Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus (original) (raw)

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1Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen, Germany

*Corresponding author. Tel: +49 241 80 89300, Fax: +49 241 80 82545, Email: nmarx@ukaachen.de

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2Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

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Received:

17 December 2015

Revision received:

19 February 2016

Accepted:

29 February 2016

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Nikolaus Marx, Darren K. McGuire, Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus, European Heart Journal, Volume 37, Issue 42, 7 November 2016, Pages 3192–3200, https://doi.org/10.1093/eurheartj/ehw110
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Patients with type 2 diabetes mellitus (T2D) exhibit an increased risk for cardiovascular (CV) events. Hyperglycaemia itself contributes to the pathogenesis of atherosclerosis and heart failure (HF) in these patients, but glucose-lowering strategies studied to date have had little to no impact on reducing CV risk, especially in patients with a long duration of T2D and prevalent CV disease (CVD). Sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel class of anti-hyperglycaemic medications that increase urinary glucose excretion, thus improving glycaemic control independent of insulin. The recently published CV outcome trial, EMPA-REG OUTCOME, demonstrated in 7020 patients with T2D and prevalent CVD that the SGLT2-inhibitor empagliflozin significantly reduced the combined CV endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke vs. placebo in a population of patients with T2D and prevalent atherosclerotic CVD. In addition and quite unexpectedly, empagliflozin significantly and robustly reduced the individual endpoints of CV death, overall mortality, and hospitalization for HF in this high-risk population. Various factors beyond glucose control such as weight loss, blood pressure lowering and sodium depletion, renal haemodynamic effects, effects on myocardial energetics, and/or neurohormonal effects, among others may contribute to these beneficial effects of SGLT2-inhibition. The present review summarizes known and postulated effects of SGLT2-inhibition on the CV system and discusses the role of SGLT2-inhibition for the treatment of high-risk patients with T2D and CVD.

See page 3201 for the editorial comment on this article (doi:10.1093/eurheartj/ehw158)

Cardiovascular risk in patients with type 2 diabetes

Patients with type 2 diabetes mellitus (T2D) have an increased risk to develop cardiovascular disease (CVD) with its key sequelae myocardial infarction (MI), stroke, and heart failure (HF).1,2 Most recent data from the emerging risk factor collaboration showed that the presence of diabetes is still associated with a doubling of the risk for CV death, and that the presence of T2D together with a history of MI is associated with a four-fold increased risk compared with subjects without T2D or prior MI.3 These data underscore the unmet clinical need for additional strategies to reduce CV risk in patients with T2D.

Glucose-lowering and cardiovascular risk reduction in diabetes

To date,4 there is little proof that glycaemic control per se affects the risk for cardiovascular (CV) events.5,6 Over the last decade, various CV outcome trials tested the effect of intensive glucose-lowering vs. standard therapy on CV outcomes. The three largest trials—ADVANCE,7 ACCORD,8 and VADT9—enrolling patients with longstanding T2D and a high proportion of patients with prevalent CVD and the remainder with clustered CV risk factors—failed to show a significant effect of more intensive glucose-lowering strategies vs. standard care on macrovascular events. Thus, lowering glucose more intensively than presently endorsed standard care is not incrementally effective in preventing CV events within the relatively few years of trial observation in populations of patients with a longer duration of T2D and a history of, or at increased risk for, atherosclerotic CVD.

In 2008, the US Food and Drug Administration and the European Medicines Agency released guidance for the pharmaceutical industry calling for at a minimum, the demonstration of CV safety of novel anti-hyperglycaemic medications in high-risk populations of patients with T2D. As a consequence, the number of CV outcome trials completed, underway and planned in patients with T2D has tremendously increased over the last few years. Three trials assessing the CV effects of the novel class of dipeptidyl peptidase (DPP)-4 inhibitors (saxagliptin (SAVOR-TIMI 53),10 alogliptin (EXAMINE),11 and sitagliptin (TECOS)12) as well as one trial with a glucagon-like protein (GLP)-1 receptor agonists (GLP1-RA) lixisenatide (ELIXA)13 have been completed and published: these studies were all designed to demonstrate non-inferiority of the respective drug vs. placebo, added to background anti-hyperglycaemic treatment, on CV outcomes. All four trials were positive with respect to demonstrating statistical non-inferiority of each medication, showing no differences for the primary CV outcomes examined; however, none of the DPP 4-inhibitors or the GLP1-RA was associated with significant CV benefits in the trial populations comprising patients with a long history of T2D and prevalent CVD or clustered CVD risk factors.10–15

Most recently, results have been reported from a CV outcome trial evaluating the sodium glucose co-transporter (SGLT) 2 inhibitor empagliflozin vs. placebo in a population of patients with T2D and prevalent atherosclerotic CVD at baseline, largely similar to the trials summarized above. The principle mechanism of anti-hyperglycaemic action of SGLT2-inhibition is increased glucosuria affected by inhibiting renal glucose reuptake via an insulin-independent mechanism.

