Top

Current Cardiology Reports

Published in:

01-01-2018 | Hypertension (DS Geller and DL Cohen, Section Editors)

SGLT2 Inhibitors and Mechanisms of Hypertension

Authors: Alexandros Briasoulis, Omar Al Dhaybi, George L. Bakris

Published in: Current Cardiology Reports | Issue 1/2018

Abstract

Purpose of Review

We sought to review currently available data on the safety and efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes mellitus patients with hypertension.

Recent Findings

Inhibition of SGLT2 in the renal proximal tubule results in increased urinary glucose excretion and modest improvements of hemoglobin A1C. Treatment with any of the three currently FDA-approved SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) results in sustained systolic and diastolic blood pressure reduction, in part via minimal natriuresis and possible reductions in sympathetic tone. Recent randomized clinical trials in high cardiovascular risk patients with type 2 diabetes suggest that the unique effects of SGLT2 inhibitors on blood pressure and body weight may translate into reduced cardiovascular events and slowed kidney disease progression. However, concerns about volume depletion and acute kidney injury have been raised.

Summary

SGLT2 inhibitors are viable second-line glucose-lowering agents for people with type 2 diabetes with high cardiovascular risk.

Fuller JH. Epidemiology of hypertension associated with diabetes mellitus. Hypertension. 1985;7(6 Pt 2):II3–7.PubMed

Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension. 1992;19(5):403–18. https://doi.org/10.1161/01.HYP.19.5.403.CrossRefPubMed

Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation. 2002;106(16):2085–90. https://doi.org/10.1161/01.CIR.0000033824.02722.F7.CrossRefPubMed

Cherney DZ, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13(1):28. https://doi.org/10.1186/1475-2840-13-28.CrossRefPubMedPubMedCentral

Nosadini R, Sambataro M, Thomaseth K, Pacini G, Cipollina MR, Brocco E, et al. Role of hyperglycemia and insulin resistance in determining sodium retention in non-insulin-dependent diabetes. Kidney Int. 1993;44(1):139–46. https://doi.org/10.1038/ki.1993.224.CrossRefPubMed

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 352(9131): p. 854–65.

•• DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol. 2017;13(1):11–26. Comprehensive review paper discussing all the relevant literature regarding metabolic and hemodynamic effects of the SGLT 2 class.CrossRefPubMed

Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci. 2011;32(2):63–71. https://doi.org/10.1016/j.tips.2010.11.011.CrossRefPubMed

Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, et al. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302(1):R75–83. https://doi.org/10.1152/ajpregu.00357.2011.CrossRefPubMed

10.

Mancia G, Cannon CP, Tikkanen I, Zeller C, Ley L, Woerle HJ, et al. Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication. Hypertension. 2016;68(6):1355–64. https://doi.org/10.1161/HYPERTENSIONAHA.116.07703.CrossRefPubMed

11.

Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012;72(17):2289–312. https://doi.org/10.2165/11209910-000000000-00000.CrossRefPubMed

12.

Lamos EM, Younk LM, Davis SN. Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus. Expert Opin Drug Metab Toxicol. 2013;9(6):763–75. https://doi.org/10.1517/17425255.2013.791282.CrossRefPubMed

13.

Scheen AJ. Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin Pharmacokinet. 2014;53(3):213–25. https://doi.org/10.1007/s40262-013-0126-x.CrossRefPubMedPubMedCentral

14.

Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335–80. https://doi.org/10.2147/DDDT.S50773.CrossRefPubMedPubMedCentral

15.

•• Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. Major CV outcome trial with empagliflozin demonstrating reduced CV risk and some renoprotection. CrossRefPubMed

16.

•• Neal, B., et al., Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med, 2017.-online. Second major CV outcome trial with canagliflozin that is consistent with empagliflozin data and demonstrates major reduction in CV risk in type 2 diabetes patients.

17.

Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–94. https://doi.org/10.1152/physrev.00055.2009.CrossRefPubMed

18.

Hediger MA, Rhoads DB. Molecular physiology of sodium-glucose cotransporters. Physiol Rev. 1994;74(4):993–1026. https://doi.org/10.1152/physrev.1994.74.4.993.CrossRefPubMed

19.

DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013;36(10):3169–76. https://doi.org/10.2337/dc13-0387.CrossRefPubMedPubMedCentral

20.

Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136–42. https://doi.org/10.1111/j.1464-5491.2009.02894.x.CrossRefPubMedPubMedCentral

21.

Clar C, Gill JA, Court R, Waugh N. Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012;2(5):e001007. https://doi.org/10.1136/bmjopen-2012-001007.CrossRefPubMedPubMedCentral

22.

Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med. 2012;44(4):375–93. https://doi.org/10.3109/07853890.2011.560181.CrossRefPubMed

23.

Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74. https://doi.org/10.7326/0003-4819-159-4-201308200-00007.CrossRefPubMed

24.

Liu XY, Zhang N, Chen R, Zhao JG, Yu P. Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2 years. J Diabetes Complicat. 2015;29(8):1295–303. https://doi.org/10.1016/j.jdiacomp.2015.07.011.CrossRefPubMed

25.

Bailey CJ, Iqbal N, T'joen C, List JF. Dapagliflozin monotherapy in drug-naive patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab. 2012;14(10):951–9. https://doi.org/10.1111/j.1463-1326.2012.01659.x.CrossRefPubMed

26.

• Mazidi, M., et al., Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc, 2017. 6(6). Doi: https://doi.org/10.1161/JAHA.116.004007. Important meta-analysis that evaluates studies of glycemic control and outcomes with the class.

27.

• Baker, W.L., et al., Effects of sodium-glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis. J Am Heart Assoc, 2017. 6(5). Important summary of ABPM data and SGLT2 inhibitors-provides a balanced summary out BP outcomes.

28.

Rosenstock J, Aggarwal N, Polidori D, Zhao Y, Arbit D, Usiskin K, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care. 2012;35(6):1232–8. https://doi.org/10.2337/dc11-1926.CrossRefPubMedPubMedCentral

29.

Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA, et al. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48(5):592–8. https://doi.org/10.1177/0091270008316885.CrossRefPubMed

30.

Gill A, Hoogwerf BJ, Burger J, Bruce S, MacConell L, Yan P, et al. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study. Cardiovasc Diabetol. 2010;9(1):6. https://doi.org/10.1186/1475-2840-9-6.CrossRefPubMedPubMedCentral

31.

Lovshin JA, Barnie A, DeAlmeida A, Logan A, Zinman B, Drucker DJ. Liraglutide promotes natriuresis but does not increase circulating levels of atrial natriuretic peptide in hypertensive subjects with type 2 diabetes. Diabetes Care. 2015;38(1):132–9. https://doi.org/10.2337/dc14-1958.CrossRefPubMed

32.

• Weber MA, et al. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211–20. Well designed clinical trial to evaluate BP lowering effects of an SGLT2 and try to estabish a mechanism in people with normal kidney function.CrossRefPubMed

33.

•• Ferrannini E. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab. 2017;26(1):27–38. Excellent basic science review of metabolic pathways and how SGLT2 inhibitors may provide reduced CV risk.CrossRefPubMed

34.

Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Barsotti E, Clerico A, et al. Renal handling of ketones in response to sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care. 2017;40(6):771–6. https://doi.org/10.2337/dc16-2724.CrossRefPubMed

35.

Sha S, Polidori D, Heise T, Natarajan J, Farrell K, Wang SS, et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2014;16(11):1087–95. https://doi.org/10.1111/dom.12322.CrossRefPubMed

36.

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. https://doi.org/10.1111/dom.12127.CrossRefPubMed

37.

•• 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. https://doi.org/10.1172/JCI72227. A very important study that for the first time shows how lactate production may contribute to the benefit of heart failure outcomes with SGLT2 inhibition.CrossRefPubMedPubMedCentral

38.

Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, et al. Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016;38(10):2265–76. https://doi.org/10.1016/j.clinthera.2016.09.001.CrossRefPubMed

39.

Kawasoe S, Maruguchi Y, Kajiya S, Uenomachi H, Miyata M, Kawasoe M, et al. Mechanism of the blood pressure-lowering effect of sodium-glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes. BMC Pharmacol Toxicol. 2017;18(1):23. https://doi.org/10.1186/s40360-017-0125-x.CrossRefPubMedPubMedCentral

40.

•• Pfeifer M, et al. Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure and markers of arterial stiffness in patients with type 2 diabetes mellitus: a post hoc analysis. Cardiovasc Diabetol. 2017;16(1):29. Evaluation of biomarkers that help support benefit of SGLT2 inhibitors on improving vascular compliance.CrossRefPubMedPubMedCentral

41.

Villafana S, Huang F, Hong E. Role of the sympathetic and renin angiotensin systems in the glucose-induced increase of blood pressure in rats. Eur J Pharmacol. 2004;506(2):143–50. https://doi.org/10.1016/j.ejphar.2004.10.055.CrossRefPubMed

42.

Yoshikawa T, Kishi T, Shinohara K, Takesue K, Shibata R, Sonoda N, et al. Arterial pressure lability is improved by sodium-glucose cotransporter 2 inhibitor in streptozotocin-induced diabetic rats. Hypertens Res. 2017;40(7):646–51. https://doi.org/10.1038/hr.2017.14.CrossRefPubMed

43.

Shin SJ, Chung S, Kim SJ, Lee EM, Yoo YH, Kim JW, et al. Effect of sodium-glucose co-transporter 2 inhibitor, dapagliflozin, on renal renin-angiotensin system in an animal model of type 2 diabetes. PLoS One. 2016;11(11):e0165703. https://doi.org/10.1371/journal.pone.0165703.CrossRefPubMedPubMedCentral

44.

Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, et al. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharmacol. 2013;715(1–3):246–55. https://doi.org/10.1016/j.ejphar.2013.05.014.CrossRefPubMed

45.

Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, et al. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE −/− mice fed a western diet. Diabetologia. 2017;60(2):364–76. https://doi.org/10.1007/s00125-016-4158-2.CrossRefPubMed

46.

•• Matthews, V.B., et al., Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens, 2017. Important paper that provides some of the first good data to argue that SGLT2 inhibitors reduces sympathetic tone.

47.

Evan AP, et al. Crystal-associated nephropathy in patients with brushite nephrolithiasis. Kidney Int. 2005;67(2):576–91. https://doi.org/10.1111/j.1523-1755.2005.67114.x.CrossRefPubMed

48.

Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97(3):1020–31. https://doi.org/10.1210/jc.2011-2260.CrossRefPubMed

49.

Evan AP, Coe FL, Lingeman JE, Shao Y, Matlaga BR, Kim SC, et al. Renal crystal deposits and histopathology in patients with cystine stones. Kidney Int. 2006;69(12):2227–35. https://doi.org/10.1038/sj.ki.5000268.CrossRefPubMed

50.

Evan AP, Lingeman JE, Worcester EM, Sommer AJ, Phillips CL, Williams JC, et al. Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones. Anat Rec (Hoboken). 2014;297(4):731–48. https://doi.org/10.1002/ar.22881.CrossRef

51.

Worcester EM, Evan AP, Coe FL, Lingeman JE, Krambeck A, Sommers A, et al. A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I. Am J Physiol Renal Physiol. 2013;305(11):F1574–84. https://doi.org/10.1152/ajprenal.00382.2013.CrossRefPubMedPubMedCentral

52.

• Kosiborod M, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249–59. Very well done database analysis to evaluate CV outcomes with all SGLT2 inhibitors.CrossRefPubMedPubMedCentral

53.

Stankus N, Hammes M, Gillen D, Worcester E. African American ESRD patients have a high pre-dialysis prevalence of kidney stones compared to NHANES III. Urol Res. 2007;35(2):83–7. https://doi.org/10.1007/s00240-007-0079-3.CrossRefPubMed

54.

Yamout H, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am J Nephrol. 2014;40(1):64–74.CrossRefPubMed

Title: SGLT2 Inhibitors and Mechanisms of Hypertension
Authors: Alexandros Briasoulis
Omar Al Dhaybi
George L. Bakris
Publication date: 01-01-2018
Publisher: Springer US
Published in: Current Cardiology Reports / Issue 1/2018
Print ISSN: 1523-3782
Electronic ISSN: 1534-3170
DOI: https://doi.org/10.1007/s11886-018-0943-5

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

SGLT2 Inhibitors and Mechanisms of Hypertension

Abstract

Purpose of Review

Recent Findings

Summary

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content

Other articles of this Issue 1/2018

Contemporary Perspectives in Durable Mechanical Circulatory Support: What Did We Learn in the Last 3 Years?

Management Strategies for Noncardiac Surgery Following a Coronary Artery Event

The Sacubitril/Valsartan, a First-in-Class, Angiotensin Receptor Neprilysin Inhibitor (ARNI): Potential Uses in Hypertension, Heart Failure, and Beyond

Bilateral Versus Single Internal Thoracic Artery Grafts

Percutaneous Mechanical Circulatory Support Devices for High-Risk Percutaneous Coronary Intervention

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page