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Dyslipidemia, morbidity, and mortality in non-insulin-dependent diabetes mellitus
ELSEVIER
Dyslipidemia, Morbidity, and Mortality in Non-Insulin-Dependent Diabetes Mellitus Lipoproteins and Coronary Heart Disease in Non-Insulin-Dependent Diabetes Mellitus Markku Laakso
ABSTRACT Lipid and lipoprotein abnormalities in non-insulindependent diabetes mellitus (NIDDM) include particularly elevated levels of total and very-lowdensity lipoprotein WLDL) triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually normal if glycemic control is adequate. The worsening of glycemic control deteriorates lipid and lipoprotein abnormalities and particularly total and LDL cholesterol levels are often elevated in patients with poor glycemic control. According to prospective population-based studies total cholesterol is a powerful risk factor for coronary heart disease (CHD) in NIDDM patients as in nondiabetic subjects. In contrast, high total
INTRODUCTION ccurrence of macrovascular complications, coronary heart disease (CHD), cerebrovascular disease, and peripheral vascular disease are substantially increased in patients with diabetes mellitus.’ The most important of these complications, CHD, is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). Data from longitudinal studies suggest that the risk of CHD mortality and morbidity rates is two to four times higher in diabetic patients than in nondiabetic subjects. Particularly patients with NIDDM
0
Department of Medicine, University of Kuopio, Kuopio, Finland. Reprint requests to be sent to: Dr. Markku Laakso, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland.
Journal of Diabetes and Its Complications 11:137-141 0 Elsevier Science Inc., 1997 655 Avenue of the Americas, New York, NY 10010
triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in NIDDM patients than in nondiabetic individuals, but more prospective studies are needed to substantiate this view. Compositional changes in LDL and VLDL particles may further increase the risk for CHD but epidemiologic data are missing to support this notion. Preliminary data from the Scandinavian Simvastatin Survival Study including 202 diabetic patients seem to indicate that diabetic patients benefit from simvastatin treatment equally to nondiabetic subjects. (Journal of Diabetes and Its Complications 11;2:137-141, 1997.1 0 Elsevier Science Inc., 1997
are at increased risk for CHD events and the risk is high already at the diagnosis of NIDDM. Dyslipidemia is very common in patients with NIDDM and significantly contributes to the risk of macrovascular complications. These patients often present adverse changes of both in the quantity and quality of lipoproteins.2 In addition to total and lowdensity lipoprotein (LDL) cholesterol levels, the potential of other lipids and lipoproteins to modulate the risk for macrovascular disease has recently gained an increasing attention. This review summarises typical characteristics of dyslipidemia in NIDDM, and its association with the risk of macrovascular complications. Finally, trial evidence on the effects of drug treatment of dyslipidemia with respect to the risk of macrovascular disease is reviewed. 1056~8727/97/$17.00 PII 3056~8727(96)00092-X
LIPIDS
AND LIPOPROTEIN ABNORMALITIES IN NON-INSULIN-DEPENDENT DIABETES MELLITUS
Dyslipidemia is very frequent in patients with NIDDM. Different studies indicate that 54%-77% of patients with NIDDM have high or borderline-high total cholesterol.“” About 20% of patients have hypertriglyceridemia or low high-density lipoprotein (HDL) cholesterol.3,4,6 Triglycerides and Very-Low-Density Lipoproteins. Elevated levels of plasma total and very-low-density lipoprotein (VLDL) triglyceride levels are often observed in patients with NIDDM.‘z2 In spite of the correction of hyperglycemia, triglyceride level often remains elevated in these patients. Increased hepatic VLDL triglyceride production and probably also an impaired clearance of VLDL contribute to the development of hypertriglyceridemia.2 Hyperinsulinemia or insulin resistance7 and obesitf apparently are at least in part responsible for increased hepatic VLDL triglyceride production.2 Insulin resistance measured by the euglycemic clamp technique has been shown to be associated with high total and VLDL triglyceride and low HDL cholesterol levels.‘-” The strongest associationof insulin resistance and lipoprotein changes is that with elevated VLDL triglyceride concentration. Total Cholesterol and Low-Density Lipoproteins. Total and LDL cholesterol levels are usually normal or slightly elevated in patients with newly or previously diagnosed NIDDM compared with corresponding control subjects. I,* Improvement of glycemic control has been shown to reduce plasma total and LDL cholesterol levels.2 Elevated VLDL cholesterol concentration in patients with NIDDM may be in part responsible for elevated plasma total cholesterol found in some studies.2 LDL particles often have compositional changes in NIDDM. The most important of these is the predominance of small, dense LDL (pattern B). Prevalence of phenotype B is substantially increased in patients with diabetes.12*13 Furthermore, LDL particles in NIDDM contain more triglycerides than in normoglycemic subjects. lJ Insulin resistance has not been associated with high LDL cholestero19-I1 High-Density Lipoproteins. Plasma HDL cholesterol level is usually decreased in patients with NIDDM compared to gender- and age-matched control subjects2 The reduction of plasma HDL cholesterol level is quite similar in newly diagnosed, untreated patients with NIDDM and in patients with previously diagnosed NIDDM treated with diet, oral drugs, or insulin. A decrease in HDL2 subfraction is responsible for decreased plasma I-IDL cholesterol in these patients. The correlation between glycemic control and plasma HDL cholesterol level has been found to be low or absent.