Effects of the sodium glucose cotransporter-2-inhibitor empagliflozin on cardiovascular outcomes

For the currently available SGLT2-inhibitors, four large CV outcome trials have been designed [canagliflozin-CANVAS (NCT01032629); dapagliflozin-DECLARE-TIMI 58 (NCT01730534); ertugliflozin-VERTIS (NCT01986881) and empagliflozin-EMPA-REG OUTCOME (NCT01131676)] (Table 1). Recently, one of them—EMPA-REG OUTCOME—has been completed and results published.16 EMPA-REG OUTCOME was a multi-centre, randomized, placebo controlled trial enrolling 7020 patients with T2D at high CV risk. Patients were randomized to placebo or one of two doses of empagliflozin (10 mg or 25 mg/day) on the background of state-of-the-art glucose-lowering therapy. The primary endpoint was the composite of CV death, non-fatal MI, and non-fatal stroke. Since this study sought to test the effect of an anti-hyperglycaemic medication compared with placebo independent of its glucose-lowering properties, the protocol was designed to achieve glycaemic equipoise between groups, allowing the addition and titration of other anti-hyperglycaemic medications in both arms to achieve the best haemoglobin A1c (HbA1c) level possible in accordance with local and regional standards of care.17 The study enrolled a population of patients at high CV risk with a long duration of T2D and the presence of atherosclerotic CVD at study entry: almost 50% of the patients had a history of MI, 75% had multi-vessel coronary artery disease, and 10% had a history of HF. This patient cohort was very well treated at baseline with anti-hypertensive medications used in 95% of the patients, low-density lipoprotein-cholesterol (LDL-C)-lowering agents in ∼80%, and almost 90% of the patients were treated with anticoagulant/antiplatelet therapy. Moreover, ∼50% of all patients were on insulin therapy at baseline. This translated into excellent control of associated CV risk factors at trial entry, with a mean blood pressure (BP) of 135/77 mmHg and an LDL-C of 2.2 mmol/L; baseline glycated HbA1c was 8.1%. In addition, one-quarter of the patients had chronic kidney disease Stage 3 with an eGFR between 30 and 60 mL/min/1.73 m2. Thus, EMPA-REG OUTCOME examined the effect of empagliflozin vs. placebo in a high-risk population of patients with T2D on top of standard CV therapy and very well-controlled CV risk factors. At the end of the study, there was a slightly lower HbA1c of 0.3–0.4% in the empagliflozin group compared with placebo with more frequent addition of other anti-hyperglycaemic medications throughout the trial, including insulin initiation, in the placebo group compared with the two empagliflozin groups. Moreover, empagliflozin compared with placebo led to a significant reduction in BP and body weight, similar to what has been reported in earlier studies. As per the prospective statistical analysis plan, hierarchical testing for all primary and secondary CV outcomes was performed combining the two empagliflozin doses for analysis. In the primary analysis, empagliflozin was proved statistically significantly non-inferior to placebo for the primary composite outcome of major adverse CV outcomes-CV death, non-fatal MI, and non-fatal stroke. Subsequently, step-down testing revealed that empagliflozin significantly reduced risk for the primary outcome of CV death, non-fatal MI, and non-fatal stroke compared with placebo with a hazard ratio of 0.86 (95%CI 0.74–0.99; P = 0.038). This reduction of the primary outcome was mainly driven by a highly significant 38% reduction in CV death (HR 0.62; 95%CI 0.49–0.77; P < 0.0001), with separation of the event curves evident as early as 2 months into the trial. There was a non-significant 13% reduction of non-fatal MI (P = 0.30) and a non-significant 24% increased risk for non-fatal stroke (HR 1.24; 95%CI 0.92–1.67; P = 0.16). In addition, in a secondary/exploratory analysis, empagliflozin led to a significant 35% reduction of hospitalization for HF (HR 0.65; 95% CI 0.50–0.85; P < 0.002), with separation of the curves evident almost immediately during trial observation, suggesting a very early effect of the SGLT2-inhibitor on HF risk (Figure 1). Finally, empagliflozin reduced overall mortality by 32% (HR 0.68; 95% CI 0.57–0.82; P < 0.0001), a highly significant effect translating into a number-needed-to-treat (NNT) of 39 over 3 years to prevent one death. The results were consistent in all subgroups reported. Major side effects of the SGLT2-inhibitor, consistent with prior studies and consistent across the class of SGLT2-inhibitors, were increased mycotic genital infection: 1.8% of the patients in the placebo group vs. 6.4% in the empagliflozin group; however, no difference was found in the occurrence of urinary tract infections.

