompensation, HCC, liver transplantation, and death) was compared between individuals with type 2 diabetes mellitus and steatotic liver diseases treated with SGLT2i (n=13,208) and propensity score-matched individuals treated with dipeptidyl peptidase-4 inhibitor (n=70,342). After computing GRS with 6 single nucleotide polymorphisms (rs4488457, rs80577326, rs11865835, rs9930811, rs34497199, and rs35445454), GRS-based MR showed that SGLT2 inhibition (per 1 SD increase of GRS, 0.1% lowering of HbA1c) was negatively associated with cirrhosis development (adjusted odds ratio=0.83, 95% CI=0.70-0.98, p =0.03) and this was consistent in the 2-sample MR (OR=0.73, 95% CI=0.60-0.90, p =0.003). In the Korean NHIS database, the risk of liver-related complications was significantly lower in the SGLT2i group than in the dipeptidyl peptidase-4 inhibitor group (adjusted hazard ratio=0.88, 95% CI=0.79-0.97, p =0.01), and this difference remained significant (adjusted hazard ratio=0.72-0.89, all p <0.05) across various sensitivity analyses. Both MRs using 2 European cohorts and a Korean nationwide population-based cohort study suggest that SGLT2 inhibition is associated with a lower risk of liver-related events.

Five-Membered Nitrogen Heterocycles Angiotensin-Converting Enzyme (ACE) Inhibitors Induced Angioedema: An Underdiagnosed Condition.

Angiotensin-converting enzyme (ACE) inhibitors are used primarily in the treatment of hypertension, heart failure, and in the acute phase of myocardial infarction. Lisinopril [N2-[(1S)-1-car-boxy-3-phenylpropyl]-L-lysyl-L-proline], enalapril [(S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline] and ramipril [2-aza-bicyclo-[3.3.0]-octane-3-carboxylic acid] are all five-membered heterocycles and three of the most prevalent ACE inhibitors in clinical use worldwide. ACE inhibitor-induced angioedema (AE) is clinically characterized by self-limited edema of the dermis and subcutaneous lipid tissue, localized on face skin, oral mucosa and tongue in most cases. However, severe episodes of intestinal AE misdiagnosed as acute appendicitis and laryngeal AE requiring incubation have been reported. The pathophysiology of ACE inhibitor-induced angioedema is attributed to the accumulation of bradykinin, which is a potent vasodilator with proinflammatory activity that is normally degraded by angiotensin-converting enzyme (ACE) and aminopeptidase P; however, a small proportion of treated patients is affected. Given that patients do not respond to anti-H1 antihistamines and steroids, early clinical recognition and discontinuation of the ACE inhibitors are the treatments of choice for the long-term management of ACE inhibitor- induced angioedema. The search period of the present review was set up until November 2023, and its aim is to shed light on the broader context of ACE inhibitor-induced angioedema, exploring aspects such as clinical presentation, pathophysiology, and therapeutic considerations in this potentially life-threatening condition. The exploration of alternative drug options such as angiotensin II receptor blockers, the potential association of coadministration of DPP-4 inhibitors with ACE inhibitors, the presentation of angioedema and the significant clinical importance of this condition are also discussed. By focusing on the chemical structure of ACE inhibitors, specifically their nitrogen-based heterocycles-an attribute shared by over 880 drugs approved by the FDA within the pharmaceutical industry-this review emphasizes the pivotal role of nitrogen scaffolds in drug design and underscores their relevance in ACE inhibitor pharmacology.

Comparing Insulin Against Glucagon-Like Peptide-1 Receptor Agonists, Dipeptidyl Peptidase-4 Inhibitors, and Sodium-Glucose Cotransporter 2 Inhibitors on 5-Year Incident Heart Failure Risk for Patients With Type 2 Diabetes Mellitus: Real-World Evidence Study Using Insurance Claims.

