The
n e w e ng l a n d j o u r na l
men in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials. Eur Heart J 2009;30:1385-94. 8. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J. Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358:2130-1. 9. Lv JC, Neal B, Ehteshami P, et al. Effects of intensive blood
of
m e dic i n e
pressure lowering on cardiovascular and renal outcomes: a systematic review and meta-analysis. PLoS Med 2012;9(8):e1001293. 10. MacMahon S, Neal B, Rodgers A. Hypertension — time to move on. Lancet 2005;365:1108-9. DOI: 10.1056/NEJMe1513301 Copyright © 2015 Massachusetts Medical Society.
Cardiovascular Risk and Sodium–Glucose Cotransporter 2 Inhibition in Type 2 Diabetes Julie R. Ingelfinger, M.D., and Clifford J. Rosen, M.D. Patients with type 2 diabetes mellitus are at increased risk for incident cardiovascular and renal disease, conditions that increase the risk of death at a young age.1 Although intensive glycemic control has improved surrogate markers of cardiovascular risk in such patients, there has been no significant reduction in the risk of major adverse cardiovascular events (MACE), including nonfatal stroke or myocardial infarction and death from cardiovascular causes.2 Now, in the results of the EMPA-REG OUTCOME trial published in this issue of the Journal, Zinman et al. report a decreased risk of death from all causes and cardiovascular causes among patients with type 2 diabetes who are at high risk for cardiovascular events.3 This study evaluated empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, which prevents renal glucose resorption, thereby lowering plasma glucose levels. To understand the implications of this trial, it is important to remember that glucose is a polar compound and that its solubility and transportability occur through specialized tissue glucose transporters, particularly in the renal tubule, the small intestine, the brain, and peripheral tissues. Two gene families are involved — the sodium–glucose cotransporters (SGLTs) and facilitated glucose transporters (GLUTs).4-6 Whereas GLUTs facilitate essentially passive transport along membranes, SGLTs are involved in active transport. SGLT2, the most important renal transporter, reabsorbs nearly 90% of the glucose that is filtered by the glomeruli and is minimally expressed elsewhere, and SGLT1 resorbs the remainder. Thus, SGLT2 inhibition is essentially kidney-specific. In contrast, SGLT1 is
2178
widely expressed, so its inhibition would be expected to have wide physiological effects. Targeting how glucose is handled in the kidney is not a new idea for treating diabetes.7 However, the concept that the inhibition of sodium–glucose transport in the kidney could improve insulin resistance and lower glycated hemoglobin levels in the management of type 2 diabetes reemerged recently and led to the development of several SGLT2 inhibitors. To date, three such drugs — canagliflozin, dapagliflozin, and empagliflozin — have been approved by international regulatory agencies for the treatment of type 2 diabetes. SGLT2 inhibitors have insulin-independent effects. Preclinical data indicate that these compounds induce weight loss and decrease blood pressure through processes that are distinct from those involved in decreasing plasma glucose levels. In experimental models of untreated diabetes, proximal tubular sodium resorption is increased, and there is less sodium delivered to distal portions of the nephron and to the juxtaglomerular apparatus. Accordingly, the transduced signal is a diminished plasma volume, which leads to increased intraglomerular pressure and, ultimately, hyperfiltration, along with increases in blood pressure. SGLT2 inhibitors reverse these changes by blocking proximal tubular sodium resorption, which results in negative sodium balance, decreased plasma volume, and reduced blood pressure. Thus, SGLT2 inhibitors alter intrarenal hemodynamics.4 And it is now recognized that renal abnormalities lead to an increase in cardiovascular risk. Unlike the patients who were enrolled in some earlier trials to assess cardiovascular risk
n engl j med 373;22 nejm.org November 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at THE CHINESE UNIVERSITY OF HONG KONG on November 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Editorials
with intensive glucose control, those in the EMPA-REG OUTCOME trial were specifically at very high cardiovascular risk. Nearly half the patients had a history of myocardial infarction, and about three quarters had evidence of coronary artery disease, a quarter had previous stroke, and a fifth had peripheral vascular disease. A majority of the patients had more than a 10-year history of type 2 diabetes, a third had microalbuminuria, and a tenth had macroalbuminuria. Not surprisingly, most patients were taking multiple medications for hyperglycemia, more than 95% were taking antihypertensive agents, and 80% were taking lipid-lowering drugs. Unfortunately, the vast majority of the patients were white, which makes the results difficult to generalize to black and Hispanic patients. In this study, among patients receiving either 10 mg or 25 mg of empagliflozin daily in addition to standard care, the significant decrease in the rate of the 3-point MACE and of reduced death from any cause was impressive. The analysis showed that 39 patients would need to be treated for 3 years to provide a benefit in these outcomes. Furthermore, the results show that a drug that reduces glycated hemoglobin has a meaningful effect on cardiovascular events.3 In addition, more patients in the placebo group had insulin and sulfonylureas added to their regimen for glycemic control than did patients in the empagliflozin groups. Furthermore, adverse events associated with empagliflozin were mild and (as anticipated with a drug that causes glycosuria) included more genital infections. It seems likely that the observed risk reduction in the study was multifactorial. The addition of an SGLT2 inhibitor to standard care may ultimately alter vascular reactivity, as well as cardiac and cardiorenal function — both of which the authors mention. A decrease in albuminuria or in uric acid that is indirectly induced by the drug may be beneficial as well. Other aspects of the effects of the drug may be at play through mechanisms that remain speculative.
