Hyperlipidemia in Diabetes Mellitus:Pathogenesis, Diagnosis, and Pharmacological Therapy

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1 Clinical Review Hyperlipidemia in Diabetes Mellitus:Pathogenesis, Diagnosis, and Pharmacological Therapy Klaus Johansen, MD From the Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh. Address reprint requests and correspondence to Dr. Johansen: Department of Medicine, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Accepted for publication 21 August Epidemiological studies have clearly shown that in diabetic patients there is a two to three times higher mortality and morbidity resulting from myocardial infarction, stroke, and atherosclerosis of the legs than in the nondiabetic population. Although decreased glucose tolerance per se is associated with macroangiopathy, in recent years increasing attention has been focused on the role of lipoprotein in the pathogenesis of atherosclerosis in diabetic subjects. This report describes changes in lipid and lipoprotein concentration, the diagnostic evaluation, and the management of lipid disorders in diabetic subjects. K Johansen, Hyperlipidemia in Diabetes Mellitus:Pathogenesis, Diagnosis, and Pharmacological Therapy. 1990; 10(2): Long-term diabetes is associated with an increased prevalence of atherosclerosis 1,2 which is the most common complication associated with long-term diabetes in the Western world. The increased cardiovascular morbidity and mortality in diabetes has naturally been related to the high prevalence of hyperlipidemia in the disease. 3-6 Lipoproteins and Lipid Transport Lipoproteins are high-molecular-weight globular particles that transport nonpolar lipids through plasma. Each lipoprotein contains a nonpolar core in which molecules of hydrophobic lipid are packed to form an oil droplet. The core consists of triglycerides and cholesteryl esters in varying proportions. A polar surface coat of phospholipid surrounds the core. The coat stabilizes the lipoprotein particle so that it can remain in solution in plasma. Each lipoprotein particle contains specific proteins, apoproteins, that are particularly exposed at the surface. The apoprotein binds to specific enzymes or transport proteins on cell membranes, thus directing the lipoprotein to its sites of metabolism. There are five major classes of lipoproteins (chylomicrons, very-low-density lipoprotein [VLDL], remnants, low-density lipoprotein [LDL], and high-density lipoprotein [HDL]), which differ in the composition of the nonpolar lipids in the core, in the composition of the apoprotein (A, B, C, E), and in the density, size, and electrophoretic mobility. Triglycerides and cholesterol from food are incorporated into large lipoprotein particles, chylomicrons, in the intestines which pass by means of the lymph system into the general circulation for subsequent transport to the capillaries of adipose tissue and skeletal muscle (Figure 1). Here they are exposed to the lipoprotein lipase and release fatty acids and monoglycerides, which are transported into fat and muscle tissue. These fatty acids are then oxidized or re-esterified to become triglycerides. The triglyceride-depleted and cholesteryester-, apoprotein-b48-, and E-rich chylomicrons, which are now called chylomicron remnants, are taken up by the liver via specific chylomicron remnant receptors. In this way triglyceride has been brought to the fat depots and cholesterol to the

2 liver. Cholesterol is transformed partly to bile acid, partly excreted unchanged in the bile, and partly distributed to extrahepatic tissue. Carbohydrates from food are transformed to fatty acids in the liver, where they are esterified with glycerol to form triglycerides. Triglycerides are incorporated into VLDL and secreted into the blood. VLDL-triglycerides containing apopro-tein-b100, -CII, and -E are hydrolyzed by the lipoprotein lipase and changed to VLDL remnants or intermediate-density lipoprotein (IDL). Because the LDL receptor recognizes both apoprotein-b-100 and -E, a portion of the IDL particles which contains both B100 and E is bound to LDL receptors in the liver and catabolized (the shunt pathway). The remaining IDLs remain in plasma and are further depleted for triglycerides and changed to cholesterol- and apoprotein-b100-rich LDL. Sixty to 80% of LDLs are normally removed from the liver but the rest are removed by extrahepatic tissue. One of the functions of LDLs is to transport cholesterol to peripheral tissue (adrenal cortex, lymphocytes, muscle and kidney cells), which also have LDL receptors. The liberated cholesterol is used for, among other things, the synthesis of membranes and as steroid hormone precursor. Nonesterified cholesterol that is released from peripheral cells is bound to HDL where it is coupled to fatty acids catabolized by lecithin-cholesterol acyltransferase (LCAT). The cholesteryl esters on the surface of HDL are transferred to VLDLs and eventually end up in LDLs. In this way a cycle has been established in which LDLs deliver cholesterol to extrahepatic tissue and cholesterol is then returned from extrahepatic tissue via HDLs. Cholesterol in the blood originates partly from food and partly from de novo synthesis of cholesterol. 3-Hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase is a rate-limiting enzyme in the cholesterol synthesis. Figure 1. Lipid transport and probable site of action of the most common lipid-lowering drugs. 1. Decrease low-density lipoprotein (LDL) synthesis: nicotinic acid and fibrates. 2. Increase high-density lipoprotein (HDL) synthesis: nicotinic acid and fibrates. 3. Stimulate lipoprotein lipase activity: fibrates. 4. Increase LDL-receptor number: bile acid sequestrants, hepatic hydroxymethylglutaryl coenzyme A reductase inhibitors, probucol? 5. Increase fecal bile acid excretion: bile acid sequestrants, probucol. (IDL = intermediate-density lipoproteins; VLDL = very-low-density lipoproteins; LCAT = lecithin-cholesterol acyltransferase.)

