European Heart Journal Advance Access originally published online on June 3, 2008
European Heart Journal 2008 29(15):1922; doi:10.1093/eurheartj/ehn244
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Possible involvement of advanced glycation end products in carry-over benefits of atorvastatin in ASCOT-BPLA
Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications
Kurume University School of Medicine
67 Asahi-machi Kurume 830-0011
Japan
Tel: +81 942 31 7873
Fax: +81 942 31 7873
Email: shoichi{at}med.kurume-u.ac.jp
I read with interest the recent study by Sever et al.,1 which reported that patients originally assigned atorvastatin continued to demonstrate lower event rates in most cardiovascular endpoints after the termination of Lipid Lowering Arm of the ASCOT (ASCOT-LLA) trial, compared with those originally assigned placebo, although LDL-cholesterol levels were almost identical in the two groups during the 2 years extended follow-up period.1 These observations suggest sustained cardioprotective effects of atorvastatin after the cessation of active treatment in at-risk patients with hypertension. A similar outcome was reported in the DCCT-EDIC Research; it revealed that original intensive therapy for 6.5 years reduced the risk of cardiovascular events to about 50% of that of conventional treatment in diabetic patients 11 years after the end of the trial, although glycosylated haemoglobin values in the two groups had almost converged during the follow-up periods.2 These clinical studies strongly suggest that so-called ‘metabolic memory’ causes chronic vascular damage in high-risk patients with hypertension and diabetes that are not easily reversed, even by subsequent, relatively good control of LDL-cholesterol or blood glucose.
Reducing sugars can react non-enzymatically with amino groups of protein to form Amadori products.3,4 These early glycation products undergo further complex reaction such as rearrangement, dehydration, and condensation to become irreversibly cross-linked, heterogeneous fluorescent derivatives, termed advanced glycation end products (AGEs).3,4 The formation and accumulation of AGEs have been known to progress at an accelerated rate under diabetes or oxidative stress conditions, thus playing a role in the development and progression of cardiovascular disease.3,4 Indeed, increased serum or skin levels of AGEs are reported to predict future cardiovascular mortality or progression of diabetic microangiopathy, respectively, in patients with diabetes.5,6 Further, increased formation and accumulation of AGEs are a possible mechanism to explain the ‘metabolic memory’, a long-term beneficial influence of early metabolic control on cardiovascular outcomes. Since we have previously found that atorvastatin not only inhibits the AGE signalling to inflammation in vitro, but also reduces serum levels of AGEs in hypercholesterolemic type 2 diabetic patients,4,7,8 it is conceivable that carry-over beneficial effects of atorvastatin on cardiovascular events in Blood Pressure Lowering Arm of the ASCOT (ASCOT-BPLA) trial could be ascribed, at least in part, to its inhibitory effects on AGE formation and/or the downstream-signalling pathways. Therefore, it is an interesting issue to clarify whether circulating or skin AGE levels at the closure of ASCOT-LLA could predict cardiovascular events at the end of ASCOT-BPLA.
References
- Sever PS, Poulter NR, Dahlof B, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes G, Mehlsen J, Nieminen MS, O'Brien ET, Ostergren J, ASCOT Investigators. The Anglo-Scandinavian Cardiac Outcomes Trial lipid lowering arm: extended observations 2 years after trial closure. Eur Heart J (2008) 29:499–508.
[Abstract/Free Full Text] - The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and cardiovascular disease in patients with type 1 diabetes. N Engl J Med (2005) 353:2643–2653.
[Abstract/Free Full Text] - Yamagishi S, Imaizumi T. Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des (2005) 11:2279–2299.[CrossRef][Web of Science][Medline]
- Yamagishi S, Nakamura K, Matsui T, Ueda S, Noda Y, Imaizumi T. Inhibitors of advanced glycation end products (AGEs): potential utility for the treatment of cardiovascular disease. Cardiovasc Ther (2008) 26:50–58.[Medline]
- Kilhovd BK, Juutilainen A, Lehto S, Rönnemaa T, Torjesen PA, Hanssen KF, Laakso M. Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study. Diabetologia (2007) 50:1409–1417.[CrossRef][Web of Science][Medline]
- Genuth S, Sun W, Cleary P, Sell DR, Dahms W, Malone J, Sivitz W, Monnier VM. DCCT Skin Collagen Ancillary Study Group. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes (2005) 54:3103–3111.
[Abstract/Free Full Text] - Jinnouchi Y, Yamagishi S, Takeuchi M, Ishida S, Jinnouchi Y, Jinnouchi J, Imaizumi T. Atorvastatin decreases serum levels of advanced glycation end products (AGEs) in patients with type 2 diabetes. Clin Exp Med (2006) 6:191–193.[CrossRef][Web of Science][Medline]
- Yamagishi S, Matsui T, Nakamura K. Atorvastatin and diabetic vascular complications. Curr Pharm Des (2006) 12:1549–1554.[CrossRef][Web of Science][Medline]
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