Type 2 diabetes mellitus (T2DM) is a common health issue, with heart failure (HF) being a common and lethal long-term complication. Although insulin is widely used for the treatment of T2DM, evidence regarding the efficacy of insulin compared to noninsulin therapies on incident HF risk is missing among randomized controlled trials. Real-world evidence on insulin's effect on long-term HF risk may supplement existing guidelines on the management of T2DM. This study aimed to compare insulin therapy against other medications on HF risk among patients with T2DM using real-world data extracted from insurance claims. A retrospective, observational study was conducted based on insurance claims data from a single health care network. The study period was from January 1, 2016, to August 11, 2021. The cohort was defined as patients having a T2DM diagnosis code. The inclusion criteria were patients who had at least 1 record of a glycated hemoglobin laboratory test result; full insurance for at least 1 year (either commercial or Medicare Part D); and received glucose-lowering therapy belonging to 1 of the following groups: insulin, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4Is), or sodium-glucose cotransporter-2 inhibitors (SGLT2Is). The main outcome was the 5-year incident HF rate. Baseline covariates, including demographic characteristics, comorbidities, and laboratory test results, were adjusted to correct for confounding. After adjusting for a broad list of confounders, patients receiving insulin were found to be associated with an 11.8% (95% CI 11.0%-12.7%), 12.0% (95% CI 11.5%-12.4%), and 15.1% (95% CI 14.3%-16.0%) higher 5-year HF rate compared to those using GLP-1 RAs, DPP-4Is, and SGLT2Is, respectively. Subgroup analysis showed that insulin's effect of a higher HF rate was significant in the subgroup with high HF risk but not significant in the subgroup with low HF risk. This study generated real-world evidence on the association of insulin therapy with a higher 5-year HF rate compared to GLP-1 RAs, DPP-4Is, and SGLT2Is based on insurance claims data. These findings also demonstrated the value of real-world data for comparative effectiveness studies to complement established guidelines. On the other hand, the study shares the common limitations of observational studies. Even though high-dimensional confounders are adjusted, remaining confounding may exist and induce bias in the analysis.

Acute and Chronic Exposure to Linagliptin, a Selective Inhibitor of Dipeptidyl Peptidase-4 (DPP-4), Has an Effect on Dopamine, Serotonin and Noradrenaline Level in the Striatum and Hippocampus of Rats.

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters-dopamine, serotonin and noradrenaline-and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices.

A comprehensive review on potential drug-drug interactions of proton pump inhibitors with antidiabetic drugs metformin and DPP-4 inhibitors.

A drug interaction is a condition in which two or more drugs are taken at the same time. Type 2 diabetes mellitusis a significant contributor to polypharmacy. Proton pump inhibitors (PPIs) are often prescribed in combination with metformin or DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) or a combined dose of metformin and DPP-4 inhibitor to treat gastritis in diabetic patients. This review article mainly focused on evaluating the potential drug-drug interactions (DDIs) between PPIs (i.e. esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) with metformin and PPIs with DPP-4 inhibitors. The findings demonstrated the existence of pharmacokinetic and pharmacodynamic DDIs between the aforementioned PPIs with metformin and DPP-4 inhibitors, which could impact the biological activities (i.e., hypoglycemia) of these drugs. Moreover, this review suggested that esomeprazole could be the best drug in the PPI group to be prescribed simultaneously with metformin and DPP-4 inhibitors, as most of the antidiabetic drugs of this study did not show any interaction with esomeprazole. The findings of this study also revealed that both antidiabetic drugs and PPIs could have positive interactions as PPIs have the potential to lessen the gastrointestinal side effects of metformin and DPP-4 inhibitors. To achieve the greatest therapeutic impact with the fewest side effects, careful dose control of these drugs is required. So, more extensive research on both human and animal subjects are needed to ascertain the veracity of this hypothesis.

Impact of treatment with GLP-1RAs on suicide attempts in adults persons with type 2 diabetes: A retrospective comparative effectiveness study based on a global TriNetX health research database.

