Management of Dyslipidemia in Patients With Type 2 Diabetes Mellitus

Transcription

1 Management of Dyslipidemia in Patients With Type 2 Diabetes Mellitus Robert E. Garrett, MD, MS ABSTRACT PURPOSE: To review the evidence defining the role of abnormal lipid levels in coronary heart disease for individuals with type 2 diabetes mellitus. EPIDEMIOLOGY: Coronary heart disease (CHD) is the leading cause of death in adult patients with type 2 diabetes, in whom it causes more than 50% of all deaths. The mortality rate after myocardial infarction is 50% to 100% higher in patients with diabetes than in the general population. The risk for CHD in patients with diabetes is 2- to 4-fold greater than that for nondiabetic patients with similar cholesterol levels. REVIEW SUMMARY: The understanding of the complexity of type 2 diabetes mellitus has advanced substantially in recent years. It is now clear that this disorder involves much more than abnormal glucose metabolism. Type 2 diabetes is characterized by a specific pattern of dyslipidemia that is associated with or contributes to a clinically significant increase in morbidity and mortality from CHD. The evidence shows that diabetic patients with dyslipidemia have a risk for coronary events equivalent to the risk of those who already have coronary artery disease. TYPE OF AVAILABLE EVIDENCE: Randomized-controlled trials, national guidelines, prospective cohort studies. GRADE OF AVAILABLE EVIDENCE: Good. CONCLUSION: Clinicians caring for patients with type 2 diabetes mellitus must strive for optimal control of lipid levels, blood glucose, and blood pressure to minimize the risk of substantial morbidity and mortality from CHD in these patients. A proper program of diet and exercise, tight glycemic control, and appropriate lipid-lowering drug therapy substantially improves the coronary risk profiles of patients with type 2 diabetes mellitus. (Adv Stud Med. 2005;5(1):28-36) Current research has shown type 2 diabetes mellitus to be more than just a disease of disordered glucose metabolism; it also is associated with dyslipidemia and an independent and significant risk of coronary heart disease (CHD). 1-3 Patients with type 2 diabetes often exhibit a specific pattern of abnormal lipid levels that is characterized by increased levels of triglycerides (TG), decreased levels of high-density lipoprotein (HDL), and, often, elevated levels of low-density lipoprotein (LDL). Recent large-scale clinical research has shown that the treatment of dyslipidemia in both diabetic and nondiabetic individuals significantly improves lipid levels and reduces the risk of CHD. 4,5 In individuals with type 2 diabetes, the normalization of lipid values has a positive effect on morbidity and mortality that is independent of the degree of glycemic control. 6 This article reviews the evidence that dyslipidemia is linked to atherosclerosis in patients with type 2 diabetes and Dr Garrett is Associate Professor of Clinical Family Medicine, Department of Family Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa. Conflict of Interest: Dr Garrett reports having no financial or advisory relationships with corporate organizations related to this activity. Off-Label Product Discussion: The author of this article does not discuss off-label use of products. Correspondence to: Robert E. Garrett, MD, Department of Family Medicine, Pomerantz Family Pavilion, 200 Hawkins Drive, Iowa City, IA Vol. 5, No. 1 January 2005

2 DIABETIC DYSLIPIDEMIA that effective management of lipid disorders in these patients results in improved morbidity and mortality rates. It concludes with an evidence-based review of therapeutic strategies for the management of dyslipidemia in patients with type 2 diabetes. The evidence grading system for clinical practice recommendations from the American Diabetes Association (ADA), 1(S1-S2) which is summarized in Table 1, was used to assess the quality of the research studies reviewed. PATHOGENESIS OF DIABETIC DYSLIPIDEMIA Although the underlying pathophysiology of dyslipidemia in patients with diabetes is not fully understood, current investigations suggest that insulin resistance is the fundamental metabolic abnormality. 