Glycemic Control and Cardiovascular Disease — Should We Reassess Clinical Goals?
http://www.100md.com
《新英格兰医药杂志》
Improved glycemic control reduces the risks of early microvascular complications, such as retinopathy, nephropathy, and neuropathy, in patients with diabetes.1,2 Such patients also have a markedly increased risk of macrovascular complications — myocardial infarction and stroke — as compared with persons without diabetes, and cardiovascular disease is the chief cause of death among patients with either type 1 or type 2 diabetes.3,4 The increased risk appears to be only partially explained by traditional risk factors. Whereas we recognize that the development of atherosclerosis is multifactorial, there is substantial evidence linking chronic hyperglycemia to an increased risk of cardiovascular disease among those with either type of diabetes.5 Therefore, we must establish the role of hyperglycemia in the natural history of atherosclerosis and assess the effect of glycemic control on the risk of cardiovascular disease. One of the most important questions in diabetes management is whether long-term glycemic control can reduce the risk of cardiovascular disease. If the answer is yes, a reassessment of our clinical goals may be in order. The data needed to argue in favor of a reassessment may be those from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, which are reported in this issue of the Journal.6 The DCCT/EDIC study demonstrated that intensive insulin treatment reduces the risk of cardiovascular disease among patients with type 1 diabetes.
The EDIC trial was a multicenter, longitudinal, observational study designed to use the well-characterized cohort from the DCCT, which compared intensive insulin therapy with conventional insulin regimens in patients with type 1 diabetes. One of the most important goals was the prospective evaluation of the long-term effects of differences in prior diabetes treatment (conventional vs. intensive) during the DCCT on the development and progression of cardiovascular disease in patients with type 1 diabetes.7 Such a goal was clearly needed, given the evidence that atherosclerosis begins in adolescence in healthy persons and is more prevalent among children with diabetes than among age-matched controls.8 It has also been suggested that cardiovascular disease has overtaken diabetic nephropathy as the leading cause of premature death among young adults with diabetes.8 Thus, the finding at year 11 of the EDIC study that intensive insulin therapy was superior to conventional regimens in reducing the risk of cardiovascular disease could not have been more timely. Specifically, as compared with conventional therapy, intensive insulin therapy reduced the risk of any cardiovascular disease by 42 percent and of nonfatal myocardial infarction, stroke, or death from cardiovascular causes by 57 percent. Furthermore, improved glycemic control, as assessed by the decrease in glycosylated hemoglobin values during the DCCT, appeared to account for much of the cardiovascular benefit attributed to intensive insulin therapy.
The EDIC study was well conceived and well designed. It took advantage of a well-characterized cohort, used validated measures, and surprisingly, maintained an extremely high retention rate. According to the study design, at the closeout of the DCCT, all participants were offered help initiating intensive insulin therapy. Clearly, the response was favorable, since approximately 94 percent of the participants in the original conventional-treatment group opted for intensive diabetes management. As a result, there were minimal differences between groups in glycosylated hemoglobin values at the end of year 11 of the EDIC study. The results strongly suggest that the mean of 6.5 years of intensive diabetes therapy during the DCCT had a sustained effect on the risk of cardiovascular disease.
These positive results raise important questions: Should glycemic goals be revisited? Is the glycosylated hemoglobin value of 7.0 percent suggested by the American Diabetes Association an acceptable glycemic goal? These clinical guidelines were suggested on the basis of cutoff points that were relevant for the prevention of microvascular complications, not for cardiovascular disease.
The glycosylated hemoglobin values currently recommended for children and adolescents with type 1 diabetes — the population most likely to benefit from the findings of the DCCT/EDIC study — are even higher than those for the adult population: the goal values are less than 8.0 percent for children 6 through 12 years of age and less than 7.5 percent for those 13 through 19 years of age.9 The rationale for these age-specific goals is based on the unique risks of hypoglycemia in this group, the low risk of complications before puberty, developmental issues, and psychological issues surrounding adherence to medication and dietary regimens. However, data suggest that atherosclerosis begins early in patients with type 1 diabetes and that the progression of cardiovascular disease is much more aggressive in this group.8 In the light of the current findings of the DCCT/EDIC Study Research Group, perhaps these goals for adolescents should be revisited. Arguing against a reassessment, however, would be the fact that achieving suggested glycosylated hemoglobin values is difficult, and despite the use of intensive therapy, the mean glycosylated hemoglobin values at the end of year 11 of the EDIC study were still well above the targets set by the American Diabetes Association. Thus, one can only imagine what the reduction in the risk of cardiovascular disease events would have been had the intensively treated group in the DCCT had a greater difference in glycemic control, as assessed by a lower glycosylated hemoglobin value. Evidence from prospective epidemiologic studies involving subjects without diabetes suggests that the association between glycosylated hemoglobin values and the risk of cardiovascular disease may extend well below the diagnostic threshold for diabetes.10,11,12 Unfortunately, even the current suggested age-specific glycemic goals for children and adolescents with type 1 diabetes are difficult to reach, and having their patients reach the target glycosylated hemoglobin value remains a challenge for even the most skilled providers. Therefore, the current hurdles to achieving glycemic goals among young patients with type 1 diabetes may prevent translation of the findings of the EDIC study to this clinical population.
The clinical relevance of the EDIC study is supported by data from other, smaller-scale trials. Regression analysis of data from the Oslo study of patients with type 1 diabetes suggested that an increase of 1 percentage point in the mean glycosylated hemoglobin value after 18 years of follow-up implied a 6.4 percent increase in stenosis of the coronary-vessel area.8,13 Given the estimates that 10 percent of children and adolescents with type 1 diabetes had glycosylated hemoglobin values of more than 10.0 percent and that 60 percent had values above 8.0 percent, the benefit of improved glycemia on the risk of cardiovascular disease was readily apparent in this population.8
The medical community needs better means, different strategies, and a different mind-set if we hope to improve and maintain glycemic control in patients with type 1 diabetes and minimize side effects. Until the latter issue is addressed by the availability of new therapies and innovative approaches, the translation of research findings from a landmark study such as the DCCT/EDIC trial may not alter clinical practice for many years. Given the complications and mortality attributed to cardiovascular disease among patients with type 1 diabetes, this delay would be most unfortunate.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Nutrition and Chronic Diseases, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge.
References
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001;44:Suppl 2:S14-S21.
Roglic G, Unwin N, Bennett PH, et al. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 2005;28:2130-2135.
Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421-431.
The 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.
Epidemiology of Diabetes Interventions and Complications (EDIC): design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care 1999;22:99-111.
Dahl-Jorgensen K, Larsen JR, Hanssen KF. Atherosclerosis in childhood and adolescent type 1 diabetes: early disease, early treatment? Diabetologia 2005;48:1445-1453.
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005;28:Suppl 1:S4-S36.
Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ 2001;322:15-18.
de Vegt F, Dekker JM, Ruhe HG, et al. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia 1999;42:926-931.
Park S, Barrett-Connor E, Wingard DL, Shan J, Edelstein S. GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes: the Rancho Bernardo Study. Diabetes Care 1996;19:450-456.
Larsen J, Brekke M, Sandvik L, Arnesen H, Hanssen KF, Dahl-Jorgensen K. Silent coronary atheromatosis in type 1 diabetic patients and its relation to long-term glycemic control. Diabetes 2002;51:2637-2641.(William T. Cefalu, M.D.)
The EDIC trial was a multicenter, longitudinal, observational study designed to use the well-characterized cohort from the DCCT, which compared intensive insulin therapy with conventional insulin regimens in patients with type 1 diabetes. One of the most important goals was the prospective evaluation of the long-term effects of differences in prior diabetes treatment (conventional vs. intensive) during the DCCT on the development and progression of cardiovascular disease in patients with type 1 diabetes.7 Such a goal was clearly needed, given the evidence that atherosclerosis begins in adolescence in healthy persons and is more prevalent among children with diabetes than among age-matched controls.8 It has also been suggested that cardiovascular disease has overtaken diabetic nephropathy as the leading cause of premature death among young adults with diabetes.8 Thus, the finding at year 11 of the EDIC study that intensive insulin therapy was superior to conventional regimens in reducing the risk of cardiovascular disease could not have been more timely. Specifically, as compared with conventional therapy, intensive insulin therapy reduced the risk of any cardiovascular disease by 42 percent and of nonfatal myocardial infarction, stroke, or death from cardiovascular causes by 57 percent. Furthermore, improved glycemic control, as assessed by the decrease in glycosylated hemoglobin values during the DCCT, appeared to account for much of the cardiovascular benefit attributed to intensive insulin therapy.
The EDIC study was well conceived and well designed. It took advantage of a well-characterized cohort, used validated measures, and surprisingly, maintained an extremely high retention rate. According to the study design, at the closeout of the DCCT, all participants were offered help initiating intensive insulin therapy. Clearly, the response was favorable, since approximately 94 percent of the participants in the original conventional-treatment group opted for intensive diabetes management. As a result, there were minimal differences between groups in glycosylated hemoglobin values at the end of year 11 of the EDIC study. The results strongly suggest that the mean of 6.5 years of intensive diabetes therapy during the DCCT had a sustained effect on the risk of cardiovascular disease.
