Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study

Anne Gill, Byron J Hoogwerf, Jude Burger, Simon Bruce, Leigh Macconell, Ping Yan, Daniel Braun, Joseph Giaconia, James Malone, Anne Gill, Byron J Hoogwerf, Jude Burger, Simon Bruce, Leigh Macconell, Ping Yan, Daniel Braun, Joseph Giaconia, James Malone

Abstract

Background: Cardiovascular effects of glucose-lowering agents are of increasing interest. Our aim was to assess the effects of the glucagon-like peptide-1 receptor agonist exenatide on heart rate (HR) and blood pressure (BP) in subjects with type 2 diabetes mellitus (T2DM).

Methods: In this double-blind, placebo-controlled trial, subjects with T2DM on metformin and/or a thiazolidinedione were randomized to receive exenatide (5 microg for 4 weeks followed by 10 microg) or placebo BID for 12 weeks. Heart rate and BP were assessed with 24-hour ambulatory BP monitoring. The primary measure was change from baseline in mean 24-hour HR.

Results: Fifty-four subjects (28 exenatide, 26 placebo) were randomized and comprised the intent-to-treat population. Baseline values (exenatide and placebo) were (mean +/- SE) 74.4 +/- 2.1 and 74.5 +/- 1.9 beats/minute for HR, 126.4 +/- 3.2 and 119.9 +/- 2.8 mm Hg for systolic BP (SBP), and 75.2 +/- 2.1 and 70.5 +/- 2.0 mm Hg for diastolic BP (DBP). At 12 weeks, no significant change from baseline in 24-hour HR was observed with exenatide or placebo (LS mean +/- SE, 2.1 +/- 1.4 versus -0.7 +/- 1.4 beats/minute, respectively; between treatments, p = 0.16). Exenatide therapy was associated with trends toward lower 24-hour, daytime, and nighttime SBP; changes in DBP were similar between groups. No changes in daytime or nighttime rate pressure product were observed. With exenatide, body weight decreased from baseline by -1.8 +/- 0.4 kg (p < 0.0001; treatment difference -1.5 +/- 0.6 kg, p < 0.05). The most frequently reported adverse event with exenatide was mild to moderate nausea.

Conclusions: Exenatide demonstrated no clinically meaningful effects on HR over 12 weeks of treatment in subjects with T2DM. The observed trends toward lower SBP with exenatide warrant future investigation.

Trial registration: NCT00516074.

Figures

Figure 1
Figure 1
Patient flow diagram.
Figure 2
Figure 2
Hourly heart rates during 24-hour monitoring. Heart rate values at baseline (A), after first dose (B), after dose escalation (C), and at Week 12 (D) for the intent-to-treat population are shown.
Figure 3
Figure 3
Effects of exenatide on 24-hour and nocturnal systolic blood pressure (SBP). Changes over the study period (A and B), at endpoint (C and D), and for subjects with high (>120 mm Hg) baseline SBP values (E and F) are shown. Seventeen exenatide-treated subjects and 11 placebo-treated subjects had high baseline 24-hour SBP values (E), and 13 exenatide-treated subjects and 9 placebo-treated subjects had high baseline nocturnal SBP values (F). P = NS. Intent-to-treat sample population and mean ± SE are shown. Last observation carried forward for Plots C through F.