7-9 Insulin resistance in adipose tissues leads to increased production and release of fatty acids that, when taken into the liver, stimulate the production of TG and very low-density lipoprotein (VLDL) particles. Triglycerides and VLDL particles 2,10 compete for binding sites on the lipase responsible for clearing lipids, which becomes saturated, resulting in an increased plasma half-life for TG. A cascade of subsequent enzymatic reactions leads to an increased percentage of small dense LDL and HDL particles in the bloodstream. The HDL particles are cleared more easily from the blood than are their LDL counterparts, which are more atherogenic due to their greater susceptibility to oxidation. 11,12 These factors collectively contribute to lower overall HDL levels. Thus, both qualitative and quantitative abnormalities of blood lipids are responsible for the increased risk for CHD in patients with diabetes. Postprandial hyperlipidemia has been associated with an increase in cardiovascular risk in both nondiabetic and diabetic patients. 13 Treatment with simvastatin for individuals with postprandial hyperlipidemia has been shown to reduce endothelial dysfunction caused by oxidative stress and produce a modest reduction in TG levels. 14 Although there is as yet no definitive evidence linking these biochemical abnormalities to clinical endpoints, 15 further research may establish such a connection, and postprandial lipid measurements may become an important part of the clinical database for patients with diabetic dyslipidemia. DYSLIPIDEMIA AND CORONARY HEART DISEASE Considerable high-quality evidence from large-scale investigations 16,17 of the general population shows an association between abnormal blood lipid values and an increased risk of serious morbidity and mortality from CHD. However, it is equally clear that appropriate pharmacotherapy leads to a significant decrease in these adverse consequences, as shown in several large-scale prospective studies of primary and secondary CHD prevention. 4,5,18-21 Such data are the rationale for the National Heart, Lung, and Blood Institute National Cholesterol Education Program (NCEP) and its associated guidelines for treatment of abnormal blood lipid levels (the Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel III, ATP III]). 22 In a more recent paper, the Adult Treatment Panel of the NCEP reviewed research results published since the original ATP III guidelines were created and suggested that in patients who are at very high risk, an LDL cholesterol level of 70 is a reasonable clinical target. 23 Among the most important new points in the ATP III is the recognition that patients with diabetes but no history of CHD have the same level of risk for adverse coronary events as do nondiabetic patients with known Table 1. American Diabetes Association Evidence Grading System for Clinical Practice* Level of Evidence A B C E Descriptions of Studies and Trials Clear evidence from well-conducted, generalizable, randomized-controlled trials, including: Evidence from a well-conducted multicenter trial Evidence from a properly performed meta-analysis Compelling nonexperimental evidence. Supportive evidence from well-conducted randomized-controlled trials that are adequately powered, including: Evidence from a well-conducted trial at 1 or more institutions Evidence from a properly performed meta-analysis. Supportive evidence from well-conducted cohort studies, including: Evidence from a well-conducted prospective cohort study or registry Evidence from a well-constructed meta-analysis of cohort studies. Supportive evidence from a well-conducted case-control study. Supportive evidence from poorly controlled or uncontrolled studies, including: Evidence from randomized clinical trials with 1 or more major or 3 or more minor methodologic flaws that could invalidate the results Evidence from observational studies with a high potential for bias Evidence from case series or case reports. Conflicting evidence, but the weight of evidence supports the recommendation. Expert consensus or clinical experience. *Copyright 2004 American Diabetes Association. From Diabetes Care. 2004;27:S1-S2. 1 Adapted with permission from the American Diabetes Association. Advanced Studies in Medicine 29

