in Heart Failure: Diabetes

Dear Author Here are the proofs of your article. •

You can submit your corrections online, via e-mail or by fax.

•

For online submission please insert your corrections in the online correction form. Always indicate the line number to which the correction refers.

•

You can also insert your corrections in the proof PDF and email the annotated PDF.

•

For fax submission, please ensure that your corrections are clearly legible. Use a fine black pen and write the correction in the margin, not too close to the edge of the page.

•

Remember to note the journal title, article number, and your name when sending your response via e-mail or fax.

•

Check the metadata sheet to make sure that the header information, especially author names and the corresponding affiliations are correctly shown.

•

Check the questions that may have arisen during copy editing and insert your answers/corrections.

•

Check that the text is complete and that all figures, tables and their legends are included. Also check the accuracy of special characters, equations, and electronic supplementary material if applicable. If necessary refer to the Edited manuscript.

•

The publication of inaccurate data such as dosages and units can have serious consequences. Please take particular care that all such details are correct.

•

Please do not make changes that involve only matters of style. We have generally introduced forms that follow the journal’s style.

•

Substantial changes in content, e.g., new results, corrected values, title and authorship are not allowed without the approval of the responsible editor. In such a case, please contact the Editorial Office and return his/her consent together with the proof.

•

If we do not receive your corrections within 48 hours, we will send you a reminder.

•

Your article will be published Online First approximately one week after receipt of your corrected proofs. This is the official first publication citable with the DOI. Further changes are, therefore, not possible.

•

The printed version will follow in a forthcoming issue.

Please note After online publication, subscribers (personal/institutional) to this journal will have access to the complete article via the DOI using the URL: http://dx.doi.org/10.1007/s11936-017-0522-x If you would like to know when your article has been published online, take advantage of our free alert service. For registration and further information, go to: http://www.link.springer.com. Due to the electronic nature of the procedure, the manuscript and the original figures will only be returned to you on special request. When you return your corrections, please inform us, if you would like to have these documents returned.

AUTHOR'S PROOF

Metadata of the article that will be visualized in OnlineFirst

1

Article Title

Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond

2

Article Sub- Title

3

Article Copyright Year

Springer Science+Business Media New York 2017 (This w ill be the copyright line in the final PDF)

4

Journal Name

Current Treatment Options in Cardiovascular Medicine

5

Family Name

6

Particle

7

Given Name

8 9

Corresponding Author

Verbrugge Frederik H.

Suffix Organization

Ziekenhuis Oost-Limburg

10

Division

Department of Cardiology

11

Address

Schiepse Bos 6, Genk 3600

12

e-mail

[email protected]

13

Family Name

Martens

14

Particle

15

Given Name

16

Suffix

17

Organization

Ziekenhuis Oost-Limburg

Division

Department of Cardiology

19

Address

Schiepse Bos 6, Genk 3600

20

Organization

Hasselt University

21

Division

Doctoral School for Medicine and Life Sciences

22

Address

Agoralaan gebouw D, Diepenbeek 3590

23

e-mail

[email protected]

24

Family Name

Mathieu

25

Particle

26

Given Name

18

27

Author

Author

Pieter

Chantal

Suffix

28

Organization

University Hospital Leuven

29

Division

Department of Clinical and Experimental Medicine

AUTHOR'S PROOF 30

Address

Herestraat 49, Leuven 3000

31

e-mail

[email protected]

32

Received

33

Schedule

34 35

Revised Accepted

Abstract

Opinion statement: This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents. By blocking sodium/glucose uptake in the proximal tubules of the nephron, they induce glycosuria. Treatment with SGLT-2 inhibitors in diabetes leads to a sustained ∼1% reduction in glycated hemoglobin levels, with favorable reductions in both arterial blood pressure (∼3–6 mmHg) and body weight (∼2–4 kg/m 2). However, those effects fail to explain fully the dramatic reduction in cardiovascular mortality, heart failure readmissions, and end-stage kidney disease. The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease. SGLT-2 inhibitors decrease proximal tubular sodium and chloride reabsorption, leading to a reset of the tubule-glomerular feedback. This induces plasma volume contraction without activation of the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to better long-term renal preservation, and improves diuretic and natriuretic responses to other diuretic agents. Moreover, SGLT-2 inhibitors might improve the efficiency of myocardial energetics by offering β-hydroxybutyrate as an attractive fuel for oxidation and increase hematocrit improving oxygen transport. Finally, decreased vascular stiffness and improved endothelial function are observed with the use of SGLT-2 inhibitors in diabetes. Those multiple nonglycemic effects reinforce SGLT-2 inhibitors as the preferred glucose-lowering drug to treat diabetic patients with heart failure. In the future, they might even be considered in heart failure or chronic kidney disease patients without diabetes.

36

Keywords separated by ' - '

Diabetes mellitus - Energy metabolism - Glomerular filtration rate Heart failure - Plasma volume - Sodium-glucose transporter 2

37

Foot note information

This article is part of the Topical Collection on Heart Failure

AUTHOR'S PROOF 1 2 3 5 4

6 7 8

Curr Treat Options Cardio Med _#####################_ DOI 10.1007/s11936-017-0522-x

Heart Failure (W Tang, Section Editor)

Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond

12 13 14 15 16 17 18 19

Address *,1 Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600, Genk, Belgium Email: [email protected] 2 Doctoral School for Medicine and Life Sciences, Hasselt University, Agoralaan gebouw D, 3590, Diepenbeek, Belgium 3 Department of Clinical and Experimental Medicine, University Hospital Leuven, Herestraat 49, 3000, Leuven, Belgium

