Diabetes Care

Volume 22 Supplement 3
Improving Prognosis in Type 1 Diabetes
Proceedings from an Official Satellite Symposium
of the 16th International Diabetes Federation Congress

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Risk Factors for Macrovascular Disease in Type 2 Diabetes

Classic lipid abnormalities

George Steiner, MD, FRCP

It is well recognized that the most frequent chronic complication of diabetes is atherosclerotic cardiovascular disease (1,2). Dyslipoproteinemias are among the many potential risk factors that may account for this. The term dyslipoproteinemia is used rather than hyperlipoproteinemia because in diabetes there may be changes in both the quantity and the quality of the lipoproteins. One of the earliest suggestions that lipid abnormalities may be responsible for atherosclerosis in diabetes was voiced by E.P. Joslin: "With fat diabetes begins. From fat diabetics die, formerly of coma recently of arteriosclerosis" (3). This article reviews some of the evidence relating dyslipoproteinemias to atherosclerosis in diabetes that has emerged since that assertion 70 years ago.

Recognizing that feeding fat to rabbits resulted in the development of atheromatous lesions, Duff and McMillan (4) reasoned that feeding similar fat loads to alloxan-diabetic rabbits would produce even more atheromata. However, when they conducted that experiment almost 50 years ago, they found just the opposite—less atherosclerosis in the diabetic animals (4). They did not recognize at that time that the activity of lipoprotein lipase is greatly reduced in diabetic rabbits. Therefore, the massive hyperlipidemia that they produced was due to an increase in chylomicrons. More recent studies, summarized later, indicate that the small triglyceride-rich lipoproteins, not the chylomicrons, are associated with the increase in atherosclerosis.

LIPOPROTEIN ABNORMALITIES IN DIABETES— Most groups that have quantified the lipoproteins in diabetes have found that the major abnormality is hypertriglyceridemia (58). The levels of cholesterol and LDL in diabetic patients are generally found to be similar to those in the general population. However, a few studies suggest that LDL decreases with short-term tight glycemic control (9). HDL levels have been noted in different studies to be reduced, normal, or elevated. This probably reflects the nature of the hypoglycemic agent used by the patient and the presence or absence of the hypertriglyceridemia of obesity and of other disorders, such as nephropathy. A recent report of the UK Prospective Diabetes Study population indicates that these abnormalities are already found in type 2 diabetes at the time of diagnosis (10). In fact, they have been noted in individuals who are normoglycemic but later develop diabetes (11).

The last observation is consistent with those studies suggesting that hypertriglyceridemia is a part of the insulin resistance syndrome (12). Some years ago, using tracer kinetic methods, we found that hypertriglyceridemia was associated with insulin resistance, even in men selected to be lean (13). We then observed that reducing plasma triglyceride levels with gemfibrozil in a group of normoglycemic people did not change their glucose levels during a glucose tolerance test but did reduce their serum levels of insulin (14). This indirectly suggested that insulin resistance was directly related to plasma triglyceride levels. Using hyperinsulinemic glucose clamp methodology, similar conclusions were reached in those with type 2 diabetes in fair control (fasting glucose >9 mmol/l), but not in those who had better glycemic control (15). Studies conducted by Vuorinen-Markkola et al. (16) did not find a similar improvement in insulin sensitivity. The discrepancy may result from the fact that the first studies produced changes from levels above to levels below 1.5 mmol/l. However, the third study did not reduce triglyceride levels below that apparent threshold.

CHOLESTEROL AND CORONARY ARTERY DISEASE IN DIABETES— The similarity of plasma cholesterol levels in those with and those without diabetes should not lead one to conclude that cholesterol has no coronary risk effect in diabetes. Recently, the Multiple Risk Factor Trial published its data on those with diabetes (17). The incidence of coronary mortality increased in a curvilinear manner, with increasing concentrations of serum cholesterol both in those with and in those without diabetes. The two curves were of similar shape but differed, with the curve for those with diabetes being higher than the curve for those without. At any given serum cholesterol concentration, those with diabetes had a risk of coronary artery disease mortality between two and four times greater than the risk in those without diabetes. There may be several reasons for this. First, the level of cholesterol in the serum reflects the level of all lipoproteins, not just LDL. Thus, an elevation of serum cholesterol may, in part, indicate an increase in the triglyceride-rich lipoproteins. Second, there may be many nonlipoprotein atherogenic factors in those with diabetes that could increase the "basal" risk of coronary artery disease. These include the presence of advanced glycation end products (18), the presence of nephropathy (19), the presence of hypertension (20), and changes in coagulation factors and platelets (21), to name but a few. An elevation of cholesterol would then add to these. Third, LDL may be modified in a way that would make any given amount of it more atherogenic. Such modifications would include nonenzymatic glycation (22), oxidation (23), and a shift toward smaller and denser particles (24).

