CLINICAL DIABETES
VOL. 14 NO. 5 SEPTEMBER/OCTOBER 1996

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PRACTICAL POINTERS

Liproprotein Disorders in Diabetes Mellitus

Morbidity and mortality in diabetes mellitus to a large degree stems from macrovascular diseases, especially coronary artery disease (CAD). The risk of CAD for people with diabetes is two- to fivefold higher, compared to people without diabetes. The occurrence of concomitant cardiac risk factors in addition to diabetes itself tends to be common in diabetes mellitus. Obesity and hypertension are 2-3 times more prevalent, and even smoking is somewhat more prevalent in the younger diabetic population.₁

Dyslipidemic phenotypes characterized by elevated triglyceride, low high-density lipoprotein (HDL) cholesterol, and alterations of low-density lipoprotein (LDL) phenotypes have a two- to threefold greater incidence in type II diabetes. This dyslipidemia may confer much of the accelerated and increased early cardiovascular disease of diabetes.

The frequency of hypercholesterolemia, and especially LDL hyperlipoproteinemia, is in most surveys equal or slightly higher in patients with diabetes. However, qualitative abnormalities of the LDL cholesterol particles, which have been characterized in the past decade, are much more common in diabetes. Thus, comparable LDL cholesterol levels are more atherogenic and may contribute to a much lower LDL cholesterol risk level in diabetes.

Alterations in LDL include more dense smaller particles, glycosylated particles, and oxidized and desialiated particles. These biochemical alterations of LDL particles increase the affinity of the endothelium towards the lipoprotein and increase its atherogenetic potential in situ after uptake into the vessel wall.²

The prevalence of hypertriglyceridemia and low HDL cholesterol is, on the other hand, much increased in diabetes mellitus, especially when blood glucose control is less than optimal. But it remains two- to threefold more common even with good control of glycemia.

These lipoproteins also exist in qualitatively altered forms in diabetes, potentiating their atherogenic capacities. Triglyceride-rich particles tend to have higher cholesterol content, and triglyceride remnant particles are proportionately increased, augmenting the triglyceride-associated contribution toward CAD. The HDL cholesterol subclass distribution trends toward the HDL² particles and away from the cardioprotective HDL³ particles, thus potentially slowing the reversed cholesterol transport.^3-7

The exact biochemical pathology that leads to these alterations of lipoprotein metabolism and levels in diabetes is not clearly understood, but derangements of lipoprotein lipase, hepatic lipase, and cholesteryl ester transfer protein activities appear to play definite roles. Hyperinsulinemia, insulin resistance, and hyperglycemia also have a role.^5,8

Table 1 shows the therapeutic considerations necessary for the successful management of lipid disorders in diabetes. Managing lipid disorders in diabetes requires knowing when to evaluate lipoprotein profiles. The American Diabetes Association (ADA) recommends testing adult patients annually with a fasting serum cholesterol, triglyceride, HDL cholesterol, and calculated LDL cholesterol. If all values are acceptable (Table 2), less frequent testing may be considered. If total cholesterol and LDL cholesterol are elevated, evaluation for secondary causes is appropriate, especially hypothyroidism or proteinuria. For pediatric patients, testing is performed at diagnosis and annually if any levels are found abnormal. For adult patients with abnormal lipid levels, retesting is tailored to individual findings, both with regards to the lipid abnormality and any underlying disease, as well as other cardiac risk factors.⁹

If no macrovascular disease is present in association with high-risk lipid levels, a 6-month vigorous lifestyle adjustment and attempt to achieve optimal diabetes control should be followed up by retesting. If high-risk levels persist, pharmaceutical intervention is to be considered. If any of the major cardiovascular risk factors are present, borderline lipid levels should be aggressively treated with pharmacologic therapies, as well. When macrovascular disease is present, the goal of lowering LDL cholesterol to 100 mg/dl and reducing triglycerides to 150 mg/dl should be pursued pharmacologically as soon as is feasible.⁹

Triglyceride levels of < 1,000 mg/dl in a person with diabetes calls for immediate intervention to prevent pancreatitis and other features of the associated hyperchylomicronemia.

