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      SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials

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          Abstract

          Given the multi-faceted pathogenesis of atherosclerosis in type 2 diabetes mellitus (T2DM), it is likely that interventions to mitigate this risk must address cardiovascular (CV) risk factors beyond glucose itself. Sodium glucose cotransporter-2 (SGLT-2) inhibitors are newer antihyperglycaemic agents with apparent multiple effects. Inherent in their mode of action to decrease glucose reabsorption by the kidneys by increasing urinary glucose excretion, these agents improve glycaemic control independent of insulin secretion with a low risk of hypoglycaemia. In this review, we outline those CV risk factors that this class appears to influence and provide the design features and trial characteristics of six ongoing outcome trials involving more than 41,000 individuals with T2DM. Those risk factors beyond glucose that can potentially be modulated positively with SGLT-2 inhibitors include blood pressure, weight, visceral adiposity, hyperinsulinaemia, arterial stiffness, albuminuria, circulating uric acid levels and oxidative stress. On the other hand, small increases in low-density lipoprotein (LDL)-cholesterol levels have also been observed for the class, which theoretically might offset some of these benefits. The potential translational impact of these effects is being tested with outcome trials, also reviewed in this article, powered to assess both macrovascular as well as certain microvascular outcomes in T2DM. These are expected to begin to report in late 2015.

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          Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin.

          Dapagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion, and weight loss is a consistent associated finding. Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components. This was a 24-wk, international, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries. Included were 182 patients with T2DM (mean values: women 63.3 and men 58.6 yr of age; hemoglobin A1c 7.17%, body mass index 31.9 kg/m2, and body weight 91.5 kg) inadequately controlled on metformin. Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk. Primary endpoint was total body weight (TBW) change from baseline at wk 24. Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass (FM) changes from baseline at wk 24, and patient proportion achieving body weight reduction of at least 5% at wk 24. In a subset of patients, magnetic resonance assessment of visceral adipose tissue (VAT) and sc adipose tissue (SAT) volume and hepatic lipid content were also evaluated. At wk 24, placebo-corrected changes with dapagliflozin were as follows: TBW, -2.08 kg [95% confidence interval (CI)=-2.84 to -1.31; P<0.0001]; waist circumference, -1.52 cm (95% CI=-2.74 to -0.31; P=0.0143); FM, -1.48 kg (95% CI=-2.22 to -0.74; P=0.0001); proportion of patients achieving weight reduction of at least 5%, +26.2% (95% CI=15.5 to 36.7; P<0.0001); VAT, -258.4 cm3 (95% CI=-448.1 to -68.6; nominal P=0.0084); SAT, -184.9 cm3 (95% CI=-359.7 to -10.1; nominal P=0.0385). In the dapagliflozin vs. placebo groups, respectively, serious adverse events were reported in 6.6 vs. 1.1%; events suggestive of vulvovaginitis, balanitis, and related genital infection in 3.3 vs. 0%; and lower urinary tract infections in 6.6 vs. 2.2%. Dapagliflozin reduces TBW, predominantly by reducing FM, VAT and SAT in T2DM inadequately controlled with metformin.
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            Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis.

            Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-C(hi) monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials

              Diabetes is defined by its association with hyperglycemia-specific microvascular complications; however, it also imparts a two- to fourfold risk of cardiovascular disease (CVD). Although microvascular complications can lead to significant morbidity and premature mortality, by far the greatest cause of death in people with diabetes is CVD. Results from randomized controlled trials have demonstrated conclusively that the risk of microvascular complications can be reduced by intensive glycemic control in patients with type 1 (1,2) and type 2 diabetes (3–5). In the Diabetes Control and Complications Trial (DCCT), there was an ∼60% reduction in development or progression of diabetic retinopathy, nephropathy, and neuropathy between the intensively treated group (goal A1C 9%) to good control (e.g., A1C <7%). All three trials were carried out in participants with established diabetes (mean duration 8–11 years) and either known CVD or multiple risk factors, suggesting the presence of established atherosclerosis. Subset analyses of the three trials suggested a significant benefit of intensive glycemic control on CVD in participants with shorter duration of diabetes, lower A1C at entry, and/or or absence of known CVD. The finding of the DCCT follow-up study, that intensive glycemic control initiated in relatively young participants free of CVD risk factors was associated with a 57% reduction in major CVD outcomes, supports the above hypothesis. Of note, the benefit on CVD in the DCCT-EDIC (Epidemiology of Diabetes Interventions and Complications) required 9 years of follow-up beyond the end of the DCCT to become statistically significant. A recent report (13) of 10 years of follow-up of the UKPDS cohort describes, for the participants originally randomized to intensive glycemic control compared with those randomized to conventional glycemic control, long-term reductions in MI (15% with sulfonylurea or insulin as initial pharmacotherapy and 33% with metformin as initial pharmacotherapy, both statistically significant) and in all-cause mortality (13 and 27%, respectively, both statistically significant). These findings support the hypothesis that glycemic control early in the course of type 2 diabetes may have CVD benefit. As is the case with microvascular complications, it may be that glycemic control plays a greater role before macrovascular disease is well developed and a minimal or no role when it is advanced. People with type 1 diabetes, in whom insulin resistance does not predominate, tend to have lower rates of coexisting obesity, hypertension, and dyslipidemia than those with type 2 diabetes and yet are also at high lifetime risk of CVD (14). It is possible that CVD is more strongly glycemia mediated in type 1 diabetes and that intervening on glycemia would ameliorate CVD to a greater extent in type 1 than in type 2 diabetes. Finally, the inability of ACCORD, ADVANCE, and VADT to demonstrate significant reduction of CVD with intensive glycemic control could also suggest that current strategies for treating hyperglycemia in patients with more advanced type 2 diabetes may have counter-balancing consequences for CVD (such as hypoglycemia, weight gain, or other metabolic changes). Results of long-term CVD outcome trials utilizing specific antihyperglycemic drugs, intensive lifestyle therapy (such as the Look AHEAD [Action for Health in Diabetes] study), bariatric surgery, or other emerging therapies may shed light on this issue. 4. What are the implications of these findings for clinical care? The benefits of intensive glycemic control on microvascular and neuropathic complications are well established for both type 1 and type 2 diabetes. The ADVANCE trial has added to that evidence base by demonstrating a significant reduction in the risk of new or worsening albuminuria when median A1C was lowered to 6.3% compared with standard glycemic control achieving an A1C of 7.0%. The lack of significant reduction in CVD events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1C <7.0% and thereby discount the benefit of good control on serious and debilitating microvascular complications. The ADA's Standards of Medical Care in Diabetes (6) and the AHA and ADA's scientific statement on prevention (15) advocate controlling nonglycemic risk factors (through blood pressure control, lipid lowering with statin therapy, aspirin therapy, and lifestyle modifications) as the primary strategies for reducing the burden of CVD in people with diabetes. The lower-than-predicted CVD rates in ACCORD, ADVANCE, and VADT, as well as the recent long-term follow-up of the Steno-2 multiple risk factor intervention (16), provide strong confirmation of the concept that comprehensive care for diabetes involves treatment of all vascular risk factors—not just hyperglycemia. The evidence for a cardiovascular benefit of intensive glycemic control remains strongest for those with type 1 diabetes. However, subset analyses of ACCORD, ADVANCE, and VADT suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap cardiovascular benefit from intensive glycemic control. Conversely, it is possible that potential risks of intensive glycemic control may outweigh its benefits in other patients, such as those with a very long duration of diabetes, known history of severe hypoglycemia, advanced atherosclerosis, and advanced age/frailty. Certainly, providers should be vigilant in preventing severe hypoglycemia in patients with advanced disease and should not aggressively attempt to achieve near-normal A1C levels in patients in whom such a target cannot be reasonably easily and safely achieved. The evidence obtained from ACCORD, ADVANCE, and VADT does not suggest the need for major changes in glycemic control targets but, rather, additional clarification of the language that has consistently stressed individualization: Microvascular disease: Lowering A1C to below or around 7% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. Therefore, the A1C goal for nonpregnant adults in general is <7%. ADA, A-level recommendation; ACC/AHA, class I recommendation (level of evidence A). Macrovascular disease: In type 1 and type 2 diabetes, randomized controlled trials of intensive versus standard glycemic control have not shown a significant reduction in CVD outcomes during the randomized portion of the trials. However, long-term follow-up of the DCCT and UKPDS cohorts suggests that treatment to A1C targets below or around 7% in the years soon after the diagnosis of diabetes is associated with long-term reduction in risk of macrovascular disease. Until more evidence becomes available, the general goal of <7% appears reasonable. ADA, B-level recommendation; ACC/AHA, class IIb recommendation (level of evidence A). For some patients, individualized glycemic targets other than the above general goal may be appropriate: Subgroup analyses of clinical trials such as the DCCT and UKPDS and the microvascular evidence from the ADVANCE trial suggest a small but incremental benefit in microvascular outcomes with A1C values closer to normal. Therefore, for selected individual patients, providers might reasonably suggest even lower A1C goals than the general goal of <7% if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Such patients might include those with short duration of diabetes, long life expectancy, and no significant cardiovascular disease. ADA, B-level recommendation; ACC/AHA, class IIa recommendation (level of evidence C). Conversely, less stringent A1C goals than the general goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions or those with long-standing diabetes in whom the general goal is difficult to attain despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. ADA, C-level recommendation; ACC/AHA, class IIa recommendation (level of evidence C). For primary and secondary CVD risk reduction in patients with diabetes, providers should continue to follow the evidence-based recommendations for blood pressure treatment, including lipid-lowering with statins, aspirin prophylaxis, smoking cessation, and healthy lifestyle behaviors delineated in the ADA Standards of Medical Care in Diabetes (6) and the AHA/ADA guidelines for primary CVD prevention (15).
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                Author and article information