TRIGLYCERIDES AND CORONARY ARTERY DISEASE IN DIABETES— As noted earlier, the most frequent quantitative abnormality in lipoproteins in diabetes is hypertriglyceridemia. There is increasing support for the concept that hypertriglyceridemia confers an increased risk for coronary artery disease in the general population (25). This is clearly recognized in univariate studies. However, meta-analysis of prospective studies also suggests that the risk effect of hypertriglyceridemia is independent of HDL (25). Thus, probably both hypertriglyceridemia and low levels of HDL, not either one alone, contribute to coronary risk.

The data in those with diabetes are more restricted. An early suggestion of an association came from the World Health Organization Multinational Study, which found a cross-sectional association of ischemic electrocardiogram changes with hypertriglyceridemia (26). More recently, the Paris Prospective Study observed that in men with diabetes or impaired glucose tolerance, coronary artery disease death was associated with an increase in plasma triglyceride concentrations (27). Unfortunately, that study did not report HDL levels. Another prospective study from Kuopio, Finland, indicated that atherosclerotic cardiovascular disease was associated with both an increase in triglyceride-rich lipoproteins and a decrease in HDL (28).

TRIGLYCERIDE-RICH LIPOPROTEIN PARTICLES AND CORONARY ARTERY DISEASE IN DIABETES— The triglyceride-rich lipoprotein particles extend across a broad range of size and density. We have made use of the observations that each particle of triglyceride-rich lipoprotein contains one molecule of apolipoprotein B. This permitted an estimate of the numbers of particles by measuring the amount of apolipoprotein B in a given sample. In both those with diabetes (29) and those without diabetes (30), we found that three-fourths of the triglyceride-rich lipoprotein particles are in the smaller denser (Sf 12–60) subfraction, a subfraction that has been called intermediate-density lipoprotein (IDL) by us and some others. Furthermore, 70% of the differences in plasma triglyceride concentrations in a population can be explained by a difference in particle number rather than in particle size. Almost 50 years ago, Jones et al. (31) found that IDL levels were higher in male myocardial infarct survivors than in control subjects and that IDL levels predicted those who were likely to reinfarct. We found that IDL particle numbers and triglyceride content were both associated with coronary artery disease in men without diabetes and that this association was independent of both LDL and HDL (32). Reardon et al. (33) found that IDL levels correlated with the severity of angiographically evaluated coronary artery disease in women without diabetes. In a recent study of men and women with type 2 diabetes, we observed that triglyceride-rich lipoprotein particle numbers were increased in those who had moderate coronary artery disease on angiography compared with those who had only mild disease (34). Multivariate analysis showed that age, low HDL, and sex were also related to coronary artery disease severity, but these were independent of each other and of the number of triglyceride-rich lipoprotein particles. Interestingly, there was no further increase in particle numbers between those with moderate and those with severe disease. This raises the intriguing and as-yet-untested possibility that triglyceride-rich lipoproteins might be more related to the early stages of atherogenesis and that other factors might have more influence on the later stages.