To assess the association between glucagon-like peptide-1 receptor agonists (GLP-1RA) treatment and the risk of suicide attempts in people with type 2 diabetes (T2D), with a focus on subgroups with and without a history of depression or suicide attempts. This retrospective cohort study utilized TriNetX, a federated network of real-world data. Using the Global Collaborative Network data, we collected electronic medical records from 113 health care organizations with 135 million patient records with 8 million with T2D, 83% from the United States. The four cohorts were identified based on age, medication, diagnosis, and presence of depression or suicide attempts. Analytic methods included measures of association and number of Instances, with propensity score matching employed to mitigate potential confounders. The primary outcome was the incidence of suicide attempts among people with T2D with GLP-1RA treatment in comparison with dipeptidyl peptidase-4 inhibitor (DPP-4i) treatment. People with T2D treated with GLP-1RA consistently exhibited a lower risk of suicide attempts compared to those treated with DPP-4i. This was particularly significant in people with a history of depression or suicide attempts. The risk and odds ratios were significantly lower in the GLP-1RA-treated cohorts than in DPP-4i across all analyses. As compared with DPP-4i, our analysis shows a protective effect associated with GLP-1RA treatment on the risk of suicide attempts among people with T2D. However, further research, particularly prospective and randomized studies, is necessary to confirm these observations and understand the underlying mechanisms.

Efficacy and Safety of the Utilization of Dipeptidyl Peptidase IV Inhibitors in Diabetic Patients with Chronic Kidney Disease: A Meta-Analysis of Randomized Clinical Trials.

To assess the efficacy and safety of Dipeptidyl Peptidase IV (DPP-4) inhibitors in patients with Type-2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) using level 1 evidence. The Cochrane and PubMed databases were searched from inception until January 1, 2022. RCTs that studied the efficacy and safety of DPP-4 inhibitors in diabetic patients with CKD were included. The primary efficacy outcome was assessed as the mean difference between HbA1c at the beginning and the end of each study for each arm, and the primary safety outcome was assessed as the incidence of adverse events and severe adverse events in each study. Twenty-one studies satisfied the pre-defined eligibility criteria. In assessing the efficacy of DPP-4 inhibitors in the treatment of T2DM and CKD, a total of 2917 patients under the DPP-4 inhibitors group and 2377 patients under the control group were included; The mean difference between the HbA1c of DPP-4 Inhibitor and the control group was -0.5295 with a 95% CI of -0.5337 to -0.5252. The included studies had high heterogeneity p < 0.00001 and I2 = 99%. In assessing the safety outcome and tolerability of DPP-4 inhibitors, a total of 8138 patients under the DPP-4 inhibitors group and 7517 patients under the control group were included; the odds ratio of adverse events between both groups was 0.9967 with a 95% CI of 0.9967 to 1.1047. The included studies had low heterogeneity p = 0.25 and I2 = 15%. The overall effect, Z = 0.06 (p = 0.95), was insignificant. Patients suffering from both T2DM and CKD exhibited a significantly enhanced glycemic control when treated with DPP-4 inhibitors in comparison to the control group. Furthermore, no significant difference in the incidence of adverse events was observed between the DPP-4 inhibitors and the control group.

Rurality is associated with lower likelihood of dipeptidyl peptidase 4 inhibitor use for treatment intensification

BackgroundAntihyperglycemic drug utilization studies are conducted frequently and describe the uptake of new drug therapies across may jurisdictions. An increasingly important, yet often absent, aspect of these studies is the impact of rurality on drug utilization. Objective(s)The objective of this study was to explore the association between place of residence (rural, urban, metropolitan) and the use of dipeptidyl peptidase 4 inhibitors (DPP-4i) for first treatment intensification of type 2 diabetes. MethodsA retrospective cohort study was conducted from April 1, 2008 to March 31, 2019 of new metformin users. A multivariable logistic regression analysis was performed to determine the association between place of residence (using postal codes) and likelihood of DPP-4i dispensing. ResultsAfter adjusting for confounders, analysis revealed that rural-dwellers are less likely to have a DPP-4i dispensed, compared with metropolitan-dwellers (aOR:0.64; 95%CI:0.61–0.67) and over-time, the uptake in rural areas was slower. ConclusionsThis study demonstrates that rurality can have an impact on drug therapy decisions at first treatment intensification, with respect to the utilization of new therapies.

Association between sodium-glucose cotransporter-2 inhibitors and arrhythmic outcomes in patients with diabetes and pre-existing atrial fibrillation.

