European Heart Journal (2000) 21, 17351737 doi:10.1053/euhj.2000.2331, available online at http://www.idealibrary.

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Blood glucose and coronary heart disease

See page 1790 for the article to which this Editorial refers Diabetes, especially Type 2 diabetes, is associated with a markedly increased risk of cardiovascular disease in general and of coronary heart disease in particular. The role of blood glucose itself in the aetiology of coronary heart disease in diabetes remains unclear. Evidence linking glycaemic control and the incidence of coronary heart disease in diabetic subjects has been conicting. The study by Otsuka et al.[1] is an important contribution to our knowledge in this eld. They have investigated factors aecting cardiac outcomes following elective PTCA in 719 subjects for a mean period of 46 years, with particular reference to vessel wall size post angioplasty and the presence of impaired glucose tolerance or diabetes in 34% of the subjects. Patients were classied as having small vessels (<25 mm) or large vessels (d25 mm) post PTCA. Unfortunately, hyperlipidaemia was classied only on the basis of serum cholesterol d220 mg . dl (57 mmol . l 1), without measurement of either serum triglyceride or HDL cholesterol. Those with either impaired glucose tolerance or diabetes had a worse prognosis in terms of cardiac events than those with normal glucose tolerance irrespective of vessel size. Event-free survival was reduced in those with impaired glucose tolerance compared with those with normal glucose tolerance and further reduced in those with diabetes. Of interest, in those with diabetes, those with good control (HbA1c<6%) had longer event free survival than those with bad control (HbA1c>6%). Indeed, those with good control had event-free survival similar to those with normal glucose tolerance until 5 years when the two groups diverged. These ndings were independent of sex, blood pressure, smoking and hyperlipidaemia. The failure to account for the major lipid abnormality in those with impaired glucose tolerance and diabetes, increased serum triglyceride and low HDL cholesterol, does limit the signicance of this study. Nevertheless it does provide some evidence that blood glucose concentration may aect prognosis following PTCA and thus the prognosis for coronary heart disease in general. The problem of how blood glucose may be implicated in coronary heart disease has been approached in three main ways, by examining: 1. The role of blood glucose as a risk factor for coronary heart disease in the general population. 2. The relationship between hyperglycaemia and coronary heart disease incidence in diabetic subjects. 3. The eect of treating hyperglycaemia on coronary heart disease incidence in diabetic subjects.

Glucose as a risk factor for coronary heart disease in the population

In the Whitehall study of about 18 000 men aged 4064, blood glucose was measured 2 h after a 50 g glucose load. After 10 years of follow-up, a signicant excess of deaths was found in those above the 95th centile[2]. The conclusion from this and other population studies is that there is an association, albeit weak, between blood glucose at the upper end of the normal distribution and coronary heart disease[3]. In studies of those with impaired glucose tolerance, the Paris Prospective study[4] showed that after 11 years those with impaired glucose tolerance had double the risk of cardiovascular disease compared with those with normal glucose tolerance, results similar to those of the Whitehall study. However, in the presence of impaired glucose tolerance other components of the metabolic syndrome are present. These factors include resistance to insulin-stimulated muscle glucose uptake, increased serum triglyceride, low HDL cholesterol and an increased proportion of circulating small dense LDL particles, which are more atherogenic than the larger more buoyant variety. Thus in impaired glucose tolerance it is dicult to disentangle the eects of blood glucose itself on coronary heart disease from those of the other risk factors.

Hyperglycaemia as risk factor for coronary heart disease in diabetes

In some, but not all studies, increasing blood glucose has emerged as a risk factor for coronary heart disease. In a prospective study of 1059 Type 2 diabetic subjects followed for 7 years aged 4564, the simultaneous presence of a markedly elevated fasting blood glucose >134 mmol . l 1 in association with low HDL cholesterol increased risk of coronary heart disease threefold[5]. In the Wisconsin Epidemiology Study of Diabetic Retinopathy[6] the relationship between HbA1c and the incidence of proliferative retinopathy and coronary heart disease was examined. A 1% increase in HbA1c was associated
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Editorials

with a 70% increase in incidence of proliferative retinopathy, but only a 10% increase in coronary heart disease incidence. Thus hyperglycaemia appears to be a much stronger risk factor for the microvascular complications of diabetes than for macrovascular disease. The United Kingdom Prospective Diabetes Study (UKPDS), probably the most important prospective study done in diabetes, has produced important information in this area. In this study of Type 2 diabetic subjects, there were complete data for coronary heart disease and risk factors in 3055 subjects, followed for mean period of 79 years[7]. Coronary heart disease was signicantly associated with increased LDL cholesterol, decreased HDL cholesterol, hypertension, smoking, HbA1c and fasting blood glucose. For each 1% increment in HbA1 there was a 111% increase in coronary heart disease. This study provides denitive evidence for the role of circulating blood glucose as risk for coronary heart disease in Type 2 diabetes, though other factors appeared more important.

The effect of treating hyperglycaemia on coronary heart disease incidence in diabetes

This has been a most dicult subject to address since large numbers of subjects need to be followed for many years. The Diabetes Control and Complications Trial (DCCT)[8] randomized 1441 Type 1 diabetic subjects to receive intensive or conventional insulin therapy and were followed for a mean period of 65 years. The main outcome measures were development or progression of retinopathy. The intensive therapy group maintained a signicantly lower HbA1c than the conventional therapy group during the study (70 vs 87%). There were signicant reductions in retinopathy development and progression in the intensive therapy group compared with the conventionally treated group. The study did not have sucient power to study macrovascular disease and the cohort was in any case too young to achieve sucient numbers of events. When all cardiovascular and peripheral vascular events were combined, there was a 40% reduction in the intensive therapy group, but the numbers were not large enough to achieve signicance. This study does not add much to knowledge of the eect on coronary heart disease of treating blood glucose. It should be noted that the aetiology of coronary heart disease and cardiovascular disease in general is dierent in Type 1 and Type 2 diabetes. In Type 1 diabetes, much of corEur Heart J, Vol. 21, issue 21, November 2000

onary heart disease is related to the development of proteinuria and early nephropathy. The results of the UKPDS study were of great importance here[9]. 3867 newly diagnosed Type 2 diabetic subjects were randomly allocated to receive intensive treatment with sulphonylureas or insulin with the aim of achieving a fasting blood glucose of <6 mmol . l 1 or conventional therapy. The intensive therapy group achieved a lower HbA1c during the study of 7%, compared with 79% in the conventional group. The absolute risk of non-fatal myocardial infarction was reduced in the intensive therapy group to 77 per 1000 patient years compared to 95 per 1000 patient years in the conventional therapy group (P =0057) which just failed to reach signicance. This contrasted with the highly signicant reduction in microvascular disease end-points. The issue of treating hyperglycaemia following myocardial infarction has been addressed in the Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction Study (DIGAMI)[10]. 620 patients with known diabetes or with plasma glucose over 11 mmol . l 1 on admission were randomized to receive either insulin infusion for at least 24 h followed by basal bolus subcutaneous insulin for up to 1 year. By the time of discharge, the insulin infusion group had an 18% reduction in mortality (non-signicant) but by 12 months when 72% of the insulin infusion group vs 59% of the conventional group were still on insulin, the mortality reduction was 29% (P =0027). HbA1c decreased in both groups signicantly during the follow-up, but more so in the insulin-infusion group. Fasting blood glucose, however, at 1 year did not dier between the two groups. It is not, however, clear whether the reduction in mortality was directly related to improvement in glycaemic control or to other factors. Nevertheless, we do now have some evidence from all these studies that a reduction in blood glucose may reduce the incidence of coronary heart disease in diabetic patients, but the eect appears far less than for microvascular disease. The relationship between hyperglycaemia and coronary heart disease is not strong and appears weaker than for other risk factors. Since coronary heart disease is multifactorial in its aetiology this should not be too surprising. While control of hyperglycaemia has been shown to be important for the prevention of microvascular complication of diabetes, we now have some evidence that this may also be important in preventing coronary heart disease. However, other known cardiovascular risk factors should be vigorously treated. R. S. ELKELES Unit for Metabolic Medicine, Imperial College School of Medicine, St Marys Hospital, London, U.K.

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References
[1] Otsuka Y, Miyazaki S, Okumara H et al. Abnormal glucose tolerance, not small vessel diameter, is a determinant of longterm prognosis in patients treated with balloon angioplasty. Eur Heart J 2000; 21: 179096. [2] Fuller JH, Shipley M, Rose G, Jarrett RJ, Keen H. Mortality from coronary heart disease and stroke in relation to degree of glycaemia: The Whitehall Study. BMJ 1983; 287: 86770. [3] Jarret RJ. The cardiovascular risk associated with impaired glucose tolerance. Diabetic Med 1996; 13 (Suppl 2): S1519. [4] Eschwege E, Richard JL, Thibult N et al. Coronary heart disease mortality in relation with diabetes, blood glucose and plasma insulin levels: The Paris Prospective Study, ten years later. Horm Metabol Res 1985; 15 (Suppl): 416. [5] Lehto S, Ronenemaa T, Haner S, Pyo ra la K, Kallio V, Laakso M. Dyslipidaemia and hyperglycaemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes Care 1997; 46: 13549. [6] Klein R. Kelly West Lecture 1994 Hyperglycaemia and microvascular and macrovascular disease in diabetes. Diabetes Care 1995; 18: 25868.

[7] Turner RC, Millns H, Neil HAW et al. For the United Kingdom Prospective Diabetes Study Group. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom prospective diabetes study (UKPDS 23). BMJ 1998; 316: 8238. [8] The Diabetes Control and Complications Trial Research Group. The eect 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: 97786. [9] UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonyureas or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33). Lancet 1998; 352: 83753. [10] Malmberg K for the DIGAMI (Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997; 314: 151215.

European Heart Journal (2000) 21, 17371738 doi:10.1053/euhj.2000.2363, available online at http://www.idealibrary.com on

Can the laser light at the end of the tunnel be used to get to the end of the tunnel?
See page 1797 for the article to which this Editorial refers Arguably, the two most important challenges facing interventional cardiology are in-stent restenosis and chronic total occlusion. The former is manifest after an initially successful procedure while the latter often prevents achievement of initial success. Indeed, there are many occlusions that appear to have such a low likelihood of success that they are never even attempted; chronic total occlusion of a vessel supplying viable but ischaemic myocardium is one of the most common indications for selection of CABG as the mode of revascularization. Published series of attempts at revascularization of total occlusions date back more than 15 years. Multiple published series have identied outcomes, favourable and unfavourable, lesion characteristics, and complications associated with chronic total occlusion dilatation. The most common failure mode has always been inability to pass a guidewire through the occlusion into the distal lumen. This problem has resulted in success rates in most published series of selected patients of approximately 60%65%. These series have also documented that while failure is usually uncomplicated, there are a small number of patients in whom attempts at traversing the lesion result in compromise of ipsilateral collaterals and development of myocardial infarction. Although chronic total occlusion remains a common clinical problem, which has been refractory to conventional therapy, when treatment is successful, outcome is improved and CABG avoided. Thus eorts continue to identify a better way to get there. The TOTAL trial reported here by Serruys et al.[1] is another important piece of the puzzle. An important consideration was the angiographic selection criteria. There was a mixture of favourable and unfavourable features the former being a requirement for excellent visualization of the distal vessel and its course and lack of multiple curves in the occlusion; the latter was inclusion of patients in both treatment limbs with occlusions documented by angiography to be greater than 4 weeks in duration and inclusion of patients irrespective of major branches at the site of occlusion (38% and 55%), blunt stump to the occlusion (44% and 41%), or bridging collaterals (15% and 18%), all features associated with markedly decreased success rates in past series.
 2000 The European Society of Cardiology