Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study

Manfredi Rizzo, Manisha Chandalia, Angelo Maria Patti, Vittoria Di Bartolo, Ali A Rizvi, Giuseppe Montalto, Nicola Abate, Manfredi Rizzo, Manisha Chandalia, Angelo Maria Patti, Vittoria Di Bartolo, Ali A Rizvi, Giuseppe Montalto, Nicola Abate

Abstract

Background: Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has several non- glycemic properties, but its effect on carotid intima-media thickness (IMT), a recognized marker of subclinical atherosclerosis, is still unknown.

Methods: A prospective study of 8 months duration in 64 patients with type-2 diabetes and no prior history of coronary artery disease evaluated whether adding liraglutide to metformin affects carotid IMT, measured by color doppler ultrasound.

Results: After 8 months, fasting glucose decreased by 2.1 mmol/l and HbA1c by 1.9% (p < 0.01 for all). Liraglutide reduced total-cholesterol and triglycerides by 10%, and LDL-cholesterol by 19%, whereas HDL-cholesterol increased by 18% (p < 0.01 for all lipid changes). Carotid IMT decreased from 1.19 ± 0.47 to 0.94 ± 0.21 mm (p < 0.01). Yet, changes in carotid IMT did not correlate with changes in any other variable studied.

Conclusions: Liraglutide decreases carotid IMT after 8 months treatment independently of its effect on plasma glucose and lipids concentrations.

Trial registration: ClinicalTrials.gov: NCT01715428.