Table 1

Cardiovascular outcome trials with sodium glucose cotransporter-2-inhibitors

EMPA-REG OUTCOME, (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; CANVAS, CANagliflozin cardioVascular Assessment Study; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events-TIMI 58. VERTIS: Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess Cardiovascular Outcomes Following Treatment With Ertugliflozin in Subjects With Type 2 Diabetes Mellitus and Established Vascular Disease.

T2D, type 2 diabetes mellitus; CV, cardiovascular.

Table 1

Cardiovascular outcome trials with sodium glucose cotransporter-2-inhibitors

EMPA-REG OUTCOME, (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; CANVAS, CANagliflozin cardioVascular Assessment Study; DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events-TIMI 58. VERTIS: Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Assess Cardiovascular Outcomes Following Treatment With Ertugliflozin in Subjects With Type 2 Diabetes Mellitus and Established Vascular Disease.

T2D, type 2 diabetes mellitus; CV, cardiovascular.

Figure 1

Primary and key secondary outcomes in the EMPA-REG OUTCOME trial demonstrating effects of empagliflozin compared with placebo on (A) the primary composite (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), (B) cardiovascular mortality, and (C) hospitalization for heart failure (adapted from ref. 16).

The results of EMPA-REG OUTCOME with a significant beneficial effect on the primary composite CV outcome, CV mortality, overall mortality, and hospitalization for HF makes this trial a landmark trial in CV risk reduction for patients with T2D. As such, EMPA-REG OUTCOME stands in line with trials such as the Scandinavian Simvastatin Survival Study (4S) and the heart outcomes prevention evaluation (HOPE) trial with regard to the magnitude of CV risk reduction. In the 4S trial, simvastatin vs. placebo led to an NNT of 30 over 5.4 years to reduce 1 death.18 HOPE, in a population with ∼25% of statin-treated patients, showed that ramipril vs. placebo prevents one death if 56 patients are treated over 5 years.19 Finally, EMPA-REG OUTCOME in a population receiving statins in >75% of the patients, and ACE-inhibitors or ARBs in >80%, showed that 39 patients must be treated over 3 years to prevent one death.16 The observations of superiority in EMPA-REG OUTCOME have raised important questions as to the mechanism underpinning the observed favourable CV effects.

Role of the kidney in glucose metabolism

Through its contribution to gluconeogenesis and its capacity to reabsorb glucose from the urine, the kidney plays an important role in glucose homeostasis. In humans without diabetes, ∼160–180 g of glucose are filtered by the kidneys per day20 and in healthy individuals without diabetes, virtually all filtered glucose is reabsorbed in the proximal tubule. As long as the filtered glucose does not exceed the maximum renal glucose reabsorption capacity, filtered glucose is reabsorbed thus allowing energy conservation.21 About 90% of glucose filtered in the glomeruli is reabsorbed in the first segment of the proximal tubule by SGLT2, which is a low-affinity, high-capacity transporter.22 The remaining 10% is reabsorbed in the more distal part of the tubule by SGLT1, a high-affinity, low-capacity transporter (Figure 2A).23,24 Sodium glucose co-transporter proteins are proteins localized in the apical membrane capable of actively transporting glucose along with sodium against a concentration gradient into the cell. This process is driven by the active transport of sodium out of the cell by the adenosine triphosphate-dependent sodium-potassium pump. Once in the intracellular space, glucose then passively diffuses from the basolateral membrane of the tubule cell into the blood via GLUT2, a member of the GLUT family of proteins25,26 (Figure 2B). However, if the blood glucose load exceeds the renal tubular glucose excretion threshold of ∼180 mg/dL, glucosuria occurs. In patients with diabetes and chronic hyperglycaemia, the threshold paradoxically increases to ∼220 mg/dL due to an enhanced maximum renal glucose reabsorption capacity mediated by up-regulation of SGLT2 in the proximal tubule. This maladaptive mechanism seems to be explained by increased SGLT2 transcription and translation resulting in increased SGLT2 density on the apical membrane in the proximal tubule (Figure 2C).23,25

