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

Scheen, André

doi:10.1016/j.diabres.2016.09.016

Article (Scientific journals)

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

Scheen, André

2016 • In Diabetes Research and Clinical Practice, 121, p. 204-214

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/203700

DOI
10.1016/j.diabres.2016.09.016

PubMed
27744129

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Keywords :

Blood pressure; Diuretic; Empagliflozin; Hypertension; SGLT2 inhibitor; Type 2 diabetes

Abstract :

[en] Empagliflozin, a sodium-glucose cotransporter type 2 (SGLT2) inhibitor, has shown a remarkable reduction in cardiovascular and all-cause mortality in patients with type 2 diabetes (T2D) and antecedents of cardiovascular disease in the EMPA-REG OUTCOME trial. This effect has been attributed to a hemodynamic rather than a metabolic effect, partly due to the osmotic/diuretic effect of empagliflozin and to the reduction in arterial blood pressure. The present review will: (1) summarize the results of specific studies having tested the blood pressure lowering effects of SGLT2 inhibitors; (2) describe the results of meta-analyses of trials having evaluated the effects on mortality and cardiovascular outcomes of lowering blood pressure in patients with T2D, with a special focus on baseline and target blood pressures; (3) compare the cardiovascular outcome results in EMPA-REG OUTCOME versus other major trials with antihypertensive agents in patients with T2D; and (4) evaluate post-hoc analyses from EMPA-REG OUTCOME, especially subgroups of patients of special interest regarding the blood pressure lowering hypothesis. Although BP reduction associated to empagliflozin therapy may partly contribute to the benefits reported in EMPA-REG OUTCOME, other mechanisms most probably play a greater role in the overall CV protection and reduction in mortality observed in this trial.

Disciplines :

Pharmacy, pharmacology & toxicology
Endocrinology, metabolism & nutrition

Author, co-author :

Scheen, André ; Université de Liège > Département des sciences cliniques > Département des sciences cliniques

Language :

English

Title :

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

Publication date :

2016

Journal title :

Diabetes Research and Clinical Practice

ISSN :

0168-8227

eISSN :

1872-8227

Publisher :

Elsevier, Amsterdam, Netherlands

Volume :

121

Pages :

