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[Application of new glucose lowering drugs: DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors].
Verburg, AFE, van den Donk, M, Wiersma, T
Nederlands tijdschrift voor geneeskunde. 2019
Abstract
A comprehensive review of the literature on DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors has resulted in small changes to the medication roadmap of the type 2 diabetes mellitus standard of the Dutch College of General Practitioners. SGLT-2 inhibitors and GLP-1 receptor agonists may have benefits related to cardiovascular outcomes in patients with high cardiovascular risk, especially in those who have experienced a cardiovascular event. However, ascribing effectiveness related to cardiovascular outcomes on the basis of a single cardiovascular safety trial is premature. Metformin, sulfonylurea derivatives and insulin are still the cornerstone of type 2 diabetes mellitus treatment in primary care.
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Heart failure drug treatment.
Rossignol, P, Hernandez, AF, Solomon, SD, Zannad, F
Lancet (London, England). 2019;(10175):1034-1044
Abstract
Heart failure is the most common cardiovascular reason for hospital admission for people older than 60 years of age. Few areas in medicine have progressed as remarkably as heart failure treatment over the past three decades. However, progress has been consistent only for chronic heart failure with reduced ejection fraction. In acutely decompensated heart failure and heart failure with preserved ejection fraction, none of the treatments tested to date have been definitively proven to improve survival. Delaying or preventing heart failure has become increasingly important in patients who are prone to heart failure. The prevention of worsening chronic heart failure and hospitalisations for acute decompensation is also of great importance. The objective of this Series paper is to provide a concise and practical summary of the available drug treatments for heart failure. We support the implementation of the international guidelines. We offer views on the basis of our personal experience in research areas that have insufficient evidence. The best possible evidence-based drug treatment (including inhibitors of the renin-angiotensin-aldosterone system and β blockers) is useful only when optimally implemented. However, implementation might be challenging. We believe that disease management programmes can be helpful in providing a multidisciplinary, holistic approach to the delivery of optimal medical care.
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The role of sodium glucose cotransporter-2 (SGLT-2) inhibitors in heart failure and chronic kidney disease in type 2 diabetes.
Woo, V, Connelly, K, Lin, P, McFarlane, P
Current medical research and opinion. 2019;(7):1283-1295
Abstract
Background: Heart failure (HF) and chronic kidney disease (CKD) are responsible for substantial morbidity and mortality in individuals with type 2 diabetes (T2D). Methods: This review discusses the significance of these comorbidities of T2D and current options for managing them, with a focus on sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Based on a focused literature search of cardiovascular outcomes trials (CVOTs), this review assessed the effects of SGLT-2 inhibitors in individuals with T2D with or without established cardiovascular disease (CVD). Results: In addition to effective glycemic control and weight loss, SGLT-2 inhibitor treatment of T2D prevents adverse cardiovascular and renal outcomes in individuals with and without these comorbidities. Reduced rate of hospitalization due to HF (HHF) and improved renal outcomes appear to be class effects of SGLT-2 inhibitors. Reduction in CV events may be more significant in individuals with established cardiovascular disease. Conclusions: CVOTs and other studies confirm that the SGLT-2 inhibitors, mostly used in combination with other glucose-lowering drugs, offer several clinical benefits beyond improved glycemic control. These include reducing HHF risk and improving renal outcomes. HF and renal benefits are observed in individuals with and without established CVD, which may simplify therapeutic selection. Ongoing SGLT-2 inhibitor CVOTs will help clarify the potential of these drugs to treat T2D comorbid with different forms of HF (HF with preserved vs reduced ejection fraction) and different degrees of renal dysfunction, and in individuals with T2D vs pre-diabetes or normal glucose metabolism.
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Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction.
Liu, B, Wang, Y, Zhang, Y, Yan, B
Current topics in medicinal chemistry. 2019;(20):1818-1849
Abstract
Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality. The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.
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Lessons from the Trials for the Desirable Effects of Sodium Glucose Co-Transporter 2 Inhibitors on Diabetic Cardiovascular Events and Renal Dysfunction.