Lifestyle adjustment for managing lipid disorders in diabetes is generally similar to the recommended nutritional and physical activity guidelines for diabetes itself. This type of intervention is fundamental to achieving control of abnormal metabolic states and should not be reduced, even if pharmaceutical therapy is required. Some limitations may apply to physical activity in certain patients with complications that could potentially be aggravated by exercise. Exercise thus needs to be planned on an individual basis to address not only physical and disease limitations but also patient preferences, costs, and other socioeconomic factors.^10-12

Dietary recommendations include calorie restriction if weight loss is needed; step I American Heart Association diet recommendations,13 followed by step II if necessary; and a carbohydrate intake of 50-60% of total calories. The ADA Exchange Lists11 provides an excellent framework of food choices to obtain these desired weight-loss and fat-reduction goals. Referral to a registered dietitian is recommended for individualization of the diet plan and appropriate nutrition education.

The findings of Reaven and associates of high conversion of cholesterol to lipids in people with diabetes who are on high cholesterol diets is of concern, however, and may indicate that monounsaturated and other unsaturated dietary fats could be more beneficial than charbohydrate diets. Further evaluation is needed, comparing such diets of high charbohydrate vs. high mono and other unstarated fat diets for longer periods, before widespread acceptance of such recommendations can be made.¹⁴

Alcohol consumption in moderation has been reported to raise HDL cholesterol slightly, but practitioners should keep in mind the adverse effects of overconsumption and the fact that most of the increase in HDL cholesterol is not in the cardioprotective HDL3. Insulin resistance has been reported to occur or worsen with alcohol, a fact that could explain the selective increase of HDL2 cholesterol. Alcohol intake will also worsen hypertriglyceridemia and precipitating pancreatitis. In addition, patients must recognize the calorie content of alcohol. For patients who use alcohol, a recommendation of limiting intake to two drinks per day is prudent.^11,15,16

The dyslipidogenia secondary to hyperglycemia is unquestionably of importance to lipid disorders in diabetes. Optimization of diabetes control should therefore be the first step in the approach to elevated triglyceride and cholesterol levels, as well as to low HDL cholesterol levels. In type I diabetes, the levels of lipoproteins may often normalize, although some qualitative abnormalities remain, as nonphysiological excursions of blood glucose and serum insulin are unavoidable. In type II patients, both abnormal levels and abnormal composition of lipoproteins frequently persist despite acceptable diabetes control. Insulin resistance and accompanied hyperinsulinemia may underpin, in part, this residual dyslipidemia, further strengthening the motivation for aggressive exercise and weight reduction in such patients.¹⁷

Insulin is, of course, the only useful agent for controlling type I diabetes. A few studies have suggested that insulin in combination with metformin may have a beneficial effect on cardiac risk factors.¹⁸ The potential clinical effects of such a combination upon insulin requirements, fibrinolysis, blood pressure, and vasotonic status is, however, intriguing, although most of these benefits have been shown in insulin resistant subjects, which excludes most type I patients. The type of insulin used may be important secondary to serum insulin concentrations over time (area under the curve). Thus, faster acting regular and lispro insulins may theoretically be less atherogenic, and are an attractive consideration.^5,19,20

For type II patients, therapeutic options are expanding rapidly. Metformin is a potent anti-diabetic agent with independent lipid-regulating properties, and insulin levels decline with metformin use.^21,22 The newer second generation sulfonylureas, which appear to have insulin-sparing effects, are also useful alone or in combination with metformin in dyslipidemic diabetes patients.²³ The alpha glucosidase inhibitor acarbose further augments our armamentarium as an agent that focuses on postprandial hyperglycemia and insulin levels.^23-26

