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Blood Pressure and Cardiovascular Effects of New and Emerging Antidiabetic Agents

  • Hypertension and Obesity (E Reisin, Section Editor)
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Abstract

Despite remarkable declines in US cardiovascular disease morbidity and mortality over the last several decades, the prevalence of risk factors such as type 2 diabetes and hypertension remains high, associated with increasing obesity rates. Although optimal glycemic control remains a primary focus to decrease the disease burden, the FDA has issued guidance recommendations for documenting cardiovascular disease-related safety with research trials on new antidiabetic agents with more demanding requirements compared to past approval of existing therapies. This review will discuss the public health impact of type 2 diabetes, specifically with comorbid hypertension; mechanisms of action of the newest antidiabetic drug classes; and preliminary findings and potential clinical significance of the favorable blood pressure and body weight effects of the sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists; and additionally discuss two recent large cardiovascular outcome trials with dipeptidyl peptidase-4 inhibitors.

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References

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  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):e28–292. This article from the American Heart Association provides the most recent data regarding cardiovascular disease morbidity and mortality.

  2. Bonow RO, Gheorghiade M. The diabetes epidemic: a national and global crisis. Am J Med. 2004;116(Suppl 5A):2S–10.

    PubMed  Google Scholar 

  3. Fox CS, Coady S, Sorlie PD, D’Agostino RBS, Pencina MJ, Vasan RS, Fox CS, Coady S, Sorlie PD, D'Agostino RB Sr, Pencina MJ, Vasan RS, Meigs JB, Levy D, Savage PJ. Increasing cardiovascular disease burden due to diabetes mellitus: the Framingham Heart Study. Circulation. 2007;115(12):1544–50.

    PubMed  Google Scholar 

  4. Meigs JB. Epidemiology of cardiovascular complications in type 2 diabetes mellitus. Acta Diabetol. 2003;40 Suppl 2:S358–61.

    PubMed  Google Scholar 

  5. Peters AL. Patient and treatment perspectives: Revisiting the link between type 2 diabetes, weight gain, and cardiovascular risk. Cleve Clin J Med. 2009;76 Suppl 5:S20–7.

    PubMed  Google Scholar 

  6. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011.

    Google Scholar 

  7. Eckel, R. H., Jakicic, J. M., Ard, J. D., Hubbard, V. S., de Jesus, J. M., Lee, I.-M., Yanovski, S. Z. (2013). 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. This article provides very recent guidelines and supporting data regarding lifestyle management for prevention of cardiovascular disease.

  8. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA, J Am Med Assoc. 2014;311(5):507–20. This article provides very recent guidelines and supporting data regarding lifestyle management for prevention of cardiovascular disease.

    CAS  PubMed  Google Scholar 

  9. Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D’Agostino RBS, Fox CS, Coady S, Sorlie PD, Levy D, Meigs JB, D'Agostino RB Sr, Wilson PW, Savage PJ. Trends in cardiovascular complications of diabetes. JAMA, J Am Med Assoc. 2004;292(20):2495–9.

  10. McFarlane SI, Sica DA, Sowers JR. Stroke in patients with diabetes and hypertension. J Clin Hypertens (Greenwich, Conn). 2005;7(5):286–92. quiz 293–294.

    Google Scholar 

  11. Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis: Off J Natl Kidney Found. 2000;36(3):646–61.

    CAS  PubMed  Google Scholar 

  12. US Food and Drug Administration. Guidance for Industry: Diabetes Mellitus—Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. Food and Drug Administration, Center for Drug Evaluation and Research, December 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf. Accessed 20 March 2014.

  13. Chaggar PS, Shaw SM, Williams SG. Review article: Thiazolidinediones and heart failure. Diabetes Vascular Dis Res: Off J Int Soc Diabetes Vascular Dis. 2009;6(3):146–52.

    Google Scholar 

  14. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, Davidson MB, Einhorn D, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez G, Davidson MH. AACE comprehensive diabetes management algorithm 2013. Endocr Pract: Offl J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2013;19(2):327–36. This document represents the most recent position statement from the American Association of Clinical Endocrinologists and the American College of Endocrinology regarding the comprehensive evaluation and management of type 2 diabetes.

    PubMed  Google Scholar 

  15. Fonseca VA. New developments in diabetes management: medications of the 21st century. Clin Ther. 2014;36(4):477–84. This manuscript provides a general review on new therapies for management of diabetes.

    CAS  PubMed  Google Scholar 

  16. Irons BK, Minze MG. Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated. Diabetes, Metab Syndr Obes: Targets Ther. 2014;7:15–24. This manuscript provides a review on therapies for management of type 2 diabetes with contraindications to metformin.

    Google Scholar 

  17. Mann DM, Woodward M, Ye F, Krousel-Wood M, Muntner P. Trends in medication use among US adults with diabetes mellitus: glycemic control at the expense of controlling cardiovascular risk factors. Arch Intern Med. 2009;169(18):1718–20.