Wakisaka, M, Kamouchi, M, Kitazono, T
International journal of molecular sciences. 2019;(22)
Abstract
Recent large placebo-controlled trials of sodium glucose co-transporter 2 (SGLT2) inhibitors revealed desirable effects on heart failure (HF) and renal dysfunction; however, the mechanisms underlying these effects are unknown. The characteristic changes in the early stage of diabetic cardiomyopathy (DCM) are myocardial and interstitial fibrosis, resulting in diastolic and subsequent systolic dysfunction, which leads to clinical HF. Pericytes are considered to play crucial roles in myocardial and interstitial fibrosis. In both DCM and diabetic retinopathy (DR), microaneurysm formation and a decrease in capillaries occur, triggered by pericyte loss. Furthermore, tubulointerstitial fibrosis develops in early diabetic nephropathy (DN), in which pericytes and mesangial cells are thought to play important roles. Previous reports indicate that pericytes and mesangial cells play key roles in the pathogenesis of DCM, DR and DN. SGLT2 is reported to be functionally expressed in pericytes and mesangial cells, and excessive glucose and Na+ entry through SGLT2 causes cellular dysfunction in a diabetic state. Since SGLT2 inhibitors can attenuate the high glucose-induced dysfunction of pericytes and mesangial cells, the desirable effects of SGLT2 inhibitors on HF and renal dysfunction might be explained by their direct actions on these cells in the heart and kidney microvasculature.
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Risk factor reduction in type 2 diabetes demands a multifactorial approach.
Rydén, L, Ferrannini, G, Mellbin, L
European journal of preventive cardiology. 2019;(2_suppl):81-91
Abstract
Dysglycaemia (i.e. type 2 diabetes mellitus or impaired glucose tolerance) is not only common in patients with cardiovascular disease but increases the risk for future cardiovascular complications. Hyperglycaemia, the hallmark of diabetes, has since long been considered to be the link between diabetes and cardiovascular disease. Diabetes is, however, a complex, multifactorial disorder to which, for example, insulin resistance, endothelial dysfunction and factors such as increased thrombogenicity, hypertension and dyslipidaemia contribute. Thus, treatment needs to be multifactorial and to take cardiovascular aspects into account. Life-style adjustments are, together with blood pressure, lipid and glucose control, important parts of such management. Recent trial data reveal a beneficial effect on cardiovascular prognosis and mortality of blood glucose lowering agents belonging to the classes: sodium-glucose-transporter 2 inhibitors and glucagon-like peptide 1 agonists. The precise mechanisms by which certain sodium-glucose-transporter 2 inhibitors and glucagon-like peptide receptor agonists lead to these beneficial effects are only partly understood. An important impact of the benefits of sodium-glucose-transporter 2 inhibitors is a reduction in heart failure while glucagon-like peptide receptor agonists may retard the development of atherosclerotic vascular disease or stabilising plaques. Although there has been a considerable improvement in the prognosis for people with atherosclerotic diseases over the last decades there is still a gap between those with dysglycaemia, who are at higher risk, than those without dysglycaemia. This residual risk is reasonably related to two major factors: a demand for improved management and a need for new and improved therapeutic opportunities of type 2 diabetes, both routes to an improved prognosis that are at hands. This review is a comprehensive description of the possibilities to improve the prognosis for patients with dysglycaemia by a multifactorial management according to the most recent European guidelines issued in 2019 by the European Society of Cardiology in collaboration with the European Association for the Study of Diabetes.
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Effects of sodium glucose cotransporter 2 inhibitors on mineral metabolism in type 2 diabetes mellitus.
