Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial
Tóm tắt
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood pressure (BP). When SGLT2i and GLP-1RA are combined, synergistic effects on BP have been observed. The mechanisms underlying these BP reductions are incompletely understood. The aim of this study was to assess the mechanisms underlying the BP reduction with the SGLT2i dapagliflozin, GLP-1RA exenatide, and dapagliflozin-exenatide compared with placebo in people with obesity and type 2 diabetes. Sixty-six people with type 2 diabetes were randomized to 16 weeks of dapagliflozin 10 mg/day, exenatide 10 µg twice daily, dapagliflozin-exenatide, or placebo treatment. The effect of treatments on estimates of: (1) plasma volume (calculated by Strauss formula, bioimpedance spectroscopy, hematocrit, (2) autonomic nervous system activity (heart rate variability), (3) arterial stiffness (pulse wave applanometry), (4) systemic hemodynamic parameters including peripheral vascular resistance, cardiac output and stroke volume (all derived from non-invasively systemic hemodynamic monitoring), and (5) natriuresis (24-hour urine collection) were assessed after 10 days and 16 weeks of treatment. After 10 days, dapagliflozin reduced systolic BP (SBP) by − 4.7 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin reduced SBP by − 4.4 mmHg, and reduced sympathetic nervous system (SNS) activity. Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks. After 10 days, dapagliflozin-exenatide reduced SBP by − 4.2 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin-exenatide reduced SBP by − 6.8 mmHg, and the reduction in plasma volume was still observed, but SNS activity was unaffected. The dapagliflozin-induced plasma volume contraction may contribute to the initial SBP reduction, while a reduction in SNS activity may contribute to the persistent SBP reduction. Dapagliflozin-exenatide resulted in the largest decrease in SBP. The effect on plasma volume was comparable to dapagliflozin monotherapy, and SNS activity was not reduced, therefore other mechanisms are likely to contribute to the blood pressure lowering effect of this combination, which need further investigation. Trial registration Clinicaltrials.gov, NCT03361098.
Tài liệu tham khảo
van Baar MJB, van Ruiten CC, Muskiet MHA, van Bloemendaal L, RG IJ, van Raalte DH. SGLT2 inhibitors in combination therapy: from mechanisms to clinical considerations in type 2 diabetes management. Diabetes Care. 2018;41(8):1543–56.
McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008.
Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(4):422–34.
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31–9.
Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262–75 e9.
Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41(2):356–63.
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.
Jordan J, Tank J, Heusser K, Heise T, Wanner C, Heer M, et al. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus. J Am Soc Hypertens. 2017;11(9):604–12.
Scheen AJ. Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep. 2019;21(8):70.
van Bommel EJM, Smits MM, Ruiter D, Muskiet MHA, Kramer MHH, Nieuwdorp M, et al. Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes. J Hypertens. 2020. https://doi.org/10.1097/HJH.0000000000002480.
Filippatos TD, Tsimihodimos V, Elisaf MS. Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors. Expert Opin Pharmacother. 2016;17(12):1581–3.
Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5(6):632–44.
Solini A, Giannini L, Seghieri M, Vitolo E, Taddei S, Ghiadoni L, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138.
Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–39.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44.
Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Kober LV, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–57.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019;139(17):2022–31.
Sun F, Chai S, Li L, Yu K, Yang Z, Wu S, et al. Effects of glucagon-like peptide-1 receptor agonists on weight loss in patients with type 2 diabetes: a systematic review and network meta-analysis. J Diabetes Res. 2015;2015:157201.
Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110(1):26–37.
Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021. https://doi.org/10.1056/NEJMoa2032183.
Muskiet MHA, Tonneijck L, Smits MM, van Baar MJB, Kramer MHH, Hoorn EJ, et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. 2017;13(10):605–28.
Jabbour SA, Frias JP, Ahmed A, Hardy E, Choi J, Sjostrom CD, et al. Efficacy and Safety over 2 years of exenatide plus dapagliflozin in the DURATION-8 study: a multicenter, double-blind, phase 3, randomized controlled trial. Diabetes Care. 2020. https://doi.org/10.2337/dc19-1350.
Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D, et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(5):356–67.
Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman P, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004–16.
Ludvik B, Frias JP, Tinahones FJ, Wainstein J, Jiang H, Robertson KE, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6(5):370–81.
van Ruiten CC, van der Aart-van der Beek AB, IJzerman RG, Nieuwdorp M, Hoogenberg K, van Raalte DH, et al. Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: a prespecified secondary analysis of a randomized controlled clinical trial. Diabetes Obes Metab. 2021. https://doi.org/10.1111/dom.14410.
Shaffer F, Ginsberg JP. An overview of heart rate variability metrics and norms. Front Public Health. 2017;5:258.
Shaffer F, Meehan ZM. A practical guide to resonance frequency assessment for heart rate variability biofeedback. Front Neurosci. 2020;14:570400.
Dekkers CCJ, Sjostrom CD, Greasley PJ, Cain V, Boulton DW, Heerspink HJL. Effects of the sodium-glucose co-transporter-2 inhibitor dapagliflozin on estimated plasma volume in patients with type 2 diabetes. Diabetes Obes Metab. 2019;21(12):2667–73.
