Current Pharmaceutical Design - Volume 27, Issue 8, 2021

Diabetic patients are considered to be at high risk for the development of atherosclerotic disease. Management of hypercholesterolemia is of paramount importance to optimize cardiovascular outcomes in this subset of patients and statins are regarded as the mainstay of treatment. However, the recent advent of PCSK-9 inhibitors has provided a useful alternative in the management of dyslipidemia, especially when statins cannot be tolerated or when hypolipidemic targets cannot be achieved. In this review, we discuss current trends in their use, and we focus on their role in the management of diabetic dyslipidemia.

Drug design based on degradation-resistant, long-acting Glucagon-like peptide-1 receptor (GLP-1R) agonists for treating type 2 diabetes is attracting a lot of attention. Here, the authors have examined in detail how in silico drug design is aiding in developing novel GLP-1 receptor agonist drugs. Their pharmacotherapy and adverse effects have also been summarized. After the analysis of currently available information on this topic, the authors feel that in silico method is a great auxiliary tool in almost all the experimental studies on GLP-1 receptors and is highly efficient in identifying novel drug molecules that can act as GLP-1 receptor agonists.

Background: Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder with increasing prevalence and a significant burden of long-term complications. Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) are a novel treatment option for T2DM, exerting optimal effects on glucose control and weight loss, and pleiotropic actions. Pharmacogenetics, a promising research field of precision medicine, investigates how gene variations can affect individual response to drug therapy, assuming that the diverse genetic architecture of patients with T2DM could be partly associated with the considerable inter-individual variability in the therapeutic response to GLP-1 RAs. This review aims to summarize current evidence related to T2DM risk variants, affecting the incretin pathway, focus on the pharmacogenetics of the GLP-1 RA liraglutide, and discuss their potential clinical implications in the management of this complex disorder. Methods: A literature search was performed using electronic biomedical databases, and the findings of key studies are summarized and discussed in this narrative review. Results: Available evidence suggests the involvement of genetic polymorphisms in GLP-1 Rgene in variation in glycemic response, metabolic parameters and gastric emptying in people treated with liraglutide. Polymorphisms in CNR1, CTRB1/2, TMEM114 and CHST3 loci were also shown to be implicated in the disturbance of the incretin homeostasis in T2DM. These findings warrant further investigation by future studies. Conclusion: Robust findings from pharmacogenetic studies might be used to identify good responders to liraglutide treatment, in terms of both glycemic and weight control, thus reinforcing the patient-centered approach of T2DM management.

During the last decade, the results of large-scale, randomized, clinical trials on newer antidiabetic agents, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium glucose cotransporter type 2 (SGLT2) inhibitor, have been published showing promising findings on cardiovascular and renal outcomes. Besides improving glycemic control, GLP-1 receptor agonists have been shown to modify cardiovascular risk factors, such as insulin resistance, body weight, blood pressure (BP), and lipid profile. Additionally, SGLT2 inhibitors except for glycemic control have been shown to induce weight loss and decrease BP. However, there are limited data regarding their effect on patients without diabetes. Therefore, the aim of the present review is to summarize the existing literature data regarding the effects of newer antidiabetic therapies on patients without diabetes.

Despite optimal treatment of diabetic kidney disease (DKD) with adequate blood pressure control and agents blocking the renin-angiotensin-system (RAS), the residual cardiorenal risk of these patients remains substantially high. There is, therefore, an unmet need for additional therapies effective to retard the progression of DKD and improve cardiovascular outcomes in this high-risk population. Sodium-glucose co-transporter 2 (SGLT-2) inhibitors represent a novel drug class that received regulatory approval for improving glycemic control in patients with type 2 diabetes and preserved kidney function. Large outcome trials designed to test their cardiovascular safety profile showed an unexpected improvement in cardiovascular outcomes and also suggested a slower progression of DKD with SGLT-2 inhibition. The Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy (CREDENCE), a trial that was designed to specifically investigate the renoprotective properties of SGLT-2 inhibitors in patients with overt DKD already receiving guideline-based therapy with a RAS-blocker, was prematurely terminated due to an impressive benefit of canagliflozin on kidney and cardiovascular outcomes. These impressive results refine the role and the indication of SGLT-2 inhibitors as a cardioand renoprotective strategy in patients with DKD. In this article, we provide an overview of the available clinical- trial evidence and explore the mechanisms mediating the cardiorenal protection afforded by SGLT-2 inhibitors. We conclude with perspectives for a potential beneficial effect of this novel drug class in patients with non-diabetic kidney disease.

