EMPA-REG OUTCOME: The Cardiologist's Point of View

Cardiologists could view empagliflozin as a cardiovascular drug that also has a beneficial effect on reducing hyperglycemia in patients with type 2 diabetes mellitus (T2DM). The effects of empagliflozin in lowering the risk of cardiovascular death and hospitalization for heart failure in T2DM patients with high cardiovascular risk during the recent Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial may be explained principally in terms of changes to cardiovascular physiology; namely, by the potential ability of empagliflozin to reduce cardiac workload and myocardial oxygen consumption by lowering blood pressure, improving aortic compliance, and improving ventricular arterial coupling. These concepts and hypotheses are discussed in this report. Cardiologists could view empagliflozin as a cardiovascular drug that also has a beneficial effect on reducing hyperglycemia in patients with type 2 diabetes mellitus (T2DM). The effects of empagliflozin in lowering the risk of cardiovascular death and hospitalization for heart failure in T2DM patients with high cardiovascular risk during the recent Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial may be explained principally in terms of changes to cardiovascular physiology; namely, by the potential ability of empagliflozin to reduce cardiac workload and myocardial oxygen consumption by lowering blood pressure, improving aortic compliance, and improving ventricular arterial coupling. These concepts and hypotheses are discussed in this report. The Steno-2 trial, which was launched in 1993 and randomized 160 patients with type 2 diabetes mellitus (T2DM) and microalbuminuria to receive either conventional multifactorial treatment or intensified multifactorial treatment for global risk reduction regarding vascular damage (mean treatment duration 7.8 years),1Gaede P. Vedel P. Parving H.H. Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study.Lancet. 1999; 353: 617-622Abstract Full Text Full Text PDF PubMed Scopus (867) Google Scholar, 2Gaede P. Oellgaard J. Carstensen B. et al.Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.Diabetologia. 2016; 59: 2298-2307Crossref PubMed Scopus (289) Google Scholar recently reported long-term follow-up data.2Gaede P. Oellgaard J. Carstensen B. et al.Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.Diabetologia. 2016; 59: 2298-2307Crossref PubMed Scopus (289) Google Scholar After a median observation period of approximately 21 years, patients in the intensive therapy group (n = 42) survived for a median of 7.9 years longer than those in the conventional therapy group (n = 24).2Gaede P. Oellgaard J. Carstensen B. et al.Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.Diabetologia. 2016; 59: 2298-2307Crossref PubMed Scopus (289) Google Scholar Nevertheless, there still was a high rate of deaths and cardiovascular (CV) events in the intensive treatment group (>30% events at 10 years).2Gaede P. Oellgaard J. Carstensen B. et al.Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.Diabetologia. 2016; 59: 2298-2307Crossref PubMed Scopus (289) Google Scholar Thus, these data demonstrate that the high CV event rate observed in T2DM patients continues unabated even with rigorous treatment. Recently, empagliflozin, “a new CV agent with antihyperglycemic effects” was reported to significantly reduce CV death and hospitalization for heart failure, and slow the progression of kidney disease in T2DM patients when compared with placebo – the median duration of treatment was 2.6 years and the median observation period was 3.1 years.3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar, 4Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2044) Google Scholar Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor. During the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose (EMPA-REG OUTCOME) trial, patients with T2DM and a high risk of CV events were randomized to receive either empagliflozin (10 mg or 25 mg) or placebo in addition to standard care.3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar More than 99% of patients had established CV disease. The trial was continued until an adjudicated primary outcome event had occurred in at least 691 patients. The primary outcome was a composite of death from CV causes, nonfatal myocardial infarction (MI; excluding silent MI), or nonfatal stroke (ie, 3-point major adverse cardiovascular events [MACE]). The key secondary outcome was a composite of the primary outcome plus hospitalization for unstable angina (ie, 4-point MACE). A total of 7020 patients were included in the primary analysis (empagliflozin groups pooled, n = 4687; placebo, n = 2333).3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar The patient population with T2DM and high-risk CV disease in EMPA-REG OUTCOME had a yearly event rate of approximately 4.5%, which was similar to that in the previously published sitagliptin CV outcome study, Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).5Green J.B. Bethel M.A. Armstrong P.W. et al.Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2015; 373: 232-242Crossref PubMed Scopus (1953) Google Scholar There was a significant reduction in the primary outcome (ie, 3-point MACE) for those receiving empagliflozin vs placebo (hazard ratio [HR] 0.86; 95.02% confidence interval [CI], 0.74-0.99; P <.001 for noninferiority, P = .04 for superiority).3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar Moreover, significant reductions in the risk of CV death (HR 0.62; 95% CI, 0.49-0.77; P <.001) and all-cause mortality (HR 0.68; 95% CI, 0.57-0.82; P <.001) for empagliflozin vs placebo were reported.3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar Separation between the empagliflozin and placebo event curves for these endpoints occurred early in the trial,3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar within 6 to 12 weeks of treatment commencement. A significant reduction in the risk of hospitalization for heart failure also occurred with empagliflozin vs placebo (HR 0.65; 95% CI, 0.50-0.85; P = .002),3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar with event curve separation occurring almost immediately (within 6 weeks). No significant risk reductions with empagliflozin vs placebo were reported for the rate of nonfatal MI (excluding silent MI) (HR 0.87; 95% CI, 0.70-1.09; P = .22) or the rate of nonfatal stroke (HR 1.24; 95% CI, 0.92-1.67; P = .16).3Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (7148) Google Scholar EMPA-REG OUTCOME also investigated renal outcomes in T2DM patients with a high risk of CV events and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2.4Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2044) Google Scholar Compared with placebo, empagliflozin was associated with reduced incident or worsening nephropathy (HR 0.61; 95% CI, 0.53-0.70; P <.001), reduced risk of doubling of serum creatinine (accompanied by eGFR ≤45 mL/min/1.73 m2) (HR 0.56; 95% CI, 0.39-0.79; P <.001), and reduced risk of renal replacement therapy initiation (HR 0.45; 95% CI, 0.21-0.97; P = .04).4Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (2044) Google Scholar Renal outcomes data and potential mechanisms of renal protection associated with SGLT2 inhibitors are discussed in detail by Wanner in this Supplement.6Wanner C. EMPA-REG OUTCOME: the nephrologist's point of view.Am J Cardiol. 2017; 120: S59-S67Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The mechanism of action of empagliflozin in reducing the risk of adverse CV outcomes in the EMPA-REG OUTCOME trial is currently unknown, and various potential explanations have been suggested, including hemodynamic, metabolic, or hormonal effects (as discussed by Staels7Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms of action.Am J Cardiol. 2017; 120: S28-S36Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar in this issue). Here, we offer an explanation based on changes in CV physiology. Some background concepts in CV function are first described for the reader to fully appreciate the mechanisms proposed (Figure 1). Myocardial oxygen supply is determined primarily by blood flow and vascular resistance in the coronary vessels. Myocardial oxygen consumption (MVO2) is governed by the frequency and strength of cardiac myocyte contraction, and these are determined primarily by heart rate, left ventricular contractility, and left ventricular wall tension (ie, mechanical stress).8Braunwald E. 50th anniversary historical article. Myocardial oxygen consumption: the quest for its determinants and some clinical fallout.J Am Coll Cardiol. 1999; 34: 1365-1368Crossref PubMed Scopus (32) Google Scholar Changes in stroke volume have only a modest influence on MVO2,8Braunwald E. 50th anniversary historical article. Myocardial oxygen consumption: the quest for its determinants and some clinical fallout.J Am Coll Cardiol. 1999; 34: 1365-1368Crossref PubMed Scopus (32) Google Scholar as does basal myocardial metabolism and activation of cardiac contraction. If cardiac afterload increases (eg, in patients with hypertension), meaning the pressure against which the heart pumps is increased, cardiac myocytes must produce greater tension to generate forward blood flow, thus increasing their oxygen consumption. The law of Laplace states that left ventricular wall tension is proportional to the product of intraventricular pressure and ventricular radius, and inversely proportional to twice the ventricular wall thickness.9Valentinuzzi M.E. Kohen A.J. Laplace's law: what it is about, where it comes from, and how it is often applied in physiology.IEEE Pulse. 