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

Inzucchi, Silvio E.; Zinman, Bernard; Wanner, Christoph; Ferrari, Roberto; Fitchett, David; Hantel, Stefan; Espadero, Rosa-Maria; Woerle, HJ; Broedl, Uli C.; Johansen, Odd Erik

doi:10.1177/1479164114559852

Cited by 366 publications

(336 citation statements)

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“…These compounds have a distinct mechanism of action in the renal proximal tubule, by blocking the reabsorption of glucose. Besides promoting glucosuria, they can exert pleiotropic effects, which could reduce several CV risk factors and potentially CV complications [24,25]. Among these pleiotropic effects, a reduction in arterial BP has been consistently reported with all SGLT2 inhibitors [26][27][28][29].…”

Section: Introductionmentioning

confidence: 99%

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Scheen

2016

Diabetes Research and Clinical Practice

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Please cite this article as: A.J. Scheen, Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME, Diabetes Research and Clinical Practice (2016), doi: http://dx.doi.org/10.1016/j.diabres. 2016.09.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. SummaryEmpagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has shown a remarkable reduction in cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D) and antecedents of cardiovascular disease in the EMPA-REG OUTCOME trial. This effect has been attributed to a hemodynamic rather than a metabolic effect, partly due to the osmotic/diuretic effect of empagliflozin and to the reduction in arterial blood pressure. The present review will : 1) summarize the results of specific studies having tested the blood pressure lowering effects of SGLT2 inhibitors; 2) describe the results of meta-analyses of trials having evaluated the effects on mortality and cardiovascular outcomes of lowering blood pressure in patients with T2D, with a special focus on baseline and target blood pressures; 3) compare the cardiovascular outcome results in EMPA-REG OUTCOME versus other major trials with antihypertensive agents in patients with T2D; and 4) evaluate post-hoc analyses from EMPA-REG OUTCOME, especially subgroups of patients of special interest regarding the blood pressure lowering hypothesis. Although BP reduction associated to empagliflozin therapy may partly contribute to the benefits reported in EMPA-REG OUTCOME, other mechanisms most probably play a greater role in the overall CV protection and reduction in mortality observed in this trial.

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Section: Introductionmentioning

confidence: 99%

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Scheen

2016

Diabetes Research and Clinical Practice

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“…Reductions in BP and arterial stiffness are two of the effects of SGLT2 inhibitors that might ameliorate CV risk and heart failure in patients with T2DM [44]. The effects of empagliflozin on CV and microvascular outcomes are being investigated in the EMPA-REG OUTCOME ® trial Baseline data are mean ± standard error (s.e.…”

Section: Placebo Empagliflozinmentioning

confidence: 99%

Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes

Chilton

Tikkanen

Cannon

et al. 2015

Diabetes Obesity Metabolism

432

283

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Aims:To determine the effects of empagliflozin on blood pressure (BP) and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes mellitus (T2DM). Methods:We conducted a post hoc analysis of data from a phase III trial in patients with T2DM and hypertension receiving 12 weeks' empagliflozin and four phase III trials in patients with T2DM receiving 24 weeks' empagliflozin (cohort 1, n = 823; cohort 2, n = 2477). BP was measured using 24-h BP monitoring (cohort 1) or seated office measurements (cohort 2).Results: Empagliflozin reduced systolic BP (SBP) and diastolic BP in both cohorts (p < 0.001 vs placebo), without increasing heart rate. Empagliflozin reduced pulse pressure (PP; adjusted mean difference vs placebo cohort 1: −2.3 mmHg; cohort 2: −2.3 mmHg), mean arterial pressure (MAP; cohort 1, −2.3 mmHg; cohort 2, −2.1 mmHg) and double product (cohort 1, −385 mmHg × bpm; cohort 2, −369 mmHg × bpm) all p < 0.001 vs placebo. There was a trend towards a reduction in the ambulatory arterial stiffness index (AASI) with empagliflozin in cohort 1 (p = 0.059 vs placebo). AASI was not measured in cohort 2. Subgroup analyses showed that there were greater reductions in PP with increasing baseline SBP in cohort 1 (p = 0.092). In cohort 2, greater reductions in MAP were achieved in patients with higher baseline SBP (p = 0.027) and greater reductions in PP were observed in older patients (p = 0.011). Conclusions IntroductionCardiovascular (CV) disease is the major cause of morbidity and mortality in patients with type 2 diabetes (T2DM) [1]. The risk of CV disease in adults with diabetes is double that in adults without diabetes, and diabetes is estimated to account for 10-12% of all vascular deaths [2]. Patients with T2DM often have numerous CV risk factors and a multifactorial approach to addressing CV risk, including controlling glycaemia, blood pressure (BP) and body weight, is recommended in these patients [1,3].The metabolic abnormalities that are characteristic of diabetes, such as hyperglycaemia, excess free fatty acids and insulin resistance, can lead to suppression of nitric oxide production and activation of the renin-angiotensin system, leading to oxidative stress, endothelial dysfunction and activation of the receptor for advanced glycation end products (RAGE) [4][5][6]. These may contribute to hypertension [7] or to increased arterial stiffness related to vascular calcification or accumulation ofCorrespondence to: Odd Erik Johansen, Boehringer Ingelheim Norway KS, Asker, Norway. E-mail: odd_erik.johansen@boehringer-ingelheim.com This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.collagen [8,9] that could partly explain the increased risk of vascular complications associated with T2DM [4].Arterial stiffness is a strong predictor of CV events, heart failure and death [10][11][12]...

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“…Ahead of the study end, the EMPA-REG OUTCOME trial investigators themselves had outlined additional risk factors that the use of SGLT2 inhibitors influences positively: visceral adiposity, hyperinsulinemia, arterial stiffness, albuminuria, and oxidative stress (6). However, isolated reductions in HbA 1c level, body weight, or uricemia of the degree seen in the trial have been generally reputed to be insufficient to explain the outcome (7)(8)(9)(10)(11).…”

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confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

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The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trialdmodest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid leveldmay be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.First among cardiovascular (CV) end point trials of glucose-lowering agents (1), the EMPA-REG OUTCOME trialdusing 10 or 25 mg/day sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin against placebo in 7,020 patients with type 2 diabetes (T2D) who were at increased CV riskdreported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years (2). Of note, all the pathologic categories of CV death (ischemic, pump failure, arrhythmic, embolic) contributed to the overall reduction in CV death in a patient cohort well treated with the use of renin-angiotensin-aldosterone inhibitors, statins, and acetylsalicylic acid. Furthermore, separation of the cumulative incidence functions between pooled-dose groups and placebo was already evident months after randomization. This unusual time course and the discrepancy between the relative risk reduction of the primary end point (nonfatal myocardial infarction, stroke, and CV mortality) and CV mortality itself suggests that active treatment affected case fatality rates more than event rates. In other words, empagliflozin treatment appeared mostly to rescue patients from impending cardiac decompensation. This interpretation is supported by the recent post hoc analyses of heart failure, documenting a large benefit in first and recurrent heart failure hospitalization across virtually every patient subgroup (3). Despite the fact that the diagnosis of heart failure was based on investigator reporting, th...

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

Cited by 366 publications

References 70 publications

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: Focus on SGLT2 inhibitors and EMPA-REG OUTCOME

Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

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