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Managing Diabetes and Preventing Heart Disease: Have We Found a Safe and Effective Agent?
Cheng, JWM, Colucci, VJ, Kalus, JS, Spinler, SA
The Annals of pharmacotherapy. 2019;(5):510-522
Abstract
OBJECTIVE While improving glycemic control with antihyperglycemics has been demonstrated to reduce microvascular complications, the benefits of reduction in cardiovascular diseases (CVDs) have not been demonstrated with older agents. This article reviews current evidence of the CV outcomes of newer antihyperglycemics approved since 2008. DATA SOURCES Peer-reviewed articles were identified from MEDLINE (1966 to October 31, 2018) using search terms exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, mortality, myocardial infarction (MI), heart failure (HF), and stroke. STUDY SELECTION AND DATA EXTRACTION A total of 12 pertinent double-blinded randomized controlled trials were included. DATA SYNTHESIS Liraglutide, empagliflozin, and canagliflozin have been shown in patients with CV diseases and high risk of developing CV disease to be superior to placebo in improving CV outcomes. Saxagliptin and alogliptin have both been demonstrated to increase HF hospitalization, whereas sitagliptin has not. Relevance to Patient Care and Clinical Practice: In contrast to older-generation antihyperglycemics, selected new antihyperglycemic agents have been shown to be superior to placebo in improving CV outcomes. Clinicians may now be able to provide high-risk patients agents that not only help in providing glycemic control, but also prevent both macrovascular and microvascular complications. CONCLUSION Liraglutide, empagliflozin, and canagliflozin have been shown to be superior to placebo in improving CV outcomes. However, there are differences among agents in terms of HF and peripheral arterial disease outcomes. Future studies should focus on evaluating other clinical CV outcomes in patients without existing CVD and perhaps single drug regimens for diabetes.
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Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT-2 inhibitors and GLP-1 receptor agonists.
Bonaventura, A, Carbone, S, Dixon, DL, Abbate, A, Montecucco, F
Journal of internal medicine. 2019;(1):16-31
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Abstract
Patients with type 2 diabetes mellitus (T2D) present an increased risk for cardiovascular (CV) complications. In addition to improvement in glycaemic control, glucose-lowering therapies, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-dependent glucose cotransporter (SGLT)-2 inhibitors, have been shown to significantly reduce CV events. In 2008, the US Food and Drug Administration mandated that all new glucose-lowering drugs undergo CV outcomes trials (CVOTs) to determine their CV safety. These trials have largely demonstrated no major CV safety concerns. Most notably, the GLP-1RAs and SGLT-2 inhibitors have been found to be not only safe, but also cardioprotective compared to placebo. The SGLT-2 inhibitors have opened a new perspective for clinicians treating patients with T2D and established CV disease in light of their 'pleiotropic' effects, specifically on heart failure, while GLP-1RAs seem to present more favourable effects on atherosclerotic events. In this review, we discuss the role of GLP-1RAs and SGLT-2 inhibitors to reduce CV risk in T2D patients and suggest an individualized therapeutic approach in this population based on the presence of metabolic and CV comorbidities.
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Neutrophil extracellular traps: The core player in vascular complications of diabetes mellitus.
Berezin, A
Diabetes & metabolic syndrome. 2019;(5):3017-3023
Abstract
Diabetes mellitus (DM) is the most important metabolic disease with major threat for public health and increased risk of premature death. The prevalence of DM steadily rises in developing and developed countries achieving the epidemic level. Manifestation and progression of DM corresponds to developing vasculopathies, such as retinopathy, micro- and macro angiopathies, which negatively influence on clinical outcomes and quality-of-life. Although there are remarkable differences in the prevalence of vasculopathy in various types of DM, hyperglycemia and lipotoxicity are discussed as a major factors contributing to vascular complications partly through inducing neutrophil extracellular trap (NET). The NET or NETosis is unique form of cell death, which is an important core component of innate immune system. The review is dedicated the role of NET as a link between endothelium, inflammation and thrombosis that is crucial for development of DM-induced vasculopathy. It has suggested that NET formation could be not just a target for the DM care, but also a biomarker for stratification of DM patients at higher risk of vascular complications.
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Perturbed Biochemical Pathways and Associated Oxidative Stress Lead to Vascular Dysfunctions in Diabetic Retinopathy.
Mahajan, N, Arora, P, Sandhir, R
Oxidative medicine and cellular longevity. 2019;:8458472
Abstract
Diabetic retinopathy (DR) is a vascular insult that accompanies the hyperglycemic state. Retinal vasculature holds a pivotal role in maintaining the integrity of the retina, and any alteration to retinal vasculature affects retinal functions. The blood retinal barrier, a prerequisite to vision acuity, is most susceptible to damage during the progression of DR. This is a consequence of impaired biochemical pathways such as the polyol, advanced end glycation products (AGE), hexosamine, protein kinase C (PKC), and tissue renin-angiotensin system (RAS) pathways. Moreover, the role of histone modification and altered miRNA expression is also emerging as a major contributor. Epigenetic changes create a link between altered protein function and redox status of retinal cells, creating a state of metabolic memory. Although various biochemical pathways underlie the etiology of DR, the major insult to the retina is due to oxidative stress, a unifying factor of altered biochemical pathways. This review primarily focuses on the critical biochemical pathways altered in DR leading to vascular dysfunctions and discusses antioxidants as plausible treatment strategies.
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The roles of endothelial nitric oxide synthase gene polymorphisms in diabetes mellitus and its associated vascular complications: a systematic review and meta-analysis.
Dong, J, Ping, Y, Wang, Y, Zhang, Y
Endocrine. 2018;(2):412-422
Abstract
PURPOSE The roles of endothelial nitric oxide synthase (eNOS) gene polymorphisms in diabetes mellitus (DM) were intensively analyzed, but the results of these studies were inconsistent. Therefore, we performed this study to better assess the relationship between eNOS genetic variations and DM. METHODS Eligible studies were searched in PubMed, Medline, Embase, and Web of Science. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess correlations between eNOS polymorphisms and DM. RESULTS A total of 91 studies were finally included in our analyses. Significant associations with the susceptibility to DM were detected for the rs891512, rs1799983, rs2070744, and rs869109213 polymorphisms. As for vascular complications in DM, significant associations with the susceptibility to diabetic nephropathy were detected for the rs1799983 and rs2070744 polymorphisms. In addition, we also found that the rs1799983 polymorphism was significantly associated with the susceptibility to peripheral artery disease, whereas the rs2070744 polymorphism was significantly associated with the susceptibility to coronary artery disease in DM patients. Further subgroup analyses on the basis of type of disease and ethnicity of participants showed similar positive results. CONCLUSIONS In conclusion, our findings indicate that rs891512, rs1799983, rs2070744, and rs869109213 polymorphisms may serve as genetic biomarkers of DM, while rs1799983, rs2070744, and rs869109213 polymorphisms may contribute to the development of vascular complications in DM.
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Diabetes medications and cardiovascular disease: at long last progress.
Lupsa, BC, Inzucchi, SE
Current opinion in endocrinology, diabetes, and obesity. 2018;(2):87-93
Abstract
PURPOSE OF REVIEW Although intensive control of hyperglycemia has been proven to decrease the risk of microvascular complications in type 2 diabetes, it has had little apparent effect on reducing cardiovascular complications - the leading cause of mortality in this disease. We review the cardiovascular effects of various glucose-lowering medications, with a particular focus on the recent studies demonstrating clear benefits from members of several drug categories. RECENT FINDINGS Recently, several randomized controlled studies have revealed significant improvements in cardiovascular outcomes from a thiazolidinedione, two sodium-glucose cotransporter 2 inhibitors and two glucagon-like peptide 1 receptor agonists. SUMMARY These data suggest that certain glucose lowering agents after metformin should be favored in type 2 diabetes mellitus patients when there is underlying cardiovascular disease.
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Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: A narrative review of head-to-head comparisons.