2011; 2: 74-84Crossref Scopus (18) Google Scholar The close relationship between MVO2 and left ventricular wall tension has important consequences for the diabetic heart. As discussed by Lehrke and Marx in this Supplement,10Lehrke M. Marx N. Diabetes mellitus and heart failure.Am J Cardiol. 2017; 120: S37-S47Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar heart failure is a common complication in patients with diabetes and a major contributor to CV morbidity and mortality.11Kasznicki J. Drzewoski J. Heart failure in the diabetic population - pathophysiology, diagnosis and management.Arch Med Sci. 2014; 10: 546-556Crossref PubMed Scopus (65) Google Scholar Furthermore, such myocardial dysfunction in diabetes may develop in the absence of risk factors such as hypertension or coronary artery disease or valvular disease, and it is known as diabetic cardiomyopathy.12Seferović P.M. Paulus W.J. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes.Eur Heart J. 2015; 36 (1727a-1727c): 1718-1727Crossref PubMed Scopus (328) Google Scholar In a diabetic patient with heart failure, various mechanisms attempt to compensate for the resulting decrease in cardiac output. Left ventricular wall tension may increase to overcome a higher cardiac afterload; thereafter, sustained elevation in intraventricular pressure and left ventricular radius may stimulate hypertrophy of ventricular myocytes. The resulting increased mass of cardiac muscle fiber maintains contractile force to counteract the increased left ventricular wall tension; however, eventual dilatation of the left ventricle may occur and lead to a decrease in the left ventricular ejection fraction.13Yelle D. Chaudhry S. Heart failure (McMaster Pathophysiology Review).http://www.pathophys.org/heartfailure/Google Scholar The dilated heart has a greater MVO2, as more energy is required to maintain cardiac output than for a normal-sized heart.13Yelle D. Chaudhry S. Heart failure (McMaster Pathophysiology Review).http://www.pathophys.org/heartfailure/Google Scholar Consequently, reducing left ventricular wall tension is a common therapeutic target in the treatment of heart failure. The left ventricle pumps the stroke volume of blood into the aorta and systemic arterial system. The interaction between the left ventricle and systemic arterial system, called ventricular arterial coupling, is a significant determinant of CV function,14Kass D.A. Age-related changes in venticular-arterial coupling: pathophysiologic implications.Heart Fail Rev. 2002; 7: 51-62Crossref PubMed Scopus (142) Google Scholar and contributes to the body's capacity to increase cardiac output, regulate systemic blood pressure (BP), and respond to increases in heart rate and cardiac preload (ie, ventricular filling pressure, which is affected by central venous pressure and venous return).14Kass D.A. Age-related changes in venticular-arterial coupling: pathophysiologic implications.Heart Fail Rev. 2002; 7: 51-62Crossref PubMed Scopus (142) Google Scholar, 15Antonini-Canterin F. Carerj S. Di Bello V. et al.Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist's point of view.Eur J Echocardiogr. 2009; 10: 36-43Crossref PubMed Scopus (117) Google Scholar In a healthy heart in which ventricular and arterial stiffness (ie, elastance) are low, the compliance (ie, increase in volume with increased pressure) in the heart and arteries prevents wide changes in pressure that could lead to vascular or end-organ damage; thus, optimal ventricular arterial coupling enables maximal cardiac work and efficiency.16Borlaug B.A. Kass D.A. Ventricular-vascular interaction in heart failure.Heart Fail Clin. 2008; 4: 23-36Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar Ventricular and arterial stiffness increase with age, and with comorbid conditions such as diabetes, hypertension, and kidney disease.17Kass D.A. Ventricular arterial stiffening: integrating the pathophysiology.Hypertension. 2005; 46: 185-193Crossref PubMed Scopus (278) Google Scholar This stiffening affects various markers of cardiac performance, including CV reserve, BP lability, ventricular systolic and diastolic function, coronary and peripheral flow regulation, and endothelial function.15Antonini-Canterin F. Carerj S. Di Bello V. et al.Arterial stiffness and ventricular stiffness: a couple of diseases or a coupling disease? A review from the cardiologist's point of view.Eur J Echocardiogr. 