3 CHD. 24 In addition, diabetic individuals who suffer a myocardial infarction (MI) have a higher case-fatality ratio than do those without diabetes. 25 DYSLIPIDEMIA, DIABETES, AND CORONARY HEART DISEASE CHD is the leading cause of death in adult patients with type 2 diabetes responsible for more than 50% of all deaths in this population The mortality rate after MI is 50% to 100% higher in patients with diabetes than in the general population. 30 Research also has shown that the risk for CHD in patients with diabetes is 2- to 4-fold greater than that for nondiabetic patients with similar cholesterol levels. 28 Substantial benefits of the diagnosis and management of dyslipidemia in diabetic patients have been confirmed by several post hoc analyses of cohorts of patients with type 2 diabetes mellitus in the major primary and secondary CHD prevention trials (Table 2) Those analyses are consistent with and validate the results of studies showing the benefit of diagnosis and management of dyslipidemia in the general population. 5,18-22 The recently completed Heart Protection Study (HPS) 35 showed that statin therapy significantly reduced the risk of major cardiovascular events in diabetic patients. The HPS was the first to examine as a primary hypothesis the effect on CHD of reducing cholesterol levels in diabetic patients, and thus was the first to clarify the nature of this relationship. In summary, the previously cited studies indicate that in the general population and in patients with type 2 diabetes: (1) dyslipidemia and type 2 diabetes mellitus are independent risk factors for CHD, and (2) medical treatment of dyslipidemia leads to significant improvement in lipid levels and clinical outcomes. NONPHARMACOLOGIC TREATMENT OF DYSLIPIDEMIA IN DIABETIC PATIENTS The ADA recommends diet and lifestyle modifications as initial therapy for the reduction of LDL cholesterol levels in all diabetic individuals and has published recommendations for dietary modification 36 and exercise for this group. 37 The combination of increased physical activity and a diet low in saturated fats and high in monounsaturated fats can lead to a decrease of 15 mg/dl to 25 mg/dl in LDL cholesterol levels. 38 A diet that restricts the intake of carbohydrates and saturated fats leads to a decrease in TG levels. 39 These interventions also increase levels of HDL cholesterol to a limited degree. All diabetic patients should receive ongoing reinforcement, encouragement, and assistance in achieving clearly defined goals for weight reduction and an increased level of physical activity. However, many patients with type 2 diabetes mellitus also require pharmacotherapy to achieve those goals. The ADA recommends a target level of <100 mg/dl for LDL in diabetic individuals. For those diabetic patients with CHD, peripheral vascular disease (PVD), or cardiovascular disease (CVD) and LDL 100 mg/dl, the ADA recommends vigorous treatment with dietary modification and lifestyle changes concomitantly with lipid-lowering medications. 40 Diabetic patients without CHD, PVD, or CVD and whose LDL levels are between 100 mg/dl and 129 mg/dl do not require drug therapy unless several months of diet/lifestyle modification fail to lower LDL Table 2. Cardiovascular Effects of Treating Dyslipidemia in Patients With Type 2 Diabetes* No. of Diabetic Mean Age Lipid Level, mg/dl Follow-up Change RRR Evidence Study Subjects (yrs) (mmol/l) Outcome Therapy (yrs) (%) (%) 1º/2º Level 4S; LDL CHD death, Simvastatin º A Pyorala et al 31 (4.8 mmol/l) nonfatal MI Helsinki Heart Study; LDL 201 CHD death, Gemfibrozil º A Koskinen et al 32 (5.2 mmol/l) nonfatal MI CARE; (3.5 CHD death, Pravastatin º A Goldberg et al 33 mmol/l) nonfatal MI 4S; Haffner 281 (DM) (4.9 Total mortality, Simvastatin º A et al (IFG) mmol/l) CHD death, nonfatal MI *RRR = relative risk reduction; 4S = Scandinavian Simvastatin Survival Study; LDL = low-density lipoprotein; CHD = coronary heart disease; MI = myocardial infarction; TG = triglyceride; HDL = high-density lipoprotein; CARE = Cholesterol and Recurrent Events Trial; DM = diabetes mellitus; IFG = impaired fasting glucose. 30 Vol. 5, No. 1 January 2005