    PubMed  Google Scholar 

  18. Chao EC, Henry RR. SGLT2 inhibition—a novel strategy for diabetes treatment. Nat Rev Drug Discovery. 2010;9(7):551–9.

    CAS  PubMed  Google Scholar 

  19. Cuypers J, Mathieu C, Benhalima K. SGLT2-inhibitors: a novel class for the treatment of type 2 diabetes introduction of SGLT2-inhibitors in clinical practice. Acta Clin Belg. 2013;68(4):287–93. This manuscript provides a focused review on sodium-glucose co-transporter inhibitors for management of diabetes.

    CAS  PubMed  Google Scholar 

  20. Foote C, Perkovic V, Neal B. Effects of SGLT2 inhibitors on cardiovascular outcomes. Diabetes Vascular Dis Res: Off J Int Soc Diabetes Vascular Dis. 2012;9(2):117–23. The authors provide evidence on the effects of sodium-glucose co-transporter inhibitors on the cardiometabolic risk profile of diabetics such as body weight, blood pressure and lipid levels.

    Google Scholar 

  21. Srinivasan BT, Jarvis J, Khunti K, Davies MJ. Recent advances in the management of type 2 diabetes mellitus: a review. Postgrad Med J. 2008;84(996):524–31.

    CAS  PubMed  Google Scholar 

  22. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262–74. This meta-analysis demonstrates short-term outcomes from recent clinical trials on SGLT-2 inhibitors in adults with T2DM.

    PubMed  Google Scholar 

  23. Valentine V. The role of the kidney and sodium-glucose cotransporter-2 inhibition in diabetes management. Clin Diabetes. 2012;30(4):151–5. The author provides a review of the vital role of the kidney in glucose homeostasis and importance of SGLT-2 inhibitors in management of T2DM.

    Google Scholar 

  24. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54(12):3427–34.

    CAS  PubMed  Google Scholar 

  25. Ehrenkranz JRL, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes/Metab Res Rev. 2005;21(1):31–8.

    CAS  Google Scholar 

  26. Macewen A, Mckay GA, Fisher M. Drugs for diabetes: part 8 SGLT2 inhibitors. Br J Cardiol. 2012;19(1):26–9. The article provides a brief review on recent trials of SGLT-2 inhibitors demonstrating effects on blood glucose, blood pressure and body weight.

    Google Scholar 

  27. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Kawaguchi M, Canovatchel W, Meininger G. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36(9):2508–15. The authors provide evidence from this trial that SGLT-2 inhibitors reduce hemoglobin A1C levels and body weight in patients with T2DM.

    CAS  PubMed Central  Google Scholar 

  28. Clar, C., Gill, J. A., Court, R., & Waugh, N. (2012). Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open, 2(5). The authors provide a review of recent evidence demonstrating overall effects of SGLT2 inhibitors on glycemic control and weight reduction.

  29. Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, Woerle HJ, von Eynatten M, Broedl UC. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:13.

    PubMed  PubMed Central  Google Scholar 

  30. Meier JJ, Nauck MA. Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes/Metab Res Rev. 2005;21(2):91–117.

    CAS  Google Scholar 

  31. Russell-Jones D, Gough S. Recent advances in incretin-based therapies. Clin Endocrinol. 2012;77(4):489–99. The authors provide a general review on the use of incretin-based therapies such as GLP-1 receptor agonists and DPP-4 inhibitors in the management of T2DM.

    CAS  Google Scholar 

  32. Vilsboll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients. Diabetes. 2001;50(3):609–13.

    CAS  PubMed  Google Scholar 

  33. US Food and Drug Administration (FDA) - Byetta http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021773s9s11s18s22s25lbl.pdf. Accessed on 24 March 2014.

  34. US Food and Drug Administration (FDA)-Victoza http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm198638.pdf. Accessed on 24 March 2014.

  35. Shyangdan, D. S., Royle, P., Clar, C., Sharma, P., Waugh, N., & Snaith, A. (2011). Glucagon-like peptide analogues for type 2 diabetes mellitus. The Cochrane Database of Systematic Reviews, (10).

  36. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009;32(1):84–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473–81.

    CAS  PubMed  Google Scholar 

  38. Robinson, L. E., Holt, T. A., Rees, K., Randeva, H. S., & O’Hare, J. P. (2013). Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis. BMJ Open, 3(1). The authors provide a review of evidence demonstrating the effects of GLP-1 receptor agonists on reducing blood pressure and body weight along with increase in heart rate.

  39. Pickering TG, White WB, Giles TD, Black HR, Izzo JL, Materson BJ, Pickering TG, White WB, Giles TD, Black HR, Izzo JL, Materson BJ, Oparil S, Weber MA. When and how to use self (home) and ambulatory blood pressure monitoring. J Am Soc Hypertens: JASH. 2010;4(2):56–61.