2009; 10: 36-43Crossref PubMed Scopus (117) Google Scholar, 16Borlaug B.A. Kass D.A. Ventricular-vascular interaction in heart failure.Heart Fail Clin. 2008; 4: 23-36Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar These parameters increase the hydraulic work required to maintain cardiac output and, in turn, increase MVO2.16Borlaug B.A. Kass D.A. Ventricular-vascular interaction in heart failure.Heart Fail Clin. 2008; 4: 23-36Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar The adverse interaction between a stiff heart and arteries has been described as a form of “coupling disease” that limits the ability of the CV system to respond to stress.16Borlaug B.A. Kass D.A. Ventricular-vascular interaction in heart failure.Heart Fail Clin. 2008; 4: 23-36Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 17Kass D.A. Ventricular arterial stiffening: integrating the pathophysiology.Hypertension. 2005; 46: 185-193Crossref PubMed Scopus (278) Google Scholar The “gold standard” noninvasive method of assessing arterial stiffness is via aortic pulse wave velocity, but pulse pressure (systolic BP minus diastolic BP) may be used as a surrogate marker.18Chilton R. Tikkanen I. Cannon C.P. et al.Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.Diabetes Obes Metab. 2015; 17: 1180-1193Crossref PubMed Scopus (335) Google Scholar A recent analysis from the Framingham Heart Study reported that a substantial proportion of patients treated for hypertension (60% of controlled treated patients and 90% of uncontrolled treated patients) had increased arterial stiffness, measured as elevated carotid-femoral pulse wave velocity, and this was associated with increased CV disease risk.19Niiranen T.J. Kalesan B. Hamburg N.M. Benjamin E.J. Mitchell G.F. Vasan R.S. Relative contributions of arterial stiffness and hypertension to cardiovascular disease: the Framingham Heart Study.J Am Heart Assoc. 2016; 5 (pii: e004271)Crossref PubMed Scopus (79) Google Scholar It is also important to note that arterial stiffness may be driven by matrix and mineralization events in the absence of atheroma, particularly in dysmetabolic states such as diabetes,20Thompson B. Towler D.A. Arterial calcification and bone physiology: role of the bone-vascular axis.Nat Rev Endocrinol. 2012; 8: 529-543Crossref PubMed Scopus (215) Google Scholar, 21Towler D.A. Commonalities between vasculature and bone: an osseocentric view of arteriosclerosis.Circulation. 2017; 135: 320-322Crossref PubMed Scopus (17) Google Scholar and the subsequent impairment of normal vessel functioning (called Windkessel physiology) is an important contributor to CV risk.22Lyle A.N. Raaz U. Killing me unsoftly: causes and mechanisms of arterial stiffness.Arterioscler Thromb Vasc Biol. 2017; 37: e1-e11Crossref PubMed Scopus (72) Google Scholar, 23Stabley J.N. Towler D.A. Arterial calcification in diabetes mellitus: preclinical models and translational implications.Arterioscler Thromb Vasc Biol. 2017; 37: 205-217Crossref PubMed Scopus (84) Google Scholar Although heart rate is one of the most important factors relating to MVO2, most SGLT2 inhibitor trials, including those investigating empagliflozin, have demonstrated no significant changes in heart rate.18Chilton R. Tikkanen I. Cannon C.P. et al.Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.Diabetes Obes Metab. 2015; 17: 1180-1193Crossref PubMed Scopus (335) Google Scholar, 24Storgaard H. Gluud L.L. Bennett C. et al.Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis.PLoS One. 2016; 11: e0166125Crossref PubMed Scopus (151) Google Scholar However, changes in other factors that influence MVO2 have been observed with SGLT2 inhibitor therapy. A post hoc analysis of data pooled from 5 Phase III trials of empagliflozin in T2DM patients (N = 3300; treatment duration 12-24 weeks) reported that markers of arterial stiffness (pulse pressure and ambulatory arterial stiffness index) and vascular resistance (mean arterial pressure) were significantly improved with empagliflozin.18Chilton R. Tikkanen I. Cannon C.P. et al.Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.Diabetes Obes Metab. 2015; 17: 1180-1193Crossref PubMed Scopus (335) Google Scholar In addition, empagliflozin had a beneficial effect on MVO2, assessed indirectly via heart rate, BP, and the double product (also known as the rate pressure product [heart rate multiplied by systolic BP], an indirect measure of MVO2, and thus, of cardiac workload).18Chilton R. Tikkanen I. Cannon C.P. et al.Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes.Diabetes Obes Metab. 2015; 17: 1180-1193Crossref PubMed Scopus (335) Google Scholar Arterial stiffness measured via aortic pulse wave velocity was also shown to be reduced in patients with type 1 diabetes mellitus after shorter-term treatment (8 weeks) with empagliflozin.25Cherney D.Z. Perkins B.A. Soleymanlou N. et al.The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus.Cardiovasc Diabetol. 