Prior studies suggest that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may decrease the incidence of atrial fibrillation (AF). However, it is unknown whether SGLT2i can attenuate the disease course of AF among patients with pre-existing AF and Type II diabetes mellitus (DM). In this study, our objective was to examine the association between SGLT2i prescription and arrhythmic outcomes among patients with DM and pre-existing AF. We conducted a population-based cohort study of adults with DM and AF between 2014 and 2019. Using a prevalent new-user design, individuals prescribed SGLT2i were matched 1:1 to those prescribed dipeptidyl peptidase-4 inhibitors (DPP4is) based on time-conditional propensity scores. The primary endpoint was a composite of AF-related healthcare utilization (i.e. hospitalization, emergency department visits, electrical cardioversion, or catheter ablation). Secondary outcome measures included all-cause mortality, heart failure (HF) hospitalization, and ischaemic stroke or transient ischaemic attack (TIA). Cox proportional hazard models were used to examine the association of SGLT2i with the study endpoint. Among 2242 patients with DM and AF followed for an average of 3.0 years, the primary endpoint occurred in 8.7% (n = 97) of patients in the SGLT2i group vs. 10.0% (n = 112) of patients in the DPP4i group [adjusted hazard ratio 0.73 (95% confidence interval 0.55-0.96; P = 0.03)]. Sodium-glucose cotransporter-2 inhibitors were associated with significant reductions in all-cause mortality and HF hospitalization, but there was no difference in the risk of ischaemic stroke/TIA. Among patients with DM and pre-existing AF, SGLT2is are associated with decreased AF-related health resource utilization and improved arrhythmic outcomes compared with DPP4is.

Network-based screening identifies sitagliptin as an antitumor drug targeting dendritic cells

BackgroundDendritic cell (DC)-mediated antigen presentation is essential for the priming and activation of tumor-specific T cells. However, few drugs that specifically manipulate DC functions are available. The identification of drugs...

Revolutionizing Treatment Strategies for Autoimmune and Inflammatory Disorders: The Impact of Dipeptidyl-Peptidase 4 Inhibitors.

DPP4 (Dipeptidyl-peptidase 4) a versatile protease, emerges as a prominent player in soluble and membrane-bound forms. Its heightened expression has been intimately linked to the initiation and severity of diverse autoimmune diseases, spanning rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (SSc), inflammatory bowel disease, autoimmune diabetes, and even SARS-CoV-2 infection. Operating as a co-stimulator of T cell activity, DPP4 propels T cell proliferation by binding adenosine deaminase (ADA), thereby augmenting the breakdown of adenosine-an influential inhibitor of T cell proliferation. However, the discovery of a wide range of DPP4 inhibitors has shown promise in alleviating these diseases' signs, symptoms, and severity. The available DPP4 inhibitors have demonstrated significant effectiveness in blocking DPP4 activity. Based on the characterization of their binding mechanisms, three distinct groups of DPP4 inhibitors have been identified: saxagliptin, alogliptin, and sitagliptin, each representing a different class. Elevated levels of angiotensin-converting enzyme 2 (ACE2) expression are associated with producing various coronavirus peptidases. With its anti-inflammatory properties, Sitagliptin may assist COVID-19 patients in preventing and managing cytokine storms. This comprehensive review delves into the burgeoning realm of DPP4 inhibitors as therapeutic interventions for diverse autoimmune diseases. With a discerning focus on their efficacy, the investigation sheds light on their remarkable capacity to alleviate the burdensome signs and symptoms intricately linked to these conditions.

DPP-4 inhibitor sitagliptin treatment results in altered myocardial metabolic proteome and oxidative phosphorylation in a swine model of chronic myocardial ischemia.

Small animal models have shown improved cardiac function with DPP-4 inhibition, but many human studies have shown worse outcomes or no benefit. We seek to bridge the gap by studying the DPP-4 inhibitor sitagliptin in a swine model of chronic myocardial ischemia using proteomic analysis. Thirteen Yorkshire swine underwent the placement of an ameroid constrictor on the left coronary circumflex artery to model chronic myocardial ischemia. Two weeks post-op, swine received either sitagliptin 100 mg daily (SIT, n = 5) or no drug (CON, n = 8). After 5 weeks of treatment, swine underwent functional measurements and tissue harvest. In the SIT group compared to CON, there was a trend towards decreased cardiac index (p = 0.06). The non-ischemic and ischemic myocardium had 396 and 166 significantly decreased proteins, respectively, in the SIT group compared to CON (all p < 0.01). This included proteins involved in fatty acid oxidation (FAO), myocardial contraction, and oxidative phosphorylation (OXPHOS). Sitagliptin treatment resulted in a trend towards decreased cardiac index and decreased expression of proteins involved in OXPHOS, FAO, and myocardial contraction in both ischemic and non-ischemic swine myocardium. These metabolic and functional changes may provide some mechanistic evidence for outcomes seen in clinical studies.

Fasting GLP-1 Levels and Albuminuria Are Negatively Associated in Patients with Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known for its pivotal role in enhancing insulin secretion and reducing glucagon release from the pancreas. Diabetic nephropathy, which is characterized by albuminuria, represents a significant microvascular complication of diabetes. Most of the previous studies mainly focused on the therapeutic renal protective effect in clinical trials after the administration of GLP-1 receptor agonists (GLP-1 RAs), rather than before administration. Hence, this study aimed to investigate the association between fasting plasma GLP-1 levels and albuminuria before GLP-1 RA administration. A cross-sectional study was designed to evaluate the association between fasting plasma GLP-1 levels and albuminuria in patients with type 2 diabetes mellitus (T2DM). A cohort of 68 participants with T2DM was analyzed using data collected at Wonkwang University Hospital in Iksan, Korea. Logistic regression analysis was employed to determine the odds ratio (OR) and 95% confidence interval (CI) of the incidence of albuminuria between two groups categorized by fasting GLP-1 levels, low (Group L) and high GLP-1 (Group H). The OR (95% CI) for the incidence of albuminuria comparing Group L with Group H of fasting plasma GLP-1 levels was 3.41 (1.16-10.02), p = 0.03 after adjustment for relevant variables including age, gender, fasting plasma glucose, HbA1c, C-peptide, creatinine, and medication use [angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors]. When analyzed as a continuous variable, each 1 pmol/L reduction in fasting plasma GLP-1 levels was associated with an OR (95% CI) of 1.67 (1.17-1.87), p = 0.02, following full adjustment. These results highlight a negative association between fasting plasma GLP-1 levels and the incidence of albuminuria in Korean patients with T2DM, before GLP-1 RA administration. These findings suggest that endogenous GLP-1 may have a beneficial impact in mitigating albuminuria.

Evaluation of Teneligliptin and Retagliptin on the Clearance of Melanosome by Melanophagy in B16F1 Cells

A specialized membrane-bound organelle, named the melanosome, is central to the storage and transport of melanin as well as melanin synthesis in melanocytes. Although previous studies have linked melanosomal degradation to autophagy, the precise mechanisms remain elusive. Autophagy, a complex catabolic process involving autophagosomes and lysosomes, plays a vital role in cellular constituent degradation. In this study, the role of autophagy in melanosomal degradation was explored, employing a cell-based screening system designed to unveil key pathway regulators. We identified specific dipeptidyl peptidase-4 inhibitors, such as teneligliptin hydrobromide and retagliptin phosphate, as novel agents inducing melanophagy through a comprehensive screening of a ubiquitination-related chemical library. We found that treatment with teneligliptin hydrobromide or retagliptin phosphate not only diminishes melanin content elevated by alpha-melanocyte-stimulating hormone (α-MSH) but also triggers autophagy activation within B16F1 cells. In addition, the targeted inhibition of unc-51-like kinase (ULK1) significantly attenuated both the anti-pigmentation effects and autophagy induced by teneligliptin hydrobromide and retagliptin phosphate in α-MSH-treated cells. Collectively, our data demonstrate a new frontier in understanding melanosomal degradation, identifying teneligliptin hydrobromide and retagliptin phosphate as promising inducers of melanophagy via autophagy activation. This study contributes essential insights into cellular degradation mechanisms and offers potential therapeutic avenues in the regulation of pigmentation.