3 Diabetes and Hyperlipidemia One of insulin's many functions is to coordinate the conversion of carbohydrate in food to stored energy (triglycerides) in fat. 7 VLDL and chylomicrons, which transport endogenous and exogenous triglycerides, are broken down by lipoprotein lipases. In insulin deficiency, the activity of the lipoprotein lipases is decreased, 8 and this is one of the most common causes of hyperlipidemia in poorly controlled diabetes. 9 Investigations in diabetic animals seem to indicate that the production of VLDL-triglycerides in the gut is also controlled by insulin because insulin-deficient animals have increased production from the gut of VLDL-triglycerides The hepatic triglyceride lipase is also insulin sensitive and is therefore also of importance for the lipoprotein abnormalities in diabetes mellitus. 13 During the action of lipoprotein lipases in fat tissue, the chylomicrons and VLDLs lose their triglycerides. These so-called chylomicron and VLDL remnants contain apoprotein E, which is mainly responsible for the LDL-receptor-mediated uptake by the liver. It is still not known how insulin influences the receptor's activity. It also still has not been determined whether insulin stimulates the VLDL triglyceride secretion from the liver directly. The most plausible explanation is based on the premise that the elevated plasma nonesterified fatty acid (NEFA) concentration, even at normal insulin levels, results in an increased hepatic VLDL-triglyceride secretion concomitant with elevated plasma triglyceride concentrations. 14 The esterified cholesterol that appears in cholesterol-rich lipoproteins LDL and IDL (i.e., VLDL remnants) arises from free cholesterol uptake by HDL from peripheral cells followed by esterification through LCAT. This peripheral cholesterol removal may be impaired by the lack of insulin. 15 Investigations done on human skin fibroblasts seem to indicate that LDL receptor activity is increased by insulin. 16 It should also be mentioned that insulin helps to balance the apoprotein composition of lipoproteins involved in enzymatic activation (e.g., apoprotein A1/A2 and apoprotein C2/C3 ratio) and receptor-mediated uptake of lipoproteins (apoprotein B and E contents). 17,18 Changes in Plasma Lipoprotein Concentration in Patients with Insulin-Dependent Diabetes Mellitus Insulin-dependent diabetes mellitus (IDDM) is characterized by absolute insulin deficiency. The deficiency results in hyperglycemia and eventually ketoacidosis and pronounced hypertriglyceridemia mainly because of insufficient activation of the lipoprotein lipase system. 19 Elimination of VLDL and chylomicrons is decreased, and especially in ketoacidosis, there is a marked increase in triglyceride-rich lipoproteins. An excess NEFA concentration resulting from increased lipolysis in fat tissue in insulin-deficient diabetes contributes to the increased hepatic triglyceride synthesis and secretion. VLDL, LDL, and HDL triglyceride contents are all increased in poorly controlled IDDM. An elevated triglyceride content in VLDL and LDL is due to the accumulation of triglycerides in these particles, but the cause of the elevated HDL triglyceride content is the result of an exchange of cholesteryl esters for triglycerides that takes place among HDLs, VLDLs, and LDLs. Insulin deficiency causes an increase in the LDL-cholesterol concentration because of decreased receptor binding, and also partly as a consequence of nonenzymatic glycation of LDL and partly because of an increased cholesterol/apoprotein B ratio in LDL in IDDM. In patients with well-controlled IDDM, the total cholesterol, total triglycerides, and LDL-cholesterol concentrations do not differ from those of non-diabetic controls. 20 IDDM patients with coronary heart disease do, however, have significantly higher levels of total triglyceride, LDL-cholesterol, and VLDL-triglyceride and lower levels of HDL-cholesterol than do IDDM patients who do not have coronary artery disease. 