Triglyceride content of HDL particles is often elevated referring to compositional changes in HDL particles.” DYSLIPIDEMIA AS A RISK FACTOR FOR MACROVASCULAR DISEASE IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES MELLITUS The most effective study that has investigated the predictive role of serum cholesterol level as a risk factor for cardiovascular mortality in diabetic patients is the Multiple Risk Factor Intervention Trial.15 This study included 5163 men, aged 35-57 years at baseline examination, who reported taking medication for diabetes, and 342,815 men not taking medication for diabetes. Cardiovascular and CHD mortality rates were approximately threefold in diabetic subjects than in nondiabetic subjects after 12-year follow-up at every level of serum cholesterol. Other longitudinal studies, the Framingham StudyI and the Whitehall Study,17 which have also included women have demonstrated that the predictive value of total cholesterol with respect to the risk of CHD death is similar in diabetic and nondiabetic subjects. In the World Health Organization (WHO) Multinational Studyls and in the Paris Prospective Study” the single risk factor that correlated most closely with the occurrence of CHD in diabetic subjects was plasma total triglyceride concentration. In the 11-year followup of the Paris Prospective Study, plasma triglyceride level was the only factor positively and significantly associated with CHD death in multivariate regression analysis. High cholesterol level increased the risk for CHD particularly in diabetic patients with simultaneously high triglyceride levels. Unfortunately, HDL cholesterol was not measured in this study. We have evaluated the prognostic significance of lipoprotein fractions for the future risk of C,HD in NIDDM patients. 2o Lipids and lipop rotein fractions were determined in 313 NIDDM patients (153 men, 160 women). During the 7-year follow-up high total (>6.2 mmol/L) and LDL cholesterol (>4.1 mmol/L) levels were not associated with an increased risk of future CHD events (CHD death or all CHD events including CHD death or nonfatal myocardial infarction). High levels of total triglycerides (>2.3 mmol/L) increased the risk of CHD death or all CHD events twofold. The most powerful single lipoprotein risk factor for CHD was low HDL cholesterol (CO.9 mmol/ L), which increased the risk of CHD death fourfold and the risk of all CHD events twofold. The simultaneous presence of low HDL cholesterol and high triglycerides did not further increase the risk for CHD. This finding has been confirmed in our own recent study including over 1000 patients with NIDDM. The most important lipoprotein fraction to predict CHD events was low HDL cholesterol, which increased the risk for CHD
1 Dinb Camp 1997; 21:137-142
DYSLIPIDEMIA,
events about twofold independently of other cardiovascular risk factors (Lehto et al., unpublished). It is interesting to note that in the same study population, dyslipidemia had much weaker effect on the risk of stroke*l and amputation.22 Goldschmidt et alz3 followed 66 men and 45 women with diabetes for an average of 16 years in a population-based study in Southern California. Although the number of diabetic subjects in this study was low CHD mortality was associated significantly with low HDL cholesterol and high VLDL cholesterol in women. Low HDL cholesterol and high VLDL cholesterol increased the risk of CHD in diabetic men, but the results were not statistically significant. LDL cholesterol was similar in diabetic and nondiabetic subjects at baseline and its association with the risk of CHD was not reported. The predictive value of lipids and lipoproteins for future CHD events seems to vary between nondiabetic and NIDDM subjects. High total cholesterol increases the risk for CHD similarly in NIDDM patients and in nondiabetic subjects. However, whereas total cholesterol mainly reflects the predictive role of LDL cholesterol in nondiabetic subjects, this relationship seems to be more complex in NIDDM patients. As shown by our follow-up study, 2o the association of total cholesterol with CHD risk was explained by elevated levels of VLDL cholesterol, not be elevated levels of LDL cholesterol. NIDDM is characterized by compositional changes in LDL and VLDL particles, and therefore, the measurement of LDL cholesterol level does not count for these changes. In contrast to total cholesterol, total and VLDL triglycerides seem to be stronger risk factors for CHD in NIDDM patients than in nondiabetic subjects. Besides direct atherogenicity, VLDL particles could be directly atherogenic through inducing the decrease in HDL cholesterol and the increase in small, dense LDL particles. CLINICAL TRIALS ASSESSING THE EFFICACY OF LIPID-LOWERING DRUG TREATMENT ON THE PROGNOSIS OF PATIENTS WITH NIDDM Subgroup Analyses. Although several randomized controlled trials have indicated that a reduction of elevated plasma cholesterol levels decreased the risk for CHD mortality and morbidity in nondiabetic subjects, no similar studies are available at this moment on patients with NIDDM. However, several studies are in progress which will give valuable information in this respect in the forthcoming years. The data available to date are mainly from post-hoc subgroup analyses of diabetic patients participating in large-scale prevention trials. The most important of these are the Helsinki Heart Study and The Scandinavian Simvastatin Survival Study. The Helsinki
Heart Study.