However, there are caveats. The results may not be generalizable (e.g., to patients with type 2 diabetes without cardiovascular disease), the risk–benefit profile for this drug class will need further elucidation (particularly for adverse events), and the ultimate position of empagliflozin among multiple drugs in the clinical management of type 2 diabetes will still need to be defined. Thus, it will be important to confirm these results with findings from other ongoing trials of SGLT2 inhibitors, including an evaluation of canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]; ClinicalTrials.gov number, NCT01032629) and of dapagliflozin (DECLARE–TIMI58, NCT01730534). For now, the study by Zinman et al. provides some hope that the risk of cardiovascular death in patients with type 2 diabetes and cardiovascular disease can indeed be modified. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From Tufts University School of Medicine, Boston, and the Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough (C.J.R.). 1. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34. 2. Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818-28. 3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. 4. Abdul-Ghani MA, Norton L, DeFronzo RA. Renal sodiumglucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol 2015 September 9 (Epub ahead of print). 5. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med 2015;66: 255-70. 6. Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis 2009;53:875-83. 7. Chasis H, Jolliffe N, Smith HW. The action of phlorizin on the excretion of glucose, 643 xylose, sucrose, creatinine, and urea by man. J Clin Invest 1933;12:1083-90. DOI: 10.1056/NEJMe1512602 Copyright © 2015 Massachusetts Medical Society.
n engl j med 373;22 nejm.org November 26, 2015
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The New England Journal of Medicine Downloaded from nejm.org at THE CHINESE UNIVERSITY OF HONG KONG on November 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
men in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials. Eur Heart J 2009;30:1385-94. 8. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Diaz R, Probstfield J. Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358:2130-1. 9. Lv JC, Neal B, Ehteshami P, et al. Effects of intensive blood
of
m e dic i n e
pressure lowering on cardiovascular and renal outcomes: a systematic review and meta-analysis. PLoS Med 2012;9(8):e1001293. 10. MacMahon S, Neal B, Rodgers A. Hypertension — time to move on. Lancet 2005;365:1108-9. DOI: 10.1056/NEJMe1513301 Copyright © 2015 Massachusetts Medical Society.
Cardiovascular Risk and Sodium–Glucose Cotransporter 2 Inhibition in Type 2 Diabetes Julie R. Ingelfinger, M.D., and Clifford J. Rosen, M.D. Patients with type 2 diabetes mellitus are at increased risk for incident cardiovascular and renal disease, conditions that increase the risk of death at a young age.1 Although intensive glycemic control has improved surrogate markers of cardiovascular risk in such patients, there has been no significant reduction in the risk of major adverse cardiovascular events (MACE), including nonfatal stroke or myocardial infarction and death from cardiovascular causes.2 Now, in the results of the EMPA-REG OUTCOME trial published in this issue of the Journal, Zinman et al. report a decreased risk of death from all causes and cardiovascular causes among patients with type 2 diabetes who are at high risk for cardiovascular events.3 This study evaluated empagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, which prevents renal glucose resorption, thereby lowering plasma glucose levels. To understand the implications of this trial, it is important to remember that glucose is a polar compound and that its solubility and transportability occur through specialized tissue glucose transporters, particularly in the renal tubule, the small intestine, the brain, and peripheral tissues. Two gene families are involved — the sodium–glucose cotransporters (SGLTs) and facilitated glucose transporters (GLUTs).4-6 Whereas GLUTs facilitate essentially passive transport along membranes, SGLTs are involved in active transport. SGLT2, the most important renal transporter, reabsorbs nearly 90% of the glucose that is filtered by the glomeruli and is minimally expressed elsewhere, and SGLT1 resorbs the remainder. Thus, SGLT2 inhibition is essentially kidney-specific. In contrast, SGLT1 is
2178