204-214

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 25 November 2016

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Bibliography

[1] Ferrannini, E., Cushman, W.C., Diabetes and hypertension: the bad companions. Lancet 380 (2012), 601–610.
[2] Blood Pressure Lowering Treatment Trialists C, Sundstrom, J., Arima, H., Woodward, M., Jackson, R., Karmali, K., Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 384 (2014), 591–598.
[3] Rapsomaniki, E., Timmis, A., George, J., Pujades-Rodriguez, M., Shah, A.D., Denaxas, S., et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1.25 million people. Lancet 383 (2014), 1899–1911.
[4] UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317 (1998), 703–713.
[5] UK Prospective Diabetes Study (UKPDS) Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34. Lancet 352 (1998), 854–865.
[6] Heart Outcomes Prevention Evaluation Study Investigators, Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355 (2000), 253–259.
[7] Patel, A., MacMahon, S., Chalmers, J., Neal, B., Woodward, M., Billot, L., et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370 (2007), 829–840.
[8] Ryden, L., Grant, P.J., Anker, S.D., Berne, C., Cosentino, F., Danchin, N., et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J 34 (2013), 3035–3087.
[9] Ettehad, D., Emdin, C.A., Kiran, A., Anderson, S.G., Callender, T., Emberson, J., et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 387 (2016), 957–967.
[10] Xie, X., Atkins, E., Lv, J., Bennett, A., Neal, B., Ninomiya, T., et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 387 (2016), 435–443.
[11] Kintscher, U., Benefit of blood pressure control in diabetic patients. Curr Hypertens Rep, 17, 2015, 50.
[12] Arguedas, J.A., Leiva, V., Wright, J.M., Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev, 10, 2013 CD008277.
[13] Esler, M., SPRINT, or false start, toward a lower universal treated blood pressure target in hypertension. Hypertension 67 (2016), 266–267.
[14] Cryer, M.J., Horani, T., DiPette, D.J., Diabetes and hypertension: a comparative review of current guidelines. J Clin Hypertens (Greenwich) 18 (2016), 95–100.
[15] Scheen, A.J., Charbonnel, B., Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal. Diabetes Metab 40 (2014), 176–185.
[16] Ferrannini, E., DeFronzo, R.A., Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J 36 (2015), 2288–2296.
[17] Schernthaner, G., Schernthaner-Reiter, M.H., Schernthaner, G.H., EMPA-REG and other cardiovascular outcome trials of glucose-lowering agents: implications for future treatment strategies in type 2 diabetes mellitus. Clin Ther 38 (2016), 1288–1298.
[18] Ryden, L., Shahim, B., Mellbin, L., Clinical implications of cardiovascular outcome trials in type 2 diabetes: from DCCT to EMPA-REG. Clin Ther 38 (2016), 1279–1287.
[19] Scheen, A.J., Cardiovascular effects of gliptins. Nat Rev Cardiol 10 (2013), 73–84.
[20] Scheen, A.J., Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf 14 (2015), 505–524.
[21] Zinman, B., Wanner, C., Lachin, J.M., Fitchett, D., Bluhmki, E., Hantel, S., et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373 (2015), 2117–2128.
[22] Marso, S.P., Daniels, G.H., Brown-Frandsen, K., Kristensen, P., Mann, J.F., Nauck, M.A., et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375 (2016), 311–322.
[23] Scheen, A.J., Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75 (2015), 33–59.
[24] Inzucchi, S.E., Zinman, B., Wanner, C., Ferrari, R., Fitchett, D., Hantel, S., et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diabetes Vasc Dis Res 12 (2015), 90–100.
[25] Ghosh, R.K., Bandyopadhyay, D., Hajra, A., Biswas, M., Gupta, A., Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: a comprehensive review of clinical and preclinical studies. Int J Cardiol 212 (2016), 29–36.
[26] Oliva, R.V., Bakris, G.L., Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens 8 (2014), 330–339.
[27] Maliha, G., Townsend, R.R., SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens 9 (2015), 48–53.
[28] Imprialos, K.P., Sarafidis, P.A., Karagiannis, A.I., Sodium-glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class?. J Hypertens 33 (2015), 2185–2197.
