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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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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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Protein Tyrosine Phosphatase 1B Inhibitors: A Novel Therapeutic Strategy for the Management of type 2 Diabetes Mellitus.
Prabhakar, PK, Sivakumar, PM
Current pharmaceutical design. 2019;(23):2526-2539
Abstract
Diabetes is one of the most common endocrine non-communicable metabolic disorders which is mainly caused either due to insufficient insulin or inefficient insulin or both together and is characterized by hyperglycemia. Diabetes emerged as a serious health issue in the industrialized and developing country especially in the Asian pacific region. Out of the two major categories of diabetes mellitus, type 2 diabetes is more prevalent, almost 90 to 95% cases, and the main cause of this is insulin resistance. The main cause of the progression of type 2 diabetes mellitus has been found to be insulin resistance. The type 2 diabetes mellitus may be managed by the change in lifestyle, physical activities, dietary modifications and medications. The major currently available management strategies are sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors, and glucagon-like peptide-1 (GLP-1) agonist. Binding of insulin on the extracellular unit of insulin receptor sparks tyrosine kinase of the insulin receptor which induces autophosphorylation. The phosphorylation of the tyrosine is regulated by insulin and leptin molecules. Protein tyrosine phosphatase-1B (PTP1B) works as a negative governor for the insulin signalling pathways, as it dephosphorylates the tyrosine of the insulin receptor and suppresses the insulin signalling cascade. The compounds or molecules which inhibit the negative regulation of PTP1B can have an inductive effect on the insulin pathway and finally help in the management of diabetes mellitus. PTP1B could be an emerging therapeutic strategy for diabetes management. There are a number of clinical and basic research results which suggest that induced expression of PTP1B reduces insulin resistance. In this review, we briefly elaborate and explain the place of PTP1B and its significance in diabetes as well as a recent development in the PTP1B inhibitors as an antidiabetic therapy.
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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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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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6.
Drugs to Control Diabetes During Pregnancy.
Feghali, MN, Umans, JG, Catalano, PM
Clinics in perinatology. 2019;(2):257-272
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Abstract
Diabetes is a common complication of pregnancy associated with both short- and long-term adverse maternal and offspring effects. All types of diabetes in pregnancy are increasing in prevalence. Treatment of diabetes in pregnancy, targeting glycemic control, improves both maternal and offspring outcomes, albeit imperfectly for many women. Pharmacologic treatment recommendations differ between pregestational and gestational diabetes. Improved treatment of diabetes in pregnancy will need to consider maternal disease heterogeneity and comorbidities as well as long-term offspring outcomes. In this review, the authors summarize recent clinical studies to highlight established pharmacologic treatments for diabetes in pregnancy and provide suggestions for further research.
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Metabolic Effects of Metformin in Humans.
Adeva-Andany, MM, Rañal-Muíño, E, Fernández-Fernández, C, Pazos-García, C, Vila-Altesor, M
Current diabetes reviews. 2019;(4):328-339
Abstract
BACKGROUND Both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and postprandial hyperglycemia in patients with diabetes. INTRODUCTION Metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive. RESULTS Patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from "de novo" synthesized glucose) owing to insulin deficiency and glucagoninduced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves β-cell function in patients with type 2 diabetes. CONCLUSION Several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown.
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Should metformin still be the first-line of treatment in type 2 diabetes mellitus? A comprehensive review and suggested algorithm.
Bin Hussain, AK, Abdelgadir, E, Rashid, F, Al Haj, A, Thadani, P, Bashier, AMK
Diabetes & metabolic syndrome. 2019;(3):1935-1942
Abstract
For more than a century, the high occurrences of coronary and peripheral artery diseases in diabetes mellitus patients has been well recognised; despite that, the ability to improve CV event rates by optimizing glycaemic control has remained elusive. Nevertheless, the last decade has seen several cardiovascular outcome clinical trials (CVOTs) of many antihyperglycemic agents that reported promising results for cardiovascular and renal outcomes. This leads to a hot debate on the ideal drug choice for first-line treatment in T2DM. The purpose of this paper is to review the evidence supporting the use of metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors and incretin-based therapies for the management of individuals with T2DM and, discuss the rationale for selection.
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Closed-loop management of inpatient hyperglycaemia.
