These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.SUMMARY Natural History of Macrovascular Disease and Classic Risk Factors for Atherosclerosis Session summary Robert H. Eckel, MD NATURAL HISTORY OF MACROVASCULAR DISEASE IN TYPE 2 DIABETES: ROLE OF INSULIN RESISTANCE Michael Stern, MD Dr. Stern begins with the "common soil" hypothesis for the development of insulin resistance. Increasing data support the importance of the intrauterine environment in the later development of insulin resistance and type 2 diabetes, but studies have been limited to European Americans and, to a lesser extent, Mexican Americans. Unfortunately, despite this relationship, no satisfactory mechanistic explanation of the pathophysiology has been provided. Nevertheless, this area is ripe for investigation, and the challenge should be increasingly placed on perinatologists, in addition to the epidemiologists, endocrinologists, pathologists, et al., wherein the inquiries have largely arisen. Without a doubt, much of the increased risk for macrovascular disease in type 2 diabetes can be attributed to a higher prevalence of conventional risk factors, many of which are part of the insulin resistance syndrome. Turning to the more "controversial" risk factors, i.e., triglycerides, plasma glucose, and insulin, the picture remains unclear. In type 2 diabetes, hypertriglyceridemia has long been associated with an increased risk of macrovascular disease (1). Whether hypertriglyceridemia is the connection between increased plasminogen activator inhibitor 1, decreased HDL cholesterol, and/or small dense LDL or is independent of these expected relationships is unclear. The fact that almost all patients with hypertriglyceridemia >200 mg/dl have small dense LDL (2) but only some are at increased risk of macrovascular disease demands further explanation. Despite the importance of hyperinsulinemia as a predictor of macrovascular disease in people without diabetes, Dr. Stern nicely points out the problems in using this variable to explain macrovascular disease outcomes in patients with type 2 diabetes. Even if the relationship between hyperinsulinemia and macrovascular disease existed before the development of type 2 diabetes, at present the data do not support a direct relationship between insulin and the atherosclerotic process. Of interest, once the diagnosis of type 2 diabetes is made, relative hypoinsulinemia progressively follows, yet the risk for macrovascular disease relates importantly to the duration of diabetes. Because many of the metabolic risk factors for macrovascular disease improve with the treatment of diabetes, particularly with exogenous insulin, there is no reason at present not to pursue optimal management of glycemia with exogenous insulin, if needed. However, the proof that more and/or near optimal control of glycemia results in a reduction in macrovascular disease remains to be established. This leaves the future. Unequivocally, a well-controlled trial is needed to determine if patients with type 2 diabetes have a reduced incidence of macrovascular disease and related events when treated more aggressively, i.e., with insulin. Although not mentioned by Dr. Stern, there are data other than those from the Pathobiological Determinants of Atherosclerosis in Youth Study (3) that indicate a relationship between relative glycemia and macrovascular disease risk in nondiabetic subjects (4,5). In patients with type 2 diabetes, the University Group Diabetes Program (6) and VA Cooperative Studies (7) said no, but these attempts were either problematic in implementation or not associated with the expected changes in metabolic risk factors and too abbreviated to make firm conclusions. In the presence of more intensive treatment with insulin, a reduction in microvascular complications should still follow; and if a benefit concerning macrovascular disease fails to ensue, our attention should move to the genome and/or the identification of yet-to-be-discovered cardiovascular risk factors associated with glycemia but inadequately modified by insulin to explain the outcome. References 2. Austin MA, King MC, Vranizan KM, Krauss RM: Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation 82:495–506, 1990 3. McGill HC, McMahan A, Malcolm GT, Oalmann MC, Strong JP, the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group: Relation of glycohemoglobin and adiposity to atherosclerosis in youth. Arterioscler Thromb Vasc Biol 15:431–440, 1995 4. Sosenko JM, Kubrusly DB, Goldberg RB, Fournier AM, Hsia SL, Gadia MT, Skyler JS: High-density lipoprotein and glycosylated hemoglobin in nondiabetic individuals. Arch Intern Med 146:1521–1524, 1986 5. Fournier AM, Gadia MT, Kubrusly DB, Skyler JS, Sosenko JM: Blood pressure, insulin, and glycemia in nondiabetic subjects. Am J Med 80:861–864, 1986 6. University Group Diabetes Program: A study of the effects of hypoglycemic vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 19:785–830, 1970 7. Abraira C, Colwell JA, Nutall FQ, Sawin CT, Johnson-Nagel N, Comstock JP, Emanuele NV, Levin SR, Henderson W, Lee HS, VA CSDM Group: Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes (VA CSDM): results of the feasibility trial. Diabetes Care 18:1113–1123, 1995 RISK FACTORS FOR MACROVASCULAR DISEASE IN TYPE 2 DIABETES: CLASSIC LIPID ABNORMALITIES IN TYPE 2 DIABETES George Steiner, MD The relationship of dyslipidemia to macrovascular disease in patients with type 2 diabetes was nicely reviewed by Dr. Steiner. Importantly, we are reminded that the increased risk of macrovascular disease is reflected by the total cholesterol concentration in diabetic patients as much as, if not more than, it is in nondiabetic control subjects. Because levels of LDL cholesterol in patients with diabetes are typically normal, but in type 2 diabetes the levels of HDL cholesterol are low, the increase in total cholesterol more likely includes increases in VLDL and intermediate-density lipoproteins (IDLs). Dr. Steiner goes on to emphasize that both small VLDL (Sf 12-60) and IDL are atherogenic and that three-fourths of the triglyceride-rich lipoprotein particles are in this range. Presumably, the greater prevalence of macrovascular disease in type 2 diabetes relates to the prevalence of such abnormalities; however, this inadequately explains the increased incidence and prevalence of macrovascular disease in type 1 diabetes, wherein fasting lipids are typically normal and improved only modestly with intensive glycemic control (1). Despite the evidence presented by Dr. Steiner that the lowering of triglycerides with gemfibrozil improves insulin sensitivity, this effect is inconsistent (2). Studies are unfortunately lacking to support that this improvement in triglycerides and/or insulin sensitivity is accompanied by reductions in macrovascular disease incidence or prevalence in patients with type 2 diabetes. In fact, it remains possible that reductions in fasting triglycerides with a fibrate may result in no benefit or predispose to a greater risk for heart disease because of associated increases in LDL cholesterol as a result of the therapy (3,4). Thus, we must turn to the existing data to examine how and what modifications in lipoproteins are most likely to benefit patients with diabetes. Dr. Steiner reviewed the recent clinical trials, all of which used statins, that included small numbers of patients with type 2 diabetes and/or impaired glucose tolerance. At present, it seems reasonable to conclude that a reduction in LDL cholesterol in patients with type 2 diabetes and coronary atherosclerosis is appropriate; however, the existing studies were in patients without moderately severe hypertriglyceridemia and were insufficiently powered to determine if there was a reduction in total mortality. Nevertheless, the recent decision by the American Diabetes Association to recommend more aggressive reduction of LDL cholesterol to <100 mg/dl, even in patients without documented coronary artery disease (5), is defensible at the present time. The Diabetes Atherosclerosis Intervention Study (6) is more appropriate for the lipoprotein disorders more commonly seen in diabetes, but this remains an angiographic study, which may not provide the hard outcomes that we all await. References 2. Jeng CY, Sheu WH, Fuh MM, Shieh SM, Chen YD, Reaven GM: Gemfibrozil treatment of endogenous hypertriglyceridemia: effect on insulin-mediated glucose disposal and plasma insulin concentrations. J Clin Endocrinol Metab 81:2550–2553, 1996 3. Shen DC, Fuh MM, Shieh SM, Chen YD, Reaven GM: Effect of gemfibrozil treatment in sulfonylurea-treated patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 73:503–510, 1991 4. Dachet C, Cavallero E, Martin C, Girardot G, Jacotot B: Effect of gemfibrozil on the concentration and composition of very low density and low density lipoprotein subfractions in hypertriglyceridemic patients. Atherosclerosis 113:1–9, 1995 5. American Diabetes Association: Management of dyslipidemia in adults with diabetes. Diabetes Care 21:179–182, 1998 6. Steiner G: The Diabetes Atherosclerosis Intervention Study (DAIS), a study conducted in cooperation with the World Health Organization. Diabetologia 39:1655–1661, 1996 DYSLIPIDEMIA OF CENTRAL OBESITY AND INSULIN RESISTANCE John D. Brunzell, MD Within the last 15 years, there has been an increasing importance attributed not only to obesity as a predictor of type 2 diabetes, dyslipidemia, and atherosclerosis, but to where the excess fat is distributed. Drs. Brunzell and Hokanson have reviewed in part this story for us, with additional emphasis placed on the modifiers of the associated dyslipidemia, including hepatic lipase and cholesteryl ester transfer protein. They conclude that the influence of these proteins on VLDL and HDL metabolism