Vinke, JSJ, Heerspink, HJL, de Borst, MH
Current opinion in nephrology and hypertension. 2019;(4):321-327
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Abstract
PURPOSE OF REVIEW Sodium glucose cotransporter 2 (SGLT2) inhibitors are relatively novel antidiabetic drugs that improve glycemic control and reduce cardiovascular outcomes as well as renal function decline. SGLT2 inhibitors act by inhibiting glucose reabsorption in the proximal tubule of the kidney. Emerging data suggest that these drugs may also influence bone and mineral metabolism. This review summarizes clinical trial data on bone and mineral outcomes, and discusses potential underlying mechanisms. RECENT FINDINGS Three large randomized controlled trials documented cardiovascular and renal protective effects of SGLT2 inhibitors. Recent studies indicate that SGLT2 inhibitors influence renal phosphate reabsorption and calciuria. Although the CANVAS trial suggested an increased fracture risk associated with canagliflozin compared with placebo, the vast majority of trials and meta-analyses did not demonstrate an increased fracture risk associated with SGLT2 inhibitor use. SUMMARY SGLT2 inhibitors have shown clinically relevant cardiovascular and renal protective effects. The long-term implications for bone health, in particular in the context of chronic kidney disease, are still incompletely understood and warrant further investigation.
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Sodium-Glucose Cotransporter 2 Inhibitors: A Case Study in Translational Research.
Beitelshees, AL, Leslie, BR, Taylor, SI
Diabetes. 2019;(6):1109-1120
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Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the most recently approved class of diabetes drugs. Unlike other agents, SGLT2 inhibitors act on the kidney to promote urinary glucose excretion. SGLT2 inhibitors provide multiple benefits, including decreased HbA1c, body weight, and blood pressure. These drugs have received special attention because they decrease the risk of major adverse cardiovascular events and slow progression of diabetic kidney disease (1-3). Balanced against these impressive benefits, the U.S. Food and Drug Administration-approved prescribing information describes a long list of side effects: genitourinary infections, ketoacidosis, bone fractures, amputations, acute kidney injury, perineal necrotizing fasciitis, and hyperkalemia. This review provides a physiological perspective to understanding the multiple actions of these drugs complemented by a clinical perspective toward balancing benefits and risks.
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Beyond type 2 diabetes: sodium glucose co-transporter-inhibition in type 1 diabetes.
Biester, T, Kordonouri, O, Danne, T
Diabetes, obesity & metabolism. 2019;:53-61
Abstract
Use of sodium glucose cotransporter (SGLT) inhibitors are a well-established therapeutic option in type 2 diabetes (T2D) with a variety of proven therapeutic benefits. They have become a pillar of current treatment guidelines. In type 1 diabetes (T1D), initial exploratory studies have shown benefits in glycemic control, weight control, and cardiovascular risk parameters, leading to trials aiming for regulatory submission with several agents. Results from four 1-year trials, which included a total of 3052 patients, are now available, demonstrating promising findings that target the unmet needs of patients with T1D with a novel insulin-independent adjunct therapy. However, these positive effects must be balanced against the risks associated with this class of drugs. Specifically, current T1D studies have shown an increased risk of diabetic ketoacidosis (DKA), which, in some cases, presented with only slightly elevated glucose levels. While this complication may be clinically manageable once detected, the metabolic shift towards ketogenesis associated with this class of agents mandates appropriate patient selection. Currently, there are no validated tools for DKA risk assessment. Although the experience gained in studies and off-label use provides some indication for appropriate patient selection, this would have to be evaluated closely in the event that these drugs would receive regulatory approval. Risk mitigation includes training in ketone measurement (preferably as blood β-hydroxybutyrate testing), teaching the concept of euglycemic DKA, and providing a clear treatment algorithm to avoid progression of ketosis to full-blown DKA. Because similar unmet needs also exist in pediatric population studies, risk mitigation in youth should be initiated as well to allow an evidence-based, risk-benefit assessment in this vulnerable population.
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Hypertension Treatment in Diabetes: Focus on Heart Failure Prevention.
Bensimhon, HF, Cavender, MA
Heart failure clinics. 2019;(4):551-563
Abstract
Diabetes is strongly associated with development of cardiovascular disease and poor cardiovascular outcomes. Management of hypertension reduces cardiovascular outcomes among patients with diabetes. Many studies have examined the benefits of various classes of antihypertensives among patients with diabetes. Based on these, the American Diabetes Association has advised that all patients (particularly those with microalbuminuria) be treated first with an angiotensin-converting enzyme inhibitor or an aldosterone receptor blocker followed by a calcium channel blocker or diuretic. Recently, sodium glucose transporter 2 inhibitors have been identified for their benefit in blood pressure control and cardiovascular risk reduction in patients with diabetes.