Current Pharmaceutical Design - Volume 26, Issue 46, 2020

Background: Concerns of elevated cardiovascular risk with some anti-diabetic medications warranted trials on the cardiovascular outcome to demonstrate cardiovascular safety of newly marketed anti-diabetic drugs. Although these trials were initially designed to evaluate safety, some of these demonstrated significant cardiovascular benefits. Purpose of Review: We reviewed the cardiovascular and safety outcomes of novel antidiabetic agents in patients with type 2 diabetes and established cardiovascular disease or at high risk of it. We included the outcomes of safety trials, randomized controlled trials, meta-analysis, large cohort studies, and real-world data, which highlighted the cardiovascular profile of DPP-4is, GLP-1RAs and SGLT-2is. Conclusion: Although DPP-4is demonstrated non-inferiority to placebo, gaining cardiovascular safety, as well market authorization, SGLT-2is and most of the GLP-1RAs have shown impressive cardiovascular benefits in patients with T2D and established CVD or at high risk of it. These favorable effects of novel antidiabetic agents on cardiovascular parameters provide novel therapeutic approaches in medical management, risk stratification and prevention.

Diabetes mellitus (DM) and heart failure (HF) are comorbid conditions associated with significant morbidity and mortality worldwide. Despite the availability of novel and effective therapeutic options and intensive glycaemic control strategies, mortality and hospitalisation rates continue to remain high and the incidence of HF persists. In this review, we described the impact of currently available glucose-lowering therapies in DM with a focus on HF clinical outcomes. Non-conventional modes of management and alternative pathophysiological mechanisms with the potential for therapeutic targeting are also discussed.

Diabetes mellitus (DM) and peripheral artery disease (PAD) are two clinical entities closely associated. They share many pathophysiological pathways such as inflammation, endothelial dysfunction, oxidative stress and pro-coagulative unbalance. Emerging data focusing on agents targeting these pathways may be promising. Moreover, due to the increased cardiovascular risk, there is a growing interest in cardiovascular and “pleiotropic” effects of novel glucose lowering drugs. This review summarizes the main clinical features of PAD in patients, the diagnostic process and current medical/interventional approaches, ranging from “classical treatment” to novel agents.

MicroRNAs represent a class of small (19-25 nucleotides) single-strand pieces of RNA that are noncoding ones. They are synthesized by RNA polymerase II from transcripts that fold back on themselves. They mostly act as gene regulatory agents that pair with complementary sequences on mRNA and produce silencing complexes, which, in turn, suppress coding genes at a post-transcriptional level. There is now evidence that microRNAs may affect insulin secretion or insulin action, as they can alter pancreatic beta cells development, insulin production, as well as insulin signaling. Any molecular disorder that affects these pathways can deteriorate insulin resistance and lead to type 2 diabetes mellitus (T2DM) onset. Furthermore, the expression of several microRNAs is up- or down-regulated in the presence of diabetic microvascular complications (i.e., peripheral neuropathy, nephropathy, retinopathy, foot ulcers), as well as in patients with coronary heart disease, stroke, and peripheral artery disease. However, more evidence is needed, specifically regarding T2DM patients, to establish the use of such microRNAs as diagnostical biomarkers or therapeutic targets in daily practice.

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.

Background: The Platelet Inhibition and Patient Outcomes (PLATO) study found that ticagrelor plus aspirin (TA) was more effective than clopidogrel plus aspirin (CA), without an increase in the risk of massive bleeding in patients undergoing percutaneous coronary intervention (PCI). Data from other studies indicate that the conclusion is controversial with the results obtained by PLATO. Aim: To investigate the efficacy and safety of TA, compared with CA, in patients with acute coronary syndrome (ACS) after PCI. Methods: A systematic literature search was performed in the MEDLINE, EMBASE, and Cochrane databases to compare the efficacy and safety of CA and TA treatment in patients with ACS after PCI. The endpoints were major adverse cardiac events (MACEs), death, stroke, myocardial infarction (MI), stent thrombosis, and bleeding events. The data analysis was performed using RevMan 5.3 software, and the odds ratios (ORs) and their 95% confidence intervals (CI) were calculated. The standards of reporting were in accordance with the PRISMA guidelines. Results: 13 studies with a total of 58,062 patients were included in this study with a subgroup analysis of the European/American and Asian populations. In terms of effectiveness for MACEs, the European, American and Asian populations benefitted more from the TA treatment than the CA treatment (European and American populations, OR = 0.82, P = 0.0002; Asian, OR = 0.66, P < 0.0001; total, OR = 0.78, P < 0.0001). In terms of specific effectiveness indicators, such as stroke, MI, and stent thrombosis, the results of TA and CA groups in the European, American, and Asian populations were not consistent. In terms of safety, there was no statistical difference in total bleeding events between TA and CA treatments (OR = 1.19, P = 0.21). However, in the Asian population, the incidence of total bleeding events (OR = 1.52, P = 0.0004) in the TA group was higher than that in the CA group. Conclusion: The TA treatment in the European and American populations is more beneficial and safer than CA treatment. However, although the Asian population has this benefit, the risk of bleeding is significantly increased as well, and antiplatelet drugs should be chosen carefully.