2014; 13: 28Crossref PubMed Scopus (365) Google Scholar New data from EMPA-REG OUTCOME about the effects of empagliflozin and its impact on MVO2 (presented at the 2016 American Heart Association Scientific Sessions) revealed reduced markers of arterial stiffness, vascular resistance, and cardiac workload for T2DM patients treated with empagliflozin vs placebo.26Chilton R. Gullestad L. Fitchett D. et al.Empagliflozin reduces markers of arterial stiffness, vascular resistance and cardiac workload in EMPA-REG OUTCOME.Circulation. 2016; 134 (A13520)Google Scholar Further analyses are needed to determine the potential contribution of these changes to risk reduction for CV outcomes, all-cause mortality, and heart failure hospitalization observed with empagliflozin.26Chilton R. Gullestad L. Fitchett D. et al.Empagliflozin reduces markers of arterial stiffness, vascular resistance and cardiac workload in EMPA-REG OUTCOME.Circulation. 2016; 134 (A13520)Google Scholar The ability of SGLT2 inhibitors to lower BP is also an important contributor in reducing cardiac workload. Modest reductions in systolic (3-5 mm Hg) and diastolic (2-3 mm Hg) BP without increases in heart rate have been reported with canagliflozin, dapagliflozin, and empagliflozin,27Tikkanen I. Chilton R. Johansen O.E. Potential role of sodium glucose cotransporter 2 inhibitors in the treatment of hypertension.Curr Opin Nephrol Hypertens. 2016; 25: 81-86Crossref PubMed Scopus (30) Google Scholar and a decrease in systolic and diastolic BP of approximately 5/2 mm Hg was observed during the EMPA-REG OUTCOME study.28Abdul-Ghani M. Del Prato S. Chilton R. DeFronzo R.A. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study.Diabetes Care. 2016; 39: 717-725Crossref PubMed Scopus (229) Google Scholar Clinical trials of SGLT2 inhibitors in T2DM patients with hypertension, in which BP was assessed via 24-hour ambulatory monitoring, recorded significant reductions in mean systolic and diastolic BP vs placebo by week 12.29Tikkanen I. Narko K. Zeller C. et al.Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension.Diabetes Care. 2015; 38: 420-428Crossref PubMed Scopus (343) Google Scholar, 30Townsend R.R. Machin I. Ren J. et al.Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension.J Clin Hypertens (Greenwich). 2016; 18: 43-52Crossref PubMed Scopus (70) Google Scholar, 31Weber M.A. Mansfield T.A. Cain V.A. Iqbal N. Parikh S. Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study.Lancet Diabetes Endocrinol. 2016; 4: 211-220Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar Previous analyses have reported beneficial effects of even small reductions in BP (≤3 mm Hg) in decreasing CV events, such as coronary heart disease and heart failure.32Cook N.R. Cohen J. Hebert P.R. Taylor J.O. Hennekens C.H. Implications of small reductions in diastolic blood pressure for primary prevention.Arch Intern Med. 1995; 155: 701-709Crossref PubMed Scopus (629) Google Scholar, 33Hardy S.T. Loehr L.R. Butler K.R. et al.Reducing the blood pressure-related burden of cardiovascular disease: impact of achievable improvements in blood pressure prevention and control.J Am Heart Assoc. 2015; 4: e002276Crossref PubMed Scopus (123) Google Scholar Reduced BP increases the compliance of the aorta, lowers cardiac afterload, and decreases ventricular filling pressure; this “unloads” the ventricle, reducing ventricular wall tension and making the ventricle smaller, which in turn reduces MVO2 and decreases the power needed to pump the stroke volume. Unloading the ventricle also lowers the pressure on the intracardial surface and helps to decrease microcellular ischemia. Thus, ventricular arterial coupling is improved and the heart functions with greater efficiency, using less energy each time it pumps. The early reductions in the risks of adverse CV events described with empagliflozin during EMPA-REG OUTCOME suggest that this agent acts promptly to reduce cardiac workload. The aforementioned reports of significant BP reductions occurring within 12 weeks of commencing SGLT2 inhibitor treatment add further support to this role for empagliflozin. Hemodynamic factors to consider regarding the possible CV effects of empagliflozin in EMPA-REG OUTCOME primarily include changes in preload (ie, venous return) and afterload. As no significant changes in heart rate were noted during the study, it is likely that the changes in preload and afterload were balanced. For example, nitroglycerin, a drug used commonly to treat angina symptoms, is primarily a preload reducing agent and is noted to produce a mild increase in heart rate via changes in baroreceptor stimulation. The precise mechanism for this is not yet determined, but it has been suggested that there is an unmasking of underlying sympathetic modulation by a decrease in vagal tone, resulting in a greater relative sympathetic influence.34Gori T. Floras J.S. Parker J.D. Effects of nitroglycerin treatment on baroreflex sensitivity and short-term heart rate variability in humans.J Am Coll Cardiol. 