When hypolipidemic medications are needed in addition to anti-diabetic therapies, fibric acid derivatives (FADs), hydroxymethylglutamyl coenzyme A reductase inhibitors (HMGs), and bile acid sequestrants (BASs) are all effective and well tolerated. The latter two are used for hypercholesterolemic conditions if triglyceride concentration is acceptable. BASs will raise triglycerides in most cases where a triglyceride abnormality exists already, but the statins have only a modest effect on triglyceride levels. Therefore, they are not indicated as first-line therapy if both triglycerides and cholesterol are increased. This may not be entirely true, as much of the data on triglyceride-lowering effects of these compounds comes from studies of primary hypercholesterolemic subjects, and reports of much more potent effects in subjects with type IIB or type IV hyperlipoproteinemias are numerous.

FADs have shown long-term benefits, but their use has been clouded by the increased overall mortality in the World Health Organization-clofibrate study. FADs do, however, remain the drugs of first choice for the low HDL cholesterol-high triglyceride dyslipidemias. In a small diabetic subpopulation, gemfibrozil improved dyslipidemia and CAD events, although not significantly, owing to the small patient sample (n = 135).^9,27-29

Statins have been shown to be of greatest importance in reducing cardiovascular morbidity, both as secondary, and more recently, as primary prevention therapy. These studies have been in hypercholesterolemic patients, with small subgroups of patients with diabetes, who have benefited in subgroup analysis. An example is the Scandinavian Simvastatin Survival Study, in which recurrent CAD was significantly reduced.³⁰

It is clear that in hypercholesterolemia, where LDL cholesterol is the main subfraction of the elevated lipids, HMGs are the first-line therapy in diabetic populations. A new, more potent triglyceride-lowering HMG is soon to be available. It will most certainly play a prominent role in the treatment of diabetic dyslipidemia.^30-32

Nicotinic acid is indicated for mixed dyslipidemias in the general population, but has been given a secondary role in diabetes-related dyslipidemias because of the related loss of diabetic control and supposed increase in insulin resistance experienced with its use. In addition, niacin is difficult to use, because most patients experience some discomfort with it. Although tolerable in most instances, a treatment plan for 2-5 decades that includes daily discomfort does not encourage patients' compliance.³³

Probucol lowers HDL cholesterol, and in the Probucol Quantitative Regression Swedish Trial was found to be ineffective. Other antioxidant therapies, excluding omega 3 fatty acids, still remain controversial but are included in several prevention trials currently under way. Recommendation for their use thus cannot be made.³⁴

A final point regarding diabetic dyslipidemia has to do with the concurrent therapy of hypertension, which afflicts 50-80% of type II patients and many type I patients who have developed microvascular complications. The choice of antihypertensive agents needs to be made with their effects on lipid concentration in mind. Thus, diuretics should be used sparingly and beta blockers probably only after myocardial infarction has occurred.

Calcium channel blockers and ACE inhibitors positively alter lipoproteins, if they affect them at all, and should be first-line therapies for diabetic hypertension with dyslipidemia. The treatment of hypertension per se in diabetes is out of the scope of this article, but it is the authors' belief that ACE inhibitors have a preferable role, substantiated by an enormous body of research and clinical experience.^35,36

Recent evidence has identified a clear role for anti-platelet therapy for both primary and secondary CAD prevention in diabetes. Thrombosis on ruptured plaques are 50-100% more common in diabetic than non-diabetic coronary disease.³⁷

In summary, the prevalence of dyslipidemia in diabetes and its major role in much of diabetes-related mortality requires undivided attention and aggressive therapeutic intervention starting at diagnosis of diabetes and continuing throughout the course of the disease. Many effective pharmaceutical interventions are available for situations in which lifestyle optimization and acceptable glucose control do not control lipoprotein abnormalities.