in patients with insulin resistance and central obesity lead to increased levels of circulating small dense LDL, an important lipoprotein modification associated with atherosclerotic cardiovascular disease (1). Recent evidence from the Quebec Cardiovascular Study goes further in confirming such a relationship (2). Yet, the story remains incomplete. With increasing levels of plasma triglycerides, small dense LDL are expected. In fact, with fasting triglycerides >200 mg/dl, nearly all patients have phenotype B or small dense LDL (3). Yet, all patients with hypertriglyceridemia do not appear to be at increased risk of cardiovascular disease. Why? Perhaps not all patients with hypertriglyceridemia are insulin resistant, and thus some do not have many of the covariates associated with insulin resistance, e.g., accelerated lipolysis, overproduction of apolipoprotein B, hyperuricemia, and hypertension. With time, glucose intolerance may fail to develop. How might these patients be distinguished from those wherein central adiposity and insulin resistance coexist? In the absence of increased levels of LDL cholesterol and fasting triglycerides >200 mg/dl, an apolipoprotein B <100 mg/dl might be reassuring (2). Presumably these patients have triglyceride-enriched large VLDL with hepatic overproduction of triglycerides but not apolipoprotein B. Thus, despite the presence of low levels of HDL2 cholesterol and small dense LDL, the absence of insulin resistance and increased production of apolipoprotein B as underlying etiologies of the hypertriglyceridemia may render such patients at no increased risk for atherosclerotic cardiovascular disease (ASCVD). The remaining dilemma is how patients with central obesity and insulin resistance might be managed. Of course, weight reduction works, and with most patients weight loss reduces the central component of excess body fat as well if not more so than the peripheral component (4). Nevertheless, weight loss is difficult to achieve, and the increased insulin sensitivity that accompanies sustained weight reduction is a metabolic predictor of weight regain (5). Here the maintenance of an active lifestyle after weight reduction is particularly important in providing a greater likelihood that the reduced obese state will be maintained. However, in the absence of sustained weight reduction, a more aggressive therapeutic approach may be needed to favorably modify the components of the insulin resistance syndrome and reduce the risk of ASCVD. This may be particularly true for those patients with hypertriglyceridemia and LDL cholesterol/HDL cholesterol ratios >5.0 (6) and/or apolipoprotein B concentrations >120 mg/dl (7). In such patients, triglyceride lowering has proven beneficial. In addition, aggressive treatment of hypertension and enhancing physical activity, even in the absence of weight loss, appear efficacious. However, at present, no evidence exists that increasing HDL in the absence of lowering LDL is beneficial. References 2. Lamarche B, Tchernof A, Mauriège P, Cantin B, Dagenais GR, Lupien PJ, Després J-P: Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 279:1955–1961, 1998 3. Austin MA, King MC, Vranizan KM, Krauss RM: Atherogenic lipoprotein phenotype: a proposed genetic marker for coronary heart disease risk. Circulation 82:495–506, 1990 4. Després J-P, Lamarche B: Effects of diet and physical activity on adiposity and body fat distribution: implications for the prevention of cardiovascular disease. Nutr Res Rev 6:137–159, 1993 5. Yost TJ, Jensen DR, Eckel RH: Weight regain following sustained weight reduction is predicted by relative insulin sensitivity. Obes Res 3:583–587, 1995 6. Tenkanen L, Manttari M, Manninen V: Some coronary risk factors related to the insulin resistance syndrome and treatment with gemfibrozil: experience from the Helsinki Heart Study. Circulation 9:1779–1785, 1995 7. Després J-P, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952–957, 1996 DIABETES AND CARDIOVASCULAR DISEASE James R. Sowers, MD Drs. Sowers and Lester have given us the wide-lens view of macrovascular disease and diabetes. This view includes the following points: 1) up to 75% of diabetes-related macrovascular disease occurs in patients with hypertension; 2) multiple disturbances in the thrombotic/fibrinolytic system render diabetes a procoagulant state; 3) oxidative and glycative modification of LDL apolipoprotein B and other proteins is enhanced in diabetes; and 4) women with diabetes have no protection from macrovascular disease compared with their nondiabetic female counterparts. Most of these issues relate to potential therapeutic interventions that could prove useful in at least retarding the development of macrovascular disease in patients with diabetes. The relationship between hyperinsulinemia
and macrovascular disease, however, is likely not cause and effect, but association.
