Skip to main content
Top
Published in: Cardiovascular Diabetology 1/2011

Open Access 01-12-2011 | Original investigation

Relationship between hemoglobin A1c and cardiovascular disease in mild-to-moderate hypercholesterolemic Japanese individuals: subanalysis of a large-scale randomized controlled trial

Authors: Rimei Nishimura, Tomoko Nakagami, Hirohito Sone, Yasuo Ohashi, Naoko Tajima

Published in: Cardiovascular Diabetology | Issue 1/2011

Login to get access

Abstract

Background

Although the ADA/EASD/IDF International Expert Committee recommends using hemoglobin A1c (HbA1c) to define diabetes, the relation between HbA1c and cardiovascular disease (CVD) has not been thoroughly investigated. We analyzed this relation using clinical data on Japanese individuals with hypercholesterolemia.

Methods

In the large-scale MEGA Study 7832 patients aged 40 to 70 years old with mild-to-moderate hypercholesterolemia without CVD were randomized to diet alone or diet plus pravastatin and followed for >5 years. In the present subanalysis of that study a total of 4002 patients with baseline and follow-up HbA1c data were stratified according to having an average HbA1c during the first year of follow-up <6.0%, 6.0%-<6.5%, or ≥6.5% and their subsequent 5-year incidence rates of CVD compared according to sex, low-density lipoprotein cholesterol (LDL-C), and treatment arm.

Results

Overall, risk of CVD was significantly 2.4 times higher in individuals with HbA1c ≥6.5% versus <6.0%. A similar relation was noted in men and women (hazard ratio [HR], 2.1; p <0.01 and HR, 3.0; p <0.01, respectively) and was regardless of treatment arm (diet alone group: HR, 2.2; p <0.001; diet plus pravastatin group: HR, 1.8; p = 0.02). Spline curves showed a continuous risk increase according to HbA1c level in all subpopulations studied.

