Liraglutide improves metabolic parameters and carotid intima-media thickness in diabetic patients with the metabolic syndrome: an 18-month prospective study

Manfredi Rizzo, Ali A Rizvi, Angelo Maria Patti, Dragana Nikolic, Rosaria Vincenza Giglio, Giuseppa Castellino, Giovanni Li Volti, Massimiliano Caprio, Giuseppe Montalto, Vincenzo Provenzano, Stefano Genovese, Antonio Ceriello, Manfredi Rizzo, Ali A Rizvi, Angelo Maria Patti, Dragana Nikolic, Rosaria Vincenza Giglio, Giuseppa Castellino, Giovanni Li Volti, Massimiliano Caprio, Giuseppe Montalto, Vincenzo Provenzano, Stefano Genovese, Antonio Ceriello

Abstract

Background: Liraglutide, a GLP-1 analogue, exerts several beneficial non-glycemic effects in patients with type-2 diabetes (T2DM), such as those on body weight, blood pressure, plasma lipids and inflammation markers. However, the effects of liraglutide on cardiovascular (CV) risk markers in subjects with the metabolic syndrome (MetS) are still largely unknown. We herein explored its effects on various cardio-metabolic risk markers of the MetS in subjects with T2DM.

Methods: We performed an 18-month prospective, real-world study. All subjects had T2DM and the MetS based on the AHA/NHLBI criteria. Subjects with a history of a major CV event were excluded. One hundred-twenty-one subjects (71 men and 50 women; mean age: 62 ± 9 years) with T2DM and the MetS, who were naïve to incretin-based therapies and treated with metformin only, were included. Liraglutide (1.2 mg/day) was added to metformin (1500-3000 mg/day) for the entire study. Fasting plasma samples for metabolic parameters were collected and carotid-intima media thickness (cIMT) was assessed by B-mode real-time ultrasound at baseline and every 6 months thereafter.

Results: There was a significant reduction in waist circumference, body mass index, fasting glycemia, HbA1c, total- and LDL-cholesterol, triglycerides, and cIMT during the 18-month follow-up. Correlation analysis showed a significant association between changes in cIMT and triglycerides (r = 0.362; p < 0.0001). The MetS prevalence significantly reduced during the study, and the 26% of subjects no longer fulfilled the criteria for the MetS after 18 months.

Conclusions: Liraglutide improves cardio-metabolic risk factors in subjects with the MetS in a real-world study. Trial Registration ClinicalTrials.gov: NCT01715428.

Keywords: Cardiovascular risk; Carotid intima-media thickness; Liraglutide; Metabolic syndrome.

Figures

Fig. 1
Fig. 1
Changes in cardio-metabolic parameters during the study. BMI body mass index, HbA1c glycated hemoglobin, TC total cholesterol, TG triglyceride, LDL low-density lipoprotein, HDL high-density lipoprotein, IMT intima media thickness. The data are presented as mean ± SE
Fig. 2
Fig. 2
Prevalence of the MetS among all patients (n = 121) during the study. MetS metabolic syndrome, n number

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. Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet. 2009;374:1606–1616. doi: 10.1016/S0140-6736(09)61375-1.
    1. Rizzo M, Nikolic D, Banach M, Giglio RV, Patti AM, Di Bartolo V, et al. The effects of liraglutide on glucose, inflammatory markers and lipoprotein metabolism: current knowledge and future perspective. Clin Lipidol. 2013;8:173–181. doi: 10.2217/clp.13.8.
    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. 2013;30:289–299. doi: 10.1111/j.1464-5491.2012.03746.x.
    1. Rizzo M, Chandalia M, Patti AM, Di Bartolo V, Rizvi AA, Montalto G, et al. Liraglutide decreases carotid intima-media thickness in patients with type 2 diabetes: 8-month prospective pilot study. Cardiovasc Diabetol. 2014;13:49. doi: 10.1186/1475-2840-13-49.
    1. Kim SH, Abbasi F, Lamendola C, Liu A, Ariel D, Schaaf P, et al. Benefits of liraglutide treatment in overweight and obese older individuals with prediabetes. Diabetes Care. 2013;36:3276–3282. doi: 10.2337/dc13-0354.
    1. Ando T, Haraguchi A, Matsunaga T, Natsuda S, Yamasaki H, Usa T, et al. Liraglutide as a potentially useful agent for regulating appetite in diabetic patients with hypothalamic hyperphagia and obesity. Intern Med. 2014;53:1791–1795. doi: 10.2169/internalmedicine.53.1646.
    1. Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human glp-1 analog, liraglutide. Int J Obes (Lond). 2012;36:843–854. doi: 10.1038/ijo.2011.158.
    1. Fadini GP, de Kreutzenberg SV, Gjini R, Avogaro A. The metabolic syndrome influences the response to incretin-based therapies. Acta Diabetol. 2011;48:219–225. doi: 10.1007/s00592-011-0296-7.
    1. Grundy SM. Metabolic syndrome scientific statement by the american heart association and the national heart, lung, and blood institute. Arterioscler Thromb Vasc Biol. 2005;25:2243–2244. doi: 10.1161/01.ATV.0000189155.75833.c7.
    1. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: a report of a workgroup of the american diabetes association and the endocrine society. Diabetes Care. 2013;36:1384–1395. doi: 10.2337/dc12-2480.
    1. Corrado E, Rizzo M, Tantillo R, Muratori I, Bonura F, Vitale G, et al. Markers of inflammation and infection influence the outcome of patients with baseline asymptomatic carotid lesions: a 5-year follow-up study. Stroke. 2006;37:482–486. doi: 10.1161/01.STR.0000198813.56398.14.
    1. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; american heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity. Circulation. 2009;120:1640–1645. doi: 10.1161/CIRCULATIONAHA.109.192644.
    1. Kostapanos MS, Katsiki N, Elisaf MS, Mikhailidis DP. Editorial: reducing cardiovascular risk: Is low-density lipoprotein-cholesterol (ldl-c) lowering enough? Curr Vasc Pharmacol. 2012;10:173–177. doi: 10.2174/157016112799305085.
    1. Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, et al. Effect of glp-1 receptor agonists on waist circumference among type 2 diabetes patients: a systematic review and network meta-analysis. Endocrine. 2015;48:794–803. doi: 10.1007/s12020-014-0373-0.
    1. Zoicas F, Droste M, Mayr B, Buchfelder M, Schofl C. Glp-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases. Eur J Endocrinol. 2013;168:699–706. doi: 10.1530/EJE-12-0997.
    1. Li CJ, Li J, Zhang QM, Lv L, Chen R, Lv CF, et al. Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in chinese subjects with poorly controlled type 2 diabetes and abdominal obesity. Cardiovasc Diabetol. 2012;11:142. doi: 10.1186/1475-2840-11-142.
    1. Inoue K, Maeda N, Fujishima Y, Fukuda S, Nagao H, Yamaoka M, et al. Long-term impact of liraglutide, a glucagon-like peptide-1 (glp-1) analogue, on body weight and glycemic control in japanese type 2 diabetes: an observational study. Diabetol Metab Syndr. 2014;6:95. doi: 10.1186/1758-5996-6-95.
    1. Plutzky J, Garber A, Falahati A, Toft AD, Poulter NR. Reductions in lipids and cv risk markers in patients with type 2 diabetes treated with liraglutide: a meta-analysis. Can J Diabetes. 2009;33:209–210. doi: 10.1016/S1499-2671(09)33072-5.
    1. Sun F, Wu S, Wang J, Guo S, Chai S, Yang Z, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther. 2015;37(225–41):e8.
    1. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (lead-4 met + tzd) Diabetes Care. 2009;32:1224–1230. doi: 10.2337/dc08-2124.