widely expressed, so its inhibition would be expected to have wide physiological effects. Targeting how glucose is handled in the kidney is not a new idea for treating diabetes.7 However, the concept that the inhibition of sodium–glucose transport in the kidney could improve insulin resistance and lower glycated hemoglobin levels in the management of type 2 diabetes reemerged recently and led to the development of several SGLT2 inhibitors. To date, three such drugs — canagliflozin, dapagliflozin, and empagliflozin — have been approved by international regulatory agencies for the treatment of type 2 diabetes. SGLT2 inhibitors have insulin-independent effects. Preclinical data indicate that these compounds induce weight loss and decrease blood pressure through processes that are distinct from those involved in decreasing plasma glucose levels. In experimental models of untreated diabetes, proximal tubular sodium resorption is increased, and there is less sodium delivered to distal portions of the nephron and to the juxtaglomerular apparatus. Accordingly, the transduced signal is a diminished plasma volume, which leads to increased intraglomerular pressure and, ultimately, hyperfiltration, along with increases in blood pressure. SGLT2 inhibitors reverse these changes by blocking proximal tubular sodium resorption, which results in negative sodium balance, decreased plasma volume, and reduced blood pressure. Thus, SGLT2 inhibitors alter intrarenal hemodynamics.4 And it is now recognized that renal abnormalities lead to an increase in cardiovascular risk. Unlike the patients who were enrolled in some earlier trials to assess cardiovascular risk
n engl j med 373;22 nejm.org November 26, 2015
The New England Journal of Medicine Downloaded from nejm.org at THE CHINESE UNIVERSITY OF HONG KONG on November 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
Editorials
with intensive glucose control, those in the EMPA-REG OUTCOME trial were specifically at very high cardiovascular risk. Nearly half the patients had a history of myocardial infarction, and about three quarters had evidence of coronary artery disease, a quarter had previous stroke, and a fifth had peripheral vascular disease. A majority of the patients had more than a 10-year history of type 2 diabetes, a third had microalbuminuria, and a tenth had macroalbuminuria. Not surprisingly, most patients were taking multiple medications for hyperglycemia, more than 95% were taking antihypertensive agents, and 80% were taking lipid-lowering drugs. Unfortunately, the vast majority of the patients were white, which makes the results difficult to generalize to black and Hispanic patients. In this study, among patients receiving either 10 mg or 25 mg of empagliflozin daily in addition to standard care, the significant decrease in the rate of the 3-point MACE and of reduced death from any cause was impressive. The analysis showed that 39 patients would need to be treated for 3 years to provide a benefit in these outcomes. Furthermore, the results show that a drug that reduces glycated hemoglobin has a meaningful effect on cardiovascular events.3 In addition, more patients in the placebo group had insulin and sulfonylureas added to their regimen for glycemic control than did patients in the empagliflozin groups. Furthermore, adverse events associated with empagliflozin were mild and (as anticipated with a drug that causes glycosuria) included more genital infections. It seems likely that the observed risk reduction in the study was multifactorial. The addition of an SGLT2 inhibitor to standard care may ultimately alter vascular reactivity, as well as cardiac and cardiorenal function — both of which the authors mention. A decrease in albuminuria or in uric acid that is indirectly induced by the drug may be beneficial as well. Other aspects of the effects of the drug may be at play through mechanisms that remain speculative.
However, there are caveats. The results may not be generalizable (e.g., to patients with type 2 diabetes without cardiovascular disease), the risk–benefit profile for this drug class will need further elucidation (particularly for adverse events), and the ultimate position of empagliflozin among multiple drugs in the clinical management of type 2 diabetes will still need to be defined. Thus, it will be important to confirm these results with findings from other ongoing trials of SGLT2 inhibitors, including an evaluation of canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]; ClinicalTrials.gov number, NCT01032629) and of dapagliflozin (DECLARE–TIMI58, NCT01730534). For now, the study by Zinman et al. provides some hope that the risk of cardiovascular death in patients with type 2 diabetes and cardiovascular disease can indeed be modified. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From Tufts University School of Medicine, Boston, and the Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough (C.J.R.). 1. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34. 2. Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818-28. 3. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28. 4. Abdul-Ghani MA, Norton L, DeFronzo RA. Renal sodiumglucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol 2015 September 9 (Epub ahead of print). 5. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med 2015;66: 255-70. 6. Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis 2009;53:875-83. 7. Chasis H, Jolliffe N, Smith HW. The action of phlorizin on the excretion of glucose, 643 xylose, sucrose, creatinine, and urea by man. J Clin Invest 1933;12:1083-90. DOI: 10.1056/NEJMe1512602 Copyright © 2015 Massachusetts Medical Society.
n engl j med 373;22 nejm.org November 26, 2015
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The New England Journal of Medicine Downloaded from nejm.org at THE CHINESE UNIVERSITY OF HONG KONG on November 25, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