[29] Baker, W.L., Smyth, L.R., Riche, D.M., Bourret, E.M., Chamberlin, K.W., White, W.B., Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens, 8(262–275), 2014, e9.
[30] Fitchett, D., Zinman, B., Wanner, C., Lachin, J.M., 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® trial. Eur Heart J 37 (2016), 1526–1534.
[31] Scheen, A.J., Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab 42 (2016), 71–76.
[32] DeFronzo, R.A., The EMPA-REG study: What has it told us? A diabetologist's perspective. J Diabetes Complications 30 (2016), 1–2.
[33] Rajasekeran, H., Lytvyn, Y., Cherney, D.Z., Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int 89 (2016), 524–526.
[34] Kimura, G., Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis. J Am Soc Hypertens 10 (2016), 271–278.
[35] Takeuchi, T., Dohi, K., Omori, T., Moriwaki, K., Sato, Y., Nakamori, S., et al. Diuretic effects of sodium-glucose cotransporter 2 inhibitor in patients with type 2 diabetes mellitus and heart failure. Int J Cardiol 201 (2015), 1–3.
[36] McMurray, J., EMPA-REG - the “diuretic hypothesis”. J Diabetes Complications 30 (2016), 3–4.
[37] Sattar, N., McLaren, J., Kristensen, S.L., Preiss, D., McMurray, J.J., SGLT2 inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms?. Diabetologia 59 (2016), 1333–1339.
[38] Scheen, A.J., Reappraisal of the diuretic effect of empagliflozin in EMPA-REG OUTCOME: comparison with classic diuretics. Diabetes Metab 42 (2016), 224–233.
[39] John, M., Empagliflozin: not just a glorified diuretic. Indian J Endocrinol Metab 20 (2016), 154–156.
[40] Zaccardi, F., Webb, D.R., Htike, Z.Z., Youssef, D., Khunti, K., Davies, M.J., Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 18 (2016), 783–794.
[41] Townsend, R.R., Machin, I., Ren, J., Trujillo, A., Kawaguchi, M., Vijapurkar, U., 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) 18 (2016), 43–52.
[42] Weir, M.R., Januszewicz, A., Gilbert, R.E., Vijapurkar, U., Kline, I., Fung, A., et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich) 16 (2014), 875–882.
[43] Lambers Heerspink, H.J., 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 15 (2013), 853–862.
[44] Weber, 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 4 (2016), 211–220.
[45] Sjostrom, C.D., Johansson, P., Ptaszynska, A., List, J., Johnsson, E., Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diabetes Vasc Dis Res 12 (2015), 352–358.
[46] Tikkanen, I., Narko, K., Zeller, C., Green, A., Salsali, A., Broedl, U.C., et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 38 (2015), 420–428.
[47] Amin, N.B., Wang, X., Mitchell, J.R., Lee, D.S., Nucci, G., Rusnak, J.M., Blood pressure-lowering effect of the sodium glucose co-transporter-2 inhibitor ertugliflozin, assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension. Diabetes Obes Metab 17 (2015), 805–808.
[48] Tamura, K., Wakui, H., Azushima, K., Uneda, K., Umemura, S., Circadian blood pressure rhythm as a possible key target of SGLT2 inhibitors used for the treatment of Type 2 diabetes. Hypertens Res 39 (2016), 396–398.
[49] Chilton, R., Tikkanen, I., Cannon, C.P., Crowe, S., Woerle, H.J., Broedl, U.C., 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 17 (2015), 1180–1193.
[50] Cherney, D.Z., Perkins, B.A., Soleymanlou, N., Har, R., Fagan, N., Johansen, O.E., et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol, 13, 2014, 28.
[51] Heerspink, H.J., Johnsson, E., Gause-Nilsson, I., Cain, V.A., Sjostrom, C.D., Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab 18 (2016), 590–597.
[52] Scheen, A.J., Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Clin Pharmacokinet 54 (2015), 691–708.
[53] Kohan, D.E., Fioretto, P., Tang, W., List, J.F., Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85 (2014), 962–971.
[54] Emdin, C.A., Rahimi, K., Neal, B., Callender, T., Perkovic, V., Patel, A., Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA 313 (2015), 603–615.
[55] Xie, X.X., Liu, P., Wan, F.Y., Lin, S.G., Zhong, W.L., Yuan, Z.K., et al. Blood pressure lowering and stroke events in type 2 diabetes: a network meta-analysis of randomized controlled trials. Int J Cardiol 208 (2016), 141–146.
[56] Brunstrom, M., Carlberg, B., Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ, 352, 2016, i717.