4 DIABETIC DYSLIPIDEMIA below 100 mg/dl; in the latter case either intensified therapy to modify diet and lifestyle or statin therapy should be implemented. 40 PHARMACOLOGIC TREATMENT OF DYSLIPIDEMIA IN DIABETIC PATIENTS GLUCOSE-LOWERING AGENTS As previously noted, many diabetic patients possess a characteristic lipid profile (ie, low levels of HDL, normal or slightly elevated LDL levels, and elevated levels of TG). LDL particles in diabetic individuals are qualitatively different from and more atherogenic than those in the general population. 11,12 Moreover, the role of elevated LDL cholesterol levels as a risk factor for CHD is more clearly defined than that of elevated TG levels. Accordingly, the ADA recommends that the drug treatment of patients with diabetic dyslipidemia focus on achieving target levels of LDL cholesterol, HDL cholesterol, and TG in roughly that order of priority. 40,41 ADA guidelines for the management of hyperlipidemia in diabetic individuals are summarized in Table 3. 1(S15-S35) Several studies have shown that improved glycemic control can lead to improved lipid profiles in patients with type 2 diabetes. In 2 studies of intensive insulin therapy in patients with type 2 diabetes, TG levels decreased and HDL cholesterol levels increased, although both levels remained abnormal indefinitely. 42,43 Metformin therapy has been shown to reduce the levels of TG, total cholesterol, and LDL cholesterol. 44,45 In addition, studies cited by Goguen and Leiter 39 show that monotherapy with thiazolidinediones such as pioglitazone reduced TG levels and increased levels of HDL cholesterol; by contrast, rosiglitazone treatment increased levels of HDL and total cholesterol. Sulfonylureas have not been shown to directly affect lipid levels in most studies. 46,47 Although the magnitude of each drug-related effect can be difficult to assess, it appears that first pioglitazone and then metformin have the most beneficial effects on lipid levels. LIPID-LOWERING AGENTS Until the introduction of hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), physicians and patients had limited choices for drug therapy of lipid disorders. Available agents had unfavorable adverse effect profiles and yielded only modest therapeutic benefit. The introduction of statins revolutionized the pharmacotherapy of lipid disorders. 48 Fibrates (fibric acid derivatives) have been shown to provide significant benefit to patients with hypertriglyceridemia. 48 Cholesterol absorption inhibitors, a new class of drugs, may prove useful in lowering lipid levels, although only a modest amount of evidence about their clinical use exists. 48 Bile acid sequestrants (cholestyramine, colestipol, colesevelam) and niacin, which are considered classic lipid-reduc- Table 3. Management of Hyperlipidemia in Diabetic Individuals* A-Level Evidence Lowering levels of LDL cholesterol is associated with a reduction in cardiovascular events. Medical nutrition therapy focusing on the reduction of saturated fat and cholesterol intake, weight loss, and increased physical activity improves the lipid profile in diabetic patients. Patients who do not achieve lipid goals with lifestyle modifications require pharmacologic therapy. Statins should be used as first-line pharmacologic therapy to lower the levels of LDL. Lowering the levels of TG and increasing the levels of HDL cholesterol with a fibrate is associated with a reduction in cardiovascular events in patients with clinical CHD. B-Level Evidence Lowering TG levels and increasing HDL levels is associated with a reduction in cardiovascular events. Lowering the levels of LDL cholesterol to <100 mg/dl is the primary goal of therapy for adults with type 2 diabetes. C-Level Evidence In patients with type 2 diabetes, lowering the TG levels to <150 mg/dl and increasing HDL levels to >45 mg/dl in men and >55 mg/dl in women are the primary goals of therapy. Expert Consensus In adult patients, test for lipid disorders at least annually (or more often if needed) to achieve goals. In adults with low-risk lipid values, repeat lipid assessments every 2 years. When fibrates or niacin are prescribed in combination with a statin, care is needed to minimize the risk of adverse effects such as myositis. *Data from the American Diabetes Association. 1 LDL = Low-density lipoprotein; TG = triglyceride; HDL = high-density lipoprotein; CHD = coronary heart disease. Note: The combination of statins with nicotinic acid, and especially with gemfibrozil or fenofibrate, may increase the risk of myositis. Advanced Studies in Medicine 31