Efficacy and Safety of Omarigliptin, a Novel Once-Weekly Dipeptidyl Peptidase-4 Inhibitor, in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

No recent meta-analysis has holistically analyzed and summarized the efficacy and safety of omarigliptin in type 2 diabetes mellitus (T2DM). We conducted a meta-analysis to address this knowledge gap. Electronic databases were searched to identify randomized controlled trials (RCTs) that included patients with T2DM who received omarigliptin in the intervention arm. The control arm consisted of either a placebo (passive control group [PCG]) or an active comparator (active control group [ACG]). The primary outcome assessed was changes in hemoglobin A1c (HbA1c), while secondary outcomes included variations in glucose levels, achievement of glycemic targets, adverse events (AEs), and hypoglycemic events. From 332 initially screened articles, data from 16 RCTs involving 8,804 subjects were analyzed. Omarigliptin demonstrated superiority over placebo in reducing HbA1c levels (mean difference, -0.58%; 95% confidence interval, -0.75 to -0.40; P<0.00001; I2=91%). Additionally, omarigliptin outperformed placebo in lowering fasting plasma glucose, 2-hour postprandial glucose, and in the percentage of participants achieving HbA1c levels below 7.0% and 6.5%. The glycemic efficacy of omarigliptin was similar to that of the ACG across all measures. Although the omarigliptin group experienced a higher incidence of hypoglycemic events compared to the PCG, the overall AEs, serious AEs, hypoglycemia, and severe hypoglycemia were comparable between the omarigliptin and control groups (PCG and ACG). Omarigliptin has a favorable glycemic efficacy and safety profile for managing T2DM.

Effect of Drugs Used in Pharmacotherapy of Type 2 Diabetes on Bone Density and Risk of Bone Fractures.

This review summarizes the complex relationship between medications used to treat type 2 diabetes and bone health. T2DM patients face an increased fracture risk despite higher bone mineral density; thus, we analyzed the impact of key drug classes, including Metformin, Sulphonylureas, SGLT-2 inhibitors, DPP-4 inhibitors, GLP-1 agonists, and Thiazolidinediones. Metformin, despite promising preclinical results, lacks a clear consensus on its role in reducing fracture risk. Sulphonylureas present conflicting data, with potential neutral effects on bone. SGLT-2 inhibitors seem to have a transient impact on serum calcium and phosphorus, but evidence on their fracture association is inconclusive. DPP-4 inhibitors emerge as promising contributors to bone health, and GLP-1 agonists exhibit positive effects on bone metabolism, reducing fracture risk. Thiazolidinediones, however, demonstrate adverse impacts on bone, inducing loss through mesenchymal stem cell effects. Insulin presents a complex relationship with bone health. While it has an anabolic effect on bone mineral density, its role in fracture risk remains inconsistent. In conclusion, a comprehensive understanding of diabetes medications' impact on bone health is crucial. Further research is needed to formulate clear guidelines for managing bone health in diabetic patients, considering individual profiles, glycemic control, and potential medication-related effects on bone.

Vildagliptin Nephroprotective Effect in Rats Model with Cisplatin-Induced Nephrotoxicity

Objective: To evaluate the nephroprotective effect of vildagliptin against cisplatin-induced nephrotoxicity in rats.&#x0D; Methods and Materials: Twenty-eight male rats have been divided into four groups: Control (received distal water), cisplatin treated group (received single dose of cisplatin (7mg/kg) intraperitoneally (IP) on day eight), vildagliptin plus cisplatin treated group (received vildagliptin 10mg/kg/day orally for 14 days, seven days before and seven days after the dose of cisplatin on day eight), and vildagliptin treated group (received the same dose and duration of vildagliptin mentioned previously). At the end, blood samples were collected to evaluate tumor necrotic factor-α (TNF-α), caspase-3, total antioxidant capacity (TAOC), urea, and creatinine. The serum levels of these biomarkers were expressed as mean ± standard error of mean. Additionally, kidneys were fixed in formalin for histopathological examination.&#x0D; Result: Vildagliptin treatment significantly reduced the serum levels of TNF-α, caspase-3, urea, and creatinine as well as increased the TAOC level in rats treated with vildagliptin plus cisplatin when compared with cisplatin treated group. Histopathological examination further supported the nephroprotective effect of vildagliptin in rats with cisplatin induced nephrotoxicity. &#x0D; Conclusion: Vildagliptin improved kidney function and reduced cisplatin nephrotoxicity which may highlight the nephroprotective effect of this DPP-4 inhibitor against cisplatin-induced nephrotoxicity.