References

    1. Montanya E, Sesti G. A review of efficacy and safety data regarding the use of liraglutide, a once-daily human glucagon-like peptide 1 analogue, in the treatment of type 2 diabetes mellitus. Clin Ther. 2009;31:2472–2488. doi: 10.1016/j.clinthera.2009.11.034.
    1. Courrèges JP, Vilsbøll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Verhoeven R, Bugáñová I, Madsbad S. et al.Beneficial effects of once-daily liraglutide, a human glucagon-like peptide-1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes. Diabet Med. 2008;25:1129–1131. doi: 10.1111/j.1464-5491.2008.02484.x.
    1. Rizzo M, Rizvi AA, Spinas GA, Rini GB, Berneis K. Glucose lowering and anti-atherogenic effects of incretin-based therapies: GLP-1 analogues and DPP-4-inhibitors. Expert Opin Investig Drugs. 2009;18:1495–1503. doi: 10.1517/14728220903241633.
    1. Burgmaier M, Heinrich C, Marx N. Cardiovascular effects of GLP-1 and GLP-1-based therapies: implications for the cardiovascular continuum in diabetes? Diabet Med. 2012. Jul 18. doi:10.1111/j.1464-5491.2012.03746.x. [Epub ahead of print]
    1. Public Access to Clinical Trials NNaS: Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation (LEADER®) . .
    1. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem. 1974;20:470–475.
    1. Nägele U, Hägele EO, Sauer G, Wiedemann E, Lehmann P, Wahlefeld AW, Gruber W. et al.Reagent for the enzymatic determination of serum total triglycerides with improved lipolytic efficiency. J Clin Chem Clin Biochem. 1984;22:165–174.
    1. Warnick GR, Nguyen T, Albers JJ. Comparison of improved precipitation methods for quantification of high density lipoprotein cholesterol. Clin Chem. 1985;31:217–222.
    1. Corrado E, Rizzo M, Tantillo R, Muratori I, Bonura F, Vitale G, Novo S. et al.Markers of inflammation and infection influence the outcome of patients with baseline asymptomatic carotid lesions: a 5 years follow-up study. Stroke. 2006;37:482–486. doi: 10.1161/01.STR.0000198813.56398.14.
    1. Hogan AE, Gaoatswe G, Lynch L, Corrigan MA, Woods C, O’Connell J, O’Shea D. Glucagon-like peptide 1 analogue therapy directly modulates innate immunemediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2013. Dec 21. [Epub ahead of print]
    1. Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, Bray GA, Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Musi N, Tripathy D, DeFronzo RA, Reaven PD. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol. 2013;33:393–399. doi: 10.1161/ATVBAHA.112.300346.
    1. Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, Baggio LL, Henkelman RM, Husain M, Drucker DJ. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:975–983. doi: 10.2337/db08-1193.
    1. Murthy SN, Hilaire RC, Casey DB, Badejo AM, McGee J, McNamara DB, Kadowitz PJ, Fonseca VA. The synthetic GLP-I receptor agonist, exenatide, reduces intimal hyperplasia in insulin resistant rats. Diab Vasc Dis Res. 2010;7:138–144. doi: 10.1177/1479164109360269.
    1. Zheng MY, Yang JH, Shan CY, Zhou HT, Xu YG, Wang Y, Ren HZ, Chang BC, Chen LM. Effects of 24-week treatment with acarbose on glucagon-like peptide 1 in newly diagnosed type 2 diabetic patients: a preliminary report. Cardiovasc Diabetol. 2013;12:73. doi: 10.1186/1475-2840-12-73.
    1. Hopkins ND, Cuthbertson DJ, Kemp GJ, Pugh C, Green DJ, Cable NT, Jones H. Effects of 6 months glucagon-like peptide-1 receptor agonist treatment on endothelial function in type 2 diabetes mellitus patients. Diabetes Obes Metab. 2013;15:770–773. doi: 10.1111/dom.12089.
    1. Fujishima Y, Maeda N, Inoue K, Kashine S, Nishizawa H, Hirata A, Kozawa J, Yasuda T, Okita K, Imagawa A, Funahashi T, Shimomura I. Efficacy of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on body weight, eating behavior, and glycemic control, in Japanese obese type 2 diabetes. Cardiovasc Diabetol. 2012;11:107. doi: 10.1186/1475-2840-11-107.
    1. Dahlén EM, Bjarnegård N, Länne T, Nystrom FH, Ostgren CJ. Sagittal abdominal diameter is a more independent measure compared with waist circumference to predict arterial stiffness in subjects with type 2 diabetes–a prospective observational cohort study. Cardiovasc Diabetol. 2013;12:55. doi: 10.1186/1475-2840-12-55.
    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. Basu A, Charkoudian N, Schrage W, Rizza RA, Basu R, Joyner MJ. Beneficial effects of GLP-1 on endothelial function in humans: dampening by glyburide but not by glimepiride. Am J Physiol Endocrinol Metab. 2007;293:E1289–E1295. doi: 10.1152/ajpendo.00373.2007.
    1. Ceriello A, Esposito K, Testa R, Bonfigli AR, Marra M, Giugliano D. The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an “endothelial resistance” to glucagon-like peptide 1 in diabetes. Diabetes Care. 2011;34:697–702. doi: 10.2337/dc10-1949.
    1. Tesauro M, Schinzari F, Adamo A, Rovella V, Martini F, Mores N, Barini A, Pitocco D, Ghirlanda G, Lauro D, Campia U, Cardillo C. Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome. Diabetes Care. 2013;36:683–689. doi: 10.2337/dc12-0763.
    1. Gaspari T, Liu H, Welungoda I, Hu Y, Widdop RE, Knudsen LB, Simpson RW, Dear AE. A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model. Diab Vasc Dis Res. 2011;8:117–124. doi: 10.1177/1479164111404257.
    1. Gaspari T, Welungoda I, Widdop RE, Simpson RW, Dear AE. The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model. Diab Vasc Dis Res. 2013;10:353–360. doi: 10.1177/1479164113481817.
    1. Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, D’Agostino RB Sr, Perez A, Provost JC, Haffner SM. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA. 2006;296:2572–2581. doi: 10.1001/jama.296.21.joc60158.
    1. Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A, Paolisso G. Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis. 2013;227:349–354. doi: 10.1016/j.atherosclerosis.2012.12.018.
    1. 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, Mozenson O, McGuire DK, Ray KK, Leiter LA, Raz I, the SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013. Sep 2. [Epub ahead of print]
    1. 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. The EXAMINE investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013. Sep 2. [Epub ahead of print]
    1. Sahin Y, Unluhizarci K, Yilmazsoy A, Yikilmaz A, Aygen E, Kelestimur F. The effects of metformin on metabolic and cardiovascular risk factors in nonobese women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2007;67:904–908. doi: 10.1111/j.1365-2265.2007.02985.x.
    1. Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, Kosugi K, Hori M. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetologia. 2004;47:1906–1913. doi: 10.1007/s00125-004-1547-8.
    1. Matsumoto K, Sera Y, Abe Y, Tominaga T, Yeki Y, Miyake S. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Pract. 2004;64:225–228. doi: 10.1016/j.diabres.2003.11.007.

Source: PubMed

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