The Helsinki
Heart
Study
MORBIDITY,
AND
MORTALITY
IN NIDDM
139
was designed to investigate the effects of lowering LDL cholesterol and increasing HDL cholesterol with gemfibrozil in men aged 40-55 years.24*25 A total of 4081 men including 135 patients with NIDDM were randomized to receive either gemfibrozil or placebo. Over the 5-year period, gemfibrozil reduced total and LDL cholesterol and particularly total triglycerides and increased the level of HDL cholesterol quite similarly in nondiabetic and diabetic subjects. In gemfibroziltreated diabetic patients the incidence of a major CHD event was 3.4% whereas in placebo-treated diabetic patients the corresponding incidence was (10.5%). The difference between the groups was not statistically significant (p = 0.19) mainly because of the low number of diabetic patients participating in the study. The Scandinavian Simvastatin Survival Study (4s). The 4s Study was designed to investigate the effects of lowering cholesterol with simvastatin on serious CHD events. A total of 4444 participants (3617 men, 827 women) aged 35-70 years at baseline and with a previous myocardial infarction or angina pectoris and elevated plasma cholesterol (5.5-8.0 mmol/L) and total triglycerides less than 2.6 mmol/L were randomized to received simvastatin or placebo for 5 years.26 Altogether 202 diabetic patients (158 men, 44 women) participated in this study. During the follow-up period of 5.4 years, 17.5% of the placebo-treated and 11.4% of the simvastatin-treated diabetic patients died of CHD. The reduction of 36% in the risk of CHD mortality did not, however, reach the limit of statistical significance (p = 0.242).27 In contrast, the incidence of a major CHD event reduced significantly in simvastatin-treated diabetic patients by 55% (p = 0.002). Because the corresponding number in nondiabetic subjects was 32%, the benefit of simvastatin treatment in diabetic patients seems to be as good as in nondiabetic subjects. The Cholesterol And Recurrent Events Study. This study is a secondary prevention trial testing the effects of cholesterol lowering in pravastatin (40 mg daily) or placebo on the occurrence of recurrent CHD events (CHD death plus nonfatal myocardial infarction) during a 5-year follow-up.28 The trial includes over 4000 patients aged 21-75 years who have survived a myocardial infarction and who have total cholesterol <6.2 mmol/L, LDL cholesterol 3.04.5 mmol/L, and total triglycerides ~4.0 mmol/L. Of the patients randomized into the trial, 14% had a history of diabetes. The results of this study should be available soon. The Long-Term Intervention with Pravastatin in lschemic Disease Study. This study is also a secondary prevention trial aiming to test the effect of pravastatin (40 mg daily) or placebo on recurrent CHD events.29 Over 9000 patients with CHD aged 31-75 years and with total cholesterol 4.0-7.0 mmol/L have been randomized in 1990-1992 into two treatment groups. Of the patients
140
1 Diab Camp
LAAKSO
randomized, 9% have diabetes. The trial has been designed to continue at least 5 years. The Bemfibrate Infarction Prevention Study. This trial investigates the effect of HDL cholesterol elevation and triglyceride reduction with bezafibrate (400 mg daily) or placebo on recurrent CHD events.30 Over 3200 patients, aged 45-74 years and with total cholesterol 4.76.4 mmol/L and HDL cholesterol cl.2 mmol/L have been randomized in 1990-1992 for a median followup of 6.25 years into two treatment groups including a large number of diabetic patients (10%). Trials on Diabetic Patients The DiabetesAtherosclerosislntetvention Trial (DAIS). The DAIS trial is the only study at this moment specifically designed to investigate the effect of hyperlipidemic drug treatment on decreased progression or regression of coronary atherosclerosis in patients with NIDDM.31 The evaluation of the primary end point is based on quantitative angiography. The study population consists of 418 patients with NIDDM (305 men, 113 women) recruited at 11 clinics located in Canada, Finland, France, and Sweden. The patients have a moderate dyslipoproteinemia (LDL cholesterol, 354.5 mmol/ L and triclyceride ~5.2 mmol/L; or triglyceride, 1.7-5.2 mmol/L and LDL cholesterol ~4.5 mmol/L and total cholesterol/HDL cholesterol ratio 24), and they have been randomized to received either fenofibrate (200 mg) or placebo. The recruitment ended in January 1996, and the second coronary angiogram will be performed after 36 months of treatment.
