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SGLT2 Inhibitors and Cardiovascular Outcomes: Current Perspectives and Future Potentials.
Jia, X, Mehta, PB, Ye, Y, Alam, M, Birnbaum, Y, Bajaj, M
Current diabetes reports. 2018;(9):63
Abstract
PURPOSE OF REVIEW Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to exert benefit on cardiac outcomes. In this review, we provide updates on available clinical data, studies on potential mechanisms for the CV effects, as well as discuss potential clinical implications of these new findings. RECENT FINDINGS Since the publications of the EMPA-REG and CANVAS trials, large multi-national cohort studies have further shown the cardioprotective effects of SGLT2i. Moreover, new studies examining SGLT2i action on sodium-hydrogen exchanger proteins in both the heart and the kidney, on myocardial energetics and impact on inflammation and atherosclerosis continue to shed light on the multitude of pleotropic effects of these agents. Though more data is needed to substantiate the safety and efficacy, SGLT2i should be considered as a valuable therapy to help reduce CV risk in patients with diabetes. Ultimately, SGLT2i may have utility in preventing progression to diabetes or providing CV protection in patients who do not have diabetes.
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2.
Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors.
Scheen, AJ
Circulation research. 2018;(10):1439-1459
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Abstract
Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.
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Randomized trial of one-hour sodium bicarbonate vs standard periprocedural saline hydration in chronic kidney disease patients undergoing cardiovascular contrast procedures.
Kooiman, J, de Vries, JPM, Van der Heyden, J, Sijpkens, YWJ, van Dijkman, PRM, Wever, JJ, van Overhagen, H, Vahl, AC, Aarts, N, Verberk-Jonkers, IJAM, et al
PloS one. 2018;(2):e0189372
Abstract
BACKGROUND Guidelines advise periprocedural saline hydration for prevention of contrast induced-acute kidney injury (CI-AKI). We analysed whether 1-hour sodium bicarbonate hydration administered solely prior to intra-arterial contrast exposure is non-inferior to standard periprocedural saline hydration in chronic kidney disease (CKD) patients undergoing elective cardiovascular diagnostic or interventional contrast procedures. METHODS We performed an open-label multicentre non-inferiority trial between 2011-2014. Patients were randomized to 1 hour pre-procedure sodium bicarbonate hydration (250 ml 1.4%, N = 168) or 4-12 hours saline hydration (1000 ml 0.9%, N = 165) prior to and following contrast administration (2000 ml of saline total). Primary outcome was the relative serum creatinine increase (%) 48-96 hours post contrast exposure. Secondary outcomes were: incidence of CI-AKI (serum creatinine increase>25% or >44μmol/L), recovery of renal function, the need for dialysis, and hospital costs within two months follow-up. RESULTS Mean relative creatinine increase was 3.1% (95%CI 0.9 to 5.2%) in the bicarbonate and 1.1% (95%CI -1.2 to 3.5%) in the saline arm, mean difference 1.9% (95%CI -1.2 to 5.1%, p-non-inferiority <0.001). CI-AKI occurred in 11 (6.7%) patients randomized to sodium bicarbonate and 12 (7.5%) to saline (p = 0.79). Renal function did not fully recover in 40.0% and 44.4% of CI-AKI patients, respectively (p = 0.84). No patient required dialysis. Mean costs for preventive hydration and clinical preparation for the contrast procedure were $1158 for sodium bicarbonate vs. $1561 for saline (p < 0.001). CONCLUSION Short hydration with sodium bicarbonate prior to elective cardiovascular diagnostic or therapeutic contrast procedures is non-inferior to standard periprocedural saline hydration in CKD patients with respect to renal safety and results in considerable healthcare savings. TRIAL REGISTRATION Netherlands Trial Register (http://www.trialregister.nl/trialreg/index.asp), Nr NTR2699.
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Cardiovascular and Renal Outcomes of Newer Anti-Diabetic Medications in High-Risk Patients.