21 The changes in the lipoprotein composition in patients with IDDM are thus dependent on the degree of glycemic control. In conclusion, in poorly controlled diabetes, VLDL, LDL, and HDL become triglyceride-rich and there is an overproduction of VLDL and LDL and decreased removal of VLDL remnants. There is a decreased cholesterol/apoprotein B ratio in LDLs and the receptor binding of these changed LDL particles is decreased. In patients with well-controlled IDDM, the single alteration may be a slightly elevated HDL-cholesterol level due to high concentration of peripheral insulin, causing high lipoprotein lipase activity. Changes in Plasma Lipoprotein Concentration in Patients with Non-Insulin-Dependent Diabetes Mellitus Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a high insulin concentration in the portal vein. This hepatic hyperin-sulinemia leads to overproduction of VLDLs and triglycerides, but the relative insulin deficiency due to insulin resistance in the periphery results in decreased catabolism of triglyceride-rich lipoprotein because of decreased lipoprotein lipase activity 22 and to an increase in the concentration of NEFA because of increased lipase activity in the fat cells. It is also possible that the particle composition of VLDL is altered as well. Increases in the proportions of apoproteins C and E compared to other components of VLDL in NIDDM have been

4 demonstrated that could lead to inhibited or delayed uptake in the liver. Generally, nearly normal LDL levels have been shown in NIDDM despite a decreased fractional catabolic rate of apoprotein B in LDLs. Large and triglyceride-rich VLDL particles especially exist in marked hyperglycemia, but the conversion to LDL is diminished. This may explain why LDL concentrations are normal or even reduced in NIDDM patients. The alterations in lipid composition and the glycation of LDL are the main causes of decreased receptor binding in NIDDM. 23 The causes of the low HDL cholesterol levels in patients with NIDDM are yet undiscovered. 22,24 This decreased level of HDL may be indicative of an atherogenic factor but may also be the result of a demonstrated increase in hepatic lipase activity (antiatherogenic action). There is no doubt that poorly controlled diabetes in patients with both IDDM and NIDDM is associated with atherogenic lipoprotein profiles in the blood. The management of the diabetes should therefore aim at regulating the blood glucose level as well as lipid concentrations. Whether the peripheral hyperinsulinism, which certainly persists for many hours per day in well-controlled patients, contributes additionally to the pathogenesis of atherosclerosis is as yet an unsettled question. 25 A review of the lipoprotein changes in diabetes mellitus has recently been published. 26 Diagnosis of Hyperlipidemias in Diabetes An accurate diagnosis of lipid disorders is essential to establish appropriate therapy (Figure 2). Various factors influence the serum concentration of lipids and lipoproteins, thus the measurement should be made under wellcontrolled conditions. Patients should be on a regular diet, not on medication that could affect lipid metabolism, have stable weight, and should not be, or have recently been, acutely ill. Diagnosis should include a comprehensive personal and family history and a complete physical examination that assesses for arcus cornea, eruptive cutaneous and tendinous xanthomas, xanthelasma, lipemia retinalis, and premature atherosclerosis. Plasma cholesterol, triglycerides, and HDL-cholesterol levels should be measured after a 12- to 14-hour overnight fast. This requirement is mainly related to the measurement of triglycerides since triglyceride concentrations vary widely throughout the day depending on food intake. It is necessary to exclude all forms of secondary hyperlipidemia, especially hypothyroidism, nephrosis, and renal insufficiency. The classification of the lipid/lipoprotein disorders in diabetes mellitus is based on the fraction of lipids that are altered, as shown in Table 1. Endogenous hypertriglyceridemia and combined hyperlipidemia are each seen in about one fourth, hypercholesterolemia in about one fifth, and chylomicronemia syndrome in about one sixth of diabetic patients with hyperlipidemia. Figure 2. The diagnostic decision process in lipid disorders in diabetes mellitus. (Adapted from reference 33.) (TG = triglycerides; HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL = very-low-density lipoprotein; HLP = hyperlipoproteinemia.)