2002; 40: 2000-2005Crossref PubMed Scopus (49) Google Scholar A simultaneous reduction in afterload would potentially balance this effect, and thus there would be no change in heart rate, as observed with “balanced” vasodilator agents such as angiotensin-converting enzyme inhibitors or dihydropyridine calcium channel blockers. A recent study using a rodent model of diabetes reported a significant reduction in both cardiac preload (defined as diastolic relaxation) and myocardial fibrosis in animals treated with empagliflozin vs untreated animals.35Habibi J. Aroor A.R. Sowers J.R. et al.Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes.Cardiovasc Diabetol. 2017; 16: 9Crossref PubMed Scopus (155) Google Scholar Diastolic dysfunction, defined by delayed diastolic relaxation,36Zile M.R. Baicu C.F. Gaasch W.H. Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle.N Engl J Med. 2004; 350: 1953-1959Crossref PubMed Scopus (1197) Google Scholar is an important component of diabetic cardiomyopathy.37Ernande L. Derumeaux G. Diabetic cardiomyopathy: myth or reality?.Arch Cardiovasc Dis. 2012; 105: 218-225Crossref PubMed Scopus (71) Google Scholar It is associated with myocardial fibrosis and results in diastolic heart failure.35Habibi J. Aroor A.R. Sowers J.R. et al.Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes.Cardiovasc Diabetol. 2017; 16: 9Crossref PubMed Scopus (155) Google Scholar The effect of empagliflozin in significantly lowering preload (ie, left ventricular end-diastolic pressure), as demonstrated in the aforementioned rodent study, could also lead to improved myocardial perfusion by increasing the myocardial perfusion pressure (defined as diastolic BP minus left ventricular end-diastolic pressure). Another important consideration of reduced preload is the associated improvement in coronary perfusion: a smaller preload would reduce ventricular wall tension, which, in turn, would reduce compression of endocardial arteries and allow greater blood to flow to the heart tissue. Also, by decreasing preload, ventricular filling is reduced and the heart has to pump a smaller volume of blood, which lowers cardiac work and MVO2. In addition, reduced coronary flow reserve is another physiologic abnormality observed in patients with diabetes. It is associated with microvascular functional or structural impairment, and is revealed by an impairment of myocardial contractile reserve (Figure 2).38Yonaha O. Matsubara T. Naruse K. et al.Effects of reduced coronary flow reserve on left ventricular function in type 2 diabetes.Diabetes Res Clin Pract. 2008; 82: 98-103Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar An improvement in coronary microvascular function would be expected to produce a decrease in mortality;39Taqueti V.R. Hachamovitch R. Murthy V.L. et al.Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization.Circulation. 2015; 131: 19-27Crossref PubMed Scopus (318) Google Scholar thus, a positive effect of empagliflozin on coronary flow reserve could contribute to the decreased risk of CV death observed in EMPA-REG OUTCOME. Preclinical studies and clinical trials are needed to investigate this hypothesis. In addition to these benefits in CV function, metabolic improvements in patients with T2DM that lead to reduced MVO2 (such as the use of ketones as a cardiac fuel source, and reduced glucose toxicity effects7Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms of action.Am J Cardiol. 2017; 120: S28-S36Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar) have the potential to play a key role in the reduction of CV death and reduced hospitalization for heart failure in the high-CV-risk patient population in EMPA-REG OUTCOME. Other effects of empagliflozin (also observed with other SGLT2 inhibitors), such as modest diuretic and natriuretic activity, and associated body weight reduction, would also be expected to contribute to reducing cardiac workload. From the cardiologist's perspective, empagliflozin could be viewed as a CV drug that also has a beneficial effect on reducing hyperglycemia in patients with T2DM. The effects of empagliflozin in reducing the risk of CV death and hospitalization for heart failure during the EMPA-REG OUTCOME study may be explained principally by its apparent ability to alter cardiac physiology; specifically, to reduce cardiac workload and MVO2 by lowering BP, improving aortic compliance, and improving ventricular arterial coupling. Clinical trials to investigate the effect of SGLT2 inhibitors on unloading the ventricle in patients with heart failure but without diabetes are commencing, and will provide valuable information on the role of these agents as CV drugs.