                Journal
                Diab Vasc Dis Res
                Diab Vasc Dis Res
                DVR
                spdvr
                Diabetes & Vascular Disease Research
                SAGE Publications (Sage UK: London, England )
                1479-1641
                1752-8984
                March 2015
                March 2015
                : 12
                : 2
                : 90-100
                Affiliations
                [1 ]Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA
                [2 ]Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
                [3 ]Division of Nephrology, University of Würzburg, Würzburg, Germany
                [4 ]Department of Cardiology and LTTA Centre, University Hospital of Ferrara, Ferrara, Italy
                [5 ]Maria Cecilia Hospital, GVM Care & Research, E.S: Health Science Foundation, Cotignola, Italy
                [6 ]St Michael’s Hospital, University of Toronto, Toronto, ON, Canada
                [7 ]Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
                [8 ]Boehringer Ingelheim España S.A, Barcelona, Spain
                [9 ]Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
                [10 ]Boehringer Ingelheim Norway K.S, Asker, Norway
                Author notes
                [*]Odd Erik Johansen, Boehringer Ingelheim Norway K.S, Drengsrudbekken 8, 1373 Asker, Norway. Email: Odd_erik.johansen@ 123456boehringer-ingelheim.com
                Article
                10.1177_1479164114559852
                10.1177/1479164114559852
                4361459
                25589482
                a18dbc03-15b9-4aca-a35d-8260ae699848
                © The Author(s) 2015

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License ( http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( http://www.uk.sagepub.com/aboutus/openaccess.htm).

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                Feature Articles

                Endocrinology & Diabetes
                type 2 diabetes,cardiovascular complications,review,macrovascular,sodium glucose cotransporter-2 inhibitors

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