    PubMed  Google Scholar 

  40. Ferdinand KC, Calhoun DA, Lonn EM, White WB, Sager P, Jiang H, Ferdinand KC, Calhoun DA, Lonn EM, White WB, Sager P, Jiang H, Threlkeld RJ. Effects of dulaglutide, a GLP-1 agonist, on ambulatory diurnal and nocturnal blood pressure in patients with type 2 diabetes [abstract]. J Clin Hypertens. 2013;15 Suppl 1:15. This abstract provides evidence from a phase 2 trial on the reduction of blood pressure with a novel GLP-1 agonist with the use of ABPM.

  41. Eli Lilly and Co. Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND). clinicaltrials.gov. Bethesda (MD): National Library of Medicine; 2011-2013:NLM Identifier NCT01394952.

  42. Barragan JM, Rodriguez RE, Blazquez 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(3 Pt 1):E459–66.

    CAS  PubMed  Google Scholar 

  43. Barragan JM, Rodriguez RE, Eng J, Blazquez E. Interactions of exendin-(9-39) with the effects of glucagon-like peptide-1-(7-36) amide and of exendin-4 on arterial blood pressure and heart rate in rats. Regul Pept. 1996;67(1):63–8.

    CAS  PubMed  Google Scholar 

  44. Isbil-Buyukcoskun N, Gulec G. Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin. Regul Pept. 2004;118(1–2):33–8.

    CAS  PubMed  Google Scholar 

  45. Nystrom T, Gonon AT, Sjoholm A, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005;125(1–3):173–7.

    PubMed  Google Scholar 

  46. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz S-S, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117(18):2340–50.

    CAS  PubMed  Google Scholar 

  47. Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, Simpson JA, Drucker DJ. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19(5):567–75. This article provides evidence using animal models on the anti-hypertensive effects of GLP-1 receptor agonists.

    CAS  PubMed  Google Scholar 

  48. Food and Drug Administration. FDA Announces New Recommendations on Evaluating Cardiovascular Risk in Drugs Intended to Treat Type 2 Diabetes. http://www.fda.gov/Newsevents/Newsroom/PressAnnouncements/2008/ucm116994.htm. Accessed 24 March 2014.

  49. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26. This manuscript provides data regarding CVD outcomes with Saxagliptin (DPP-4 inhibitor) and suggests potential link with increased heart failure events prompting further investigation by the FDA.

    CAS  Google Scholar 

  50. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. Engl J Med. 2013;369(14):1327–35. This manuscript provides data demonstrating no increased CVD events with alogliptin (DPP-4 inhibitor) in adults with T2DM.

    CAS  Google Scholar 

  51. Food and Drug Administration. FDA Drug Safety Communication: FDA to review heart failure risk with diabetes drug saxagliptin (marketed as Onglyza and Kombiglyze XR). http://www.fda.gov/Drugs/DrugSafety/ucm385287.htm. Accessed 24 March 2014.

  52. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974;34(1):29–34.

    CAS  PubMed  Google Scholar 

  53. Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Hulley SB, Grady D, Bibbins-Domingo K, Lin F, Vittinghoff E, Barrett-Connor E, Hulley SB, Grady D, and Shlipak MG. Predictors of heart failure among women with coronary disease. Circulation. 2004;110(11):1424–30.

    PubMed  Google Scholar 

  54. Bertoni AG, Goff DCJ, D’Agostino RBJ, Liu K, Hundley WG, Lima JA, Bertoni AG, Goff DC Jr, D'Agostino RB Jr, Liu K, Hundley WG, Lima JA, Polak JF, Saad MF, Szklo M, Tracy RP, Siscovick DS. Diabetic cardiomyopathy and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care. 2006;29(3):588–94.

    PubMed  Google Scholar 

  55. Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DCJ. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004;27(3):699–703.

    PubMed  Google Scholar 

  56. Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Lee ET, Welty TK, Devereux RB, Roman MJ, Paranicas M, O'Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Howard BV. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation. 2000;101(19):2271–6.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Pelbreton C. Balfour Jr. & Carlos J. Rodriguez

  2. Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, USA

    Keith C. Ferdinand

  3. Tulane School of Medicine, Tulane Heart and Vascular Institute, 1430 Tulane Ave. SL-48, New Orleans, LA, 70112, USA

    Keith C. Ferdinand

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  1. Pelbreton C. Balfour Jr.
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Correspondence to Keith C. Ferdinand.

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Conflict of Interest Pelbreton C. Balfour, Jr., declares that he has no conflict of interest.

Carlos J. Rodriguez has received grants from the NIH/NHLBI (R01 HL104199 and R01HL104199-03S1).

Keith C. Ferdinand has received a grant and paid travel expenses from Eli Lilly. He also has received consulting or honoraria payments from Amgen, Sanofi, Boerhinger Ingelheim, Astra Zeneca, Daiichi Sankyo and Novartis. Dr. Ferdinand has also received paid travel expenses from Boerhinger Ingelheim, grants from Daichii Sankyo and lecture payments from Astra Zeneca.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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Balfour, P.C., Rodriguez, C.J. & Ferdinand, K.C. Blood Pressure and Cardiovascular Effects of New and Emerging Antidiabetic Agents. Curr Hypertens Rep 16, 455 (2014). https://doi.org/10.1007/s11906-014-0455-7

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