SPECIAL ARTICLE
Abhimanyu Garg, MBBS, MD Scott M. Crundy, MD, PhD
Management of Dyslipidemia in NIDDM
Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy From the Center for Human Nutrition and the Departments of Clinical Nutrition, Internal Medicine, and Biochemistry, University of Texas Southwestern Medical Center at Dallas; and the Veterans Administration Medical Center, Dallas, Texas. Address correspondence and reprint requests to Scott M. Grundy, MD, PhD, Director, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9052. Received for publication 29 June 1989 and accepted in revised form 20 September 1989.
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990
may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia. Diabetes Care 13:153-69, 1990
P
atients with non-insulin-dependent diabetes mellitus (NIDDM) commonly have dyslipidemia that may contribute to accelerated coronary atherosclerosis, the leading cause of death among NIDDM patients (1). Lipoprotein abnormalities in NIDDM patients involve all classes of lipoproteins and may consist of chylomicronemia, high levels of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL) (2). In some patients with NIDDM, dyslipidemia is secondary to derangement in intermediary metabolism caused by insulin deficiency and insulin resistance; in these patients, improved control of hyperglycemia will mitigate the dyslipidemia. Unfortunately, complete reversal of deranged metabolism is rarely possible in NIDDM patients. Consequently, some degree of dyslipidemia usually persists despite good glycemic control (3). Some diabetic patients will have concomitant genetic hyperlipidemia; in these patients, diabetes mellitus worsens the dyslipidemia, but correction of hyperglycemia will not normalize lipid levels (4). Frequently, in practice, it
153
MANAGEMENT OF DYSLIPIDEMIA IN NIDDM
is not possible to determine with certainty the contributions of diabetes and genetics to elevated serum lipids.
TABLE 2 Prevalence (%) of dyslipidemia in non-insulin-dependent diabetes mellitus (NIDDM): Diabetes Intervention Study, German Democratic Repulic
PREVALENCE OF DYSLIPIDEMIA The prevalence of dyslipidemia in NIDDM patients undoubtedly varies among different populations. The World Health Organization multinational study of vascular disease in diabetic subjects revealed a high frequency of both hypercholesterolemia and hypertriglyceridemia among adult diabetic individuals from many countries (5,6; Table 1). The Diabetes Intervention Study found a twofold increase in hyperlipidemia in men and women with NIDDM compared with the general population of Dresden, GDR (Table 2; 7). Likewise, the Framingham Heart Study noted that hypertriglyceridemia and reduced levels of HDL cholesterol (HDL-chol) were increased twofold in adult diabetic patients compared with nondiabetic subjects of both sexes (Table 3; 8). The Prospective Cardiovascular Munster Study (9) further confirmed a two- to threefold increase in prevalence of hypertriglyceridemia, mixed hyperlipidemia, and low levels of HDL-chol in middle-aged subjects with NIDDM. According to the National Cholesterol Education Program (NCEP; 10), people should receive medical supervision to lower serum cholesterol if they have an LDL-chol level constantly >4.1 mM or a level ranging from 3.4 to 4.1 mM in the presence of coronary heart disease (CHD) or two other CHD risk factors (Table 4). Stern et al. (11) recently assessed the frequency at which NIDDM patients and nondiabetic individuals fall into one of these two risk categories. Among 460 NIDDM patients, 43.5% qualified for active medical management on the basis of high LDL-chol levels and other risk factors, whereas only 23.1% of 4666 nondiabetic subjects were so qualified. An additional 22.8% of patients with NIDDM had serum triglyceride levels >2.8 mM and/or HDL-chol 6.72 4.65-6.70 7.76 mM) Mixed hyperlipoproteinemia Total