Background: Type 2 diabetes mellitus (DM) is associated with a considerable risk of cardiovascular and renal diseases, including heart failure. Sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated unprecedented cardiorenal protective effects in large-scale clinical trials of patients with or without diabetes and either established cardiovascular disease (CV) or multiple CV risk factors. Objective: Herein we aim to focus on the role of SGLT2 inhibitors regarding the improvement in heart failure outcomes and the proposed mechanisms of action by which these drugs confer their beneficial effect. Methods: PubMed, Embase, and Google Scholar databases were searched to identify eligible articles that are comprehensively summarized and discussed in this study. Results: The most commonly discussed mechanisms of action are diuresis and natriuresis, reduction in preload, afterload, and ventricular mass, as well as stimulation of erythropoietin production and improved myocardial energetics. SGLT2 inhibitors improve outcomes in patients with established heart failure (HF) and reduce the risk of death and HF admissions in patients with established chronic HF with reduced ejection fraction (HFrEF), either with or without diabetes. Conclusion: Potential key mechanisms that may explain the notable cardioprotective benefits of SGLT2 inhibitors have been outlined. These agents have recently received class Ia recommendation in specific groups of people with DM to lower the risk of hospitalization for HF and risk of death, while these benefits may also extend to people without diabetes. It remains to be seen whether they will also emerge as treatment approaches in the acute phase of CV episodes.

Type 2 diabetes mellitus (T2DM) has an ever-growing prevalence worldwide, affecting 1 in 11 adults. It continues to significantly impact patients in terms of morbidity and mortality, in addition to impairing quality of life while adding to the spiralling healthcare costs. Metformin was first used over half a century ago, and for the past two decades, it has been considered first-line oral therapy to treat patients with T2DM, in whom lifestyle measures failed to improve glycaemic control. Early landmark studies supported a glycaemic benefit with metformin use with a relatively safe adverse effect profile, particularly with avoidance of hypoglycaemia. Moreover, studies have indicated other potential beneficial role for metformin on organs typically affected by diabetes complications. However, more recently, with the discovery of newer hypoglycaemic agents and the wealth of data provided by large-scale cardiovascular safety studies, algorithms for the treatment of patients with T2DM have become increasingly complex. Indeed, recent guidelines challenge current thinking and advocate the use of agents other than metformin as first-line agents in those with higher cardiovascular risk, potentially unseating metformin from its long-held throne. This narrative review aims to summarize the background and origins of metformin, assess its role in the current management of patients with T2DM, highlighting the clinical efficacy and safety profile of this agent. Also, the position of metformin in the clinical algorithms is discussed in light of the most recent evidence in the field, helping with an ever-increasing shift towards individualized patient care to maximize benefits and minimize risks.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a new antihyperglycemic class with the demonstrated advantage of reducing major adverse cardiovascular events (MACE) among individuals with type 2 diabetes (T2DM), atherosclerotic cardiovascular disease, or high cardiovascular risk. Objective: o summarize the evidence of systematic reviews (SRs) that assess MACE (cardiovascular mortality, nonfatal myocardial infarction, and stroke) and hospitalizations for heart failure in GLP-1RAs-treated patients and to evaluate possible overlap in pertinent SRs. Methods: We performed a comprehensive search via MEDLINE, Cochrane Library, and PROSPERO databases up to February 23, 2020, for SRs examining cardiovascular outcomes of GLP-1RAs in T2DM patients. Three independent authors extracted data and assessed the methodological quality of the included SRs using the ROBIS tool. Results: We found 37 SRs – published between 2009 and 2020 in English – of which 35 collected data only from randomized clinical trials while two from observational studies as well. The methodological quality of the 37 SRs ranged from low to high, while only 3 have evaluated the overall quality of evidence outcome using the Grading of Recommendations Assessments, Development and Evaluation (GRADE) approach. All the included SRs showed cardiovascular safety of GLP-1RAs while the latest ones demonstrated a reduction in composite MACE endpoint as well as its every individual component and heart failure hospitalizations. Conclusion: In the first overview of SRs about cardiovascular outcomes of GLP-1RAs, they proved favorable effects on reducing cardiovascular events in T2DM patients. There are, however, many overlapping reviews based on relatively few cardiovascular outcomes trials.