Objective: Due to the inconsistent results of current studies on the association between urinary and blood vascular cell adhesion molecule-1 (VCAM-1) and systemic lupus erythematosus (SLE) disease activity, we conducted this study and analyzed its influencing factors. Methods: A literature search was conducted in PubMed, EMBASE, Web of Science, and Cochrane Library. Data were extracted from eligible studies to calculate standardized mean differences (SMD) with 95% confidence intervals (CI). Cochrane Q test and I2 statistics were used to examine heterogeneity. The sources of heterogeneity were assessed through sensitivity analysis and subgroup analysis. Publication bias was evaluated by funnel plots and Egger's test. Results: A total of 15 studies met the inclusion criteria, including 473 active SLE patients and 674 inactive SLE patients. The random effects model was used for data analysis. In both urine and blood samples, VCAM- 1 level in active SLE patients was significantly higher than those in inactive SLE patients (urine: SMD: 0.769; 95% CI: 0.260-1.278; blood: SMD=0.655, 95% CI: 0.084-1.226). No publication bias was found in this study. Conclusion: Compared with inactive SLE patients, patients with active SLE have higher levels of VCAM-1 in both urine and blood. VCAM-1 may be a potential indicator of SLE disease activity.

Background: Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer. Methods: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine. Results: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04). Conclusion: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.

Background: 6-Mercaptopurine (6-MP) is widely used to treat pediatric acute lymphoblastic leukemia (ALL). Mini-tablets of 5 mg per tablet were developed for precision individual therapy for children and individuals with poor thiopurine S-methyltransferase (TPMT) or nucleoside diphophate-linked moiety X-type motif 15 (NUDT15) metabolism. This study investigated the pharmacokinetic profiles of mini-tablets and conventional tablets with an improved ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Methods: After giving 8 healthy beagle dogs 50 mg 6-MP in different dosage forms, plasma samples collected at different time points were analyzed for pharmacokinetic evaluation. The samples were precipitated by methanol with 0.05% formic acid and separated on a Waters Atlantis T3 column (2.1 × 150 mm, 3 μm particles) using 0.1% formic acid in water and methanol at a flow rate of 0.4 mL/min in 4 min. Results: This method showed good linearity, accuracy, precision and stability with a detection range of 5.0-500.0 ng/mL for 6-MP, 6-methylmercaptopurine (6-MMP) and 6-thioguanine (6-TG). The main parameters, half-life of apparent terminal disposition, maximum observed plasma concentration, total AUC extrapolated to infinity, AUC since initiation of the experiment, mean residence time, distribution volume and clearance were 1.62 ± 0.87 hours, 90.58 ± 60.43 ng/mL, 151.20 ± 94.18 ng·h/mL, 292.06 ± 184.02 ng·h2/mL, 1.90 ± 0.92 hours, 864.08 ± 538.52 L, and 432.75 ± 360.64 L/h for conventional tablets and 1.70 ± 1.10 hours, 84.15 ± 39.50 ng/mL, 147.70 ± 51.80 ng·h/mL, 300.92 ± 124.48 ng·h2/mL, 2.07 ± 0.50 hours, 756.90 ± 324.00 L, and 340.75 ± 125.81 L/h for minitablets, respectively. Paired t-tests showed no significant difference in any of the evaluated pharmacokinetic parameters between the two types tablets (P > 0.05). Conclusion: Two dosage forms showed the same pharmacokinetic characteristics. This developing, novel formulation will help to provide a more accurate and optimal dosing regimen of 6-MP for humans in the future.

Background: We recently developed a liposomal nanoparticle system that can be used for drug delivery and simultaneously be monitored by optical or photoacoustic imaging devices. Here we tested the efficacy of alendronate as a homing molecule in SM-liposomes for bone targeting. Methods: Alendronate was immobilized covalently on the liposomal surface and the fluorescent dye indocyanine green was used as a payload in the liposomes. The indocyanine green delivery was analyzed by 3D optical tomography, optical fluorescence scanner, photoacoustic imaging, and by ex-vivo biodistribution studies. Results: The results show that the alendronate, coupled to the liposomal surface, increases sphingomyelin containing liposome targeting up to several-folds. Conclusion: The alendronate targeted liposomes open possibilities for an application in active bone targeting.