Figure 2

Glucose filtration and reabsorption in the kidney. (A) In healthy, normoglycaemic individuals, all glomerular filtered glucose is reabsorbed in the proximal tubule through sodium glucose co-transporter proteins. (B) Sodium glucose co-transporter proteins are localized in the apical membrane capable of actively transporting glucose along with sodium against a concentration gradient into the cell. This process is driven by the active transport of sodium out of the cell by the adenosine triphosphate-dependent sodium-potassium pump. Once in the intracellular space, glucose then passively diffuses from the basolateral membrane of the tubule cell into the blood via glucose transporters. (C) In patients with diabetes and hyperglycaemia, increased glucose filtration may exceed the maximum glucose transport capacity of the sodium glucose co-transporter proteins, thus leading to urinary glucose excretion. In a maladaptive compensatory mechanism in the setting of type 2 diabetes mellitus and hyperglycaemia, sodium glucose cotransporter-2 expression in the proximal tubule is upregulated with resultant increased glucose reabsorption. (D) Sodium glucose cotransporter-2-inhibitors block glucose and sodium absorption in the proximal tubule, resulting in an increase in urinary glucose excretion of up to 100 g (400 kcal) per day.

Sodium glucose cotransporter-2-inhibitors

Mode of action and glucose-lowering properties

Sodium glucose cotransporter-2-inhibitors are a novel class of glucose-lowering drugs that act in the kidney by inhibiting SGLT2-mediated glucose reabsorption in the proximal tubule. The resulting increase in urinary glucose excretion leads to a reduction in plasma glucose levels (Figure 2D).27,28 The concept of SGLT2-inhibition is different from other glucose-lowering strategies since glucose is removed from the ‘system’, thus reducing total-body and cellular glucose toxicity, a mechanism that is completely independent of insulin. Overall, 24-h urinary glucose excretion in patients treated with SGLT2-inhibitors lies between 60 and 100 g/day, corresponding to a loss of 240–400 kcal/day upon chronic administration.29 In addition to their glucosuric effects, SGLT2-inhibitors lead—at least temporarily—to an increase in sodium excretion,30 as well as a reduction in plasma volume due to glucose osmotic diuretic effects and natriuresis.31

Currently, three SGLT2-inhibitors are approved in Europe and the USA: dapagliflozin, canagliflozin, and empagliflozin.32 Meta-analyses for these SGLT2-inhibitors suggest that they lower HbA1c levels between 0.7 and 0.8% relative to placebo.33 Sodium glucose cotransporter-2-inhibitor effects are glucose-dependent, thus leading to a very low risk of hypoglycaemia. In addition, SGLT2-inhibitors can be combined with any other anti-hyperglycaemic medication since the mechanism of action is different from all other agents presently available and is completely independent of insulin.34 Interestingly, various studies suggest that SGLT2-inhibitors may improve insulin-sensitivity potentially through an increase in insulin-mediated glucose tissue disposal,35,36 and over time, due to the net caloric loss and enhanced insulin-sensitivity mediated by weight loss. Moreover, recent data have shown that SGLT2-inhibitors increase glucagon secretion from α-cells in the pancreatic islet, a mechanism that may contribute to enhanced endogenous glucose production in treated patients.37 In addition to these effects on glucose homeostasis, SGLT2-inhibitors exhibit potential beneficial effects on CV risk factors, as has been previously published with selected observations summarized below.38,39

Effects of sodium glucose cotransporter-2-inhibitors beyond glucose control

Anthropometrics

The glucosuric effect of SGLT2-inhibitors causing a negative energy balance results in an average weight-reduction of 2–3 kg that occurs gradually over the first few months on treatment, a consistent observation across the class of medications in studies over 1–2 years.40 Interestingly, the weight loss appears to reach a nadir and thereafter stabilizes after 3–6 months, most likely through a compensatory increased energy intake.41 These medications seem to have no effect on energy expenditure.42–44