The care of the individual with diabetic foot disease (DFD) represents a significant challenge. In addition to the primary foot pathology, individuals with DFD are frequently compromised by multiple co-existent medical complications. Successful management of DFD, therefore requires simultaneous addressal of these issues alongside high-quality foot care. We explore the pharmacological treatments in DFD with an emphasis on the emerging putative technologies centred on addressing the pathobiology of wound healing but also discuss developments in infection control, Charcot neuroarthropathy, cardiovascular and diabetes care. Many of these will have a significant impact on future treatment paradigms and how we amalgamate these novel technologies may help shape the standard of care in DFD hereafter. However, there is a need for better quality of evidence and cost-effectiveness data prior to widespread adoption into routine care is considered.

Background: Rational drug molecular design based on virtual screening requires the ligand binding site to be known. Recently, the recognition of ion ligand binding site has become an important research direction in pharmacology. Methods: In this work, we selected the binding residues of 4 acid radical ion ligands (NO2^-, CO3^2-, SO4^2- and PO4^3-) and 10 metal ion ligands (Zn²⁺, Cu²⁺, Fe²⁺, Fe³⁺, Ca²⁺, Mg²⁺, Mn²⁺, Na⁺, K⁺ and Co²⁺) as research objects. Based on the protein sequence information, we extracted amino acid features, energy, physicochemical, and structure features. Then, we incorporated the above features and input them into the MultilayerPerceptron (MLP) and support vector machine (SVM) algorithms. Results: In the independent test, the best accuracy was higher than 92.5%, which was better than the previous results on the same dataset. In addition, we found that energy information is an important factor affecting the prediction results. Conclusion: Finally, we set up a free web server for the prediction of protein-ion ligand binding sites (http://39.104.77.103:8081/lsb/HomePage/HomePage.html). This study is helpful for molecular drug design.

Purpose: In cancer therapies, drug combinations have shown significant accuracy and minimal side effects than the single drug administration. Therefore, drug synergy has drawn great interest from pharmaceutical companies and researchers. Unfortunately, the prediction of drug synergy score was carried out based on the small group of drugs. Methods: Due to the advancement in high-throughput screening (HTS), the size of drug synergy datasets has grown enormously in recent years. Hence, machine learning models have been utilized to predict the drug synergy score. However, the majority of these machine learning models suffer from over-fitting and hyperparameters tuning issues. Results: A novel deep bidirectional mixture density network (BMDN) model is proposed. A dynamic mutationbased multi-objective differential evolution is used to optimize the hyper-parameters of BMDN. Extensive is conducted on the NCI-ALMANAC drug synergy dataset that consists of 2,90,000 synergy determinations. Conclusions: Experimental results reveal that BMDN outperforms the existing drug synergy models in terms of various performance metrics.

Background: Breast cancer is one of the leading cancers in women in the Western world. Cancer treatment, especially chemotherapy, is often associated with physical and psychosocial side effects. Objective: To improve the quality of life and manage side effects, a new integrative mind-body-medicine group concept for breast cancer patients receiving chemotherapy was developed and pilot tested. Methods: Breast cancer patients participated in a 66 hours mind-body-medicine group program tailored to the needs of cancer patients during chemotherapy. The program was integrated into standard care encompassing mindfulness training, yoga, moderate exercise, nutrition, complementary self-help strategies, cognitive restructuring, and acupuncture. Quality of life (EORTC QLQ-C30), depression and anxiety (HADS), stress (PSS-10), and fatigue (BFI) were assessed before and after the program, as well as satisfaction and safety. Analyses were carried out on exploratory basis with paired samples t-tests. Results: Fifty-seven female patients, aged 51.3±10.5 years, with breast cancer diagnoses were enrolled. After completing the program, global EORTC quality of life was improved (D=9.5; 95%-CI=[2.9|16.1]; p=.005), although the EORTC-symptom scales assessing fatigue (D=9.9; 95%-CI=[1|18.8]; p=.030), nausea (D=7.1; 95%- CI=[0.6|13.6]; p=.031), and dyspnea (D=12.5; 95%-CI=[2.9|22.1]; p=.011) were found to be increased. Stress (D=-3.5; 95%-CI=[-5|-2.1]; p=.000), anxiety (D=-3.8; 95%-CI=[-4.9|-2.7]; p=.000) and depression (D=-3.9; 95%-CI=[-4.9|-2.8]; p=.000) were also found to be significantly reduced. Regarding the severity of (D=0.2; 95%- CI=[-0.8|0.5]; p=.644) and the impairment due to fatigue (D=0.1; 95%-CI=[-0.8|0.6]; p=.696), no significant worsening was observed. Patients were satisfied with the program. No serious adverse events were reported. Conclusion: Breast cancer patients benefit from an integrative mind-body-medicine group program during chemotherapy regarding the quality of life and psychological symptoms. Randomized controlled trials are warranted.