Conclusions

In hypercholesterolemic individuals the risk of CVD increases linearly with HbA1c level. This significant contribution by elevated HbA1c to increased CVD is independent of pravastatin therapy, and thus requires appropriate HbA1c management in addition to lipids reduction.
Appendix
Available only for authorised users
Literature
1.
go back to reference Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Diabetic Med. 1998, 15: 539-553. 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S.CrossRefPubMed Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Diabetic Med. 1998, 15: 539-553. 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S.CrossRefPubMed
2.
go back to reference Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2000, 23: S4-S19. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2000, 23: S4-S19.
3.
go back to reference Ceriello A, Colagiuri S: International Diabetes Federation guideline for management of postmeal glucose: a review of recommendations. Diabetic Med. 2008, 25: 1151-1156. 10.1111/j.1464-5491.2008.02565.x.PubMedCentralCrossRefPubMed Ceriello A, Colagiuri S: International Diabetes Federation guideline for management of postmeal glucose: a review of recommendations. Diabetic Med. 2008, 25: 1151-1156. 10.1111/j.1464-5491.2008.02565.x.PubMedCentralCrossRefPubMed
4.
go back to reference International Expert Committee: International Expert Committee Report on the Role of the HbA1c Assay in the Diagnosis of Diabetes. Diabetes Care. 2009, 32: 1327-1334.CrossRef International Expert Committee: International Expert Committee Report on the Role of the HbA1c Assay in the Diagnosis of Diabetes. Diabetes Care. 2009, 32: 1327-1334.CrossRef
5.
go back to reference Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Golden SH: Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004, 141: 421-431.CrossRefPubMed Selvin E, Marinopoulos S, Berkenblit G, Rami T, Brancati FL, Powe NR, Golden SH: Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004, 141: 421-431.CrossRefPubMed
6.
go back to reference Blake GJ, Pradhan AD, Manson JE, Williams GR, Buring J, Ridker PM, Glynn RJ: Hemoglobin A1c level and future cardiovascular events among women. Arch Intern Med. 2004, 164: 757-761. 10.1001/archinte.164.7.757.CrossRefPubMed Blake GJ, Pradhan AD, Manson JE, Williams GR, Buring J, Ridker PM, Glynn RJ: Hemoglobin A1c level and future cardiovascular events among women. Arch Intern Med. 2004, 164: 757-761. 10.1001/archinte.164.7.757.CrossRefPubMed
7.
go back to reference Gao L, Matthews FE, Sargeant LA, Brayne C, MRC CFAS: An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study. BMC Public Health. 2008, 8: 54-10.1186/1471-2458-8-54.PubMedCentralCrossRefPubMed Gao L, Matthews FE, Sargeant LA, Brayne C, MRC CFAS: An investigation of the population impact of variation in HbA1c levels in older people in England and Wales: from a population based multi-centre longitudinal study. BMC Public Health. 2008, 8: 54-10.1186/1471-2458-8-54.PubMedCentralCrossRefPubMed
8.
go back to reference Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study Group: Design and baseline characteristics of a study of primary prevention of coronary events with pravastatin among Japanese with mildly elevated cholesterol levels. Circ J. 2004, 68: 860-867. 10.1253/circj.68.860.CrossRef Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study Group: Design and baseline characteristics of a study of primary prevention of coronary events with pravastatin among Japanese with mildly elevated cholesterol levels. Circ J. 2004, 68: 860-867. 10.1253/circj.68.860.CrossRef
9.
go back to reference Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, Yamamoto A, Mizuno K, Ohashi Y: Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006, 368: 1155-1163. 10.1016/S0140-6736(06)69472-5.CrossRefPubMed Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, Nakaya N, Nishimoto S, Muranaka M, Yamamoto A, Mizuno K, Ohashi Y: Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet. 2006, 368: 1155-1163. 10.1016/S0140-6736(06)69472-5.CrossRefPubMed
10.
go back to reference National Cholesterol Education Program: Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP II). 1993, Washington, DC: US Department of Health and Human Services National Cholesterol Education Program: Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP II). 1993, Washington, DC: US Department of Health and Human Services
11.
go back to reference Committee on Diabetes Mellitus Indices, Japan Society of Clinical Chemistry: Japanese guideline for reporting HbA1c results reported in IFCC units and JDS units. Rinsho Kagaku. 2008, 37: 393-409. (In Japanese) Committee on Diabetes Mellitus Indices, Japan Society of Clinical Chemistry: Japanese guideline for reporting HbA1c results reported in IFCC units and JDS units. Rinsho Kagaku. 2008, 37: 393-409. (In Japanese)
12.
go back to reference Watanabe M, Kokubo Y, Higashiyama A, Ono Y, Okayama A, Okamura T: New diagnosis criteria for diabetes with hemoglobin HbA1c and risks of macro-vascular complications in an urban Japanese cohort: the Suita Study. Diabetes Res Clin Pract. 2010, 88: e20-e23. 10.1016/j.diabres.2010.01.019.CrossRefPubMed Watanabe M, Kokubo Y, Higashiyama A, Ono Y, Okayama A, Okamura T: New diagnosis criteria for diabetes with hemoglobin HbA1c and risks of macro-vascular complications in an urban Japanese cohort: the Suita Study. Diabetes Res Clin Pract. 2010, 88: e20-e23. 10.1016/j.diabres.2010.01.019.CrossRefPubMed
13.
go back to reference Greenland S: Dose-response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology. 1995, 6: 356-365. 10.1097/00001648-199507000-00005.CrossRefPubMed Greenland S: Dose-response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology. 1995, 6: 356-365. 10.1097/00001648-199507000-00005.CrossRefPubMed
14.
go back to reference Chien KL, Lin HJ, Lee BC, Hsu HC, Chen MF: Prediction model for high glycated hemoglobin concentration among ethnic Chinese in Taiwan. Cardiovasc Diabetol. 2010, 9: 59-67. 10.1186/1475-2840-9-59.PubMedCentralCrossRefPubMed Chien KL, Lin HJ, Lee BC, Hsu HC, Chen MF: Prediction model for high glycated hemoglobin concentration among ethnic Chinese in Taiwan. Cardiovasc Diabetol. 2010, 9: 59-67. 10.1186/1475-2840-9-59.PubMedCentralCrossRefPubMed
15.
go back to reference Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997, 20: 1183-1197.CrossRef Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997, 20: 1183-1197.CrossRef
16.
go back to reference Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995, 28: 103-117. 10.1016/0168-8227(95)01064-K.CrossRefPubMed Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995, 28: 103-117. 10.1016/0168-8227(95)01064-K.CrossRefPubMed
17.
go back to reference Singer E, Nathan J, Anderson SH, Wilson PW, Evans JC: Association of HbA1c with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study. Diabetes. 1992, 41: 202-208. 10.2337/diabetes.41.2.202.CrossRefPubMed Singer E, Nathan J, Anderson SH, Wilson PW, Evans JC: Association of HbA1c with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study. Diabetes. 1992, 41: 202-208. 10.2337/diabetes.41.2.202.CrossRefPubMed
18.
go back to reference Selvin E, Coresh J, Golden SH, Boland LL, Brancati FL, Steffes MW, Atherosclerosis Risk in Communities Study: Glycemic control, atherosclerosis, and risk factors for cardiovascular disease in individuals with diabetes: the Atherosclerosis Risk in Communities Study. Diabetes Care. 2005, 28: 1965-1973. 10.2337/diacare.28.8.1965.CrossRefPubMed Selvin E, Coresh J, Golden SH, Boland LL, Brancati FL, Steffes MW, Atherosclerosis Risk in Communities Study: Glycemic control, atherosclerosis, and risk factors for cardiovascular disease in individuals with diabetes: the Atherosclerosis Risk in Communities Study. Diabetes Care. 2005, 28: 1965-1973. 10.2337/diacare.28.8.1965.CrossRefPubMed
19.
go back to reference Tajima N, Kurata H, Nakaya N, Mizuno K, Ohashi Y, Kushiro T, Teramoto T, Uchiyama S, Nakamura H, Primary Prevention Group of Adult Japanese (MEGA) Study: Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study. Atherosclerosis. 2008, 199: 455-462. 10.1016/j.atherosclerosis.2008.05.027.CrossRefPubMed Tajima N, Kurata H, Nakaya N, Mizuno K, Ohashi Y, Kushiro T, Teramoto T, Uchiyama S, Nakamura H, Primary Prevention Group of Adult Japanese (MEGA) Study: Pravastatin reduces the risk for cardiovascular disease in Japanese hypercholesterolemic patients with impaired fasting glucose or diabetes: diabetes subanalysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study. Atherosclerosis. 2008, 199: 455-462. 10.1016/j.atherosclerosis.2008.05.027.CrossRefPubMed
20.
go back to reference Monnier L, Lapinski H, Colette C: Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care. 2003, 26: 881-885. 10.2337/diacare.26.3.881.CrossRefPubMed Monnier L, Lapinski H, Colette C: Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care. 2003, 26: 881-885. 10.2337/diacare.26.3.881.CrossRefPubMed
21.
go back to reference Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, Mckillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995, 333: 1301-1307. 10.1056/NEJM199511163332001.CrossRefPubMed Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, Mckillop JH, Packard CJ: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995, 333: 1301-1307. 10.1056/NEJM199511163332001.CrossRefPubMed
22.
go back to reference Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996, 335: 1001-1009. 10.1056/NEJM199610033351401.CrossRefPubMed Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996, 335: 1001-1009. 10.1056/NEJM199610033351401.CrossRefPubMed
23.
go back to reference Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998, 339: 1349-1357.CrossRef Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group: Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998, 339: 1349-1357.CrossRef
24.
go back to reference Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J, ASCOT Investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003, 361: 1149-1158. 10.1016/S0140-6736(03)12948-0.CrossRefPubMed Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J, ASCOT Investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003, 361: 1149-1158. 10.1016/S0140-6736(03)12948-0.CrossRefPubMed
25.
go back to reference Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E: Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol And Recurrent Events (CARE) Trial. The Care Investigators. Circulation. 1998, 98: 2513-2519.CrossRefPubMed Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E: Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol And Recurrent Events (CARE) Trial. The Care Investigators. Circulation. 1998, 98: 2513-2519.CrossRefPubMed
26.
go back to reference Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004, 364: 685-696. 10.1016/S0140-6736(04)16895-5.CrossRefPubMed Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH: Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004, 364: 685-696. 10.1016/S0140-6736(04)16895-5.CrossRefPubMed
27.
go back to reference Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C, Cholesterol Treatment Trialists' (CTT) Collaborators: Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008, 371: 117-125. 10.1016/S0140-6736(08)60104-X.CrossRefPubMed Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C, Cholesterol Treatment Trialists' (CTT) Collaborators: Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008, 371: 117-125. 10.1016/S0140-6736(08)60104-X.CrossRefPubMed
28.
go back to reference Kurukulasuriya LR, Sowers JR: Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors. Cardiovasc Diabetol. 2010, 9: 45-58. 10.1186/1475-2840-9-45.PubMedCentralCrossRefPubMed Kurukulasuriya LR, Sowers JR: Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors. Cardiovasc Diabetol. 2010, 9: 45-58. 10.1186/1475-2840-9-45.PubMedCentralCrossRefPubMed
29.
go back to reference Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS: Do statins beneficially or adversely affect glucose homeostasis?. Curr Vasc Pharmacol. 2010, 8: 612-631. 10.2174/157016110792006879.CrossRefPubMed Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS: Do statins beneficially or adversely affect glucose homeostasis?. Curr Vasc Pharmacol. 2010, 8: 612-631. 10.2174/157016110792006879.CrossRefPubMed
30.
go back to reference Carson AP, Fox CS, McGuire DK, Levitan EB, Laclaustra M, Mann DM, Muntner P: Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. Circ Cardiovasc Qual Outcomes. 2010, 3: 661-667. 10.1161/CIRCOUTCOMES.110.957936.CrossRefPubMed Carson AP, Fox CS, McGuire DK, Levitan EB, Laclaustra M, Mann DM, Muntner P: Low hemoglobin A1c and risk of all-cause mortality among US adults without diabetes. Circ Cardiovasc Qual Outcomes. 2010, 3: 661-667. 10.1161/CIRCOUTCOMES.110.957936.CrossRefPubMed
Metadata
Title
Relationship between hemoglobin A1c and cardiovascular disease in mild-to-moderate hypercholesterolemic Japanese individuals: subanalysis of a large-scale randomized controlled trial
Authors
Rimei Nishimura
Tomoko Nakagami
Hirohito Sone
Yasuo Ohashi
Naoko Tajima
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Cardiovascular Diabetology / Issue 1/2011
Electronic ISSN: 1475-2840
DOI
https://doi.org/10.1186/1475-2840-10-58

Other articles of this Issue 1/2011

Cardiovascular Diabetology 1/2011 Go to the issue