Lawrence, L, Menon, V, Kashyap, S
Current cardiology reports. 2018;(8):65
Abstract
PURPOSE OF REVIEW We review the cardiovascular and renal outcomes and safety of newer anti-diabetic medications in high-risk patients. We examine the outcomes of the IRIS, EMPA-REG OUTCOME, CANVAS, LEADER, SAVOR-TIMI 53, and EXAMINE trials demonstrating the cardiovascular and renal benefits of thiazolidinediones, SGLT2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors. RECENT FINDINGS Diabetes mellitus is a leading risk factor for cardiovascular disease with rising prevalence and disease burden. The microvascular and macrovascular complications of diabetes are well-recognized and include increased risk of cardiovascular disease, myocardial infarction, and stroke. Newer diabetes medications have demonstrated significant cerebrovascular, cardiovascular, renal, and mortality benefits in high risk patients with diabetes. In addition to their glucose-lowering effects, the thiazolidinedione pioglitazone, SGLT2 inhibitors, GLP-1 agonist, and DPP-4 inhibitors have demonstrated significant cerebrovascular, cardiovascular, renal, and mortality effects. The outcomes and safety data of newer diabetes medications from recent trials demonstrate cardiovascular and mortality effects with significant implications for clinical practice.
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Dietary fats and cardiovascular health: a summary of the scientific evidence and current debate.
Fattore, E, Massa, E
International journal of food sciences and nutrition. 2018;(8):916-927
Abstract
This narrative review summarises the main studies of the role of the different fatty acids in coronary heart disease (CHD) and cardiovascular disease (CVD) risk and the current scientific debate on dietary recommendations. Reduction and substitution of the saturated fatty acids (SFAs) with the polyunsaturated fatty acids (PUFAs) are still the main dietary recommendation to prevent CHD and CVD. In the last few years, however, the strength of the scientific evidence underlying this dietary advice has been questioned. Recent investigations reappraise the previously declared deleterious role of the SFAs and reduce the positive role of PUFAs, mainly the omega-6, whereas the role of monounsaturated fatty acids (MUFAs) remains unclear. In contrast, the negative effects of trans fatty acids (TFAs) seem stronger than previously thought. Finally, criticisms have emerged from a dietary recommendation approach focussed on individual components rather than on wide food items and eating habits.
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The effect of antidiabetic medications on the cardiovascular system: a critical appraisal of current data.
Anagnostis, P, Siolos, P, Christou, K, Gkekas, NK, Kosmidou, N, Athyros, VG, Karagiannis, A
Hormones (Athens, Greece). 2018;(1):83-95
Abstract
Both type 1 and type 2 diabetes are associated with increased risk for cardiovascular disease (CVD) events. This risk seems to be reduced by achievement of euglycemia. However, after the withdrawal of rosiglitazone from the market, the question arose as to whether this risk concerns simply a matter of euglycemia or the distinct role played by each antidiabetic drug with respect to its effect on CVD risk. To address this issue, many studies have been published during the last decade involving old and new antidiabetic agents, which however yielded contradictory results. Briefly, metformin is still considered safe and confers a beneficial effect on CVD risk. Conflicting data exist as concerns sulfonylureas, although the second and third generation representatives are regarded as relatively safe. Pioglitazone use seems to be associated with a reduction in CVD risk, whereas the dipeptidyl-dipeptidase-4 inhibitors (DPP-4i), lixisenatide and exenatide-LAR [from the category of glucagon-like-peptide-1 receptor (GLP-1R) agonists], confer a neutral effect. Two other GLP-1R agonists, liraglutide and semaglutide, as well as the sodium-glucose transporter-2 (SGLT2)-inhibitors, empagliflozin and cangliflozin, have shown an additional effect on CVD risk reduction, although their safety is in doubt. Insulin analogues and newer long-acting compounds are also safe for the cadiovascular system. The aim of this narrative review is to present and critically analyse the current data for each antidiabetic drug category with regard to their effect on CVD risk.
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Increasing vegetable intake to obtain the health promoting and ergogenic effects of dietary nitrate.
Van der Avoort, CMT, Van Loon, LJC, Hopman, MTE, Verdijk, LB
European journal of clinical nutrition. 2018;(11):1485-1489
Abstract
Increased consumption of dietary nitrate increases plasma nitrate and nitrite concentrations, and has been shown to elicit cardio-protective effects and improve exercise performance. Nitrate consumption in the habitual diet is mainly dependent on nitrate-rich vegetables, such as green leafy and root vegetables, with total vegetable consumption accounting for approximately 50-85% of our daily nitrate intake. Whereas 'supplementation' with dietary nitrate in research studies has mainly been accomplished through the use of (concentrated) nitrate-rich beetroot juice, dietary strategies focusing on increased intake of nitrate-rich vegetables may represent a similarly effective alternative for increasing dietary nitrate intake and, as such, obtaining the associated cardiovascular health and ergogenic benefits.
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Cardiovascular Outcomes Trials in Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors' Expert Forum.
Cefalu, WT, Kaul, S, Gerstein, HC, Holman, RR, Zinman, B, Skyler, JS, Green, JB, Buse, JB, Inzucchi, SE, Leiter, LA, et al
Diabetes care. 2018;(1):14-31
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Abstract
In December 2008, the U.S. Food and Drug Administration issued guidance to the pharmaceutical industry setting new expectations for the development of antidiabetes drugs for type 2 diabetes. This guidance expanded the scope and cost of research necessary for approval of such drugs by mandating long-term cardiovascular outcomes trials (CVOTs) for safety. Since 2008, 9 CVOTs have been reported, 13 are under way, and 4 have been terminated. Reassuringly, each of the completed trials demonstrated the noninferiority of their respective drugs to placebo for their primary cardiovascular (CV) composite end point. Notably, four additionally provided evidence of CV benefit in the form of significant decreases in the primary CV composite end point, two suggested reductions in CV death, and three suggested reductions in all-cause mortality. Although these trials have yielded much valuable information, whether that information justifies the investment of time and resources is controversial. In June 2016, a Diabetes Care Editors' Expert Forum convened to review the processes and challenges of CVOTs, discuss the benefits and limitations of their current designs, and weigh the merits of modifications that might improve the efficiency and clinical value of future trials. Discussion and analysis continued with the CVOT trial results released in June 2017 at the American Diabetes Association's Scientific Sessions and in September 2017 at the European Association for the Study of Diabetes scientific meeting. This article summarizes the discussion and findings to date.
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The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes.
Groti, K, Žuran, I, Antonič, B, Foršnarič, L, Pfeifer, M
The aging male : the official journal of the International Society for the Study of the Aging Male. 2018;(3):158-169
Abstract
OBJECTIVE This study set out to assess effects of testosterone replacement therapy (TRT) on parameters of metabolic syndrome and vascular function in obese hypogonadal males with type 2 diabetes mellitus (DM2). STUDY DESIGN Fifty-five obese hypogonadal diabetic males on oral hypoglycemic treatment were enrolled into this one-year, double-blind, randomized, placebo-controlled clinical study. Group T (n = 28) was treated with testosterone undecanoate (1000 mg i.m. every 10 weeks) while group P (n = 27) received placebo. METHODS Anthropometrical and vascular measurements - flow-mediated dilatation (FMD) and intima media thickness (IMT) - biochemical and hormonal blood sample analyses were performed at the start of the study and after one year. Derived parameters (BMI, HOMA-IR, calculated free testosterone (cFT) and bioavailable testosterone (BT)) were calculated. RESULTS TRT resulted in reduction of HOMA-IR by 4.64 ± 4.25 (p < .001), HbA1c by 0.94 ± 0.88% points (p < .001), and an increase in FMD by 2.40 ± 4.16% points (p = .005). CONCLUSION TRT normalized serum testosterone levels, improved glycemic control and endothelial function while exerting no ill effects on the study population.
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Cardiovascular benefits of combined interval training and post-exercise nutrition in type 2 diabetes.
Francois, ME, Pistawka, KJ, Halperin, FA, Little, JP
Journal of diabetes and its complications. 2018;(2):226-233
Abstract
AIM: The purpose of this study was to examine whether the combination of high-intensity interval training (HIIT) and post-exercise protein supplementation would improve cardiovascular outcomes in individuals with T2D. METHODS In a double-blind controlled trial, fifty-three adults with T2D (free of CVD and not on exogenous insulin) were randomized to 12weeks of cardio and resistance-based HIIT (4-10×1min at 90% maximal heart rate) with post-exercise milk, milk-protein, or placebo supplementation, thrice weekly. Before and after, carotid and femoral artery intima media thickness (IMT) and femoral flow profiles were assessed using high-resolution ultrasound. Central and peripheral arterial stiffness were assessed by pulse wave velocity (PWV), and resting and maximal heart rate rates were measured. RESULTS After 12weeks of HIIT femoral IMT (Pre: 0.84±0.21mm vs. Post: 0.81±0.16mm, p=0.03), carotid-femoral PWV (Pre: 10.1±3.2m/s vs. Post: 8.6±1.8m/s, p<0.01) and resting heart rate (Pre: 70.4±10.8bpm vs. Post: 67.8±8.6 bpm, p=0.01) were all significantly lower. There were no differences between nutrition groups (all significant main effects of time) for all outcomes. CONCLUSION HIIT reduces femoral IMT, arterial stiffness and resting heart rate in individuals with T2D. The addition of post-exercise milk or protein to HIIT did not have additive effects for improving cardiovascular outcomes in the present study. Taken together, HIIT alone may be an effective means to reduce the burden of cardiovascular complications in T2D.