Blood pressure and diuresis

A reduction in BP in patients treated with SGLT2-inhibitors is another effect beyond glucose control consistently observed across the class of medications. Several trials have shown that SGLT2-inhibitors lead to a reduction in systolic BP in a range of 3–5 mmHg and ∼2–3 mmHg in diastolic BP.40 In addition, SGLT2-inhibitors reduce pulse pressure, mean arterial pressure, and the product of heart rate-X-systolic BP (a.k.a. ‘double product’, or rate-pressure product) vs. placebo suggesting an effect on different markers and mediators of arterial stiffness.45 Interestingly, these BP effects occurred without a compensatory increase in heart rate, suggesting a lack of compensatory sympathetic activation. In addition, clamp studies in patients with uncomplicated type 1 diabetes suggest that empagliflozin reduces carotid-radial pulse wave velocity also without inducing a reflex sympathomimetic activity.46

Renal haemodynamic effects

Sodium glucose cotransporter-2-inhibition has been suggested to directly affect the tubulo-glomerular feedback mechanism in the kidney. The increased delivery of solute (sodium and chloride) to the macula densa in the setting of SGLT2-inhibition may reduce hyperglycaemia-induced glomerular hyperfiltration via tubulo-glomerular feedback invoking adenosine-dependent pathways, with direct effects on afferent glomerular arteriolar tone that may diminish hyperfiltration acutely and consistently during treatment.47

Effects on mediators and markers of cardiovascular risk

With respect to lipids, SGLT2-inhibitors mildly increase both LDL-C as well as HDL-C through an as of yet unexplained mechanism.39,48,49 These observations may reflect direct effects on lipoprotein particle metabolism, but could also simply reflect haemoconcentration resulting from the diuretic effects of SGLT2-inhibition, thereby having no net effect on circulating lipid particle numbers.

Cardiac effects

Experimental data in obese and diabetic mice demonstrated that the SGLT2-inhibitor empagliflozin significantly ameliorates cardiac fibrosis, coronary arterial thickening, as well as cardiac macrophage infiltration suggesting a direct cardiac effect along with an attenuation of oxidative stress on the myocardium.50

Other potential direct or indirect cardiac effects might include alterations of myocardial energetics and potential anti-arrhythmic effects, postulated mechanisms that have arisen in attempts to understand the EMPA-REG OUTCOME trial results, but with little data to date to evaluate. From a myocardial energetics perspective, SGLT1 but not SGLT2 is expressed in cardiac myocytes.51 In the kidney, SGLT2-inhibition results in increased SGLT1-mediated glucose reabsorption,52 and if this is a humoral-mediated response, the possibility remains for upregulation of cardiac SGLT1. This could directly affect myocardial substrate metabolism and energetics with enhanced glucose and decreased fatty acid (FA) metabolism that could favourably affect myocardial function. In addition, shifting from β-oxidation of free FA to glycolysis in the myocardium might reduce the potential pro-arrhythmia effects of free FA metabolites.53

Potential mechanisms explaining the results in EMPA-REG OUTCOME

The surprising and unexpected results of EMPA-REG OUTCOME on mortality and HF cannot be explained by glucose control per se nor by a reduction of atherosclerotic events since the effect of empagliflozin on non-fatal MI and hospitalization for unstable angina was not statistically significant. More likely, the favourable outcomes are related to effects of empagliflozin on HF and CV mortality, direct or indirect, that are independent of effects on hyperglycaemia or on atherosclerotic CVD (Figure 3).

Figure 3

Potential mechanisms involved in the reduction of cardiovascular events (cardiovascular death, total mortality, and heart failure hospitalization) observed in the EMPA-REG OUTCOME trial for empagliflozin-treated patients with type 2 diabetes mellitus and prevalent atherosclerotic cardiovascular disease.

In the trial, 10% of the patients enrolled had a history of HF, but no data on left-ventricular function or surrogate parameters like NT-proBNP were collected. Empagliflozin led to a highly significant reduction in hospitalization for HF with an effect that became evident very early in the trial in the overall study population. Subgroup analyses stratified by presence or absence of HF at baseline suggest a consistent benefit observed in patients with and without baseline HF with no evident heterogeneity of efficacy by HF status.54 It is important to note that the outcomes analysed in the study only evaluated first events, and no conclusion on the effects of empagliflozin therapy on total HF events (i.e. first + recurrent) can yet be made.