5 tion agents, are still useful as adjuncts to statin or fibrate therapy. 48 Tables 4 and present an overview of the available agents used in treating dyslipidemia in diabetic patients. Statins. Statins are the drugs most commonly used in the treatment of dyslipidemia in diabetic individuals as well as in the general population. 48 Statins act by inhibiting the rate-limiting step in cholesterol synthesis. 39 Lower levels of intracellular cholesterol lead to upregulation of LDL cholesterol cell-surface receptors Table 4. Overview of Lipid-Lowering Agents for Treatment of Diabetic Dyslipidemia* Usual Decrease FDA-Approved in LDL Cholesterol Class Drug Daily Dosage Levels (%) AWP Comments Statins Atorvastatin Initial, 10 mg mg: $260/100 ct Greatest decrease (Lipitor ) qd; max: 80 mg qd mg: $323/90 ct in TG levels Fluvastatin Lescol: Initial, 20 mg q /40 mg: $58 (Lescol, immediate release; evening; max, 40 mg bid XL 80 mg: $75 Lescol-XL, extended release) Lescol-XL: mg q evening Lovastatin Mevacor: Initial, 20 mg Mevacor, (Mevacor, immediate release; every evening; mg: $158/60 ct Altocor, extended release) max, 80 mg every 40 mg: $284/60 ct evening Altocor: Initial, 20 mg Altocor XL, at bedtime; max, 60 mg 20/40 mg: $54 at bedtime Pravastatin Initial, 40 mg q evening; /80 mg: $418/90 ct (Pravachol ) max, 80 mg q evening Rosuvastatin Initial, 10 mg once; mg: $227/90 ct Greatest decrease (Crestor ) max, 40 mg once mg: $76 in LDL levels Simvastatin Initial, 20 mg q evening; /80 mg: $138 Greatest increase (Zocor ) max, 80 mg q evening in HDL levels Bile-Acid Cholestyramine 8 g once or Up to 20 4-g packets: Sequestrants (Questran) 4 g bid $181/60 ct Colestipol 10 g qd or 5 g bid Up to 20 5 g: $58 (Colestid ) Colesevelam 3.75 g qd or Up to mg: (WelChol ) 1.9 g bid $161/180 ct Cholesterol Ezetimibe 10 mg qd mg: $78 Works well with Absorption (Zetia ) statins Inhibitor Fibrates Gemfibrozil 600 mg bid Generic, 600 mg: Most effective in (Lopid ) $105/60 ct insulin-resistant patients Fenofibrate mg qd Tricor, (Tricor, Lofibra ) 160 mg: $290/90 ct Lofibra, 67 mg: $82/100 ct 134 mg: $157/100 ct 200 mg: $245/100 ct Vitamin Niacin Niacor: 1 g tid 5 25 Generic, 500 mg: Supplement (Niacor, immediate Niaspan: 1 g q $4/100 ct release; Niaspan, evening extended release) *Data from Treatment Guidelines From The Medical Letter. 48 FDA = Food and Drug Administration; LDL = low-density lipoprotein; AWP = average wholesale price; qd = every day; TG = triglyceride; q = every; bid = twice daily. Costs estimated based on 2004 Drug Topics Redbook average wholesale pricing. Pricing based on a 30-day supply unless otherwise noted; actual costs may vary. 32 Vol. 5, No. 1 January 2005

6 DIABETIC DYSLIPIDEMIA (and subsequently to better LDL clearance) and a decrease in the levels of VLDL, resulting in lower blood levels of TG and LDL cholesterol. 39 Six statins (Table 4) are available in the United States. Recent research has shown that rosuvastatin produces the greatest decrease in LDL cholesterol levels and the greatest increase in levels of HDL cholesterol. 51 However, all statins will decrease the levels of LDL cholesterol by 25% to 40%, 49 and other factors may influence the choice of agent. Lovastatin, which is the only generic statin currently available in the United States, is typically the least expensive. Many healthcare Table 5. Lipid-Lowering Agents: Monitoring, Contraindications, and Side Effects/Interactions* Drug-Drug Class Monitoring Contraindications Adverse Effects Interactions Comments Statins Baseline LFT and at 12 wks Active or chronic liver Elevated LFT; Azole antifungals Patients treated with after the initiation of treat- disease; pregnancy; myopathy (myalgia); and macrolides: cyclosporine, niacin, ment or the dosage is lactation headache; diarrhea; increased risk of or fibrates should changed; then every 6 wks. dyspepsia myopathy not exceed a dosage Monitor CPK prn for of 10 mg of simvasigns of myopathy statin qd Bile-Acid Check PT/INR if Hypertriglyceridemia GI distress; constipation; Decreased absorption Colesevelam exerts Sequestrants patient complains of easy (>400 mg/dl; decreased absorption of of many common an effect on drug bruising, which may result administer with caution drugs and vitamins; drugs (thiazides, absorption less from decreased vitamin K if TG levels are flatulence; nausea; fatigue β-blockers, severe than that absorption >200 mg/dl); statins, thyroid of cholestyramine GI obstruction hormone replacement, or colestipol with niacin, warfarin) fewer GI effects Cholesterol LFT at initiation of Administer with caution Diarrhea; myalgia; Bile-acid sequestrants: Absorption therapy and as clinically to patients with fatigue; cough decreased effect of Inhibitors indicated; especially impor- decreased liver function ezetimibe; works well tant for patients treated with statins; do not with both ezetimibe and a statin administer