Effect of insulin glargine and n-3FA on carotid intima-media thickness in people with dysglycemia at high risk for cardiovascular events: the glucose reduction and atherosclerosis continuing evaluation study (ORIGIN-GRACE)

Eva M Lonn, Jackie Bosch, Rafael Diaz, Patricio Lopez-Jaramillo, Ambady Ramachandran, Nicolae Hâncu, Markolf Hanefeld, Henry Krum, Lars Ryden, Sandra Smith, Matthew J McQueen, Leanne Dyal, Salim Yusuf, Hertzel C Gerstein, GRACE and ORIGIN Investigators, R Diaz, A Alebuena, M Alzogaray, F Bello, B Bustos, A Caccavo, A Camino, M Cantero, M Capozzi, L Cartasegna, A Cassetari, R Castellanos, R Chavez Caballero, J Coria, G Costa, C Crespo, C Cuneo, M Farah, A Ferrari, N Ferrari, N Gutierrez, L Guzman, P Guzman, R Henquin, A Hershon, M Hominal, M La Grutta, L Lobo Marquez, J Lowenstein, S Mainini, M Marino, M Molina, O Montaña, A Orlandini, M Quiroz, F Risso Patron, T Smith Casabella, D Stisman, P Streitenberger, J Valdez, A Villarino, V Visco, C Zaidman, H Krum, F De Looze, M Kwan, S Luu, V Mohabbati, N Perera, D Sullivan, F Tiong, E Lonn, L R Bhargava, G Dagenais, W Harper, I Hramiak, C Jones, T Paul, J Shaban, J Singh, W Warnica, M Weingert, R Wilson, P Lopez-Jaramillo, J Accini, C Cure, M Figueredo, E Hernandez-Triana, L Orozco, A Quintero, R Quiros, M Urina, M Hanefeld, A Koehler, M Nishwitz, J Seissler, C von Schacky, A Ramachandran, S Aravind, P Devi Manduva, O George, P George, V Karthik, G Koshy, L Krishnan, V Mohan, V Moses, R Oomen, P Pati, M Ramu, U Ranjit, P Rao, V Senthil, R Siddharth, A Shobha, K Sudeep, C Sunil, S Sunitha, N Thomas, M Viswanathan, N Hâncu, M Rosu, V Serban, A Sima, A Vlad, S Bérgamo, M Bocanera, H Brescia, L Caccavo, A Carrique, P Carrique, G Cendali, M Chatelain, C Cristofaro, P Crunger, M Espinosa, L Esposito, V Fracaro, A Guzman, M Hominal, M Izzicupo, C Luciani, G Martinez, M Molina, I Moreno Cepeda, G Niemann, V Novas, H Rodriguez, M Rodriguez, C Schulte, C Tinnirello, S Vignau, M Zarate, N Lai, K McNamara, A Moroney, C Chambers, C Colborne, D Eichmann, M Poulin, D Scarcelli, N Schmidt, B Smith, C Stafford, C Stata, R Vienneau, M Accini, S Camargo, J Figueroa, M Florez, M Martinez, C Ramos, D Rodriguez, A Santamaria, T Valencia, M Anuradha, R Gayatri, R Gnanasundram, U Gopal, S Govindaraj, P Indira, K Karkuzhli, S Mani, B Manmhan, S Poongothai, K Sangeetha, K Sankar, S Shetty, R Umashankar, E Lonn, H C Gerstein, S Yusuf, J Bosch, L Dyal, J Castelli, J Tyrwhitt, K Simek, C Williamson, K Pohl, E Lonn, R Djuric, L Newkirk, S Smith, Eva M Lonn, Jackie Bosch, Rafael Diaz, Patricio Lopez-Jaramillo, Ambady Ramachandran, Nicolae Hâncu, Markolf Hanefeld, Henry Krum, Lars Ryden, Sandra Smith, Matthew J McQueen, Leanne Dyal, Salim Yusuf, Hertzel C Gerstein, GRACE and ORIGIN Investigators, R Diaz, A Alebuena, M Alzogaray, F Bello, B Bustos, A Caccavo, A Camino, M Cantero, M Capozzi, L Cartasegna, A Cassetari, R Castellanos, R Chavez Caballero, J Coria, G Costa, C Crespo, C Cuneo, M Farah, A Ferrari, N Ferrari, N Gutierrez, L Guzman, P Guzman, R Henquin, A Hershon, M Hominal, M La Grutta, L Lobo Marquez, J Lowenstein, S Mainini, M Marino, M Molina, O Montaña, A Orlandini, M Quiroz, F Risso Patron, T Smith Casabella, D Stisman, P Streitenberger, J Valdez, A Villarino, V Visco, C Zaidman, H Krum, F De Looze, M Kwan, S Luu, V Mohabbati, N Perera, D Sullivan, F Tiong, E Lonn, L R Bhargava, G Dagenais, W Harper, I Hramiak, C Jones, T Paul, J Shaban, J Singh, W Warnica, M Weingert, R Wilson, P Lopez-Jaramillo, J Accini, C Cure, M Figueredo, E Hernandez-Triana, L Orozco, A Quintero, R Quiros, M Urina, M Hanefeld, A Koehler, M Nishwitz, J Seissler, C von Schacky, A Ramachandran, S Aravind, P Devi Manduva, O George, P George, V Karthik, G Koshy, L Krishnan, V Mohan, V Moses, R Oomen, P Pati, M Ramu, U Ranjit, P Rao, V Senthil, R Siddharth, A Shobha, K Sudeep, C Sunil, S Sunitha, N Thomas, M Viswanathan, N Hâncu, M Rosu, V Serban, A Sima, A Vlad, S Bérgamo, M Bocanera, H Brescia, L Caccavo, A Carrique, P Carrique, G Cendali, M Chatelain, C Cristofaro, P Crunger, M Espinosa, L Esposito, V Fracaro, A Guzman, M Hominal, M Izzicupo, C Luciani, G Martinez, M Molina, I Moreno Cepeda, G Niemann, V Novas, H Rodriguez, M Rodriguez, C Schulte, C Tinnirello, S Vignau, M Zarate, N Lai, K McNamara, A Moroney, C Chambers, C Colborne, D Eichmann, M Poulin, D Scarcelli, N Schmidt, B Smith, C Stafford, C Stata, R Vienneau, M Accini, S Camargo, J Figueroa, M Florez, M Martinez, C Ramos, D Rodriguez, A Santamaria, T Valencia, M Anuradha, R Gayatri, R Gnanasundram, U Gopal, S Govindaraj, P Indira, K Karkuzhli, S Mani, B Manmhan, S Poongothai, K Sangeetha, K Sankar, S Shetty, R Umashankar, E Lonn, H C Gerstein, S Yusuf, J Bosch, L Dyal, J Castelli, J Tyrwhitt, K Simek, C Williamson, K Pohl, E Lonn, R Djuric, L Newkirk, S Smith