20 21 22

* Springer Science+Business Media New York 2017

23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

U N C O R R EC TE D

10

PR O O F

11

Pieter Martens, MD1,2 Chantal Mathieu, MD, PhD3 Frederik H. Verbrugge, MD, PhD1,*

9

This article is part of the Topical Collection on Heart Failure

Keywords Diabetes mellitus I Energy metabolism I Glomerular filtration rate I Heart failure I Plasma volume I Sodium-glucose transporter 2

Opinion statement

This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents. By blocking sodium/glucose uptake in the proximal tubules of the nephron, they induce glycosuria. Treatment with SGLT-2 inhibitors in diabetes leads to a sustained ∼1% reduction in glycated hemoglobin levels, with favorable reductions in both arterial blood pressure (∼3–6 mmHg) and body weight (∼2–4 kg/m2). However, those effects fail to explain fully the dramatic reduction in cardiovascular mortality, heart failure readmissions, and end-stage kidney disease. The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease. SGLT-2 inhibitors decrease proximal tubular sodium and chloride reabsorption, leading to a reset of the tubule-glomerular feedback. This induces plasma volume contraction without activation of the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to better long-term renal preservation, and improves diuretic and natriuretic responses to other diuretic agents. Moreover,

AUTHOR'S PROOF _####_ Page 2 of 14 49 50 51 52 53 54 55 56

Curr Treat Options Cardio Med _#####################_

SGLT-2 inhibitors might improve the efficiency of myocardial energetics by offering βhydroxybutyrate as an attractive fuel for oxidation and increase hematocrit improving oxygen transport. Finally, decreased vascular stiffness and improved endothelial function are observed with the use of SGLT-2 inhibitors in diabetes. Those multiple nonglycemic effects reinforce SGLT-2 inhibitors as the preferred glucose-lowering drug to treat diabetic patients with heart failure. In the future, they might even be considered in heart failure or chronic kidney disease patients without diabetes.

Introduction

57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75

Diabetes frequently concurs with heart failure (HF) and may contribute to its development [1]. Indeed, registries indicate that diabetes is found in 40% of HF patients with reduced and up to 45% with preserved ejection fraction [2–4]. In the Framingham cohort, diabetic men and women had a 2.4- and 5-fold increased risk to develop HF, respectively [5]. Moreover, the presence of diabetes confers a 30% greater risk for hospital admissions due to HF [6]. Potentially mediating the detrimental effects of diabetes in HF are metabolic alterations with lipotoxicity, renin-angiotensin-aldosterone system activation, oxidative stress, microcirculatory and endothelial dysfunction, and altered myocardial calciumcycling [7•]. Treatment of diabetes in HF—as in the general population—has focused on increasing β-cell activity, replacing insulin, or restoring insulin sensitivity. For these purposes, numerous pharmacological agents and medication classes are available. Disturbingly, however, an increased incidence of HF hospitalizations has

95

Mechanism of action of sodium-glucose transporter2 inhibitors

PR O O F

U N C O R R EC TE D

96 97 98 99 100 101 102 103 104 105 106 107 108 109 110

been observed with peroxisome proliferatoractivated receptor gamma (PPARγ) agonists and the dipeptidyl peptidase-4 (DPP-4) inhibitor saxagliptin [8, 9, 10•]. On this background, inhibitors of the sodium-glucose transporter-2 (SGLT-2) have emerged as the latest class of agents to improve glycemic control. Remarkably, the SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality which might be due at least in part to a reduction in worsening HF [11••]. These results have gathered strong interest of the scientific community to test whether SGLT-2 inhibitors may constitute a dedicated HF treatment—even without the presence of concurrent diabetes—and studies testing this hypothesis are currently underway. This review article provides essential mechanistic insight in the pleiotropic effects of SGLT-2 inhibitors, with a particular interest to the pathophysiology of HF.

In normal circumstances, assuming an average blood glucose level of 100 mg/ dL and glomerular filtration rate (GFR) of 125 mL/min/1.73 m2, 180 g glucose is filtered by the renal glomeruli on a daily base. Importantly, this glucose load presented to the renal tubules is completely reabsorbed, preventing an unfavorable waste of energy [12]. The high capacity, low affinity SGLT-2 is located almost exclusively in the S1 and S2 segments of the proximal tubules. Residing there at the luminal membrane of proximal tubular cells, it is responsible for approximately 90% of glucose reabsorption. The remaining glucose is reabsorbed by a related transporter that is predominant in the S3 segment of the proximal tubules, i.e., the sodium-glucose transporter-1 (SGLT-1), which has lower capacity but higher affinity for glucose. Importantly, there is marked upregulation of the SGLT-2 in the case of hyperglycemia, explaining the much higher threshold of approximately 300-g filtered glucose before occurrence of glycosuria in diabetes [13, 14]. Thus, in the setting of untreated diabetes with