with fibrates doing so may increase risk of hepatobiliary disease Fibrates CBC and LFT q 3 months Severe renal or hepatic Cholelithiasis; β-blockers and thiazides: for the first year of therapy disease myopathy; hepatitis; decreased effect of fibrates; dyspepsia; abnormal statins: increased risk of LFT myopathy; meglitinides and thiazolidinediones: increased hypoglycemic effect; warfarin: increased anticoagulant effect; estrogens: decreased fenofibrate effect, increased risk of hypertriglyceridemia, biliary-tract disease; do not administer with fibrates doing so may increase the risk of hepatobiliary disease. Vitamin Monitor LFT, uric acid Severe renal or hepatic Flushing, pruritus, Bile-acid sequestrants: decreased Supplements levels, and glucose levels disease; administer with dyspepsia, diarrhea, absorption of niacin; ethanol: periodically caution in patients with decreased glucose increased flushing and pruritus, diabetes tolerance at high doses increased hepatotoxicity; sulfonylureas, metformin, thiazolidinediones: decreased hypoglycemic effect; statins: increased risk of myopathy *Data from McEvoy et al 49 and Fleming et al. 50 LFT = liver function test; CPK = creatine phosphokinase; prn = as needed; PT/INR = prothrombin/international normalized ratio; TG = triglycerides; GI = gastrointestinal; CBC = complete blood count; qd = every day; q = every. Advanced Studies in Medicine 33

7 organizations now have formularies that may restrict the choice of agents available under their insurance plans. Most patients tolerate statins, although some experience nonspecific treatment-related adverse effects such as malaise, headache, rash, or mild gastrointestinal symptoms. 48 The few patients in whom significant myalgias develop should be monitored for myotoxicity, which may include myositis and rhabdomyolysis. 52 About 2% of patients treated with a statin will exhibit elevated levels of transaminase 39 and should be monitored during statin therapy as clinically indicated. Symptomatic hepatitis associated with statin therapy is rare. 11,48 The ADA recommends statins as the treatment of choice for diabetic patients with elevated LDL levels and as part of a multidrug regimen for patients with both hypertriglyceridemia and combined dyslipidemia. 40 Fibric Acid Derivatives (Fibrates). Because fibric acid derivatives (gemfibrozil and fenofibrate) lower the levels of TG and elevate the levels of HDL cholesterol, they are often used in the treatment of dyslipidemia in diabetic patients. They promote the clearance and inhibit the synthesis of VLDL particles. 39 Fibrates also may shift the distribution of LDL particles in favor of the lighter, less atherogenic type. 53 Although most patients tolerate fibrates, hepatitis and myositis may occur (especially if gemfibrozil is used), 39,48 and patients should be monitored as clinically indicated. Both gemfibrozil and fenofibrate may potentiate the actions of oral anticoagulants such as warfarin, as well as the effect of oral hypoglycemic agents. 48 Patients treated with both gemfibrozil and a statin should be monitored closely for the development of rhabdomyolysis. 48 Fibrates are recommended by the ADA as the initial agent in the treatment of hypertriglyceridemia and as second-choice therapy (after statins) in the treatment of combined dyslipidemia. 40 Cholesterol Absorption Inhibitors. Ezetimibe (Zetia ) is the only cholesterol absorption inhibitor currently available in the United States. It acts by blocking the absorption of both dietary and biliary cholesterol at the intestinal brush border. 48,53 As a single agent, it can lower levels of LDL cholesterol by about 18%, and it produces minimal improvement in the levels of TG and HDL cholesterol. 48 If ezetimibe is administered in addition to a statin, it decreases the levels of LDL cholesterol by at least as much as would doubling the statin dosage. 48 Ezetimibe is generally well tolerated, especially when compared with bile-acid binding agents. When taken with a statin, elevated results of liver function tests have been noted slightly more often than when a statin alone is used as therapy. Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe. 54 Niacin and Bile-Acid Sequestrants. Niacin has a greater potential than bile-acid sequestrants for increasing levels of HDL cholesterol. 47 It also lowers levels of LDL cholesterol and shifts the particle-size profile to the less atherogenic form (increases particle size). 