Abstract

Objective: To evaluate the effects of insulin glargine and n-3 polyunsaturated fatty acid (n-3FA) supplements on carotid intima-media thickness (CIMT).

Research design and methods: We enrolled 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes in a randomized multicenter 2 × 2 factorial design trial. Participants received open-label insulin glargine (targeting fasting glucose levels ≤ 5.3 mmol/L [95 mg/dL]) or standard glycemic care and double-blind therapy with a 1-g capsule of n-3FA or placebo. The primary trial outcome was the annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments. Secondary outcomes were the annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation, respectively. Baseline followed by annual ultrasounds were obtained during a median follow-up of 4.9 years.

Results: Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups.

Conclusions: In people with CV disease and/or CV risk factors and dysglycemia, insulin glargine used to target normoglycemia modestly reduced CIMT progression, whereas daily supplementation with n-3FA had no effect on CIMT progression.

Trial registration: ClinicalTrials.gov NCT00069784.

Figures

Figure 1
Figure 1
Changes in levels of FPG (A), HbA1c (B), and triglycerides (C) in patients receiving insulin glargine and standard care.
Figure 2
Figure 2
Changes in the primary and secondary CIMT outcomes by treatment group for the insulin glargine (A) and n-3FA (B) arms of the trial (slopes of carotid intima-media change and 95% CIs). BIF, bifurcation; CC, common carotid.