11:13i-141
REFERENCES 1.
Pyiirala K, Laakso M, Uusitupa M: Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Xea 3~463-524, 1987.
2.
Taskinen M-R Quantitative abnormalities in diabetes 1992.
3.
Ronnemaa J, Puukka teins and disease in ] Epidemiol
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Laasko M, Ronnemaa T, Pyorala K, Kallio V, Puukka P, Penttila I: Atherosclerotic vascular disease and its risk factors in non-insulin-dependent diabetic and nondiabetic subjects in Finland. Diabetes Care 11~449-463, 1988.
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Harris MI: Hypercholesterolemia in diabetes and glucose intolerance in the U.S. population. Diabetes Care 14:366-374, 1991.
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Stern MI’, Patterson JK, Haffner SM, Haxuda HP, Mitchell BD: Lack of awareness and treatment in hyperlipidemia in type II diabetes in a community survey. ]AMA 262:36O-264, 1989.
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Reaven GM, Greenfield MS: Diabetic hypertriglyceridaemia: Evidence for three clinical syndromes. Diabetes 30:66-75, 1981.
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Laakso M, PyBrala lipid and lipoprotein non-insulin-dependent 122,1988.
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Abbott WG, Lillioja S, Young AA, et al.: Relationships between plasma lipoprotein concentrations and insulin action in an obese hyperinsulinemic population. Diabetes 36:897-904, 1987.
10.
Garg A, Helderman JH, Koffler M, Ayoso R, Rosenstock J, Raskin P: Relationship between lipoprotein levels and in vivo insulin action in normal white young white men. Metabolism 37~982-987, 1988.
11
Laakso M, Sarhmd H, Mykkanen L: Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance. Arteriosclerosis 10:223-231, 1990.
12.
Selby JV, Austin MA, Newman B, et al.: LDL subclass phenotypes and the insulin resistance syndrome in women. Circulation 88:381-387, 1993.
CONCLUSIONS In addition to hypertension and smoking, total and LDL cholesterol are as powerful risk factors for CHD in NIDDM patients as in nondiabetic subjects. Epidemiologic evidence supports the notion that high total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in NIDDM patients than in nondiabetic individuals. Compositional changes particularly in LDL particles (small, dense LDL, or increased triglyceride content of LDL particles) could be important determinants of accelerated atherosclerosis in NIDDM patients. no primary or secondary prevention studies are available on NIDDM patients to evaluate whether the correction of dyslipidemia by diet, exercise, or pharmacologic therapy results in the reduction in the risk of atherosclerotic complications. However, a subgroup analysis of the 4s Study indicated that hypercholesterolemic diabetic patients benefit similarly to nondiabetic patients of simvastatin treatment. Several studies are currently carried out which will in forthcoming years give data on the effects of different drugs on the reduction of CHD risk in diabetic patients with dyslipidemia.
199i;
and qualitative lipoprotein mellitus. Diabetes 41:12-17,
T, Laakso M, Kallio V, Pyorala K, Marniemi P: Serum lipids, lipoproteins, and apolipoprothe excessive occurrence of coronary heart non-insulin-dependent diabetic patients. Am 130:632-645, 1989.
K: Adverse effects of obesity on levels in insulin-dependent and diabetes. Metabolism 39:117-
13 Barakat HA, Carpenter JW, McLendon ’ ence of obesity, impaired glucose
VD, et al.: Influtolerance, and NIDDM on LDL structure and composition. Possible link between hyperinsulinemia and atherosclerosis. Diabetes 39:1527-1533, 1990.
14.
Manzato, E, Zambon A, Lapolla A, et al.: Lipoprotein abnormalities in well-treated type II diabetic patients. Diabetes Care 16:469475, 1993. Stamler J, Vaccaro 0, Neaton JD, Wentworth D, for the 15. Multiple Risk Factor Intervention TrialResearch Group: Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk factor Intervention Trial. Diabetes Care 16:434-&I, 1993. 16. Kannel WB, McGee DL: Diabetes and cardiovascular
r Diab Camp 1997; 11:137-141
risk factors: the Framingham 1979.
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Study. Circulation
598-13, 25.
17.
Jarrett RJ, Shipley MJ: Mortality and associated risk factors in diabetics. Acta Endocrinol 110:21-26, 1985.