76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

AUTHOR'S PROOF Curr Treat Options Cardio Med _#####################_

134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158

PR O O F

hyperglycemia, the SGLT-2 is working at maximal capacity to minimize urinary glucose loss, thereby contributing to hyperglycemia. SGLT-2 hyperactivity also implies increased proximal tubular reabsorption of sodium as well as chloride—the latter is following sodium, driven by the lumen-negative potential present in the S1 and S2 segments of the proximal tubules. The result is a lower chloride concentration presented to the macula densa, which in turn stimulates an increase in GFR through dilation of the afferent arteriole, a mechanism called tubulo-glomerular feedback [15]. This mechanism is responsible for the phenomenon of glomerular hyper-filtration, often observed early on in diabetes and probably accountable for the development of glomerular hypertension and diabetic nephropathy, as is suggested by animal experiments with SGLT-2 knockout mice [16–18]. SGLT-2 inhibitors, at commercially available doses in patients with normal or elevated GFR, induce glycosuria of approximately 60-90 g/day by blocking SGLT-2-mediated proximal tubular glucose reabsorption [19]. Remarkably, this amount of glucose constitutes only about half the load filtered by the glomerulus, indicating some compensatory activity of the SGLT-1. Furthermore, the efficacy of SGLT-2 inhibitors to induce glycosuria decreases with lower plasma glucose levels or a drop in GFR, explaining their inherent low risk for development of hypoglycemia. Treatment of a diabetic patient with an SGLT-2 inhibitor leads to a sustained 0.4–0.6% reduction in glycated hemoglobin (HbA1c) levels, with favorable reductions in both arterial blood pressure (approximately 3–6 mmHg) and body weight (approximately 1–2 kg/m2) [20–22].

U N C O R R EC TE D

111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133

Page 3 of 14 _####_

Glucose-lowering drugs in diabetes and cardiovascular risk The United Kingdom Prospective Diabetes Study (UKPDS) was the first large trial that assessed the impact of glycemic control on cardiovascular endpoints. In the original trial, 3867 patients with newly diagnosed diabetes were randomized toward intensive (HbA1c achieved 7.0%) versus conventional glycemic control (HbA1c achieved 7.9%). Pharmacological interventions used were insulin and sulfonylurea at that time. UKPDS demonstrated a highly significant 25% reduction in microvascular complications of diabetes after 10 years, yet no significant reduction in cardiovascular endpoints was observed [23]. However, results of a subsequent 10-year post-interventional follow-up of the UKPDS survivor cohort did show a significant reduction of all-cause mortality and myocardial infarction in the original intervention group, despite similar glycemic control compared to the control group during the post-intervention period [24]. This observation, termed the legacy effect, may indicate that the benefits of glycemic control on macrovascular endpoints accrue slowly over time and are more likely to occur when treatment is started early after the diagnosis of diabetes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was subsequently designed to determine whether a strategy of targeting normal HbA1c levels G6.0% compared to G7.5% would reduce the cardiovascular risk even further. In contrast to UKPDS, patients in the ACCORD trial had established diabetes and were at high cardiovascular risk. The study was stopped early in 2008 because of increased all-cause mortality in the tight glucose control arm [25]. Concerns that the increased mortality risk was due to a higher use of the PPARγ agonist rosiglitazone let the Food and Drug

AUTHOR'S PROOF _####_ Page 4 of 14 159 160 161 162 163 164 165 166

Administration and European Medicines Agency to decide that new diabetes drugs should demonstrate cardiovascular safety using a primary end-point of major adverse cardiac events [26]. Table 1 provides an overview of currently available glucose-lowering drugs and a summary regarding their effects on cardiovascular risk. Currently, only the SGLT-2 inhibitor empagliflozin (relative risk reduction 38% after 3 years) and the glucagon-like peptide-1 agonists liraglutide (relative risk reduction 22% after 4 years) have shown a significant reduction in cardiovascular mortality.

Glucose-lowering drugs in diabetes and heart failure risk

168 169 170 171 172 173

Despite the fact that the incidence of HF hospitalizations is inversely associated with HbA1c levels, there is little evidence in support of intensive glycemic control to prevent worsening HF [27]. In fact, some glucose-lowering drugs have been associated with an increased HF risk (Table 1) [28•, 29]. PPARγ agonists induce weight gain by increasing fat acid storage in adipocytes and

PR O O F

167


Table 1. Glucose-lowering agents and cardiovascular as well as heart failure risk

Medication class Insulin

t1:2

Unsure, but some degree of fluid retention is promoted

Unsure, neutral effect indicated by observational data

Unsure, neutral effect indicated by observational data

Rosiglitazone

Increased risk

Increased risk

Pioglitazone

Potentially decreased risk

Increased risk

Neutral effect Neutral effect Neutral effect

Increased risk Potentially increased riska Neutral effect

Neutral effect Decreased risk

Neutral effect Potentially decreased riska

Decreased riskb

Neutral effect

Decreased riskc Safe, no adequately powered RCT available Safe, no adequately powered RCT available

Markedly decreased risk Unknown Unknown

Sulphonylureas

t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10

DPP-4 inhibitors Saxagliptin Alogliptin Sitagliptin

GLP-1 agonists Lixisenatide Liraglutide

SGLT-2 inhibitors

t1:14

Empagliflozin Canagliflozin Dapagliflozin

t1:16 t1:17 t1:18

Unsure, but potentially protective as indicated by observational data

PPARγ agonists

t1:11 t1:12 t1:13

t1:15

Heart failure risk

Unknown. Observational studies indicate increased risk, but are probably confounded by indication. RCT deemed not ethical. Unsure, but likely beneficial as indicated by abundant observational data

Metformin

t1:3

Cardiovascular risk

U N C O R R EC TE D

t1:1

Semaglutide

DPP-4 dipeptidyl peptidase-4, GLP-1 glucagon-like peptide-1, PPARγ peroxisome proliferator-activated receptor gamma, RCT randomized clinical trial, SGLT-2 sodium-glucose transporter-2 a Indicate nonsignificant trend in randomized clinical trial b Driven by nonfatal myocardial infarction without difference in cardiovascular mortality c Although potentially elevated stroke risk


184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221

Sodium-glucose transporter-2 inhibitors and heart failure risk

PR O O F

183

promote sodium retention through activation of epithelial sodium channels in the distal tubules of the nephron. Therefore, it should not be surprising that their use in diabetes is associated with a 42% increased risk for HF admissions [28•, 30]. The risk for worsening HF with DPP-4 inhibitors is less consistent, not readily explained, and might depend on the specific agent used [28•]. Finally, there is concern that any glucose-lowering drug that induces weight gain (i.e., insulin, sulphonylurea, and PPARγ agonists) may thereby contribute to worsening HF, as every 1 kg of weight gain in diabetes is associated with a 7% increased risk for HF readmissions [28•].

Only one SGLT-2 trial powered for cardiovascular safety evaluation has been completed to date. The BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) randomized 7020 patients with type 2 diabetes, an estimated GFR 930 mL/min/1.73 m2, and established cardiovascular disease (11% were previously admitted for HF and 47% had a myocardial infarction) to receive placebo, empagliflozin 10 mg, or empagliflozin 25 mg on top of usual glucose-lowering care [11••]. The trial was eventdriven by occurrence of the primary endpoint which was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Treatment with empagliflozin not only demonstrated noninferiority but actually proved superior with a 14% risk reduction (HR 0.86, 95%CI 0.74-0.99, P = 0.04) and few differences among both dosing strategies. Interestingly, this significant difference was driven by a 38% reduction in cardiovascular mortality (HR 0.62, 95%CI 0.49 0.77, P G 0.001), while the risk of either nonfatal myocardial infarction or nonfatal stroke was not reduced. Furthermore, the effect on cardiovascular mortality occurred early within 2–3 months, suggesting that it was unlikely to be explained by an effect of better glycemic control on atherosclerosis progression. Looking at predefined secondary endpoints in EMPA-REG OUTCOME may hint toward the mechanisms driving improved cardiovascular outcomes. Empagliflozin strikingly reduced HF hospitalizations by a third, which was consistent among subgroups [31•]. In addition, the SGLT-2 inhibitor slowed progression of renal disease and reduced the need for dialysis [32••]. Conclusively, it is unlikely that the modest differences in glycemic control between the placebo and empagliflozin arms account for the dramatic reductions in cardiovascular, heart failure, and kidney disease. More evidence supporting a class effect of SGLT-2 inhibitors will arise when the results of the CANagliflozin cardiovascular Assessment Study (CANVAS) with canagliflozin (NCT01032629), the Multicenter Trial to Evaluate the Effect of Dapagliflozin on the incidence of Cardiovascular Events (DECLARE-TIMI58) with dapagliflozin (NCT01730534), and the Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS CV) study with ertugliflozin (NCT01986881) become available. CANVAS is expected to report in 2017, with DECLARE-TIMI58 later in 2019 and the VERTIS-CV study in 2020.

U N C O R R EC TE D

174 175 176 177 178 179 180 181 182

Page 5 of 14 _####_

AUTHOR'S PROOF _####_ Page 6 of 14

222

Nonglycemic effects of sodium-glucose transporter-2 inhibitors

223 224 225 226 227 228 229 230

The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease (Fig. 1). As HF is more and more recognized as a systemic condition with broad implications for every organ in the body, it should not be surprising that SGLT-2 inhibitors—with their pleiotropic effects—look especially promising as a treatment.

PR O O F

Sodium-glucose transporter-2 inhibitors reduce plasma volume and increase hematocrit Neurohumoral activation in HF results in enhanced renal sodium avidity [33•]. As 65% of retained sodium is buffered in the extracellular compartment in an isoosmotic fashion, it is not surprising that HF patients demonstrate plasma volume expansion [34, 35]. Direct measurements of plasma volume in HF illustrate that such an expansion is positively correlated with all-cause mortality and readmissions, even when congestion is subclinical and not reflected by clear signs of volume overload [36]. Furthermore, plasma volume reduction in acute HF, reflected by the occurrence of hemoconcentration, is associated with improved outcomes [37–39]. SGLT-2 inhibitors result in a 1:1 stoichiometric inhibition of sodium and glucose uptake in the proximal tubules of the nephron [40]. This leads to more tubular chloride offered to the macula densa at the end of Henle’s loop, resulting in a reset of the tubulo-glomerular feedback at lower plasma volume [15, 33•, 40]. Indeed, already within 1 week of treatment with SGLT-2 inhibitors, body weight drops significantly, probably tracking better with sodium and water loss than with caloric loss due to glycosuria [21]. Moreover, direct measurements of plasma volume after 12 weeks of treatment with dapagliflozin have demonstrated a 7% reduction with a parallel increase in hematocrit [41•]. Although erythropoietin concentration—stimulating red blood cell mass and thus hematocrit—also rises following initiation of SGLT-2 inhibitors, this effect dissipates quickly within 6–8 weeks and is unlikely to explain the observed drop in plasma volume [41•]. Instead, because SGLT-2 inhibitors reduce the afferent arteriolar tone by means of the tubulo-glomerular feedback as explained above, blood flow in the renal medulla is decreased. Specialized peritubular fibroblast-

U N C O R R EC TE D

231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254

Q1


Fig. 1. Pleiotropic effect of sodium-glucose transporter-2 inhibitors. ADHF acute decompensated heart failure.