Various factors may contribute to the observed reduction in CV death and HF hospitalization. As with the atherosclerotic event endpoints discussed above, blood glucose reduction itself is very unlikely to account for the results observed given the minor difference in HbA1c levels between groups as well as the fact that previous studies showed that intensified glucose control does not influence the incidence of these events in similar populations. The significant reductions in BP and body weight seen in EMPA-REG OUTCOME have been proposed as potential contributors to the beneficial results. However, BP lowering only translates into CV risk reduction after 6–12 months or even longer, making the early beneficial effects seen unlikely to be attributable to BP reduction per se.19 Still, the decrease in markers of arterial stiffness found in SGLT2-inhibitor-treated patients,45 all closely linked to BP reduction, may have a direct, potentially beneficial effect on myocardial oxygen consumption via afterload reduction. Weight loss seems to play a minor role in this context given the data from the Look- Action for Health in Diabetes study, showing that intensive lifestyle intervention, focused on weight loss, did not improve CV risk in patients with T2D.55

The diuretic effect of empagliflozin has been discussed as a potential contributor to the observed reduction of hospitalization for HF through an at least temporary reduction in plasma volume as shown for SGLT2-inhibitors.31 However, similar or greater decreases in intravascular volume and net sodium balance is affected by most commonly used diuretic medications but—in contrast to empagliflozin—treatment with loop-diuretics or thiazides has not been demonstrated to reduce CV death in previous studies, and their effects on hospitalization for HF risk, when demonstrated, have been much more modest in magnitude compared with the large reduction observed with empagliflozin. Yet, SGLT2-inhibitors are different from the loop and thiazide diuretics in several important ways. First, they do not lead to a reflex activation of the sympathetic nervous system. In addition, thiazides work in the distal tubule while SGLT2-inhibitors act proximal of the macula densa, thus leading to an increased urinary sodium and chloride delivery to the juxta-glomerular apparatus. This has been suggested to restore the tubulo-glomerular feedback mechanism in diabetes with afferent arteriolar vasoconstriction and subsequent reduction of hyperfiltration and normalization of transglomerular perfusion pressures.47 Similarly, the increased sodium and chloride delivery to the macular densa upon SGLT2-inhibitor treatment may affect other neurohormonal factors such as local RAAS inhibition,27,56–58 which may have contributed to pre-glomerular vasoconstriction in diabetes. It is tempting to speculate that these effects possibly result in aldosterone withdrawal and reduced sympathetic nerve activity—either or both of which could directly benefit CV death and HF risk. Moreover, other yet unknown mechanisms influencing the renal–cardiac interaction may be of important in this context.

Still, the depletion of sodium and potential reduction in body sodium content by SGLT2-inhibition may play a crucial in HF in diabetes. It has been hypothesized that patients with diabetes exhibit an excess of total-body sodium, mainly because of increased sodium retention in the kidney as a consequence of hyperglycaemia and hyperinsulinaemia.59–61 Sodium-loading studies in animals and humans suggest that excess sodium is not only distributed in the extracellular space but possibly also intracellularly as well as in osmotically inactive compartments, e.g. matrix components of skin and muscle. Increased intracellular sodium in the myocardium may increase the risk of arrhythmias and impair myocardial function,62,63 most likely through an impairment of mitochondrial function.64 Interestingly, experimental data in an animal model of HF showed an increase in myocardial intracellular sodium and in this model, blockade of the mitochondrial Na+/Ca2+ exchange prolonged survival of these animals and significantly decreased arrhythmias.64 Sodium glucose cotransporter-2-inhibition leads to an early and transient increase in urinary sodium excretion that normalizes after ∼2 weeks.65 This increase in sodium depletion is not reflected by changes in plasma sodium concentration, but since plasma sodium does not directly mirror whole body sodium content, the increase in urinary sodium excretion is likely to rapidly reduce total-body sodium. This mechanism may thus contribute to the early beneficial effect of empagliflozin on CV death and HF hospitalization not only through a reduction of volume load but also through direct effects in the myocardium. Still, to date, little is known about these potential effects of empagliflozin and future research is warranted to further explore this issue.