Boughton, CK, Hovorka, R
British journal of hospital medicine (London, England : 2005). 2019;(11):665-669
Abstract
The prevalence of diabetes in the inpatient setting is increasing, and suboptimal glucose control in hospital is associated with increased morbidity and mortality. Attaining the recommended glucose levels is challenging with standard insulin therapy. Hypoglycaemia and hyperglycaemia are common and diabetes management in hospital can be a considerable workload burden for health-care professionals. Fully automated insulin delivery (closed-loop) has been shown to be safe, and achieves superior glucose control than standard insulin therapy in the hospital, including in those patients receiving haemodialysis and enteral or parenteral nutrition where glucose control can be particularly challenging. Evidence that the improved glucose control achieved using closed-loop systems can translate into improved clinical outcomes for patients is key to support widespread adoption of this technology. The closed-loop approach has the potential to provide a paradigm shift in the management of inpatient diabetes, particularly in the most challenging inpatient populations, and may reduce staff work burden and the health-care costs associated with inpatient diabetes.
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Effects of glucose-lowering on outcome incidence in diabetes mellitus and the modulating role of blood pressure and other clinical variables: overview, meta-analysis of randomized trials.
Thomopoulos, C, Bazoukis, G, Ilias, I, Tsioufis, C, Makris, T
Journal of hypertension. 2019;(10):1939-1949
Abstract
BACKGROUND Randomized controlled trials (RCTs) of antidiabetic agents started in the 1960s. Updated meta-analyses of RCTs investigating glucose-lowering in patients with type 2 diabetes mellitus are lacking. Also, no previous attempt was made to evaluate the role of blood pressure (BP) reduction and LDL cholesterol (LDL-C) change on outcome incidence following glucose-lowering. OBJECTIVES Three main clinical questions were investigated: the extent of different outcome reductions by glucose-lowering in patients with diabetes, the proportionality of outcome reductions to glycated hemoglobin (HBA1c) reductions and whether ongoing BP and LDL-C difference in RCTs can change glucose-lowering outcome effects. METHODS PubMed between 1960 and January 2019 (any language), Cochrane Collaboration Library and previous overviews were used as data sources to identify and select all RCTs comparing the glucose-lowering drugs with placebo or less intense treatment (intentional glucose-lowering RCTs); comparing glucose-lowering drugs with placebo without glucose-lowering intention, but HBA1c difference (nonintentional glucose-lowering RCTs); enrolling type 2 diabetes mellitus patients; and reporting ongoing SBP and DBP difference. We excluded RCTs of acute care, glucose intolerance, type 1 diabetes, multiple interventions applied and glucose-lowering by lifestyle or other interventions. Risk ratios and 95% confidence intervals, of seven fatal and nonfatal outcomes and of treatment-related discontinuations were calculated (random-effects model) before and after adjustment for the ongoing BP difference, while LDL-C difference was also considered. The relationships of different outcome reductions to HBA1c reductions were investigated by meta-regressions. RESULTS A total of 25 RCTs (174 235 individuals, follow-up 3.5 years) were eligible, and the resulted ongoing SBP/DBP difference was -1.4/-0.4 mmHg. Both before and after adjustment for BP difference, glucose-lowering reduced CHD (coronary heart disease) and both composites of major cardiovascular events were reduced by a mean of 8 and 5%, respectively, while before BP-adjustment the risk of treatment-related discontinuations was increased by 26% and the risk of stroke and all-cause death was reduced by 7 and 6%, respectively. Logarithmic risk ratios were related to HBA1c reductions for the composite of CHD and stroke and for treatment-related discontinuations. Glucose-lowering had no differential outcome effects, before and after estimate adjustment for the ongoing BP difference, at different HBA1c thresholds and targets, as well as when both baseline BP and achieved BP, overall cardiovascular risk and diabetes mellitus duration were considered as dichotomous effect modifiers. Although heart failure incidence was found increased by 15% in the early glucose-lowering RCTs, this effect faded away in contemporary RCTs. LDL-C change was overall trivial and did not change glucose-lowering outcome effects. CONCLUSION Meta-analyses of all glucose-lowering RCTs involving patients with diabetes provide precise estimates of benefits for CHD and major cardiovascular events after consideration of the resulting ongoing BP difference. No benefit or harm on mortality, heart failure and stroke were noticed, while discontinuations related to adverse events because of treatment were increased following glucose-lowering. The extent of glucose-lowering is proportionally related to changes of CHD and stroke composite, and treatment-related discontinuations.