LIPOPROTEIN ABNORMALITIES The most common lipid abnormality of NIDDM is elevated serum triglycerides (12-16). High levels of serum triglycerides occur mainly in VLDL and can result from two abnormalities. First, patients with NIDDM overproduce triglyceride-rich VLDL, and this response probably results from increased serum levels of free fatty acids and glucose (17-19). In many patients, overproduction of VLDL results partly from obesity and insulin resistance, but a decrease in insulin secretion in NIDDM may further enhance synthesis of VLDL triglycerides (20). A second cause of hypertriglyceridemia is retarded lipolysis of VLDL triglycerides, most likely due to reduced lipoprotein lipase activity (15). If the latter becomes severe due to marked insulin deficiency, patients can develop chylomicronemia in addition to elevated VLDL (type V hyperlipoproteinemia), and such patients are at high risk for acute pancreatitis (21,22). Beyond high concentrations of VLDL, which include VLDL remnants or Svedberg flotation constant Sf 20-100 lipoproteins, VLDL particles of diabetic patients contain excess unesterified cholesterol; the latter may interfere with reverse cholesterol transport and perhaps even make VLDL more prone to uptake by arterial wall macrophages (23,24). In some diabetic patients, the presence of homozygosity for apolipoprotein E2 (apoE2) may predispose them to development of dysbetalipoproteinemia. Patients with NIDDM often do not manifest high LDLchol concentrations compared with nondiabetic subjects of the same population, but many will have an increase in LDL-apoB levels, similar to that of other hypertriglyceridemic states (25,26). Kissebah et al. (27) reported that patients with NIDDM frequently have high turnover rates for LDL-apoB, due to either overproduction of apoB-containing lipoproteins or to increased conversion of VLDL to LDL. This increased input of LDL may raise LDL-chol levels, but even when they are not elevated, LDL-apoB concentrations can be increased (hyperapobetalipoproteinemia). Furthermore, LDL particles frequently are abnormal in NIDDM patients; many particles are small and dense, but the overall LDL frac-
DIABETES CARE, V O L . 13, N O . 2, FEBRUARY
1990
A. GARG AND S.M. GRUNDY
TABLE 3 Prevalence (%) of dyslipidemia in adult patients with diabetes mellitus (DM): Framingham heart study Women
Men
Total cholesterol (mM) Triglycerides (mM) Very-low-density lipoprotein cholesterol (mM) Low-density lipoprotein cholesterol (mM) High-density lipoprotein cholesterol (mM)
LRC cutoff value*
Normal (n = 1074)
DM (n = 130)
LRC cutoff value*
Normal (n = 1449)
DM (n - 135)
>6.72 >2.65
14 9
13 19t
>7.11 >2.26
21 8
24
>1.03
26
34t
>0.91
31
38
>4.91
11
9
>4.91
16
15
Abhimanyu Garg, MBBS, MD Scott M. Crundy, MD, PhD
Management of Dyslipidemia in NIDDM
Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy From the Center for Human Nutrition and the Departments of Clinical Nutrition, Internal Medicine, and Biochemistry, University of Texas Southwestern Medical Center at Dallas; and the Veterans Administration Medical Center, Dallas, Texas. Address correspondence and reprint requests to Scott M. Grundy, MD, PhD, Director, Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75235-9052. Received for publication 29 June 1989 and accepted in revised form 20 September 1989.
DIABETES CARE, VOL. 13, N O . 2, FEBRUARY 1990
may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia. Diabetes Care 13:153-69, 1990
P
atients with non-insulin-dependent diabetes mellitus (NIDDM) commonly have dyslipidemia that may contribute to accelerated coronary atherosclerosis, the leading cause of death among NIDDM patients (1). Lipoprotein abnormalities in NIDDM patients involve all classes of lipoproteins and may consist of chylomicronemia, high levels of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL) (2). In some patients with NIDDM, dyslipidemia is secondary to derangement in intermediary metabolism caused by insulin deficiency and insulin resistance; in these patients, improved control of hyperglycemia will mitigate the dyslipidemia. Unfortunately, complete reversal of deranged metabolism is rarely possible in NIDDM patients. Consequently, some degree of dyslipidemia usually persists despite good glycemic control (3). Some diabetic patients will have concomitant genetic hyperlipidemia; in these patients, diabetes mellitus worsens the dyslipidemia, but correction of hyperglycemia will not normalize lipid levels (4). Frequently, in practice, it
153
MANAGEMENT OF DYSLIPIDEMIA IN NIDDM
is not possible to determine with certainty the contributions of diabetes and genetics to elevated serum lipids.
TABLE 2 Prevalence (%) of dyslipidemia in non-insulin-dependent diabetes mellitus (NIDDM): Diabetes Intervention Study, German Democratic Repulic
PREVALENCE OF DYSLIPIDEMIA The prevalence of dyslipidemia in NIDDM patients undoubtedly varies among different populations. The World Health Organization multinational study of vascular disease in diabetic subjects revealed a high frequency of both hypercholesterolemia and hypertriglyceridemia among adult diabetic individuals from many countries (5,6; Table 1). The Diabetes Intervention Study found a twofold increase in hyperlipidemia in men and women with NIDDM compared with the general population of Dresden, GDR (Table 2; 7). Likewise, the Framingham Heart Study noted that hypertriglyceridemia and reduced levels of HDL cholesterol (HDL-chol) were increased twofold in adult diabetic patients compared with nondiabetic subjects of both sexes (Table 3; 8). The Prospective Cardiovascular Munster Study (9) further confirmed a two- to threefold increase in prevalence of hypertriglyceridemia, mixed hyperlipidemia, and low levels of HDL-chol in middle-aged subjects with NIDDM. According to the National Cholesterol Education Program (NCEP; 10), people should receive medical supervision to lower serum cholesterol if they have an LDL-chol level constantly >4.1 mM or a level ranging from 3.4 to 4.1 mM in the presence of coronary heart disease (CHD) or two other CHD risk factors (Table 4). Stern et al. (11) recently assessed the frequency at which NIDDM patients and nondiabetic individuals fall into one of these two risk categories. Among 460 NIDDM patients, 43.5% qualified for active medical management on the basis of high LDL-chol levels and other risk factors, whereas only 23.1% of 4666 nondiabetic subjects were so qualified. An additional 22.8% of patients with NIDDM had serum triglyceride levels >2.8 mM and/or HDL-chol 6.72 4.65-6.70 7.76 mM) Mixed hyperlipoproteinemia Total
LIPOPROTEIN ABNORMALITIES The most common lipid abnormality of NIDDM is elevated serum triglycerides (12-16). High levels of serum triglycerides occur mainly in VLDL and can result from two abnormalities. First, patients with NIDDM overproduce triglyceride-rich VLDL, and this response probably results from increased serum levels of free fatty acids and glucose (17-19). In many patients, overproduction of VLDL results partly from obesity and insulin resistance, but a decrease in insulin secretion in NIDDM may further enhance synthesis of VLDL triglycerides (20). A second cause of hypertriglyceridemia is retarded lipolysis of VLDL triglycerides, most likely due to reduced lipoprotein lipase activity (15). If the latter becomes severe due to marked insulin deficiency, patients can develop chylomicronemia in addition to elevated VLDL (type V hyperlipoproteinemia), and such patients are at high risk for acute pancreatitis (21,22). Beyond high concentrations of VLDL, which include VLDL remnants or Svedberg flotation constant Sf 20-100 lipoproteins, VLDL particles of diabetic patients contain excess unesterified cholesterol; the latter may interfere with reverse cholesterol transport and perhaps even make VLDL more prone to uptake by arterial wall macrophages (23,24). In some diabetic patients, the presence of homozygosity for apolipoprotein E2 (apoE2) may predispose them to development of dysbetalipoproteinemia. Patients with NIDDM often do not manifest high LDLchol concentrations compared with nondiabetic subjects of the same population, but many will have an increase in LDL-apoB levels, similar to that of other hypertriglyceridemic states (25,26). Kissebah et al. (27) reported that patients with NIDDM frequently have high turnover rates for LDL-apoB, due to either overproduction of apoB-containing lipoproteins or to increased conversion of VLDL to LDL. This increased input of LDL may raise LDL-chol levels, but even when they are not elevated, LDL-apoB concentrations can be increased (hyperapobetalipoproteinemia). Furthermore, LDL particles frequently are abnormal in NIDDM patients; many particles are small and dense, but the overall LDL frac-
DIABETES CARE, V O L . 13, N O . 2, FEBRUARY
1990
A. GARG AND S.M. GRUNDY
TABLE 3 Prevalence (%) of dyslipidemia in adult patients with diabetes mellitus (DM): Framingham heart study Women
Men
Total cholesterol (mM) Triglycerides (mM) Very-low-density lipoprotein cholesterol (mM) Low-density lipoprotein cholesterol (mM) High-density lipoprotein cholesterol (mM)
LRC cutoff value*
Normal (n = 1074)
DM (n = 130)
LRC cutoff value*
Normal (n = 1449)
DM (n - 135)
>6.72 >2.65
14 9
13 19t
>7.11 >2.26
21 8
24
>1.03
26
34t
>0.91
31
38
>4.91
11
9
>4.91
16
15