References

    1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131–57. doi: 10.1053/j.gastro.2007.03.054.
    1. Yamamoto H, Lee CE, Marcus JN, Williams TD, Overton JM, Lopez ME, Hollenberg AN, Baggio L, Saper CB, Drucker DJ, Elmquist JK. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J Clin Invest. 2002;110:43–52.
    1. Barragán JM, Rodríguez RE, Blázquez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-1-(7-36) amide in rats. Am J Physiol. 1994;266:E459–E466.
    1. Yu M, Moreno C, Hoagland KM, Dahly A, Ditter K, Mistry M, Roman RJ. Antihypertensive effect of glucagon-like peptide 1 in Dahl salt-sensitive rats. J Hypertens. 2003;21:1125–1135. doi: 10.1097/00004872-200306000-00012.
    1. Golpon HA, Puechner A, Welte T, Wichert PV, Feddersen CO. Vasorelaxant effect of glucagon-like peptide-(7-36)amide and amylin on the pulmonary circulation of the rat. Regul Pept. 2001;102:81–86. doi: 10.1016/S0167-0115(01)00300-7.
    1. Nikolaidis LA, Doverspike A, Hentosz T, Zourelias L, Shen YT, Elahi D, Shannon RP. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious canines. J Pharmacol Exp Ther. 2005;312:303–308. doi: 10.1124/jpet.104.073890.
    1. Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, Stolarski C, Shen YT, Shannon RP. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004;110:955–961. doi: 10.1161/01.CIR.0000139339.85840.DD.
    1. Kavianipour M, Ehlers MR, Malmberg K, Ronquist G, Ryden L, Wikström G, Gutniak M. Glucagon-like peptide-1 (7 - 36) amide prevents the accumulation of pyruvate and lactate in the ischemic and non-ischemic porcine myocardium. Peptides. 2003;24:569–578. doi: 10.1016/S0196-9781(03)00108-6.
    1. Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, Verlaan CW, Kerver M, Piek JJ, Doevendans PA, Pasterkamp G, Hoefer IE. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol. 2009;53:501–10. doi: 10.1016/j.jacc.2008.10.033.
    1. Edwards CM, Edwards AV, Bloom SR. Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf. Exp Physiol. 1997;82:709–16.
    1. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients. Diabetes Care. 1999;22:1137–1143. doi: 10.2337/diacare.22.7.1137.
    1. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830. doi: 10.1016/S0140-6736(02)07952-7.
    1. Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, Kim D, Baron AD. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 2003;26:2370–7. doi: 10.2337/diacare.26.8.2370.
    1. Nyström T, Gutniak MK, Zhang Q, Zhang F, Holst JJ, Ahrén B, Sjöholm A. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004;287:E1209–E1215. doi: 10.1152/ajpendo.00237.2004.
    1. Thrainsdottir I, Malmberg K, Olsson A, Gutniak M, Rydén L. Initial experience with GLP-1 treatment on metabolic control and myocardial function in patients with type 2 diabetes mellitus and heart failure. Diab Vasc Dis Res. 2004;1:40–3. doi: 10.3132/dvdr.2004.005.
    1. Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12:694–9. doi: 10.1016/j.cardfail.2006.08.211.
    1. Gentilella R, Bianchi C, Rossi A, Rotella CM. Exenatide: a review from pharmacology to clinical practice. Diabetes Obes Metab. 2009;11:544–56. doi: 10.1111/j.1463-1326.2008.01018.x.
    1. Moretto TJ, Milton DR, Ridge TD, Macconell LA, Okerson T, Wolka AM, Brodows RG. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30:1448–60. doi: 10.1016/j.clinthera.2008.08.006.
    1. Klonoff DC, Buse JB, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Wintle ME, Maggs DG. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24:275–86.
    1. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L. DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240–50. doi: 10.1016/S0140-6736(08)61206-4.
    1. Okerson T, Yan P, Stonehouse A, Brodows R, Bhole D. Exenatide improved systolic blood pressure compared to insulin or placebo in patients with type 2 diabetes. Diabetologia. 2008;51:S350.
    1. Bergenstal R, Kim T, Yan P, Darsow T, Walsh B, Okerson T, Han J. Exenatide once weekly improved cardiometabolic risk factors in subjects with type 2 diabetes during one year of treatment. Diabetes. 2009;58:A43.
    1. Kothare PA, Linnebjerg H, Isaka Y, Uenaka K, Yamamura A, Yeo KP, de la Peña A, Teng CH, Mace K, Fineman M, Shigeta H, Sakata Y, Irie S. Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus. J Clin Pharmacol. 2008;48:1389–99. doi: 10.1177/0091270008323750.
    1. Linnebjerg H, Kothare P, Park S, Mace K, Mitchell M. The effect of exenatide on lisinopril pharmacodynamics and pharmacokinetics in patients with hypertension. Int J Clin Pharmacol Ther. in press .
    1. Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75) Diabetologia. 2006;49:1761–9. doi: 10.1007/s00125-006-0297-1.
    1. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ. 2000;321:412–9. doi: 10.1136/bmj.321.7258.412.
    1. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Ménard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755–62. doi: 10.1016/S0140-6736(98)04311-6.
    1. Shen L, Han J, Yushmanova I, Bruce S, Porter L. Cardiovascular safety of exenatide BID: an integrated analysis from long-term controlled clinical trials in subjects with type 2 diabetes [abstract] Diabetes. 2009;58:A96–97. doi: 10.2337/db08-0617.
    1. Fabunmi R, McAdam-Marx C, Ye X, Misurski D, Brixner D. Blood pressure outcomes after 6 months of exenatide treatment in patients with type 2 diabetes in a real world study [abstract] Diabetes. 2009;58:A125. doi: 10.2337/db08-0400.
    1. Edwards CM, Todd JF, Ghatei MA, Bloom SR. Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects. Clin Sci. 1998;95:719–24. doi: 10.1042/CS19980028.
    1. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2003;42:878–84. doi: 10.1161/.
    1. Nyström T, Gonon AT, Sjöholm A, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005;125:173–7. doi: 10.1016/j.regpep.2004.08.024.

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