51 Niacin acts by inhibiting the hepatic synthesis of VLDL and reducing the clearance of HDL cholesterol from the blood. 39 Niacin has not previously been recommended for use in diabetic individuals because it might diminish glycemic control. However, recent studies have shown that immediate-release niacin 55 and extended-release niacin 56 do not significantly affect glycemic control in diabetic patients. Many patients do not tolerate niacin well because it produces frequent and distressing adverse effects (eg, flushing, pruritus, fatigue, gastrointestinal disturbances). These symptoms can be lessened by beginning niacin therapy at a low dose and slowly titrating upwards until the desired effect is achieved. Pretreatment with aspirin (325 mg) or ibuprofen (200 mg) also may attenuate undesired effects. 48 Bile-acid sequestrants can lower the levels of LDL and increase the levels of HDL but also may increase TG levels in patients with hypertriglyceridemia. 48 As their name suggests, these agents bind bile acids in the gut, thereby reducing the enterohepatic circulation of lipid components. The hepatic synthesis of cholesterol is diminished because of the relative paucity of precursor molecules; this results in an upregulation of LDL receptors on the cell surface and subsequent increased clearance of LDL cholesterol. 39 Bile-acid sequestrants also commonly cause gastrointestinal distress and may affect the absorption of other medications. Colesevelam, the newest agent in this category, may be better tolerated and interfere less with the action of other therapeutic agents MONITORING LIVER FUNCTION Many of the drugs used to manage diabetic dyslipidemia can cause elevations in the results of common liver function tests (eg, in the levels of transaminases), as well as symptomatic hepatitis, although the former effect is much more common than the latter. Most authorities believe that an elevation of transaminases that is less than 3 the upper limit of the normal level does not warrant dose reduction or cessation of treatment. 11 Whereas the manufacturers of all 6 statins currently available in the United States recommend regular monitoring of transaminase levels, 50 some researchers have questioned the necessity of this monitoring process. 57,58 The rationale behind these opinions is that postmarketing experience with statins has shown a very low level of clinically significant liver problems. 57,58 Although this area is still controversial, further experience with statins in clinical practice should allow the development of evidence-based guidelines for liver function monitoring in the near future. 59,60 34 Vol. 5, No. 1 January 2005

8 DIABETIC DYSLIPIDEMIA CONCLUSION The fact that type 2 diabetes mellitus is not just a disorder of glucose metabolism but rather a complex multifactorial syndrome is better understood now than in the past. Diabetic dyslipidemia is a significant contributor to morbidity and mortality in patients with type 2 diabetes mellitus, primarily due to the associated increase in risk for CHD. The NCEP and ADA have identified type 2 diabetes as a risk factor for CHD equal in magnitude to documented CHD. 23,36 However, currently available treatments for dyslipidemia are effective at reducing CHD risk in the general population as well as in patients with type 2 diabetes mellitus. Clinicians caring for patients with type 2 diabetes mellitus must strive for optimal control of lipid levels, blood glucose, and blood pressure to minimize the risk of substantial morbidity and mortality from CHD in these patients. A proper program of diet and exercise, tight glycemic control, and appropriate lipid-lowering drug therapy can substantially improve the coronary outcomes in patients with type 2 diabetes mellitus. ACKNOWLEDGEMENTS The author wishes to thank Eileen Fisher, MD, for her critical review of an earlier version of this paper, and Ms Kimberly Hobbs and Ms Jane Vail for their assistance in the preparation of this manuscript. REFERENCES 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2004;27(suppl 1):S1-S2, S5-S10, S15-S Reusch JE. Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Am J Cardiol. 2002;90(5A):19G-26G. 3 Powers AC. Diabetes mellitus. In: Braunwald E, Fauci AS, Kasper DL, et al, eds. Harrison s Principles of Internal Medicine. 15th ed. 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