[57] Hansson, L., Zanchetti, A., Carruthers, S.G., Dahlof, B., Elmfeldt, D., Julius, S., et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 351 (1998), 1755–1762.
[58] ACCORD Study Group, Cushman, W.C., Evans, G.W., Byington, R.P., Goff, D.C. Jr., Grimm, R.H. Jr., et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 362 (2010), 1575–1585.
[59] Weber, M.A., Bloch, M., Bakris, G.L., Weir, M.R., Zappe, D.H., Dahlof, B., et al. Cardiovascular outcomes according to systolic blood pressure in patients with and without diabetes: an ACCOMPLISH substudy. J Clin Hypertens (Greenwich) 18 (2016), 299–307.
[60] SPRINT Research Group, Wright, J.T. Jr., Williamson, J.D., Whelton, P.K., Snyder, J.K., Sink, K.M., et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 373 (2015), 2103–2116.
[61] Turnbull, F., Neal, B., Algert, C., Chalmers, J., Chapman, N., Cutler, J., et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 165 (2005), 1410–1419.
[62] Bangalore, S., Kumar, S., Lobach, I., Messerli, F.H., Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and bayesian random-effects meta-analyses of randomized trials. Circulation 123 (2011), 2799–2810 [9 p following 810].
[63] Lonn, E.M., Bosch, J., Lopez-Jaramillo, P., Zhu, J., Liu, L., Pais, P., et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 374 (2016), 2009–2020.
[64] Psaty, B.M., Lumley, T., Furberg, C.D., Schellenbaum, G., Pahor, M., Alderman, M.H., et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 289 (2003), 2534–2544.
[65] Davis, B.R., Piller, L.B., Cutler, J.A., Furberg, C., Dunn, K., Franklin, S., et al. Role of diuretics in the prevention of heart failure: the Antihypertensive and Lipid-lowering treatment to prevent heart attack trial. Circulation 113 (2006), 2201–2210.
[66] Grossman, E., Verdecchia, P., Shamiss, A., Angeli, F., Reboldi, G., Diuretic treatment of hypertension. Diabetes Care 34:Suppl. 2 (2011), S313–S319.
[67] Sweileh, W.M., Target blood pressure attainment in diabetic hypertensive patients: need for more diuretics?. Int J Clin Pharmacol Ther 47 (2009), 434–438.
[68] Chen, P., Chaugai, S., Zhao, F., Wang, D.W., Cardioprotective effect of thiazide-like diuretics: a meta-analysis. Am J Hypertens 28 (2015), 1453–1463.
[69] Olde Engberink, R.H., Frenkel, W.J., van den Bogaard, B., Brewster, L.M., Vogt, L., van den Born, B.J., Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension 65 (2015), 1033–1040.
[70] Lievre, M., Gueyffier, F., Ekbom, T., Fagard, R., Cutler, J., Schron, E., et al. Efficacy of diuretics and beta-blockers in diabetic hypertensive patients. Results from a meta-analysis. The INDANA Steering Committee. Diabetes Care 23:Suppl. 2 (2000), B65–B71.
[71] Remonti, L.R., Dias, S., Leitao, C.B., Kramer, C.K., Klassman, L.P., Welton, N.J., et al. Classes of antihypertensive agents and mortality in hypertensive patients with type 2 diabetes-Network meta-analysis of randomized trials. J Diabetes Complications 30 (2016), 1192–1200.
[72] Takahashi, S., Katada, J., Daida, H., Kitamura, F., Yokoyama, K., Effects of mineralocorticoid receptor antagonists in patients with hypertension and diabetes mellitus: a systematic review and meta-analysis. J Hum Hypertens 30 (2016), 534–542.
[73] Chen, M.D., Dong, S.S., Cai, N.Y., Fan, M.D., Gu, S.P., Zheng, J.J., et al. Efficacy and safety of mineralocorticoid receptor antagonists for patients with heart failure and diabetes mellitus: a systematic review and meta-analysis. BMC Cardiovasc Disord, 16, 2016, 28.
[74] Pelliccia, F., Patti, G., Rosano, G., Greco, C., Gaudio, C., Efficacy and safety of eplerenone in the management of mild to moderate arterial hypertension: systematic review and meta-analysis. Int J Cardiol 177 (2014), 219–228.
[75] Wu, J.H., 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 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 4 (2016), 411–419.
[76] Monami, M., Dicembrini, I., Mannucci, E., Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol, 2016 [Epub ahead of print].
[77] Muskiet, M.H., van Raalte, D.H., van Bommel, E., Smits, M.M., Tonneijck, L., Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol 3 (2015), 928–929.
[78] Wanner, C., Inzucchi, S.E., Lachin, J.M., Fitchett, D., von Eynatten, M., Mattheus, M., et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 375 (2016), 323–334.