References

    1. Seshasai SR, Kaptoge S, Thompson A, et al. Emerging Risk Factors Collaboration Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829–841
    1. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800–811
    1. Gerstein HC, Islam S, Anand S, et al. Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups: an analysis of 15,780 patients from the INTERHEART study. Diabetologia 2010;53:2509–2517
    1. Sarwar N, Gao P, Seshasai SR, et al. Emerging Risk Factors Collaboration Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:2215–2222
    1. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab 2011;14:575–585
    1. Muntoni S, Muntoni S, Draznin B. Effects of chronic hyperinsulinemia in insulin-resistant patients. Curr Diab Rep 2008;8:233–238
    1. Nandish S, Bailon O, Wyatt J, et al. Vasculotoxic effects of insulin and its role in atherosclerosis: what is the evidence? Curr Atheroscler Rep 2011;13:123–128
    1. Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010;376:540–550
    1. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985;312:1205–1209
    1. Dolecek TA, Granditis G. Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT). World Rev Nutr Diet 1991;66:205–216
    1. Sekikawa A, Ueshima H, Kadowaki T, et al. Less subclinical atherosclerosis in Japanese men in Japan than in white men in the United States in the post-World War II birth cohort. Am J Epidemiol 2007;165:617–624
    1. Sekikawa A, Curb JD, Ueshima H, et al. ERA JUMP (Electron-Beam Tomography, Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort) Study Group Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese-American, and white men: a cross-sectional study. J Am Coll Cardiol 2008;52:417–424
    1. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: diet and reinfarction trial (DART). Lancet 1989;2:757–761
    1. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto. miocardico Lancet 1999;354:447–455
    1. Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipid intervention study (JELIS) Investigators Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090–1098
    1. Rizos EC, Ntzani EE, Bika E, Kostapanos MS, Elisaf MS. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012;308:1024–1033
    1. Sacks FM, Stone PH, Gibson CM, Silverman DI, Rosner B, Pasternak RC, HARP Research Group Controlled trial of fish oil for regression of human coronary atherosclerosis. J Am Coll Cardiol 1995;25:1492–1498
    1. Thies F, Garry JM, Yaqoob P, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 2003;361:477–485
    1. von Schacky C, Angerer P, Kothny W, Theisen K, Mudra H. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999;130:554–562
    1. Angerer P, Kothny W, Störk S, von Schacky C. Effect of dietary supplementation with omega-3 fatty acids on progression of atherosclerosis in carotid arteries. Cardiovasc Res 2002;54:183–190
    1. Hjerkinn EM, Abdelnoor M, Breivik L, et al. Effect of diet or very long chain omega-3 fatty acids on progression of atherosclerosis, evaluated by carotid plaques, intima-media thickness and by pulse wave propagation in elderly men with hypercholesterolaemia. Eur J Cardiovasc Prev Rehabil 2006;13:325–333
    1. Origin Trial Investigators, Gerstein H, Yusuf S, Riddle MC, Ryden L, Bosch J. Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention). Am Heart J 2008;155:26-32
    1. Gerstein HC, Bosch J, Dagenais GR, et al. ORIGIN Trial Investigators Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319–328
    1. Bosch J, Gerstein HC, Dagenais GR, et al. ORIGIN Trial Investigators n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309–318
    1. Lonn EM, Gerstein HC, Sheridan P, et al. DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) and STARR Investigators Effect of ramipril and of rosiglitazone on carotid intima-media thickness in people with impaired glucose tolerance or impaired fasting glucose: STARR (STudy of Atherosclerosis with Ramipril and Rosiglitazone). J Am Coll Cardiol 2009;53:2028–2035
    1. Lonn E, Yusuf S, Dzavik V, et al. SECURE Investigators Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation 2001;103:919–925
    1. Crouse JR, 3rd, Raichlen JS, Riley WA, et al. METEOR Study Group Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007;297:1344–1353
    1. Kastelein JJ, van Leuven SI, Burgess L, et al. RADIANCE 1 Investigators Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;356:1620–1630
    1. Bots ML, Visseren FL, Evans GW, et al. RADIANCE 2 Investigators Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007;370:153–160
    1. Bots ML, Evans GW, Riley WA, Grobbee DE. Carotid intima-media thickness measurements in intervention studies: design options, progression rates, and sample size considerations: a point of view. Stroke 2003;34:2985–2994
    1. Dogan S, Kastelein JJ, Grobbee DE, Bots ML. Mean common or mean maximum carotid intima-media thickness as primary outcome in lipid-modifying intervention studies. J Atheroscler Thromb 2011;18:946–957
    1. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Diabetes Mellitus – Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes [Internet], December 2008. Available from Accessed October 2012
    1. Chaudhuri A, Janicke D, Wilson MF, et al. Anti-inflammatory and profibrinolytic effect of insulin in acute ST-segment-elevation myocardial infarction. Circulation 2004;109:849–854
    1. Vehkavaara S, Yki-Järvinen H. 3.5 years of insulin therapy with insulin glargine improves in vivo endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol 2004;24:325–330
    1. Taskinen MR, Kuusi T, Helve E, Nikkilä EA, Yki-Järvinen H. Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes. Arteriosclerosis 1988;8:168–177
    1. Nathan DM, Cleary PA, Backlund JY, et al. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653
    1. Brohall G, Odén A, Fagerberg B. Carotid artery intima-media thickness in patients with type 2 diabetes mellitus and impaired glucose tolerance: a systematic review. Diabet Med 2006;23:609–616
    1. Miyashita Y, Nishimura R, Nemoto M, et al. Prospective randomized study for optimal insulin therapy in type 2 diabetic patients with secondary failure. Cardiovasc Diabetol 2008;7:16.
    1. Joya-Galeana J, Fernandez M, Cervera A, et al. Effects of insulin and oral anti-diabetic agents on glucose metabolism, vascular dysfunction and skeletal muscle inflammation in type 2 diabetic subjects. Diabetes Metab Res Rev 2011;27:373–382
    1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577–1589
    1. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011;343:d4169.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever