Cardiovascular disease refers to illnesses affecting the larger arteries supplying the heart (heart disease including heart attacks and heart failure), brain (stroke) and the legs (gangrene and amputations). These are collectively referred to as macrovascular disease which accounts for 70% of the deaths of people with diabetes. Diabetics also experience microvascular disease which refers to damage to the small blood vessels supplying the eye (loss of vision), kidney (kidney failure resulting in dialysis or transplantation) and nerves (numbness or pain in the legs). One of the major remaining controversies in diabetes management is the uncertainty of the effect of glucose control on macrovascular disease. Many studies have now shown unequivocally that good glucose control reduces the development and progression of microvascular complications. The major randomized trials of diabetes control (the DCCT (1), UKPDS (2, 3) and Kumamoto (4); see references) all showed a trend to lower heart macrovascular disease (heart disease) but did not reach statistical significance.
The DIGAMI (5) study examined only patients who had suffered a heart attack. One of the study groups had usual management of their diabetes while the other group had its average glucose levels lowered significantly. In contrast to the other studies the group with the lower glucose levels had a significantly higher survival rate which persisted for 3 years after the heart attack. Another study, the Wisconsin early diabetic retinopathy study, a prospective but not randomized cohort study, showed significantly more macrovascular disease in patients with poor glucose control compared to those with good glucose control. In general, outcomes after macrovascular events such as heart attack and stroke are related to the degree of glucose elevation – the higher the glucose the worse the outcome.
There are reasons to believe that good glucose control should be effective in decreasing the risk of macrovascular disease that begins at a lower glucose elevation than microvascular disease. A direct relation exists between the degree of glucose elevation and the incidence of macrovascular disease, this lower glucose threshold being the main reason for establishing the categories of impaired fasting glucose and impaired glucose tolerance. Since glucose reduction reduces microvascular complications one would expect this should also apply to macrovascular disease that begins at even lower glucose thresholds.
Why have research studies been unable to demonstrate this?
There are several possible explanations for this discrepancy.
- The first one is that good glucose control is simply not very effective in preventing macrovascular complications. The explanation is counter-intuitive – if diabetes causes both micro and macrovascular disease why should treatment prevent one type and not the other?
- Another explanation is that glucose levels must be reduced to normal in order to prevent macrovasacular complications. In all studies to date the best glucose control achieved was still only near normal. This explanation is plausible although it assumes a different dose response for micro vs macrovascular disease. A National Institute of Health study, with normal glucose levels in diabetics as one of the goals, is currently underway and may address this issue.
- A third possibility is that good glucose control is necessary but not sufficient on its own, to reduce the macrovascular complications in diabetes. Atherosclerosis, the process that causes damage to large arteries, has several factors that cause its development. This is in contrast to microvascular disease where elevated glucose levels are the only causative factor. The known risk factors for atherosclerosis include smoking, hypertension, elevated cholesterol levels and damage to the lining of the arteries.
Diabetes and Risk Factors
Diabetes is known to worsen the effects of some of these risk factors. For example, the UKPDS showed that hypertension must be more tightly controlled in diabetes than in any other condition. Diabetes makes elevated cholesterol levels even more damaging by changing the chemical nature of the cholesterol particle in a way that makes it more toxic to blood vessel walls. This hypothesis proposes that by the time a person has had diabetes for several years, these other factors as well as glucose levels must be treated to achieve significant benefit.
This is similar to the findings in advanced microvascular complications. Diabetic patients with eye damage benefit more from laser therapy and good glucose control than from good glucose control alone. Patients with kidney damage require the addition of a class of drugs called ACE inhibitors, along with good glucose control, to prevent progression of the kidney damage. Additional evidence comes from the HOPE study and Hellman’s study on multiple risk factor management. These studies showed that diabetic patients with good control of blood pressure and cholesterol had fewer macrovascular events than the group which was not treated in such a manner.
The final answer will come from further research. We have started a study attempting to improve outcomes in patients with diabetes undergoing cardiac bypass surgery. Diabetic patients have approximately double the complication rate compared to people without diabetes having the same surgery. We are going to test the hypothesis that controlling all the metabolic risk factors discussed above – glucose, cholesterol, blood pressure and protecting the arterial wall – will significantly reduce complications. Not only could this benefit the patient but it may also reduce the average length of hospital stay and reduce the costs to the health care system. This project and others will, we hope, shed light on the relationship between blood sugar control and macrovascular disease. Regardless of the findings, however, it is still very important to control glucose levels in people with diabetes because of the dramatic benefit that this has on reducing the risk of microvascular complications.
Dr. David Thompson is the acting head of the Division of Endocrinology at University of British Columbia. He is an expert in diabetes and maintains a medical practice as well as a research program.
- The Diabetes Care and Complications Trial Research Group. Effect of intensive diabetes management on macrovascular events and risk factors in the The Diabetes Care and Complications Trial. Am. J. Cardiol. 1995; 75: 984-903.
- UKPDS (United Kingdom Prospective Diabetes Study);. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865.
- UKPDS (United Kingdom Prospective Diabetes Study). 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.
- 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. Diab Res Clin Pract 1995;28:103-117.
- Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin I. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): Effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57-65.