Dalsgaard, NB, Vilsbøll, T, Knop, FK
Diabetes, obesity & metabolism. 2018;(3):508-519
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Abstract
Cardiovascular (CV) disease is the leading cause of death and morbidity in patients with type 2 diabetes. Five CV risk factors (blood pressure, resting heart rate, body weight, cholesterol levels and blood glucose) are monitored routinely as safety and efficacy endpoints in randomized clinical trials for diabetes therapies. To determine if different glucagon-like peptide-1 receptor agonists (GLP-1RAs) had varying effects on these CV risk factors, we reviewed 16 head-to-head trials directly comparing GLP-1RAs that included at least one of the five factors. Few trials reported statistical differences between GLP-1RAs in terms of systolic blood pressure (SBP), body weight and total cholesterol. Liraglutide increased heart rate vs its comparators in three separate trials. All GLP-1RAs reduced glycated haemoglobin (HbA1c), but exenatide twice daily and lixisenatide had statistically smaller effects compared with other GLP-1RAs. These descriptive data indicate that individual GLP-1RAs affect CV risk factors differently, potentially because of their individual pharmacokinetics and/or size. Short-acting GLP-1RAs appeared to result in smaller changes in SBP and total cholesterol compared with continuous-acting treatments, while large GLP-1RAs had a reduced effect on body weight compared with small GLP-1RAs. For glycaemic control, short-acting GLP-1RAs had a greater impact on postprandial glucose levels vs continuous-acting GLP-1RAs, but for fasting plasma glucose levels and HbA1c, continuous-acting treatments had the greater effect. No differentiating trends were obvious in heart rate data. These diverse actions of GLP-1RAs on CV risk factors should aid individualized patient treatment.
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Diabetic retinopathy and endothelin system: microangiopathy versus endothelial dysfunction.
Sorrentino, FS, Matteini, S, Bonifazzi, C, Sebastiani, A, Parmeggiani, F
Eye (London, England). 2018;(7):1157-1163
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Abstract
In the face of the global epidemic of diabetes, it is critical that we update our knowledge about the pathogenesis of diabetes and the related micro alterations on the vascular network in the body. This may ultimately lead to early diagnosis and novel treatment options for delaying the progression of diabetic complications. Research has recently revealed the pivotal role of endothelin in the pathogenesis of diabetic complications, particularly in the regulation of the capillary flow, which is affected in the course of retinopathy. Although there are several reviews on various approaches to the treatment of diabetes, including normalization of glucose and fat metabolism, no reviews in literature have focused on the endothelin system as a therapeutic target or early indicator of diabetic microangiopathy. In this review, we summarize some of the experimental and clinical evidence suggesting that current therapeutic approaches to diabetes may include the modulation of the blood concentration of compounds of the endothelin system. In addition, we will briefly discuss the beneficial effects produced by the inhibition of the production of high levels of endothelin in vasculopathy, with focus on diabetic retinopathy. The cutting-edge technology currently widely used in opththalmology, such as the OCT angiography, allows us to detect very early retinal morphological changes alongside alterations in choroidal and retinal vascular network. Combination of such changes with highly sensitive measurements of alterations in serum concentrations of endothelin may lead to more efficient early detection and treatment of diabetes and related macro/microvascular complications.
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Unilateral retinopathy in a patient with diabetes and coronary heart disease.
Abalem, MF, Eagle, KA, Rao, RC
BMJ (Clinical research ed.). 2018;:k1703
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Glycemic control in type 2 diabetes: from medication nonadherence to residual vascular risk.
Giugliano, D, Maiorino, MI, Bellastella, G, Esposito, K
Endocrine. 2018;(1):23-27
Abstract
Despite the availability of many new treatment options for type 2 diabetes, the proportion of patients achieving the HbA1c target < 7.0% remains around 50%. We put forward the hypothesis that the unchanged HbA1c results, observed in the last decade in type 2 diabetes patients, are also a consequence of medication nonadherence and clinical inertia. Poor medication-taking behavior is usually defined as medication nonadherence and is responsible for uncontrolled hemoglobin A1c level in 23% of cases. Medication nonadherence may also affect clinical outcomes, as diabetic patients with good adherence (≥80%) had a significant 10% lower rate of hospitalization events and a significant 28% lower rate of all-cause mortality when compared with patients with poor adherence (<80%). Residual vascular risk may be defined as the risk of macrovascular (major cardiovascular events) and microvascular (retinopathy, nephropathy, neuropathy) complications that remains after intensive and successful glycemic control in type 2 diabetes. For major cardiovascular events, risk reduction following intensive glycemic control is 9% and, therefore, residual vascular risk is 91%. For microvascular complications, as nephropathy, residual vascular risk is as high as 80%. Residual vascular risk remains high in type 2 diabetes despite intensive glycemic control. Medication nonadherence by the diabetic patient and clinical inertia by the clinician may have contributed to the high level of residual vascular risk (both macro and microvascular) of type 2 diabetic patients.