    1. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (lead-6) Lancet. 2009;374:39–47. doi: 10.1016/S0140-6736(09)60659-0.
    1. Buysschaert M, D’Hooge D, Preumont V, Roots Study G Roots: a multicenter study in belgium to evaluate the effectiveness and safety of liraglutide (victoza(r)) in type 2 diabetic patients. Diabetes Metab Syndr. 2015;9:139–142. doi: 10.1016/j.dsx.2015.05.001.
    1. Kim JY, Choi EY, Mun HS, Min PK, Yoon YW, Lee BK, et al. Usefulness of metabolic syndrome score in the prediction of angiographic coronary artery disease severity according to the presence of diabetes mellitus: relation with inflammatory markers and adipokines. Cardiovasc Diabetol. 2013;12:140. doi: 10.1186/1475-2840-12-140.
    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. Diabetes Vasc Dis Res. 2013;10:353–360. doi: 10.1177/1479164113481817.
    1. Noyan-Ashraf MH, Momen MA, Ban K, Sadi AM, Zhou YQ, Riazi AM, et al. 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. Song X, Jia H, Jiang Y, Wang L, Zhang Y, Mu Y, et al. Anti-atherosclerotic effects of the glucagon-like peptide-1 (glp-1) based therapies in patients with type 2 diabetes mellitus: a meta-analysis. Sci Rep. 2015;5:10202. doi: 10.1038/srep10202.
    1. 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;375:311–322. doi: 10.1056/NEJMoa1603827.
    1. European Society of Hypertension-European Society of Cardiology Guidelines C European society of hypertension-european society of cardiology guidelines for the management of arterial hypertension. J Hypertens. 2003;2003(21):1011–1053.
    1. Corrado E, Rizzo M, Coppola G, Muratori I, Carella M, Novo S. Endothelial dysfunction and carotid lesions are strong predictors of clinical events in patients with early stages of atherosclerosis: a 24-month follow-up study. Coron Artery Dis. 2008;19:139–144. doi: 10.1097/MCA.0b013e3282f3fbde.
    1. Sonmez A, Yilmaz MI, Saglam M, Unal HU, Gok M, Cetinkaya H, et al. The role of plasma triglyceride/high-density lipoprotein cholesterol ratio to predict cardiovascular outcomes in chronic kidney disease. Lipids Health Dis. 2015;14:29. doi: 10.1186/s12944-015-0031-4.
    1. Qamar A, Khetarpal SA, Khera AV, Qasim A, Rader DJ, Reilly MP. Plasma apolipoprotein c-iii levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol. 2015;35:1880–1888. doi: 10.1161/ATVBAHA.115.305415.
    1. Miselli MA, Nora ED, Passaro A, Tomasi F, Zuliani G. Plasma triglycerides predict ten-years all-cause mortality in outpatients with type 2 diabetes mellitus: a longitudinal observational study. Cardiovasc Diabetol. 2014;13:135. doi: 10.1186/s12933-014-0135-6.
    1. Al-Aubaidy HA, Jelinek HF. Oxidative stress and triglycerides as predictors of subclinical atherosclerosis in prediabetes. Redox Rep. 2014;19:87–91. doi: 10.1179/1351000213Y.0000000080.
    1. Rizzo M, Abate N, Chandalia M, Rizvi AA, Giglio RV, Nikolic D, et al. Liraglutide reduces oxidative stress and restores heme oxygenase-1 and ghrelin levels in patients with type 2 diabetes: a prospective pilot study. J Clin Endocrinol Metab. 2015;100:603–606. doi: 10.1210/jc.2014-2291.
    1. Kim SK, Choi YJ, Huh BW, Park SW, Lee EJ, Cho YW, et al. Nonalcoholic fatty liver disease is associated with increased carotid intima-media thickness only in type 2 diabetic subjects with insulin resistance. J Clin Endocrinol Metab. 2014;99:1879–1884. doi: 10.1210/jc.2013-4133.
    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. 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, et al. 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. Esteghamati A, Ghasemiesfe M, Mousavizadeh M, Noshad S, Nakhjavani M. Pioglitazone and metformin are equally effective in reduction of chemerin in patients with type 2 diabetes. J Diabetes Investig. 2014;5:327–332. doi: 10.1111/jdi.12157.
    1. Lim SS, Norman RJ, Clifton PM, Noakes M. The effect of comprehensive lifestyle intervention or metformin on obesity in young women. Nutr Metab Cardiovasc Dis. 2011;21:261–268.
    1. Fontbonne A, Diouf I, Baccara-Dinet M, Eschwege E, Charles MA. Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: a post hoc analysis of the bigpro1 trial. Diabetes Metab. 2009;35:385–391. doi: 10.1016/j.diabet.2009.03.005.
    1. Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P, Quartet Study G Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004;89:6068–6076. doi: 10.1210/jc.2003-030861.

Source: PubMed

3
Se inscrever