References

¹Diabetes in America. 2nd edition; National Diabetes Data Group, 1995, Cowie CC, Harris MI, Ch. 7, p. 117-64, NIH Publ., No.95-1468.

²Taskinen MR: Quantitative and qualitative lipoprotein abnormalities in diabetes mellitus. Diabetes 41:12-17, 1992.

³Byrne CD, Wareham NJ, Brown DC, Clark PMS, Cox LJ, Day NE, Palmer CR, Wang TWM, Williams DDR, Hales CN: Hypertriglyceridemia in subjects with normal and abnormal glucose tolerance: relative contributions of insulin secretion, insulin resistance, and suppression of plasma by non-esterized fatty acids. Diabetologia 37:889-96, 1994.

⁴Patsch JR, Miesenbrock G, Hopferweiser T, Mulhberger V, Knapp E, Dunn JK, Gotto AM, Patsch W: Relation of triglyceride metabolism and coronary artery disease. Studies in postprandial state. Arterioschlerosis and Thrombosis 12:1336-45, 1992.

⁵Ducimetre P, Eschwege E, Papoz L, Richard J, Claude G, Rosselin G: Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart mortality in a middle-aged population. Diabetologia 19:205-210, 1980.

⁶Gotto, AM: Hypertriglyceridemia: risks and perspectives. Am J Cardiol 70:19H-25H, 1992.

⁷Musliner TA, Krauss RM: Lipoprotein subspecies and risk of coronary disease. Clin Chem 34:B78-B83, 1988.

⁸Krauss RM: Low-density lipoprotein subclass and risk of coronary artery disease. Current Op Lipidology 2:248-52, 1991.

⁹American Diabetes Association: Consensus statement: Detection and management of lipid disorders in diabetes. Diabetes Care 19(Suppl 1): S96-102, 1996.

¹⁰American Diabetes Association: Position statement: Diabetes mellitus and exercise. Diabetes Care 19(Suppl 1):S30-36, 1996.

¹¹American Diabetes Association: Position statement: Nutritional recommendations and principles for individuals with diabetes mellitus. Diabetes Care 19 (Suppl 1):S16-19, 1996.

¹²NIH Consensus Development Panel on Physical Activity and Cardiovascular Health: Physical activity and cardiovascular health. J Am Med Assoc 276:241-46, 1996.

¹³Vinik A, Wing RR: Nutritional management of the person with diabetes. In Diabetes Mellitus Theory and Practice. Ellenberg & Rifkin, Rifkin H, Porte J Eds., p. 488-91, 1990.

¹⁴Chen YD, Coulston AM, Zhou MY, Hollenbeck CB, Reaven GM: Why do low fat high-carbohydrate diets accentuate postprandial lipemia in patients with NIDDM? Diabetes Care 18:10-16, 1995.

¹⁵Yki-Jarvinen H, Koivisto VA, Ylikahri R, Taskinen MR: Acute effects of ethanol and acetate on glucose kinetics in normal subjects. Am J Physiol 254:E175-180, 1988.

¹⁶Ben G, Gnidi L, Maran A, Gigante A, Duner E, Iori E, Tiengo A, Avogar A: Effects of chronic alcohol intake on carbohydrate and lipid metabolism in subjects with type II (non-insulin-dependent) diabetes. Am J Med 90:70-76, 1991.

¹⁷Davidson, MB: Clinical implications of insulin resistance syndromes. Am J Med 99:420-26, 1995.

¹⁸Bailey CJ: Biguanides and NIDDM. Diabetes Care 15:755-72, 1992.

¹⁹The DCCT Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 329:977-86, 1993.

²⁰Reaven GM: Role of insulin resistance in human disease. Diabetes 37:1595-1607, 1988.

²¹Karlsson FO, Garber AJ: Dual therapy with sulfonylureas and metformin for type II diabetes. Progress in diabetes (Excerpta Medica); 2:1-5, 1995.

²²Karlsson FO, Garber AJ: Metformin comes to America: what to do now? Clinical Diabetes 13:78-83, 1995.