18.
West KM, Ahuja MM, Bennett PH, et al.: The role of circulating glucose and triglyceride concentrations and their interactions with other “risk factors” as determinants of arterial disease in nine diabetic population samples from the WHO multinational study. Diabetes Care 6:361-369, 1983.
19.
Fontbonne A, Eschwege E, Cambien R, et al.: Hypertriglyceridaemia as a risk factor of coronary heart disease mortality in subjects with impaired glucose tolerance or diabetes. Results from the ll-year follow-up of the Paris Prospective Study. Diabetologia 32:300-304, 1989.
28.
Laakso M, Lehto S, Penttila I, Pyorala K: Lipids and lipoproteins predicting coronary heart disease mortality and morbidity in patients with non-insulin-dependent diabetes. Circulation 88:1421-1430, 1993.
29.
Lehto S, Ronnemaa T, Pyorala K, Laakso M: Predictors of stroke in middle-aged patients with non-insulindependent diabetes. Stroke 27:63-68; 48, 1996. . . K, Laakso M: Risk factors Lehto S, Ronnemaa T, Pyorala
30.
20.
21.
22.
predicting lower extremity amputations NIDDM. Diabetes Care 1996 (in press).
26.
27.
in patients with
23.
Goldschmidt MG, Barrett-Connor E, Edelstein SL, Wingard DL, Cohn BA, Herman WH: Dyslipidaemia and ischaemic heart disease mortality among men and women with diabetes. Circulation 89:991-997, 1994.
24.
Frick MH, Elo 0, Haapa K, et al.: Helsinki Heart Study: Primary revention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in
31.
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risk factors, and incidence of coronary heart disease. N Engl J Med 317:1237-1345, 1987. Tenkanen L, Pietila K, Manninen V, Manttari M: The triglyceride issue revisited. Findings from the Helsinki Heart Study. Arch Intern Med 154:2714-2720, 1994. Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4s). Lancef 344:1383-1389, 1994. Pyorala K, Pedersen TR, Kjekshus J, for the Scandinavian Simvastatin Survival Study (4s) Group: The effect of cholesterol lowering with simvastatin on coronary events in diabetic patients with coronary heart disease. Diabetes 44:35A, 1995. Pfeffer MA, Sacks FM, Moye LA, et al., for the CARE Investigators: Cholesterol and recurrent events: a secondary prevention trial in normolipidemic patients. Am J Cardiol 76:98C-106C, 1995. Tonkin AM, for the LIPID Study Group: Management of the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study after the Scandinavian Simvastatin Survival Study (4s). Am J Cardiol 76:107C112c, 1995. Goldbourt U, Behar S, Reicher-Reiss H, et al. for the Bezafibrate Infarction Prevention Study Group: Rationale and design of a secondary prevention trial of increasing serum high-density lipoprotein cholesterol and reducing triglycerides in patients with clinically manifest atherosclerotic heart disease (the Bezafibrate Infarction Prevention Trial). Am J Cavdiol71:909-934,1993. Steiner G, for the DAIS Project Group: The Diabetes Atherosclerosis Intervention Study (DAIS). A study conducted in cooperation with the World Health Organization. Diabefologia 1996 (in press).
Dyslipidemia, Morbidity, and Mortality in Non-Insulin-Dependent Diabetes Mellitus Lipoproteins and Coronary Heart Disease in Non-Insulin-Dependent Diabetes Mellitus Markku Laakso
ABSTRACT Lipid and lipoprotein abnormalities in non-insulindependent diabetes mellitus (NIDDM) include particularly elevated levels of total and very-lowdensity lipoprotein WLDL) triglycerides and reduced levels of high-density lipoprotein (HDL) cholesterol. Total and low-density lipoprotein (LDL) cholesterol levels are usually normal if glycemic control is adequate. The worsening of glycemic control deteriorates lipid and lipoprotein abnormalities and particularly total and LDL cholesterol levels are often elevated in patients with poor glycemic control. According to prospective population-based studies total cholesterol is a powerful risk factor for coronary heart disease (CHD) in NIDDM patients as in nondiabetic subjects. In contrast, high total
INTRODUCTION ccurrence of macrovascular complications, coronary heart disease (CHD), cerebrovascular disease, and peripheral vascular disease are substantially increased in patients with diabetes mellitus.’ The most important of these complications, CHD, is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). Data from longitudinal studies suggest that the risk of CHD mortality and morbidity rates is two to four times higher in diabetic patients than in nondiabetic subjects. Particularly patients with NIDDM
0
Department of Medicine, University of Kuopio, Kuopio, Finland. Reprint requests to be sent to: Dr. Markku Laakso, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland.
Journal of Diabetes and Its Complications 11:137-141 0 Elsevier Science Inc., 1997 655 Avenue of the Americas, New York, NY 10010
triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in NIDDM patients than in nondiabetic individuals, but more prospective studies are needed to substantiate this view. Compositional changes in LDL and VLDL particles may further increase the risk for CHD but epidemiologic data are missing to support this notion. Preliminary data from the Scandinavian Simvastatin Survival Study including 202 diabetic patients seem to indicate that diabetic patients benefit from simvastatin treatment equally to nondiabetic subjects. (Journal of Diabetes and Its Complications 11;2:137-141, 1997.1 0 Elsevier Science Inc., 1997
are at increased risk for CHD events and the risk is high already at the diagnosis of NIDDM. Dyslipidemia is very common in patients with NIDDM and significantly contributes to the risk of macrovascular complications. These patients often present adverse changes of both in the quantity and quality of lipoproteins.2 In addition to total and lowdensity lipoprotein (LDL) cholesterol levels, the potential of other lipids and lipoproteins to modulate the risk for macrovascular disease has recently gained an increasing attention. This review summarises typical characteristics of dyslipidemia in NIDDM, and its association with the risk of macrovascular complications. Finally, trial evidence on the effects of drug treatment of dyslipidemia with respect to the risk of macrovascular disease is reviewed. 1056~8727/97/$17.00 PII 3056~8727(96)00092-X
LIPIDS
AND LIPOPROTEIN ABNORMALITIES IN NON-INSULIN-DEPENDENT DIABETES MELLITUS
Dyslipidemia is very frequent in patients with NIDDM. Different studies indicate that 54%-77% of patients with NIDDM have high or borderline-high total cholesterol.“” About 20% of patients have hypertriglyceridemia or low high-density lipoprotein (HDL) cholesterol.3,4,6 Triglycerides and Very-Low-Density Lipoproteins. Elevated levels of plasma total and very-low-density lipoprotein (VLDL) triglyceride levels are often observed in patients with NIDDM.‘z2 In spite of the correction of hyperglycemia, triglyceride level often remains elevated in these patients. Increased hepatic VLDL triglyceride production and probably also an impaired clearance of VLDL contribute to the development of hypertriglyceridemia.2 Hyperinsulinemia or insulin resistance7 and obesitf apparently are at least in part responsible for increased hepatic VLDL triglyceride production.2 Insulin resistance measured by the euglycemic clamp technique has been shown to be associated with high total and VLDL triglyceride and low HDL cholesterol levels.‘-” The strongest associationof insulin resistance and lipoprotein changes is that with elevated VLDL triglyceride concentration. Total Cholesterol and Low-Density Lipoproteins. Total and LDL cholesterol levels are usually normal or slightly elevated in patients with newly or previously diagnosed NIDDM compared with corresponding control subjects. I,* Improvement of glycemic control has been shown to reduce plasma total and LDL cholesterol levels.2 Elevated VLDL cholesterol concentration in patients with NIDDM may be in part responsible for elevated plasma total cholesterol found in some studies.2 LDL particles often have compositional changes in NIDDM. The most important of these is the predominance of small, dense LDL (pattern B). Prevalence of phenotype B is substantially increased in patients with diabetes.12*13 Furthermore, LDL particles in NIDDM contain more triglycerides than in normoglycemic subjects. lJ Insulin resistance has not been associated with high LDL cholestero19-I1 High-Density Lipoproteins. Plasma HDL cholesterol level is usually decreased in patients with NIDDM compared to gender- and age-matched control subjects2 The reduction of plasma HDL cholesterol level is quite similar in newly diagnosed, untreated patients with NIDDM and in patients with previously diagnosed NIDDM treated with diet, oral drugs, or insulin. A decrease in HDL2 subfraction is responsible for decreased plasma I-IDL cholesterol in these patients. The correlation between glycemic control and plasma HDL cholesterol level has been found to be low or absent.
Triglyceride content of HDL particles is often elevated referring to compositional changes in HDL particles.” DYSLIPIDEMIA AS A RISK FACTOR FOR MACROVASCULAR DISEASE IN PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES MELLITUS The most effective study that has investigated the predictive role of serum cholesterol level as a risk factor for cardiovascular mortality in diabetic patients is the Multiple Risk Factor Intervention Trial.15 This study included 5163 men, aged 35-57 years at baseline examination, who reported taking medication for diabetes, and 342,815 men not taking medication for diabetes. Cardiovascular and CHD mortality rates were approximately threefold in diabetic subjects than in nondiabetic subjects after 12-year follow-up at every level of serum cholesterol. Other longitudinal studies, the Framingham StudyI and the Whitehall Study,17 which have also included women have demonstrated that the predictive value of total cholesterol with respect to the risk of CHD death is similar in diabetic and nondiabetic subjects. In the World Health Organization (WHO) Multinational Studyls and in the Paris Prospective Study” the single risk factor that correlated most closely with the occurrence of CHD in diabetic subjects was plasma total triglyceride concentration. In the 11-year followup of the Paris Prospective Study, plasma triglyceride level was the only factor positively and significantly associated with CHD death in multivariate regression analysis. High cholesterol level increased the risk for CHD particularly in diabetic patients with simultaneously high triglyceride levels. Unfortunately, HDL cholesterol was not measured in this study. We have evaluated the prognostic significance of lipoprotein fractions for the future risk of C,HD in NIDDM patients. 2o Lipids and lipop rotein fractions were determined in 313 NIDDM patients (153 men, 160 women). During the 7-year follow-up high total (>6.2 mmol/L) and LDL cholesterol (>4.1 mmol/L) levels were not associated with an increased risk of future CHD events (CHD death or all CHD events including CHD death or nonfatal myocardial infarction). High levels of total triglycerides (>2.3 mmol/L) increased the risk of CHD death or all CHD events twofold. The most powerful single lipoprotein risk factor for CHD was low HDL cholesterol (CO.9 mmol/ L), which increased the risk of CHD death fourfold and the risk of all CHD events twofold. The simultaneous presence of low HDL cholesterol and high triglycerides did not further increase the risk for CHD. This finding has been confirmed in our own recent study including over 1000 patients with NIDDM. The most important lipoprotein fraction to predict CHD events was low HDL cholesterol, which increased the risk for CHD
1 Dinb Camp 1997; 21:137-142
DYSLIPIDEMIA,
events about twofold independently of other cardiovascular risk factors (Lehto et al., unpublished). It is interesting to note that in the same study population, dyslipidemia had much weaker effect on the risk of stroke*l and amputation.22 Goldschmidt et alz3 followed 66 men and 45 women with diabetes for an average of 16 years in a population-based study in Southern California. Although the number of diabetic subjects in this study was low CHD mortality was associated significantly with low HDL cholesterol and high VLDL cholesterol in women. Low HDL cholesterol and high VLDL cholesterol increased the risk of CHD in diabetic men, but the results were not statistically significant. LDL cholesterol was similar in diabetic and nondiabetic subjects at baseline and its association with the risk of CHD was not reported. The predictive value of lipids and lipoproteins for future CHD events seems to vary between nondiabetic and NIDDM subjects. High total cholesterol increases the risk for CHD similarly in NIDDM patients and in nondiabetic subjects. However, whereas total cholesterol mainly reflects the predictive role of LDL cholesterol in nondiabetic subjects, this relationship seems to be more complex in NIDDM patients. As shown by our follow-up study, 2o the association of total cholesterol with CHD risk was explained by elevated levels of VLDL cholesterol, not be elevated levels of LDL cholesterol. NIDDM is characterized by compositional changes in LDL and VLDL particles, and therefore, the measurement of LDL cholesterol level does not count for these changes. In contrast to total cholesterol, total and VLDL triglycerides seem to be stronger risk factors for CHD in NIDDM patients than in nondiabetic subjects. Besides direct atherogenicity, VLDL particles could be directly atherogenic through inducing the decrease in HDL cholesterol and the increase in small, dense LDL particles. CLINICAL TRIALS ASSESSING THE EFFICACY OF LIPID-LOWERING DRUG TREATMENT ON THE PROGNOSIS OF PATIENTS WITH NIDDM Subgroup Analyses. Although several randomized controlled trials have indicated that a reduction of elevated plasma cholesterol levels decreased the risk for CHD mortality and morbidity in nondiabetic subjects, no similar studies are available at this moment on patients with NIDDM. However, several studies are in progress which will give valuable information in this respect in the forthcoming years. The data available to date are mainly from post-hoc subgroup analyses of diabetic patients participating in large-scale prevention trials. The most important of these are the Helsinki Heart Study and The Scandinavian Simvastatin Survival Study. The Helsinki
Heart Study.
The Helsinki
Heart
Study
MORBIDITY,
AND
MORTALITY
IN NIDDM
139
was designed to investigate the effects of lowering LDL cholesterol and increasing HDL cholesterol with gemfibrozil in men aged 40-55 years.24*25 A total of 4081 men including 135 patients with NIDDM were randomized to receive either gemfibrozil or placebo. Over the 5-year period, gemfibrozil reduced total and LDL cholesterol and particularly total triglycerides and increased the level of HDL cholesterol quite similarly in nondiabetic and diabetic subjects. In gemfibroziltreated diabetic patients the incidence of a major CHD event was 3.4% whereas in placebo-treated diabetic patients the corresponding incidence was (10.5%). The difference between the groups was not statistically significant (p = 0.19) mainly because of the low number of diabetic patients participating in the study. The Scandinavian Simvastatin Survival Study (4s). The 4s Study was designed to investigate the effects of lowering cholesterol with simvastatin on serious CHD events. A total of 4444 participants (3617 men, 827 women) aged 35-70 years at baseline and with a previous myocardial infarction or angina pectoris and elevated plasma cholesterol (5.5-8.0 mmol/L) and total triglycerides less than 2.6 mmol/L were randomized to received simvastatin or placebo for 5 years.26 Altogether 202 diabetic patients (158 men, 44 women) participated in this study. During the follow-up period of 5.4 years, 17.5% of the placebo-treated and 11.4% of the simvastatin-treated diabetic patients died of CHD. The reduction of 36% in the risk of CHD mortality did not, however, reach the limit of statistical significance (p = 0.242).27 In contrast, the incidence of a major CHD event reduced significantly in simvastatin-treated diabetic patients by 55% (p = 0.002). Because the corresponding number in nondiabetic subjects was 32%, the benefit of simvastatin treatment in diabetic patients seems to be as good as in nondiabetic subjects. The Cholesterol And Recurrent Events Study. This study is a secondary prevention trial testing the effects of cholesterol lowering in pravastatin (40 mg daily) or placebo on the occurrence of recurrent CHD events (CHD death plus nonfatal myocardial infarction) during a 5-year follow-up.28 The trial includes over 4000 patients aged 21-75 years who have survived a myocardial infarction and who have total cholesterol <6.2 mmol/L, LDL cholesterol 3.04.5 mmol/L, and total triglycerides ~4.0 mmol/L. Of the patients randomized into the trial, 14% had a history of diabetes. The results of this study should be available soon. The Long-Term Intervention with Pravastatin in lschemic Disease Study. This study is also a secondary prevention trial aiming to test the effect of pravastatin (40 mg daily) or placebo on recurrent CHD events.29 Over 9000 patients with CHD aged 31-75 years and with total cholesterol 4.0-7.0 mmol/L have been randomized in 1990-1992 into two treatment groups. Of the patients
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randomized, 9% have diabetes. The trial has been designed to continue at least 5 years. The Bemfibrate Infarction Prevention Study. This trial investigates the effect of HDL cholesterol elevation and triglyceride reduction with bezafibrate (400 mg daily) or placebo on recurrent CHD events.30 Over 3200 patients, aged 45-74 years and with total cholesterol 4.76.4 mmol/L and HDL cholesterol cl.2 mmol/L have been randomized in 1990-1992 for a median followup of 6.25 years into two treatment groups including a large number of diabetic patients (10%). Trials on Diabetic Patients The DiabetesAtherosclerosislntetvention Trial (DAIS). The DAIS trial is the only study at this moment specifically designed to investigate the effect of hyperlipidemic drug treatment on decreased progression or regression of coronary atherosclerosis in patients with NIDDM.31 The evaluation of the primary end point is based on quantitative angiography. The study population consists of 418 patients with NIDDM (305 men, 113 women) recruited at 11 clinics located in Canada, Finland, France, and Sweden. The patients have a moderate dyslipoproteinemia (LDL cholesterol, 354.5 mmol/ L and triclyceride ~5.2 mmol/L; or triglyceride, 1.7-5.2 mmol/L and LDL cholesterol ~4.5 mmol/L and total cholesterol/HDL cholesterol ratio 24), and they have been randomized to received either fenofibrate (200 mg) or placebo. The recruitment ended in January 1996, and the second coronary angiogram will be performed after 36 months of treatment.
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CONCLUSIONS In addition to hypertension and smoking, total and LDL cholesterol are as powerful risk factors for CHD in NIDDM patients as in nondiabetic subjects. Epidemiologic evidence supports the notion that high total triglycerides and low HDL cholesterol may be even stronger risk factors for CHD in NIDDM patients than in nondiabetic individuals. Compositional changes particularly in LDL particles (small, dense LDL, or increased triglyceride content of LDL particles) could be important determinants of accelerated atherosclerosis in NIDDM patients. no primary or secondary prevention studies are available on NIDDM patients to evaluate whether the correction of dyslipidemia by diet, exercise, or pharmacologic therapy results in the reduction in the risk of atherosclerotic complications. However, a subgroup analysis of the 4s Study indicated that hypercholesterolemic diabetic patients benefit similarly to nondiabetic patients of simvastatin treatment. Several studies are currently carried out which will in forthcoming years give data on the effects of different drugs on the reduction of CHD risk in diabetic patients with dyslipidemia.
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