Despite the many effects of insulin outlined by Sowers and Lester that could be
pro-atherogenic, e.g., mitogenic stimulation of vascular wall cells in vitro, there is
precious little evidence of such effects in vivo. In fact, much of the recent work of King
and Brownlee (1) suggests that insulin may, in fact, inhibit
protein kinase C- At present, much attention is being given to the relationship between endothelial dysfunction and macrovascular disease. This has largely been attributed to defects in the generation of nitric oxide by endothelial nitric oxide synthase. Although endothelial dysfunction is common in diabetes, the concomitant presence of vascular disease could be the cause rather than the result. It remains to be proven that endothelial dysfunction leads to the development of macrovascular disease. Of interest, however, is the contention of Sowers and Lester that the lack of protection of women with diabetes from macrovascular disease development could relate to the inadequate nitric oxide–mediated vasodilatory response of the vasculature to estrogens in women with diabetes. At present, it remains unclear if postmenopausal hormone replacement therapy is less effective in reducing the risk of macrovascular disease in women with diabetes than in women without diabetes. Finally, a strong case for the use of ACE inhibitors was made. Not only is the natural history of diabetic nephropathy favorably altered by ACE inhibitors (3,4), recent evidence suggests that the benefit of ACE inhibitors on the myocardium may relate not only to the blood pressure–reducing effects of this class of drugs, but other effects, e.g., the inhibition of the growth-promoting effects of angiotensin II (5). With the current state of knowledge, it would appear that all adult patients with diabetes, except those with specific contraindications, should be on ACE inhibitors, or perhaps angiotensin II receptor antagonists, after the diagnosis of diabetes. References 2. Lind L, Lithell H, Pollare T, Ljunghall S: On the interplay between insulin secretion and sensitivity as determinants of glucose intolerance. Acta Diabetologica 31:26–30, 1994 3. Breyer JA: Therapeutic interventions for nephropathy in type I diabetes mellitus. Semin Nephrol 17:114–123, 1997 4. Yokoyama H, Tomonaga O, Hirayama M, Ishii A, Takeda M, Babazono T, Ujihara U, Takahashi C, Omori Y: Predictors of the progression of diabetic nephropathy and the beneficial effect of angiotensin-converting enzyme inhibitors in NIDDM patients. Diabetologia 40:405–411, 1997 5. Makino N, Sugano M, Otsuka S, Hata T: Molecular mechanism of angiotensin II type I and type II receptors in cardiac hypertrophy of spontaneously hypertensive rats. Hypertension 30:796–802, 1997 SUMMARY Identification of the risk factors for macrovascular disease in diabetes is increasing, but associations—not cause-and-effect relationships—have for the most part affected only the clinician. At present, there remains a substantial lack of knowledge about pathophysiological mechanisms that mediate the higher risk of macrovascular disease development in diabetes. Moreover, clinical trials in which risk factors have been adequately and/or consistently modified are, to a large extent, absent. Why does excessive adipose tissue develop in the abdomen, and, when present, what is the mechanism by which the insulin resistance syndrome results? To what extent is the relationship between insulin resistance and macrovascular diseases the lipoprotein disturbances? Is it the increase in triglyceride-rich particles themselves, including intermediate-density lipoproteins; or is it the small dense LDL; and/or is it reduced levels of HDL cholesterol? Moreover, the mechanisms by which small dense LDL and reduced levels of HDL cholesterol contribute to the atherosclerotic process in the presence or absence of diabetes remain theoretical. Diabetes as a procoagulant state is supported by the literature. But what is it about diabetes that alters the many processes that relate to thrombosis/fibrinolysis in a way that adversely modifies coagulation pathways and enhances thrombotic tendency? So where does that leave us in the late 1990s? Presently, sufficient—although certainly less than definitive—evidence exists for two therapeutic strategies. First, aspirin appears to be as effective in reducing morbidity and mortality in patients with diabetes as in those without (1,2). Thus, all patients with diabetes should be aspirin-treated in their adult years. This should probably begin at age 18 in patients with type 1 diabetes, and at or even before the diagnosis of diabetes in adults. The age at which aspirin prophylaxis should begin in adults remains unclear from the clinical trials, but 35 for men and 45 for women seems reasonable. Second, the evidence from clinical trials wherein lowering LDL cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors has been utilized appears to indicate that patients with diabetes and coronary artery disease do as well as those without, at least in secondary prevention (3,4). Thus, the current recommendation that all patients with diabetes have reductions in LDL cholesterol <100 mg/dl may be overzealous, but it is entirely appropriate for what is currently known (5). What remains is insufficient evidence to support other therapeutic decisions that seem obvious, e.g., reductions in glycemia, triglyceridemia, and blood pressure. Smoking cessation, of course, is assumed. The Diabetes Atherosclerosis Intervention Study (6) may begin to provide an answer to the triglyceride/macrovascular disease relationship, whereas the important aspect of blood pressure–lowering may not be simply the level, but also which lowering agent is chosen. Recent evidence indicates that for similar degrees of blood pressure reduction in patients with type 2 diabetes, an ACE inhibitor may reduce the risk of coronary-related death more than a calcium channel blocker (7). The time has come for the Diabetes Control and Complications Trial of type 2 diabetes. Although several attempts have been made, the studies have either been too small or flawed, and conclusions remain ambiguous. Of course, it could be suggested that near-normal glycemia should be achieved in all patients with type 2 diabetes to delay or prevent the onset of microangiopathy and the neuropathic complications of diabetes. Yet, macrovascular disease morbidity and mortality so very often antedate the morbidity and/or mortality associated with the other complications of diabetes. An aggressive approach to the near-normalization of glycemia in patients with type 2 diabetes is often not simple, and it is associated with the need for a concentrated effort in patient education and compliance, weight gain, and financial expense. An answer to this incredibly important question is clearly needed—let's get on with it. References 2. Yudkin JS: How can we best prolong life? Benefits of coronary risk factor reduction in non-diabetic and diabetic subjects. BMJ 306:1313–1318, 1993 [published errata appear in BMJ 306:1739, 1993 and 307:1161, 1993] 3. Pyorala K, Pedersen TR Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 20:614–620, 1997 4. Goldberg RB, Mellics MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MP, Braunwald E, for the CARE Investigators: Cardiovascular events and their reduction with provastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) Trial. Circulation 98:2513–2519, 1998 5. American Diabetes Association: Management of dyslipidemia in adults with diabetes. Diabetes Care 21:179–182, 1998 6. Steiner G: The Diabetes Atherosclerosis Intervention Study (DAIS), a study conducted in cooperation with the World Health Organization. Diabetologia 39:1655–1661, 1996 7. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW: The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 338:645–652, 1998 From the University of Colorado Health Sciences Center, Denver, Colorado. Address correspondence and reprint requests to Robert H. Eckel, MD, Box B151, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262. Received for publication 12 August 1998 and accepted in revised form 12 November 1998. Abbreviations: ASCVD, atherosclerotic cardiovascular disease; IDL, intermediate-density lipoproteins. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. This article is based on presentations 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. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
, an effect that
would, if anything, limit the atherogenic process. More likely is that hyperinsulinemia is
a consequence of insulin resistance that reflects the inadequacy of insulin action
peripherally. Insulin resistance, therefore, could be an explanation as to why patients
with impaired glucose tolerance have an increased risk for macrovascular disease in the
setting of hyperinsulinemia, whereas that risk increases as insulin secretion fails but
insulin resistance increases with a longer duration of type 2 diabetes (