Pharmacogenetics of new classes of antidiabetic drugs.
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ABSTRACT:
SUBMITTER: Imamovic Kadric S
PROVIDER: S-EPMC8554705 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oral antidiabetic drugs (OADs) are used for more than a half-century in the treatment of type 2 diabetes. Only in the last five years, intensive research has been conducted in the pharmacogenetics of these drugs based mainly on the retrospective register studies, but only a handful of associations detected in these studies were replicated. The gene variants in CYP2C9, ABCC8/KCNJ11, and TCF7L2 were associated with the effect of sulfonylureas. CYP2C9 encodes sulfonylurea metabolizing cytochrome P450 isoenzyme 2C9, ABCC8 and KCNJ11 genes encode proteins constituting ATP-sensitive K(+) channel which is a therapeutic target for sulfonylureas, and TCF7L2 is a gene with the strongest association with type 2 diabetes. SLC22A1, SLC47A1, and ATM gene variants were repeatedly associated with the response to metformin. SLC22A1 and SLC47A1 encode metformin transporters OCT1 and MATE1, respectively. The function of a gene variant near ATM gene identified by a genome-wide association study is not elucidated so far. The first variant associated with the response to gliptins is a polymorphism in the proximity of CTRB1/2 gene which encodes chymotrypsinogen. Establishment of diabetes pharmacogenetics consortia and reduction in costs of genomics might lead to some significant clinical breakthroughs in this field in a near future.
| S-EPMC3845331 | biostudies-literature
Project description:BackgroundRecent trials suggested that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduced cardiovascular events. Comparative effectiveness of these new antidiabetic drug classes remains unclear. We therefore performed a network meta-analysis to compare the effect on cardiovascular outcomes among GLP-1 RAs, SGLT-2 and dipeptidyl peptidase-4 (DPP-4) inhibitors.MethodsMEDLINE, EMBASE, Cochrane database, ClinicalTrials.gov, and congress proceedings from recent cardiology conferences were searched up to April 20, 2019. Cardiovascular outcome trials and renal outcome trials reporting cardiovascular outcomes on GLP-1 RAs, SGLT-2 and DPP-4 inhibitors in patients with type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes were nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality, all-cause mortality, hospitalisation for heart failure (HF), and renal composite outcome. ORs and 95% CI were calculated using random-effects models.ResultsFourteen trials enrolling 121,047 patients were included. SGLT-2 inhibitors reduced cardiovascular deaths and all-cause deaths compared to placebo (OR 0.82, 95% CI 0.73-0.93 and OR 0.84, 95% CI 0.77-0.92) and DPP-4 inhibitors (OR 0.83, 95% CI 0.70-0.99 and OR 0.83, 95% CI 0.73-0.94), respectively. SGLT-2 inhibitors and GLP-1 RAs significantly reduced MACE (OR 0.88, 95% CI 0.82-0.95 and OR 0.87, 95% CI 0.82-0.93), hospitalisation for HF (OR 0.68, 95% CI 0.61-0.77 and OR 0.87, 95% CI 0.82-0.93), and renal composite outcome (OR 0.59, 95% CI 0.52-0.67 and OR 0.86, 95% CI 0.78-0.94) compared to placebo, but SGLT-2 inhibitors reduced hospitalisation for HF (OR 0.79, 95% CI 0.69-0.90) and renal composite outcome (OR 0.69, 95% CI 0.59-0.80) more than GLP-1 RAs. Only GLP-1 RAs reduced nonfatal stroke (OR 0.88, 95% CI 0.77-0.99). DPP-4 inhibitors did not lower the risk of these outcomes when compared to placebo and were associated with higher risks of MACE, hospitalisation for HF, and renal composite outcome when compared to the other two drug classes.ConclusionsSGLT-2 inhibitors show clear superiority in reducing cardiovascular and all-cause deaths, hospitalisation for HF, and renal events among new antidiabetic drug classes. GLP-1 RAs also have cardiovascular and renal protective effects. DPP-4 inhibitors have no beneficial cardiovascular effects and are therefore inferior to the other two drug classes. SGLT-2 inhibitors should now be the preferred treatment for type 2 diabetes mellitus.
| S-EPMC6714383 | biostudies-literature
Project description:In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.
| S-EPMC7428791 | biostudies-literature
Project description:•?Individual variability in pain perception and differences in the efficacy of analgesic drugs are complex phenomena and are partly genetically predetermined. •?Analgesics act in various ways on the peripheral and central pain pathways and are regarded as one of the most valuable but equally dangerous groups of medications. •?While pharmacokinetic properties of drugs, metabolism in particular, have been scrutinised by genotype-phenotype correlation studies, the clinical significance of inherited variants in genes governing pharmacodynamics of analgesics remains largely unexplored (apart from the µ-opioid receptor). •?Lack of replication of the findings from one study to another makes meaningful personalised analgesic regime still a distant future. •?This narrative review will focus on findings related to pharmacogenetics of commonly used analgesic medications and highlight authors' views on future clinical implications of pharmacogenetics in the context of pharmacological treatment of chronic pain.
| S-EPMC4590162 | biostudies-literature
Project description:A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of 'response' can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for "individualized medicine" for patients with T2D.
| S-EPMC2951319 | biostudies-literature
Project description:Antipsychotic medications are the gold-standard treatment for schizophrenia, and are often prescribed for other mental conditions. However, the efficacy and side-effect profiles of these drugs are heterogeneous, with large interindividual variability. As a result, treatment selection remains a largely trial-and-error process, with many failed treatment regimens endured before finding a tolerable balance between symptom management and side effects. Much of the interindividual variability in response and side effects is due to genetic factors (heritability, h(2)~ 0.60-0.80). Pharmacogenetics is an emerging field that holds the potential to facilitate the selection of the best medication for a particular patient, based on his or her genetic information. In this review we discuss the most promising genetic markers of antipsychotic treatment outcomes, and present current translational research efforts that aim to bring these pharmacogenetic findings to the clinic in the near future.
| S-EPMC4336924 | biostudies-literature
Project description:The aim of this work was to review studies in which genetic variants were assessed with respect to metabolic response to treatment with novel glucose-lowering drugs: dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i). In total, 22 studies were retrieved from the literature (MEDLINE). Variants of the GLP-1 receptor gene (GLP1R) were associated with a smaller reduction in HbA1c in response to DPP-4i. Variants of a number of other genes (KCNQ1, KCNJ11, CTRB1/2, PRKD1, CDKAL1, IL6 promoter region, TCF7L2, DPP4, PNPLA3) have also been related to DPP-4i response, although replication studies are lacking. The GLP1R gene was also reported to play a role in the response to GLP-1 RA, with larger weight reductions being reported in carriers of GLP1R variant alleles. There were variants of a few other genes (CNR1, TCF7L2, SORCS1) described to be related to GLP-1 RA. For SGLT2i, studies have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2) but no relationship between SLC5A2 variants and response to empagliflozin has been found. The relevance of the included studies is limited due to small genetic effects, low sample sizes, limited statistical power, inadequate statistics (lack of gene-drug interactions), inadequate accounting for confounders and effects modifiers, and a lack of replication studies. Most studies have been based on candidate genes. Genome-wide association studies, in that respect, may be a more promising approach to providing novel insights. However, the identification of distinct subgroups of type 2 diabetes might also be necessary before pharmacogenetic studies can be successfully used for a stratified prescription of novel glucose-lowering drugs.
| S-EPMC8099830 | biostudies-literature
Project description:Metabolic diseases and diabetes represent an increasing global challenge for human health care. As associated with a strongly elevated risk of developing atherosclerosis, kidney failure and death from myocardial infarction or stroke, the treatment of diabetes requires a more effective approach than lowering blood glucose levels. This review summarizes the evidence for the cardioprotective benefits induced by antidiabetic agents, including sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), along with sometimes conversely discussed effects of dipeptidyl peptidase-4 inhibitor (DPP4i) and metformin in patients with high cardiovascular risk with or without type 2 diabetes. Moreover, the proposed mechanisms of the different drugs are described based on the results of preclinical studies. Recent cardiovascular outcome trials unexpectedly confirmed a beneficial effect of GLP-1RA and SGLT2i in type 2 diabetes patients with high cardiovascular risk and with standard care, which was independent of glycaemic control. These results triggered a plethora of studies to clarify the underlying mechanisms and the relevance of these effects. Taken together, the available data strongly highlight the potential of repurposing the original antidiabetics GLP1-RA and SGLT2i to improve cardiovascular outcome even in non-diabetic patients with cardiovascular diseases.
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Project description:Diabetes is one of the leading chronic conditions worldwide, and breast cancer is the most prevalent cancer in women worldwide. The linkage between diabetes and its ability to increase the risk of breast cancer should always be analyzed in patients. This review focuses on the impact of antihyperglycemic therapy in breast cancer patients. Patients with diabetes have a higher risk of developing cancer than the general population. Moreover, diabetes patients have a higher incidence and mortality of breast cancer. In this review, we describe the influence of antidiabetic drugs from insulin and metformin to the current and emerging therapies, incretins and SGLT-2 inhibitors, on breast cancer prognosis. We also emphasize the role of obesity and the metastasis process in breast cancer patients who are treated with antidiabetic drugs.
| S-EPMC10813754 | biostudies-literature
Project description:Type 2 diabetes is a debilitating disease that impacts the life expectancy, quality of life, and health of an individual. Cardiovascular disease (CVD) is a common diabetes-associated complication and a principal cause for death in diabetic patients. This review aims to investigate and summarize the effect of Type 2 diabetes mellitus (T2DM) medications on CVD issues. A comprehensive literature review mainly from level 1 evidence was performed. Thirty-seven articles were extracted from Google Scholar, ScienceDirect, ProQuest, and PubMed Database using a combination of keywords. The findings suggest that different glucose-lowering agents have been tested for their efficacy and safety in T2DM with CVD. Some of the recent trials such as the "United Kingdom Prospective Diabetes Study," "Empagliflozin (EMPA) Cardiovascular (CV) Outcome Event Trial in T2DM Patients-Removing Excess Glucose" (EMPA-REG OUTCOME), "Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results," and "Trial to Evaluate CV and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes" (SUSTAIN6) have shed important light on this vital clinical concern, thus demonstrating a convincing effect of liraglutide, semaglutide, and EMPA on CVD outcomes, while metformin is thought to be the first-line optimal oral agent to manage Type 2 diabetics. Some classes of drugs demonstrate CV protection, some of them may be a result of a class effect, and some differences might be based on the population enrolled individually. Most of the trials failed to show a significant benefit with regard to mortality and morbidity in spite of intensive glycemic control. This study, therefore, enabled us to develop a guide of potential antidiabetic medication that can influence or promote CV health. Health professionals in future should weigh the CV risk against possible advantages while prescribing antidiabetic medications.
| S-EPMC6124835 | biostudies-other