²³Cefalu, WT, Bell-Farrow AD, Wang ZQ, McBride DG, Terry JG, Tive L, Fischette CT: Combination Glipizide GITS/metformin normalizes glucose and improves insulin sensitivity in hyperinsulinemic moderately well controlled NIDDM. Diabetes (Abstract) 45(Suppl 2): 201A, 1996.

²⁴Berelowitz M, Fischette C, Cefalu W, Schade DS, Sutfin T, Kourides IA: Comparative efficacy of once daily controlled-released formulation of glipizide and immediate-release glipizide in patients with NIDDM Diabetes Care 17:1460-64, 1994.

²⁵Blonde L, Guthrie RD, Tive L, Fischette C, Glipizide GITS efficacy and safety trial study group: Glipizide GITS is effective and safe in a wide range of NIDDM Patients: Results of a Double Blind Placebo Controlled Efficacy and Safety Trial. Diabetes (Abstract) 45(Suppl 2): 285A, 1996.

²⁶Coniff RF, Shapiro JA, Seaton TB, Bray GA: Multicenter, placebo-controlled trial comparing Acarbose (BAYgS421) with placebo, tolbutamide, and tolbutamide-plus-acarbose in non-insulin-dependent diabetes mellitus. Am J Med 98:443-51, 1995.

²⁷Grundy SM, Vega GL: Two different views of the relationship of hypertriglyceridemia to coronary heart disease. Implications for treatment. Arch Int Med 152:28-34, 1992.

²⁸Garg A, Grundy SM. Management of dyslipidemia in NIDDM. Diabetes Care 13:153-69, 1990.

²⁹Karlsson FO, Garber AJ: Insulin resistance and lipoproteins in hypertriglyceridemia: effects of hypolipidemic drug treatment. In Proceedings of the XII International Symposium on Drugs Affecting Lipid Metabolism, 1996, p. 389-96.

³⁰Scandinavian Simvastatin Survival Study Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383-89, 1994.

³¹Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301-07, 1995.

³²Bakker-Arkema R, Davidson MH, Goldstein RJ, Davigon J, Isaacsohn J, Weiss ST, Keilson LM, Brown WV, Miller VT, Shurzinske LJ, Black D: Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia. J Am Med Assoc 275:128-33, 1996.

³³Henkin Y, Oberman A, Hurst DC, Segrest JP: Niacin revisited: clinical observations on an important but underutilized drug. Am J Med 91:239-46, 1991.

³⁴Walldius G, Erikson U, Olsson AG, Bergstrand L, Hadell K, Johansson J, Kaisjer L, Lassvik C, Molgaard J, Nilsson S, Schafer-Elinder L, Stenport G, Holme I: The effect of probucol on femoral atherosclerosis: The Probucol Quantitative Regression Swedish Trial (PQRST) Am J Cardiol 74:875-83, 1994.

³⁵Karlsson FO, Garber AJ: Prevention and treatment of diabetic nephropathy: the role of angiotensin converting enzyme inhibitors. Endocrine Pract 2:215-19, 1996.

³⁶American Diabetes Association: Consensus statement: Treatment of hypertension in diabetes. Diabetes Care 19(Suppl 1):S107-113, 1996.

³⁷Silva JA, Escobar A, Collins TJ,Ramee SR, White CJ: Unstable angina. A comparison of angioscopic findings between diabetic and non-diabetic patients. Circulation 92:1731-36, 1995.

Finnbogi 0. Karlsson, MD, is an assistant professor in the Departments of Community Medicine and Internal Medicine at Baylor College of Medicine and The Methodist Hospital in Houston, Tex. Alan J. Garber, MD, PhD, is a professor of medicine, biochemistry, and cell biology at Baylor and chief of Endocrinology, Diabetes, and Metabolism at Methodist. He is also editor-in-chief of Clinical Diabetes.

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