Jensen J, Omar M, Kistorp C, Tuxen C, Gustafsson I, Kober L, et al. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (empire HF renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2021;9(2):106–16.
Tanaka A, Shimabukuro M, Teragawa H, Okada Y, Takamura T, Taguchi I, et al. Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial. Cardiovasc Diabetol. 2021;20(1):105.
Chen CH, Nevo E, Fetics B, Pak PH, Yin FC, Maughan WL, et al. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Validation of generalized transfer function. Circulation. 1997;95(7):1827–36.
Pauca AL, O’Rourke MF, Kon ND. Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension. 2001;38(4):932–7.
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.
Georgianos PI, Agarwal R. Ambulatory blood pressure reduction with SGLT-2 inhibitors: dose-response meta-analysis and comparative evaluation with low-dose hydrochlorothiazide. Diabetes Care. 2019;42(4):693–700.
Tanaka H, Takano K, Iijima H, Kubo H, Maruyama N, Hashimoto T, et al. Factors affecting canagliflozin-induced transient urine volume increase in patients with type 2 diabetes mellitus. Adv Ther. 2017;34(2):436–51.
Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93(1):231–44.
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.
Scholtes RA, Muskiet MHA, van Baar MJB, Hesp AC, Greasley PJ, Karlsson C, et al. Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT trial. Diabetes Care. 2021;44(2):440–7.
Wan N, Rahman A, Hitomi H, Nishiyama A. The effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity. Front Endocrinol. 2018;9:421.
Conde SV, Sacramento JF, Guarino MP, Gonzalez C, Obeso A, Diogo LN, et al. Carotid body, insulin, and metabolic diseases: unraveling the links. Front Physiol. 2014;5:418.
Yamada T, Oka Y, Katagiri H. Inter-organ metabolic communication involved in energy homeostasis: potential therapeutic targets for obesity and metabolic syndrome. Pharmacol Ther. 2008;117(1):188–98.
Bonora BM, Avogaro A, Fadini GP. Extraglycemic effects of SGLT2 inhibitors: a review of the evidence. Diabetes Metab Syndr Obes. 2020;13:161–74.
Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180–93.
Ramirez AJ, Sanchez MJ, Sanchez RA. Diabetic patients with essential hypertension treated with amlodipine: blood pressure and arterial stiffness effects of canagliflozin or perindopril. J Hypertens. 2019;37(3):636–42.
McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR, et al. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46(9):1753–60.
Tsapas A, Karagiannis T, Kakotrichi P, Avgerinos I, Mantsiou C, Tousinas G, et al. Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Obes Metab. 2021;23(9):2116–24.
Abd El Aziz MS, Kahle M, Meier JJ, Nauck MA. A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients. Diabetes Obes Metab. 2017;19(2):216–27.
Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240–50.
Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertens. 2010;23(3):334–9.
Tonneijck L, Smits MM, Muskiet MH, Hoekstra T, Kramer MH, Danser AH, et al. Renal effects of DPP-4 inhibitor sitagliptin or GLP-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2016;39(11):2042–50.
Smits MM, Muskiet MH, Tonneijck L, Hoekstra T, Kramer MH, Diamant M, et al. Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males. Br J Clin Pharmacol. 2016;81(4):613–20.
Smits MM, Tonneijck L, Muskiet MH, Hoekstra T, Kramer MH, Diamant M, et al. Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients: an acute and 12-week randomised, double-blind, placebo-controlled trial. Eur J Endocrinol. 2017;176(1):77–86.
Zima E, Lippert M, Czygan G, Merkely B. Determination of left ventricular volume changes by intracardiac conductance using a biventricular electrode configuration. Europace. 2006;8(7):537–44.
Goud A, Zhong J, Peters M, Brook RD, Rajagopalan S. GLP-1 agonists and blood pressure: a review of the evidence. Curr Hypertens Rep. 2016;18(2):16.
Katsurada K, Nakata M, Saito T, Zhang B, Maejima Y, Nandi SS, et al. Central glucagon-like peptide-1 receptor signaling via brainstem catecholamine neurons counteracts hypertension in spontaneously hypertensive rats. Sci Rep. 2019;9(1):12986.
Griffioen KJ, Wan R, Okun E, Wang X, Lovett-Barr MR, Li Y, et al. GLP-1 receptor stimulation depresses heart rate variability and inhibits neurotransmission to cardiac vagal neurons. Cardiovasc Res. 2011;89(1):72–8.
Baggio LL, Ussher JR, McLean BA, Cao X, Kabir MG, Mulvihill EE, et al. The autonomic nervous system and cardiac GLP-1 receptors control heart rate in mice. Mol Metab. 2017;6(11):1339–49.
Lerchl K, Rakova N, Dahlmann A, Rauh M, Goller U, Basner M, et al. Agreement between 24-hour salt ingestion and sodium excretion in a controlled environment. Hypertension. 2015;66(4):850–7.
Bogert LW, Wesseling KH, Schraa O, Van Lieshout EJ, de Mol BA, van Goudoever J, et al. Pulse contour cardiac output derived from non-invasive arterial pressure in cardiovascular disease. Anaesthesia. 2010;65(11):1119–25.