Other mechanisms that may explain the profound effects of empagliflozin on CV events include anti-oxidative, anti-inflammatory, or anti-apoptotic properties of SGLT2-inhibitors as shown in experimental models, as well as counterbalancing effects of these drugs on cellular senescence.66,67 Still, hitherto, it remains speculative whether such effects seen in preclinical studies translate into humans.

Finally, the increase in glucagon secretion induced by SGLT2 inhibiton37 may be interesting in light of the EMPA-REG OUTCOME results. Work in the 1970s suggested that glucagon exhibits inotropic effects with an increased myocardial contractility and cardiac output in glucagon-treated patients with MI.68,69 In the myocardium, glucagon generates cAMP, thus exhibiting positive inotropic and chronotropic action without the need for beta-1 adrenoreceptor stimulation.70 In addition, glucagon has been shown to exhibit anti-arrhythmic effects.71 Clinically, glucagon has previously been employed as an adjunctive therapy in shock situations and HF, but given that catecholamines are much more effective in these conditions, glucagon is no longer used for this indication. Still, a continous increase in glucagon levels in SGLT2-inhibitor-treated patients could contribute to a cardioprotective effect.

Most likely, the early and profound reduction on CV death and hospitalization for HF by empagliflozin is not caused by a single mechanism, but can rather be explained by the interplay of some of the effects outlined above, as well as by as of yet unknown mechanisms. Future studies are warranted to further explore the underlying mechanisms to explain the findings in EMPA-REG OUTCOME, and importantly to assess whether such effects are evident across the SGLT2-inhibitor class of medications or unique to empagliflozin. In addition, the point estimate of increase in the risk for non-fatal stroke—although not significant—needs to be examined in more detail to identify potentially harmful mechanisms and to figure out whether this trend may become significant in larger patient populations or is just a play of chance. In addition, like with all new drugs, post-marketing analyses are required to evaluate the long-term beneficial action of SGLT2-inhibitors or to detect undefined side effects. However, for clinicians, the data from this trial are straightforward with a clear reduction in the primary CV composite outcome, CV death, HF hospitalization, and most importantly, overall mortality in empagliflozin-treated patients. These convincing data provide diabetologists, cardiologists, and primary care providers with a potent, evidence-based medication to reduce CV events in the high-risk population of patients with T2D who have prevalent atherosclerotic CV disease. Finally, so far, only data for the effects of empagliflozin on CV risk are available. Since many of the mechanistic effects outlined above have also been described for other SGLT2-inhibitors, it will be interesting to see the results of the ongoing CV outcome trials with dapagliflozin, canagliflozin, and ertugliflozin to find out whether the beneficial CV outcome effects reported from the EMPA-REG OUTCOME trial are a class effect or unique to empagliflozin.

Authors’ contributions

N.M. and D.M. conceived and designed the research. N.M. drafted the manuscript. D.M. made critical revision of the manuscript for key intellectual content.

Funding

This work was supported by grants from the Hans-Lamers-Stiftung as well as the European Foundation for the Study of Diabetes to N.M.

Conflict of interest: N.M. has given lectures for Amgen, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, NovoNordisk, has received unrestricted research grants from Boehringer Ingelheim, and has served as an advisor for Amgen, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, NovoNordisk. In addition, N.M. reports honoraria for trial leadership from Boehringer Ingelheim. D.K.M. reports honoraria for trial leadership from Boehringer Ingelheim, Janssen Research and Development LLC, Merck Sharp and Dohme Corp, Lilly USA, Novo Nordisk, GlaxoSmithKline, Takeda Pharmaceuticals North America, AstraZeneca, Lexicon, and honoraria for consultancy from Janssen Research and Development LLC, Sanofi Aventis Groupe, Merck Sharp and Dohme Corp., Novo Nordisk and Regeneron.

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Effect of glucagon on ventricular arrhythmias after coronary artery occlusion and on ventricular automaticity in the dog

.

Br J Pharmacol

1971

;

43

:

279

–

286

.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Topic:

• cardiovascular diseases
• diabetes mellitus
• heart disease risk factors
• heart failure
• diabetes mellitus, type 2
• glucose
• cardiovascular system
• kidney
• sodium
• glycemic control
• cardiovascular event
• sodium-glucose transporter 2 inhibitors
• empagliflozin

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