5 Table 1. Types of lipid/lipoprotein disorders in diabetes mellitus. Lipid disorder Lipoprotein abnormality Chylomicronemia syndrome Endogenous hypertriglyceridemia Combined hyperlipidemia Dysbetalipoproteinemia Hypercholesterolemia Hypoalphalipoproteinemia Raised VLDL and chylo; lowered HDL Raised VLDL; lowered HDL Raised VLDL and LDL Raised chylo and VLDL- remnants Raised LDL Lowered HDL VLDL = very-low-density lipoprotein; Chylo = chylomicron; HDL = high-density lipoprotein; LDL = low-density lipoprotein. Treatment of Hyperlipidemias in Diabetics with Drugs The results of the Lipid Research Clinic investigation 27 showed unequivocally that lowering of the high LDLcholesterol concentration leads to a decreased incidence of coronary artery disease. This finding was further supported by a study that showed a significant reduced mortality in patients with heart disease treated with nicotinic acid (niacin). 28 Elevated plasma lipid levels may be found in 25 to 50% of diabetic patients. 29 There are two main objects to reducing plasma lipid levels, both in diabetic and nondiabetic subjects, namely to avoid the occurrence of acute abdominal pain and pancreatitis because of severe hypertriglyceridemia, and to try to prevent, stop, or reverse atherosclerosis. Therapy for diabetic patients aims at the normalization of lipid and lipoprotein levels, the establishment of adequate glucose hemostasis, and the prevention or treatment of other factors that may contribute to acceleration of atherosclerosis or to pancreatitis. To attain the first goal, the normal level for lipid and lipoprotein must be precisely defined (Table 2). A LDL/HDL ratio of more than 4 or a total-cholesterol/hdl ratio of more than 4.5 is considered atherogenic. When the total triglyceride level is below 5 mmol/l, LDL-cholesterol can be calculated from the Friedewald equation: LDL = total cholesterol (HDL-cholesterol + triglycerides/2.19). The initial treatment is dietary management for at least three months before drug therapy is started. The principle of diet management of hyperlipidemia is out of the scope of this paper and will not be discussed. In the case of familial hypercholesterolemia with a cholesterol concentration over 10.4 mmol/l, the drug treatment can be started at the same time as the diet. Because dyslipoproteinemia responds well to pharmacological therapy and most cases will require drug therapy, drug and diet treatment may be initiated simultaneously. The flow chart in Figure 3 shows the decision process to follow in establishing drug therapy. NIH Consensus* Cholesterol Table 2. Guidelines for lipid and lipoprotein levels. Under 30 years of age Over 40 years of age < 4.6 mmol/l < 5.3 mmol/l Study Group of the European Atherosclerosis Society Cholesterol Triglyceride High-density lipoprotein < 5.2 mmol/l < 2.3 mmol/l > 0.9 mmol/l *National Institutes of Health Consensus Conference. Lowering blood cholesterol to prevent heart disease. JATMA 1985; 253: Study group of the European Atherosclerosis Society. Strategies for the prevention of coronary heart disease: A policy statement of the European Atherosclerosis Society. Eur Heart J 1987;8: Table 3 lists the lipid-lowering drugs and their method of action. Table 4 shows the first and second choices in pharmacological therapy. For further description of the different drugs, pharmacology, and dosages, pharmacological textbooks should be consulted. In cases of severe hypolipidemia, it is often necessary to combine hypolipidemic drugs. Almost all first-choice drugs (Table 4) can be combined. The combination of cholestyramine or cholestipol with niacin is very effective in lowering LDL-cholesterol. The combination of niacin and fibrate is useful in the event of severe hypertriglyceridemia. Probucol or fibrates are used together in the treatment of mild combined hyper-lipidemia. The usual first choice of drug for the treatment of hypercholesterolemia is not always ideal for diabetics, however. Bile