Q2

Sodium-glucose transporter-2 inhibitors protect against glomerular hypertension Because of glomerular autoregulation mechanisms, GFR is well-maintained until a substantial drop in renal blood flow (RBF) occurs, which is also true in HF [33•]. Indeed, with decreasing RBF, the glomerulus responds by increasing the proportion of plasma that is filtered toward the tubular system. A major determinant of this filtration fraction is the hydrostatic pressure residing inside the glomerular capillaries. This pressure, which increases upon afferent arteriolar vasodilation or efferent arteriolar vasoconstriction, promotes increased filtration. Renin-angiotensin-aldosterone system activation, characteristically present in HF as well as many other conditions including chronic kidney disease and liver disease, causes potent efferent arteriolar vasoconstriction [45]. In chronic kidney disease whereas the number of functional nephrons is rapidly declining, this increase in efferent arteriolar vasoconstriction augments filtration in the remaining nephrons to preserve total GFR, but does so at the cost of elevated hydrostatic pressure inside the glomerular capillaries. The consequence of such glomerular hypertension is damage to the glomerular basement membrane with accelerated podocyte loss and eventually complete atrophy of the nephron [46]. Upon initiation of a renin-angiotensin system blocker in this context, an initial rise in serum creatinine is often observed, indicating a drop in GFR because of acute lowering of the intra-glomerular hydrostatic pressure. Nevertheless, the final result is better renal preservation on the long-term. Indeed, it has been shown that patients with chronic kidney disease who exhibit the most pronounced acute drop in GFR upon introduction of the angiotensin receptor blocker losartan have the slowest subsequent deterioration over time [47]. Similarly, early worsening renal function after introduction of a reninangiotensin system blocker in heart failure is associated with better, not worse prognosis [48]. A very similar pattern of an acute drop in GFR with subsequent renal preservation was observed with empagliflozin in the EMPA-REG trial [32••]. Intriguingly, just like renin-angiotensin system blockers, SGLT-2 inhibitors decrease the intra-glomerular hydrostatic pressure. Yet, they achieve this through promotion of afferent arteriolar vasoconstriction rather than efferent arteriolar vasodilation. The mechanism is again explained by tubuloglomerular feedback. As mentioned, decreased proximal tubular reabsorption of sodium with SGLT-2 inhibitors results in more sodium and chloride being presented to the macula densa that were taken up at the luminal side of the tubules by the Na/K/2Cl-symporter [49]. This process requires energy that requires breakdown of adenosine triphosphate to adenosine, with the latter promoting afferent arteriolar vasoconstriction after paracrine secretion. In an

PR O O F

265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303

type cells in the renal medulla subsequently respond to decreased loco-regional oxygen concentration with erythropoietin release [42]. Intriguingly, because the tubulo-glomerular feedback is reset with SGLT-2 inhibitors, there is a lack of sympathetic nerve system activation, despite a potent reduction in plasma volume, which is especially attractive in HF from a pathophysiological perspective [43•]. The decreased plasma volume also increases hematocrit, possibly resulting in a better oxygen transport [44•]. However, this increase in hematocrit was also suggested to be implicated in the (nonsignificant) trend in increased risk for nonfatal stroke observed in the EMPA-REG OUTCOME study [11••].

U N C O R R EC TE D

255 256 257 258 259 260 261 262 264 263

Page 7 of 14 _####_


elegant experiment, Cherney et al. measured GFR and RBF directly through inulin and para-amino-hippurate in 13 diabetic patients with and 27 diabetic patients without glomerular hyper-filtration [50]. Empagliflozin at a dose of 25 mg once daily reduced RBF and GFR, but only in patients with glomerular hyper-filtration, without any meaningful effect on glomerular hemodynamics in the other group. This may indicate that SGLT-2 inhibitors specifically target disturbed glomerular hemodynamics, correcting the culprit lesion of glomerular hypertension in renal disease progression. Analysis of the EMPA-REG trial suggests that by doing so, there could be a 55% relative risk reduction in the need for renal replacement therapy for the population studied [32••]. Whether this holds true also with other SGLT-2 inhibitors or in different populations such as patients with HF but without diabetes, or even in chronic kidney disease or liver disease, remains the subject of further study. Additionally, more data are needed regarding the simultaneous use of renin-angiotensin system blockers and SGLT-2 inhibitors and their influence on glomerular hemodynamics. Theoretically, both medications might work synergistically to protect the glomerulus from hyper-filtration [51].

PR O O F

304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 321 320


322 323 324 325 326 327 328 329 330 331 332 333 335 334

Sodium-glucose transporter-2 inhibitors may improve diuretic efficiency

336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352

Sodium-glucose transporter-2 inhibitors improve cardiac metabolism

U N C O R R EC TE D

Reduction of proximal sodium reabsorption by SGLT-2 inhibitors, together with enhanced tubular flow secondary to osmotic diuresis, causes more sodium being offered to Henle’s loop and the distal nephron. Therefore, though increased substrate availability, SGLT-2 inhibitors might improve the diuretic and natriuretic response to loop and thiazide-type diuretics, which are often used in HF but exert their effects more distally in the nephron. In acute HF, combinational diuretic therapy with acetazolamide—another inhibitor of sodium reabsorption in the proximal renal tubules—results in the excretion of approximately 100 mmol sodium in excess per milligram of bumetanide administered intravenously over 24 h [52]. Similar effects might be expected with SGLT-2 inhibitors. This is especially important as diuretic efficiency has recently been emerging as a powerful prognosticator in HF, independently of underlying kidney function [53].

An adult heart consumes 6 kg of adenosine triphosphate on a daily basis [54]. In patients with diabetes and insulin resistance, there is increased cardiac uptake of glucose, lactate, and pyruvate at the cost of free fatty acids and βhydroxybutyrate, as insulin suppresses whole-body lipolysis [55]. As pyruvate is a far less favorable substrate to mitochondrial oxidation compared to βhydroxybutyrate, this is associated with substantially increased myocardial oxygen demands [56]. Indeed, the phosphocreatine/adenosine triphosphate ratio, representative of the effectiveness of the myocardium to meet its metabolic demands, is diminished in patients with diabetes [57]. In addition, impaired lipolysis enhances mitochondrial oxygen species production and the accumulation of toxic lipid intermediates [58]. SGLT-2 inhibitors might beneficially influence this cardiac metabolic disarray. In patients with type 2 diabetes, treatment with empagliflozin results in a drop in insulin levels, while enhancing postprandial glucagon concentration [59]. The subsequently reduced insulin-to-glucagon ratio in the vena porta stimulates hepatic ketogenesis. Therefore, treatment with empagliflozin results in a 2- to 3-fold increase in


361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390

Sodium-glucose transporter-2 inhibitors reduce arterial stiffness and improve endothelial function Arterial stiffness is a predictor of HF morbidity and mortality [62]. Mechanistically, increased arterial stiffness imposes a higher load upon the ventricles, further deteriorating pump failure. Cardio-protective medications such as angiotensinconverting enzyme inhibitors and statins have demonstrated to reduce arterial stiffness [63]. Also, treatment with SGLT-2 inhibitors results in significant improvements in markers of arterial stiffness such as pulse wave velocity and pulse pressure difference [43•]. Although the underlying mechanisms for this observation are insufficiently elucidated, reduction of total body sodium might be implied. Indeed, sodium overload is associated with damage to the endothelial glycocalyx in HF, resulting in decreased bio-availability of nitric oxide for vascular smooth muscle cell relaxation [35]. Further supporting beneficial effects of SGLT2 inhibitors on vascular health is the observation that treatment with dapagliflozin reduces C-reactive protein levels in diabetic patients [64]. Finally, SGLT-2 inhibition results in a drop of plasma uric acid levels, which have also been related to endothelial function in observational studies [31•, 65].

PR O O F

360

fasting and postprandial levels of β-hydroxybutyrate [60]. Consequently, increased fuel usage of ketone bodies by the heart is associated with lower oxygen consumption to achieve the same amount of work [44•]. Furthermore, βhydroxybutyrate combustion results in less production of reactive oxygen species compared to free fatty acid oxidation, and it is capable of stabilizing the inner mitochondrial membrane potential [61].

U N C O R R EC TE D

353 354 355 356 357 358 359

Page 9 of 14 _####_

Potential adverse effects of sodium-glucose transporter-2 inhibitors A clear link has been shown between glycosuria induced by SGLT-2 inhibitors and an increased risk for urinary, but especially genital infections, mainly due to Candida species [66•]. A large meta-analysis of more than 35,000 patients has illustrated a relative risk of 15% (HR 1.15, 95%CI 1.06–1.26) for urinary tract infections, while the risk for genital infections was nearly five times increased with SGLT-2 inhibitors (HR 4.75, 95%CI 4.00–5.63). Besides, volume depletion secondary to natriuresis and osmotic diuresis may occur in patients at risk including older patients, patients using diuretics or suffering from preexisting chronic kidney disease [66•]. Larger meta-analyses do not confirm early reports of an enhanced risk for bladder cancer, bone fraction due to accelerated osteoporosis, venous thrombosis or keto-acidosis—at least when prescribed on label for type 2 diabetes [66•].

392

The prospect of sodium-glucose transporter-2 inhibitors in heart failure

393 394 395 396 397

The beneficial pleiotropic effects of SGLT-2 inhibitors within the cardiovascular system, together with their favorable safety profile, make this medication class attractive for the treatment of diabetes in patients with HF as well as cardiovascular diseases in general. As the risk for hypoglycemic episodes is low, SGLT-2

391



Table 2. Registered trials evaluating SGLT-2 inhibitors with a primary heart failure endpoint

Diabetes required

Design

Comparators

Primary outcome

Sample size

NCT02397421

Yes

NCT02653482

Yes

Dapagliflozin vs. placebo Dapagliflozin vs. placebo

t2:4

NCT02920918

Yes

Randomized and double-blind

Canagliflozin vs. sitagliptin

t2:5

NCT02728453

Yes

t2:6

NCT02862067

Yes

Randomized and double-blind Prospective observational

Empagliflozin vs. glimepiride Empagliflozin

Change in LVESV and LVESV after 1 year on MRI Change in NT-proBNP and KCCQ after 12 weeks. Improvement of VO2max and VE/VCO2 at 12 weeks. Change in LV-mass on MRI after 24 weeks. Improvement of VO2max and VE/VCO2 at 12 weeks.

N = 56

t2:3

Randomized and double-blind Randomized and double-blind

t2:7

RCT randomized controlled trial, LVESV left ventricular end-systolic volume, LVESD left ventricular end-diastolic volume, KCCQ Kansas City cardiomyopathy questionnaire, LV left ventricle

418 419 420 421 422 423 424

N = 250

N = 88

N = 60 N = 31

inhibitors might even benefit HF patients in the absence of diabetes because they reduce plasma volume expansion, improve natriuretic and diuretic responses, as well as shift the myocardial metabolism toward more favorable energetics [40, 51]19. Furthermore, in patient with impaired GFR G30 mL/min/1.73 m2, SGLT-2 inhibitors exhibit a blunted or complete loss of glycosuric effects, yet presumably without complete loss of influence on the tubulo-glomerular feedback system, which then remains an attractive target to protect the glomerulus against hyperfiltration. Results from the EMPA-REG trial suggest that SGLT-2 inhibitors might become a viable candidate to slow the progression of renal dysfunction in HF, chronic kidney disease, and other conditions associated with glomerular hypertension. This may also prove to be a particularly attractive target in HF patients with preserved ejection fraction for whom no current pharmacological therapies have demonstrated clear benefits [67]. This hypothesis is further reinforced by the beneficial effects that are observed with SGLT-2 inhibitors on endothelial function which is believed to be a pathophysiological culprit in HF with preserved ejection fraction. Table 2 highlights currently registered studies with SGLT-2 inhibitors in patients with HF. Undoubtedly, the near future will bring more registrations and publications of dedicated and large HF trials with SGLT-2 inhibitors. Their future looks bright!