INTERVENTION STUDIES— Although a number of trials have examined the effect on coronary disease of correcting dyslipoproteinemias (3341), none that have been completed have specifically addressed the question in those with diabetes. Three of the published clinical trials have included some individuals with diabetes in their study population and have conducted a post hoc analysis of the data obtained from that subgroup. The first, the Helsinki Heart Study, was a primary prevention trial. Its diabetic subpopulation was too small to show a statistical difference. However, there was a trend in those with diabetes who were treated with gemfibrozil toward a reduction in coronary events (42). The second was the Scandinavian Simvastatin Survival Study (4S). A secondary intervention study demonstrated that treatment of hypercholesterolemic individuals with simvastatin reduced coronary events and total mortality (35). In the post hoc analysis of the diabetic subpopulation, there were also fewer coronary events, but there was no reduction in mortality (43). In addition to the problems inherent in a post hoc subgroup analysis, those with diabetes in this population probably were not representative of the general diabetic population in the participating countries. Four percent of the 4S population had diabetes. This is about one-fourth the prevalence of diabetes in similarly aged people in those countries. Probably this is because of the exclusion criteria for the study. Among many of these criteria was the exclusion of those with a serum triglyceride >2.5 mmol/l. The post hoc analysis of the diabetic population in a similar study that used pravastatin, the Cholesterol and Recurrent Events (CARE) Study (39), led to similar conclusions. Unfortunately, insufficient information is published about its diabetic subpopulation to be able to draw further conclusions. However, within the limitations of a post hoc analysis of secondary intervention studies in hypercholesterolemic populations treated with statins, both suggest that reducing hypercholesterolemia will reduce the risk of recurrence of coronary disease. Recently, the Veteran's Administration HDL Intervention Trial (VA-HIT) Study presented data indicating that treating those with low HDL but normal LDL levels with gemfibrozil resulted in a significant reduction in fatal and nonfatal coronary events and strokes (44). Those with diabetes within the VA-HIT population had a very strong, but not quite significant, trend toward a similar benefit in clinical events. The recently completed St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Prevention (SENDCAP) Study was designed to examine the effects of bezafibrate on carotid artery intima-media thickness in those with type 2 diabetes. No effect was found. However, there was a reduction in the number of people who had electrocardiogram-defined probable ischemia or myocardial infarction (45).

Some studies have now started with the primary a priori aim of determining whether lipid reduction in type 2 diabetes will result in less coronary atherosclerosis. The first of these is the Diabetes Atherosclerosis Intervention Study (46). It is an angiographic study examining whether correcting dyslipoproteinemia in men and women with type 2 diabetes with micronized fenofibrate will alter the rate of progression or regression of their coronary artery disease. The protocol for this study has been published (44). It is due for completion at some point in 1999. Other studies are designed to evaluate clinical events as their primary endpoint. They are in their early stages of recruitment and have not yet published their protocols. They include the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study, a study using fenofibrate in those with type 2 diabetes who have triglycerides >1.0 mmol/l and a total cholesterol <5.5 mmol/l if there is coronary disease and <6.5 mmol/l if there is not (A. Keech, personal communication). Another is the Lipids in Diabetes Study (LDS), which is examining 4,000 men and women who will be treated with micronized fenofibrate, cerivastatin, both, or neither (R. R. Holman, personal communication). Finally, the Collaborative Atorvastatin Diabetes Study (CARDS) is examining the effects of treating with atorvastatin 2,120 people with type 2 diabetes who have no clinical coronary disease, an LDL cholesterol <4.14 mmol/l, and triglycerides <6.78 mmol/l (D.J. Betteridge, personal communication).

CONCLUSIONS— At this time, there is no direct information to indicate whether treating the hyperlipidemia of diabetes will or will not be beneficial in terms of coronary disease. However, inference from pathophysiological information and extrapolation from post hoc analyses support the treatment of hyperlipidemia where it exists in diabetes. The treatment regimens should optimize glycemic control and use diet and lifestyle modifications, as well as drug therapy directed to the specific lipoprotein disorder that is present.

Acknowledgments— The work conducted in the author's laboratory that is described was supported by the Canadian Diabetes Association and the Heart and Stroke Foundation of Ontario.

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44. Rubins HB: VA-HIT (presented at Late- Breaking Clinical Trials Session Am. Heart Assn. Meeting Nov. 1998)

45. Elekeles RS, Diamond JR, Poulter C, Dhanjil S, Nicolaides AN, Mahmood S, Richmond W, Mather H, Sharp P, Feher MD, The SENDCAP study group: Cardiovascular outcomes in type 2 diabetes: a double-blind placebo-controlled study of bezafibrate: St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study. Diabetes Care 21:641–648, 1998

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From the Department of Medicine, The Toronto Hospital (General Division), and the World Health Organization Collaborating Centre for the Study of Atherosclerosis in Diabetes, University of Toronto, Toronto, Canada.

Address correspondence and reprint requests to Dr. George Steiner, DAIS Project Office, Room NUW9-112, The Toronto Hospital (General Division), 200 Elizabeth St., Toronto, Ontario, Canada M5G 2C4.

Received for publication 6 July 1998 and accepted in revised form 25 November 1998.

Abbreviations: 4S, Scandinavian Simvastatin Survival Study; IDL, intermediate-density lipoprotein; VA-HIT, Veteran's Administration HDL Intervention Trial Study.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company.

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Last updated: 3/99
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