Comparison between sodium-glucose cotransporter 2 inhibitors and dipeptidyl peptidase 4 inhibitors on the risk of incident cancer in patients with diabetes mellitus: A real-world evidence study.

Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) have been demonstrated to be associated with cancer cell mechanisms. However, whether they increase the risk of cancer remains unclear. Thus, this study aimed to determine the association between SGLT-2i use and the incidence of cancer in patients with diabetes mellitus (DM) in Taiwan. This retrospective cohort study was based on the Taiwan National Health Insurance database. The study population comprised patients with DM, and those who first used SGLT-2is during 2016-2018 were assigned to the study group. Greedy propensity score matching was performed to select patients who first used dipeptidyl peptidase 4 inhibitors (DPP-4is), and these patients were assigned to the control group. A Cox proportional hazards model was used to estimate the adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for cancer risk in the study and control groups; this model was adjusted for demographic characteristics, DM severity, comorbidities and concomitant medication use. After controlling for relevant variables, the SGLT-2i cohort (aHR=0.90, 95% CI=0.87-0.93) had a significantly lower risk of developing cancer than the DPP-4i cohort, particularly when the SGLT-2i was dapagliflozin (aHR=0.91, 95% CI=0.87-0.95) or empagliflozin (aHR=0.90, 95% CI=0.86-0.94). Regarding cancer type, the SGLT-2i cohort's risk of cancer was significantly lower than that of the DPP-4i cohort for leukaemia, oesophageal, colorectal, liver, pancreatic, lung, skin and bladder cancer. SGLT-2i use was associated with a significantly lower risk of cancer than DPP-4i use.

In vitro and in silico studies reveal antidiabetic properties of arylbenzofurans from the root bark of Morus mesozygia Stapf.

Diabetes remains an important disease worldwide with about 500 million patients globally. In tropical Africa, Morus mesozygia is traditionally used in the treatment of diabetes. Biological and phytochemical investigation of the root bark extracts of the plant led to the isolation of a new prenylated arylbenzofuran named 7-(3-hydroxy-3-methylbutyl)moracin M (1) and two congeners, moracins P (2) and M (3). When compared to acarbose (IC50 = 486µM), all the isolated compounds are better inhibitors of α-glucosidase with in vitro IC50 values of 16.9, 16.6, and 40.9 µM, respectively. However, they were not active against α-amylase. The compounds also demonstrated moderate inhibition of dipeptidyl peptidase-4 (DPP4). Based on in silico docking studies, all isolates (1, 2, and 3) exhibit binding affinities of -8.7, -9.5, and -8.5kcal/mol, respectively against α-glucosidase enzyme (PDB: 3AJ7). They are stabilized within the α-glucosidase active site through hydrogen bonds, pi interactions, and hydrophobic interactions. This study provides scientific support for the traditional use of Morus mesozygia in the treatment of diabetes as well as adding to the repository of α-glucosidase inhibitory agents.

Comparative analysis of newer classes of antidiabetics and the concept of pharmaceutical care – dealing with therapeutic problems

The prevalence of obesity is increasing rapidly. The latest World Health Organization – WHO report declares the disease as an epidemic. After pharmacodynamic, pharmacokinetic, clinical and pharmacoepidemiologic data analysis and comparison of the three classes of antidiabetic medicinal products: GLP-1 receptor agonists, DPP-4 inhibitors and SGLT2 inhibitors, a literature review of the topic, patient education and the concept of pharmaceutical care emerged as methods for dealing with the most common adverse drug reactions, safety concerns, and drug interactions.