U N C O R R EC TE D

398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417

PR O O F

NCT number

t2:1 t2:2

Compliance with Ethical Standards Conflict of Interest Pieter Martens is supported by a doctoral fellowship by the Research Foundation – Flanders (FWO, 1127917N) and is a researcher for the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital.


Page 11 of 14 _####_

425

Chantal Mathieu and Frederik H. Verbrugge each declare no potential conflicts of interest.

426 427 428

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

429 430 431 432 433 434

References and Recommended Reading

435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479

1.

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

PR O O F

rosiglitazone in type 2 diabetes: data from the RECORD clinical trial. Eur Heart J. 2010;31(7):824–31. 10.• Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. Large trial designed to prove cardiovascular safety of the dipeptidyl peptidase-4 inhibitor saxagliptin that showed an increased risk for heart failure. 11.•• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. The only trial powered for cardiovascular end-points evaluation with a sodium-glucose transporter-2 inhibitor showing an unprecedented 38% reduction in cardiovascular mortality. 12. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94. 13. Freitas HS, Anhe GF, Melo KF, Okamoto MM, OliveiraSouza M, Bordin S, et al. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology. 2008;149(2):717–24. 14. Vidotti DB, Arnoni CP, Maquigussa E, Boim MA. Effect of long-term type 1 diabetes on renal sodium and water transporters in rats. Am J Nephrol. 2008;28(1):107–14. 15. Schnermann J. Juxtaglomerular cell complex in the regulation of renal salt excretion. Am J Physiol. 1998;274(2 Pt 2):R263–79. 16. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10(12):2569–76. 17. Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, et al. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Ren Physiol. 2013;304(2):F156–67. 18. Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to

U N C O R R EC TE D

Mentz RJ, Kelly JP, von Lueder TG, Voors AA, Lam CS, Cowie MR, et al. Noncardiac comorbidities in heart failure with reduced versus preserved ejection fraction. J Am Coll Cardiol. 2014;64(21):2281–93. 2. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, management, and in-hospital outcomes of patients admitted with acute decompensated heart failure with preserved systolic function: a report from the Acute Decompensated Heart Failure National Registry (ADHERE) Database. J Am Coll Cardiol. 2006;47(1):76–84. 3. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, Greenberg BH, et al. Characteristics, treatments, and outcomes of patients with preserved systolic function hospitalized for heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol. 2007;50(8):768–77. 4. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol. 2012;59(11):998–1005. 5. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34(1):29–34. 6. Cubbon RM, Woolston A, Adams B, Gale CP, Gilthorpe MS, Baxter PD, et al. Prospective development and validation of a model to predict heart failure hospitalisation. Heart. 2014;100(12):923–9. 7.• Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2016. Recent meta-analysis providing an insightful overview of heart failure outcomes in clinical trials with glucose lowering drugs in patients with diabetes. 8. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89. 9. Komajda M, McMurray JJ, Beck-Nielsen H, Gomis R, Hanefeld M, Pocock SJ, et al. Heart failure events with

480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524

AUTHOR'S PROOF hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Ren Physiol. 2014;306(2):F194–204. 19. Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013;1(2):140–51. 20. Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2014;16(5):457–66. 21. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose cotransporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262–75. e9. 22. Oliva RV, Bakris GL. Blood pressure effects of sodiumglucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8(5):330–9. 23. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837–53. 24. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89. 25. Group AS, Gerstein HC, Miller ME, Genuth S, IsmailBeigi F, Buse JB, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–28. 26. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71. 27. Control G, Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288–98. 28.• Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 2015;3(5):356–66. Recent meta-analysis providing an insightful overview of cardiovascular outcomes in clinical trials with glucose lowering drugs in patients with diabetes. 29. Hippisley-Cox J, Coupland C. Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care. BMJ. 2016;354:i3477. 30. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care. 2004;27(1):256–63. 31.• Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high

cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37(19):1526–34. Subanalysis of the EMPA-REG trial with empagliflozin (reference 11) with focus on heart failure reduction achieved with this medication. 32.•• Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323–34. Subanalysis of the EMPA-REG trial with empagliflozin (reference 11) clearly demonstrating the renoprotective effect of empagliflozin in diabetes. 33.• Verbrugge FH, Dupont M, Steels P, Grieten L, Swennen Q, Tang WH, et al. The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’. Eur J Heart Fail. 2014;16(2):133–42. This review on renal sodium handling in heart failure comprehensively explains the rationale behind inhibition of proximal tubular sodium reabsorption in heart failure which is a major effect of sodium-glucose transporter-2 inhibitors. 34. Miller WL, Mullan BP. Understanding the heterogeneity in volume overload and fluid distribution in decompensated heart failure is key to optimal volume management: role for blood volume quantitation. JACC Heart Fail. 2014;2(3):298–305. 35. Nijst P, Verbrugge FH, Grieten L, Dupont M, Steels P, Tang WH, et al. The pathophysiological role of interstitial sodium in heart failure. J Am Coll Cardiol. 2015;65(4):378–88. 36. Kalra PR, Anagnostopoulos C, Bolger AP, Coats AJ, Anker SD. The regulation and measurement of plasma volume in heart failure. J Am Coll Cardiol. 2002;39(12):1901–8. 37. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation. 2010;122(3):265–72. 38. van der Meer P, Postmus D, Ponikowski P, Cleland JG, O’Connor CM, Cotter G, et al. The predictive value of short-term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure. J Am Coll Cardiol. 2013;61(19):1973–81. 39. Testani JM, Brisco MA, Chen J, McCauley BD, Parikh CR, Tang WH. Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion. J Am Coll Cardiol. 2013;62(6):516–24. 40. Verbrugge FH, Vangoitsenhoven R, Mullens W, Van der Schueren BJ, Mathieu C, Tang WH. SGLT-2 inhibitors: potential novel strategy to prevent congestive heart failure in diabetes? Curr Cardiovasc Risk Rep. 2015;9:38. 41.• Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853–62. Important study highlighting that plasma volume is decreased

U N C O R R EC TE D

Q3

525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583


PR O O F

_####_ Page 12 of 14

584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642

AUTHOR'S PROOF Curr Treat Options Cardio Med _#####################_ 53. 54. 55.

56. 57.

Verbrugge FH, Mullens W, Tang WH. Management of cardio-renal syndrome and diuretic resistance. Curr Treat Options Cardiovasc Med. 2016;18(2):11. Neubauer S. The failing heart–an engine out of fuel. N Engl J Med. 2007;356(11):1140–51. Ferrannini E, Santoro D, Bonadonna R, Natali A, Parodi O, Camici PG. Metabolic and hemodynamic effects of insulin on human hearts. Am J Physiol. 1993;264(2 Pt 1):E308–15. Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, et al. Insulin, ketone bodies, and mitochondrial energy transduction. Faseb J. 1995;9(8):651–8. Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, et al. Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with wellcontrolled type 2 diabetes mellitus. J Am Coll Cardiol. 2003;42(2):328–35. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes. 2002;51(8):2587–95. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508. Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24week, randomized, double-blind, placebo-controlled, Phase III study. Expert Opin Pharmacother. 2014;15(11):1501–15. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 2013;339(6116):211–4. Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol. 2012;60(16):1455–69. Mackenzie IS, McEniery CM, Dhakam Z, Brown MJ, Cockcroft JR, Wilkinson IB. Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension. 2009;54(2):409–13. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217–24. Lytvyn Y, Perkins BA, Cherney DZ. Uric acid as a biomarker and a therapeutic target in diabetes. Can J Diabetes. 2015;39(3):239–46. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundstrom J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2

PR O O F

after treatment with the sodium-glucose transporter-2 inhibitor dapagliflozin in diabetes. 42. Cheungpasitporn W, Thongprayoon C, Chiasakul T, Korpaisarn S, Erickson SB. Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis. QJM. 2015;108(11):879–84. 43.• Cherney DZ, Scholey JW, Jiang S, Har R, Lai V, Sochett EB, et al. The effect of direct renin inhibition alone and in combination with ACE inhibition on endothelial function, arterial stiffness, and renal function in type 1 diabetes. Diabetes Care. 2012;35(11):2324–30. Insightful study demonstrating that the sodium-glucose transporter-2 inhibitor empagliflozin was able to reverse glomerular hyperfiltration in diabetes. 44.• Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108–14. Interesting review explaining the hypothesis that sodiumglucose transporter-2 inhibitors improve cardiac metabolism in diabetes by stimulating β-hydroxybutyrate oxidation as an efficient energy fuel. 45. Carlstrom M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol Rev. 2015;95(2):405–511. 46. Kriz W, Shirato I, Nagata M, LeHir M, Lemley KV. The podocyte’s response to stress: the enigma of foot process effacement. Am J Physiol Ren Physiol. 2013;304(4):F333–47. 47. Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011;80(3):282–7. 48. Testani JM, Kimmel SE, Dries DL, Coca SG. Prognostic importance of early worsening renal function after initiation of angiotensin-converting enzyme inhibitor therapy in patients with cardiac dysfunction. Circ Heart Fail. 2011;4(6):685–91. 49. Zingerman B, Herman-Edelstein M, Erman A, Bar Sheshet Itach S, Ori Y, Rozen-Zvi B, et al. Effect of acetazolamide on obesity-induced glomerular hyperfiltration: a randomized controlled trial. PLoS One. 2015;10(9):e0137163. 50. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–97. 51. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752–72. 52. Verbrugge FH, Dupont M, Bertrand PB, Nijst P, Penders J, Dens J, et al. Determinants and impact of the natriuretic response to diuretic therapy in heart failure with reduced ejection fraction and volume overload. Acta Cardiol. 2015;70(3):265–73.

58.

59.

U N C O R R EC TE D

643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701

Page 13 of 14 _####_

60.

61.

62.

63.

64.

65. 66.•

702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760

AUTHOR'S PROOF 761 762 763 764 765

_####_ Page 14 of 14


diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4(5):411–9. Recent meta-analysis comprising over 35,000 patients focusing on safety and adverse events of sodium-glucose transporter-2 inhibitors in diabetes.

67.

Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr., Drazner MH, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013.

U N C O R R EC TE D

PR O O F

772

766 767 768 769 770 771

AUTHOR'S PROOF AUTHOR QUERIES AUTHOR PLEASE ANSWER ALL QUERIES.

U N C O R R EC TE D

PR O O F

Q1. Figure 1 contains poor quality of text. Please provide replacement figure file. Q2. The sentence “As mentioned, decreased proximal tubular reabsorption of sodium with…” was edited for clarity. Please check if the intended meaning was retained. Q3. Please provide complete bibliographic details of this reference.