These positive results raise important questions: Should glycemic goals be revisited? Is the glycosylated hemoglobin value of 7.0 percent suggested by the American Diabetes Association an acceptable glycemic goal? These clinical guidelines were suggested on the basis of cutoff points that were relevant for the prevention of microvascular complications, not for cardiovascular disease.
The glycosylated hemoglobin values currently recommended for children and adolescents with type 1 diabetes — the population most likely to benefit from the findings of the DCCT/EDIC study — are even higher than those for the adult population: the goal values are less than 8.0 percent for children 6 through 12 years of age and less than 7.5 percent for those 13 through 19 years of age.9 The rationale for these age-specific goals is based on the unique risks of hypoglycemia in this group, the low risk of complications before puberty, developmental issues, and psychological issues surrounding adherence to medication and dietary regimens. However, data suggest that atherosclerosis begins early in patients with type 1 diabetes and that the progression of cardiovascular disease is much more aggressive in this group.8 In the light of the current findings of the DCCT/EDIC Study Research Group, perhaps these goals for adolescents should be revisited. Arguing against a reassessment, however, would be the fact that achieving suggested glycosylated hemoglobin values is difficult, and despite the use of intensive therapy, the mean glycosylated hemoglobin values at the end of year 11 of the EDIC study were still well above the targets set by the American Diabetes Association. Thus, one can only imagine what the reduction in the risk of cardiovascular disease events would have been had the intensively treated group in the DCCT had a greater difference in glycemic control, as assessed by a lower glycosylated hemoglobin value. Evidence from prospective epidemiologic studies involving subjects without diabetes suggests that the association between glycosylated hemoglobin values and the risk of cardiovascular disease may extend well below the diagnostic threshold for diabetes.10,11,12 Unfortunately, even the current suggested age-specific glycemic goals for children and adolescents with type 1 diabetes are difficult to reach, and having their patients reach the target glycosylated hemoglobin value remains a challenge for even the most skilled providers. Therefore, the current hurdles to achieving glycemic goals among young patients with type 1 diabetes may prevent translation of the findings of the EDIC study to this clinical population.
The clinical relevance of the EDIC study is supported by data from other, smaller-scale trials. Regression analysis of data from the Oslo study of patients with type 1 diabetes suggested that an increase of 1 percentage point in the mean glycosylated hemoglobin value after 18 years of follow-up implied a 6.4 percent increase in stenosis of the coronary-vessel area.8,13 Given the estimates that 10 percent of children and adolescents with type 1 diabetes had glycosylated hemoglobin values of more than 10.0 percent and that 60 percent had values above 8.0 percent, the benefit of improved glycemia on the risk of cardiovascular disease was readily apparent in this population.8
The medical community needs better means, different strategies, and a different mind-set if we hope to improve and maintain glycemic control in patients with type 1 diabetes and minimize side effects. Until the latter issue is addressed by the availability of new therapies and innovative approaches, the translation of research findings from a landmark study such as the DCCT/EDIC trial may not alter clinical practice for many years. Given the complications and mortality attributed to cardiovascular disease among patients with type 1 diabetes, this delay would be most unfortunate.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Division of Nutrition and Chronic Diseases, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge.
References
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986.
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001;44:Suppl 2:S14-S21.
Roglic G, Unwin N, Bennett PH, et al. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Diabetes Care 2005;28:2130-2135.
Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:421-431.
The 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.
Epidemiology of Diabetes Interventions and Complications (EDIC): design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care 1999;22:99-111.
Dahl-Jorgensen K, Larsen JR, Hanssen KF. Atherosclerosis in childhood and adolescent type 1 diabetes: early disease, early treatment? Diabetologia 2005;48:1445-1453.
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005;28:Suppl 1:S4-S36.
Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ 2001;322:15-18.
de Vegt F, Dekker JM, Ruhe HG, et al. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia 1999;42:926-931.
Park S, Barrett-Connor E, Wingard DL, Shan J, Edelstein S. GHb is a better predictor of cardiovascular disease than fasting or postchallenge plasma glucose in women without diabetes: the Rancho Bernardo Study. Diabetes Care 1996;19:450-456.
Larsen J, Brekke M, Sandvik L, Arnesen H, Hanssen KF, Dahl-Jorgensen K. Silent coronary atheromatosis in type 1 diabetic patients and its relation to long-term glycemic control. Diabetes 2002;51:2637-2641.(William T. Cefalu, M.D.)