6 acid sequestrants can accentuate hypertriglyceridemia and niacin can decrease the glucose tolerance. HMG CoA reductase inhibitors decrease cholesterol synthesis and increase LDL receptor synthesis in the liver, resulting in increased removal of LDL-cholesterol and VLDL remnants from the circulation and in a significant decrease (compared with placebo) in total cholesterol (26%), LDL-cholesterol (28%), triglyceride (31%), and VLDL-triglyceride (42%) concentrations in the blood of patients with NIDDM and mild to moderate hypercholesterolemia. No change in the HDL-cholesterol concentration is noticed in these patients. 30 Bezafibrate is perhaps an even more ideal drug for diabetics with hyperlipoproteinemia because, in addition to increasing the HDL-cholesterol content (15%) and lowering the total cholesterol (17%) and triglyceride (36%) levels, bezafibrate also lowers fasting blood glucose (1 mmol/l) (31%) and glycated hemoglobin (hemoglobin A 1 ). 31,32 Figure 3. Flow chart showing the decision process for determining therapy in lipid disorders in diabetes mellitus. (Adapted from reference 33.) Diuretics increase triglyceride and LDL-choles-terol concentrations and lower HDL-cholesterol levels. The alpha blocker prazosin increases the concentration of HDL. The angiotensin converting enzyme inhibitor Captopril does not have any atherogenic effect on the lipid metabolism. Enzyme inductors such as barbiturates, Phenytoin, and alcohol tend to increase the HDL-cholesterol concentration. Two review papers on the pharmacological treatment of lipid disturbances in diabetes mellitus have recently been published. 33,34

7 Table 3. Effects of hypolipidemic drugs on lipids and lipoproteins. Effects Inhibitors of bile acid absorption: Cholestyramine, colestipol, neomycin Increase fecal bile acid excretion, increase LDL-receptor synthesis, inhibits cholesterol absorption from gut Results Decreased cholesterol, increasing LDL-receptors Antilipolytics: Niacin (nicotinic acid) Inhibits lipolysis in fat tissue Decreased cholesterol, triglycerides, and VLDL; increased HDL Fibrates: Clofibrate, bezafibrate, gemfibrozil, fenofibrate, ciprofibrate Probucol HMG-CoA reductase inhibitors: Mevastatin, lovastatin, simvastin Increase lipoprotein lipase activity, inhibit HMG-CoA reductase (?) Increase fecal bile acid excretion, inhibit hepatic cholesterol synthesis and apoprotein B synthesis Inhibit cholesterol synthesis in liver, increase LDL-receptor synthesis Decreased triglycerides and VLDL Decreased LDL-cholesterol and VLDL Decreased LDL-cholesterol and VLDL LDL = low-density lipoproteins; VLDL = very-low-density lipoproteins; HDL = high-density lipoproteins; HMG-CoA = 3-hydroxy-3-methylglutanyl-coenzyme A. Table 4. Drugs used in the treatment of lipid/lipoprotein disorders in diabetes mellitus. Pharmacologic therapy Lipid disorder 1st choice 2nd choice Chylomicronemia syndrome Gemfibrozil Niacin, Clofibrate bezafibrate Endogenous hypertriglyceridemia Gemfibrozil Niacin, Clofibrate bezafibrate Combined hyperlipidemia HMG-CoA Probucol reductase inhibitors, niacin, gemfibrozil, colestipol, cholestyramine Dysbetalipoproteinemia HMG-CoA reductase inhibitors, Clofibrate, bezafibrate Gemfibrozil, niacin Hypercholesterolemia HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A. HMG-CoA reductase inhibitors, colestipol, cholestyramine, niacin Probucol Conclusion The first step in the treatment of hyperlipidemia in diabetics is control of blood glucose. Dietary control of both hyperglycemia and hyperlipidemia should precede the treatment using antidiabetic and hypolipidemic drugs. Weight loss, exercise, and avoidance of excessive alcohol intake, as well as discontinuation of drugs known to increase the plasma lipid concentration, are necessary. Hypolipidemic drugs should only be used when satisfactory results are not obtained through optimal diet. Optimal treatment with antidiabetic agents precedes treatment with hypolipidemic drugs. References 1. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetes in the Framingham population. Diabetes 1974;23: Ganda OP. Pathogenesis of macrovascular disease in the human diabetic. Diabetes 1980;29:

8 3. Sorge F, Swartkopff W, Neuhaus GA. Insulin response to oral glucose in patients with previous myocardial infarction and in patients with peripheral vascular disease: hyperinsulinemia and its relationship to hypertriglyceridemia and overweight. Diabetes 1976;25: Bierman EL, Brunzell JD. Interrelation of atherosclerosis, abnormal lipid metabolism, and diabetes mellitus. In: Ktzen HM, Mahler I, eds. Advances in modern nutrition, Vol. 7. New York: Wiley, 1978: Bierman EL, Amaral AP, Belknap BH. Hyperlipidemia and diabetes mellitus. Diabetes 1966;15: Howard BV, Savage PJ, Bennion LJ, Bennett PH. Lipoprotein composition in diabetes mellitus. Atherosclerosis 1978;30: Gibbons GF. Hyperlipidemia of diabetes. Clin Sci 1986;71: Taskinen M-R, Nikkila EA, Kunsi T, Harno K. Lipoprotein lipase activity and serum lipoproteins in untreated type 2 (insulinindependent) diabetes associated with obesity. Diabetologia 1982;22: Bagdade JD, Porte D, Bierman EL. Diabetic lipemia: a form of acquired fat-induced lipemia. N Engl J Med 1967;276: Risser TR, Reaven GM, Reaven EP. Intestinal very low density lipoprotein secretion in insulin deficient rats. Diabetes 1978;27: Steiner GS, Poapst M, Davidson JK. Production of chylomicron-like lipoproteins from endogenous lipid by intestine and liver in diabetic dogs. Diabetes 1975;24: Popper DA, Shian Y-F, Reed M. Role of small intestine in pathogenesis of hyperlipidemia in diabetic rats. Am J Physiol 1985;249:G Howard BV. Lipoprotein metabolism in diabetes mellitus. J Lipid Res 1987;28: Reaven GM. Non-insulin-dependent diabetes mellitus, abnormal lipoprotein metabolism, and atherosclerosis. Metabolism 1987;36: Fielding CJ, Reaven GM, Liu G, Fielding PE. Increased free cholesterol in plasma low and very low density lipo- proteins in non-insulin-dependent diabetes mellitus: its role in the inhibition of cholesteryl ester transfer. Proc Natl Acad Sci USA 1984;81: Hiramatsu K, Bierman EL, Chait A. Metabolism of low density lipoproteins from patients with diabetic hypertriglyceridemia by cultured human skin fibroblasts. Diabetes 1985;34: Briones ER, Mao SJT, Palumbo PJ, et al. Analysis of plasma lipids and apolipoproteins in insulin-dependent and non-insulindependent diabetics. Metabolism 1984;33: Weisweiler P, Schwandt P. Type 1 (insulin-dependent) versus Type 2 (non-insulin-dependent) diabetes mellitus: characterization of serum lipoprotein alterations. Eur J Clin Invest 1987;17: Nikkila EA, Huttunen JK, Ehnholm C. Postheparin plasma lipoprotein lipase and hepatic lipase in diabetes mellitus. Diabetes 1977;26: Nikkila EA, Hormila P. Serum lipids and lipoproteins in insulin-treated diabetics: demonstration of increased high density lipoprotein concentrations. Diabetes 1978;27: Laakso M, Pyorala K, Sarlund H, Voutilainen E. Lipid and lipoprotein abnormalities associated with coronary heart disease in patients with insulin-dependent diabetes mellitus. Arteriosclerosis 1986;6: Nikkila EA. Are plasma lipoproteins responsible for excess atherosclerosis in diabetes? Acta Endocrinol [Suppl] (Copenh) 1985;110(272): Kesaniemi YA, Witztum JL, Steinbrecher UP. Receptor-mediated metabolism of low density lipoproteins in man: quantitation using glucosylated low density lipoprotein. J Clin Invest 1983;71: Barrett-Connor E, Witztum J, Hodbrook M. A community study of high density lipoproteins in adult non-insulin-dependent diabetes. Am J Epidemiol 1983;117: Jarret RJ. Is insulin atherogenic? Diabetologia 1988;31: Kostner GM, Karadi I. Lipoprotein alterations in diabetes mellitus. Diabetologia 1988;31: National Institutes of Health Consensus Conference: lowering blood cholesterol to prevent heart disease. JAMA 1985;253: Canner PL. Mortality in coronary drug project patients during a nine-year posttreatment period. J Am Coll Cardiol

9 1985;5: Goldberg RB. Lipid disorders in diabetes. Diabetes Care 1981;4: Garg A, Grundy SM. Lovastatin for lowering cholesterol levels in non-insulin-dependent diabetes mellitus. N Engl J Med 1988;318: Ruth E, Vollmar J. Verbesserung des Diabeteseinstellung unter de Therapie mit Bezafibrat. Dtsch Med Wochensch 1982;107: Bruneder H, Klein HJ. Hyperlipoprotein und diabetes mellitus: Langzeitbehandlung mit Bezafibrat bei 115 patienten. Welt 1984;35: Lopes-Virella MF, Colwell JA. Pharmacological treatment of lipid disorders in diabetes mellitus. Diabetes/Metabolism Rev 1987;3: Fears R. Mode of action of lipid-lowering drugs. In: Shephard J, ed. Baillieres clinical endocrinology and metabolism. London: Bailliere Tindall, 1987;1: