When target LDL-C levels are not achieved, especially in the patients at high risk, clinicians face treatment options, including increasing the statin dose, changing to another statin of higher potency, and adding a complementary Coadministration of Multidrug drug to statin therapy.4 In clinical prac- Therapy to Achieve Lipid Goals tice, these options are not effectively used, leaving patients short of goal. An addi- Margo A. Denke, MD tional treatment option is the use of coad- ministered drug therapy.2,5 Coadministration of two lipid-low- ering agents is a valid therapeutic option for those patients with severe dyslipi- demia, those who cannot achieve LDL-C target levels on monotherapy, and those patients in whom intolerance to higher 6 Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are the doses of medications develops. Because drug of first choice for lowering low-density lipoprotein cholesterol (LDL-C) statins are proved to be effective in low- levels and reducing risk of coronary heart disease (CHD). Current therapeutic ering LDL-C levels, coadministration use of statins, however, has resulted in only a small percentage of patients therapy should include a statin unless 5 reaching their LDL-C treatment goal. Despite the clinical trial data supporting use of a statin is contraindicated. The early aggressive use of statins, prescribing physicians are more likely to use choice of the other drug in the coadmin- lower doses of statins, leaving many patients at high risk of CHD short of istration therapy is broad. Each class of goals. The barrier to achieving cholesterol treatment goals does not appear to lipid-lowering drugs has a distinct mech- be the decision to initiate statin therapy, but the failure of prescribers to titrate anism of action that has different effects 7 statin therapy to a dose sufficient to achieve goals. on lipids (Figure). An alternative to statin monotherapy is coadministration of a statin and a Coadministration therapy uses two second agent that has a different mechanism of action. This approach can or more drugs, each with different, and increase the likelihood of achieving target lipid levels and may be more accept- likely complementary, mechanisms of able to physicians. The coadministration of ezetimibe and simvastatin reduces action, making it possible to tailor cholesterol derived from both endogenous and exogenous sources. Simva- therapy to the specific lipid-lowering statin reduces the hepatic production of cholesterol, and ezetimibe decreases needs of the patient and the patient’s 7 the intestinal absorption of dietary and biliary free cholesterol. The coadmin- ability to tolerate drugs. The coadmin- istration of low doses of these agents has been proved to be as effective as istration of multiple drugs should, at a high-dose statin therapy in reducing LDL-C levels and assisting patients minimum, provide sufficient LDL-C low- achieve their treatment goals. ering to achieve target; it may, in addi- tion, provide triglyceride lowering and increases in high-density lipoprotein ccording to the Adult Treatment should be used as first-line therapy for (HDL-C). Although doubling the dose APanel III (ATP III) treatment guide- lowering low-density lipoprotein choles- of a statin usually achieves a 6% reduc- lines, 3-hydroxy-3-methylglutaryl coen- terol (LDL-C) levels.1 Because of their tion in LDL-C levels, at least a 10% addi- zyme A reductase inhibitors (statins) proven ability to lower LDL-C levels tional reduction in LDL-C levels can be and reduce cardiovascular events, statins achieved with coadministration therapy.5 Dr Denke is on the advisory board of remain the preferred treatment for most Merck/Schering–Plough Pharmaceuticals and on patients with dyslipidemia.2 Despite the Commonly Used Modes of Lipid- the speakers bureau for Merck & Co and overwhelming evidence supporting the lowering Coadministration Therapy Merck/Schering–Plough Pharmaceuticals. She also is an adviser and a coauthor on the Ezetimibe efficacy of statin therapy, clinical prac- Bile Acid Sequestrants and Statins Add-on to Statin for Effectiveness (EASE) trial. tices outside of clinical trials find that a A bile acid sequestrant coadministered Address correspondence to Margo A. Denke, high percentage of patients do not reach with statin therapy has been shown to MD, FACP, FACE, Clinical Professor, The University 3 of Texas Health Science Center at San Antonio, their ATP III target LDL-C goals. reduce LDL-C levels by an additional 7703 Floyd Curl Dr, San Antonio, TX 78284. Among the many possible reasons for 20% to 30%.8 In their study, Knapp and Email: [email protected] this trend are underidentification of colleagues9 observed a 42% mean reduc- patients at high risk of coronary heart tion in LDL-C levels in patients who were Supported by an unrestricted disease (CHD), insufficient dosing of treated with coadministration of a bile educational grant from Merck/ statins, and side effects associated with acid sequestrant (colesevelam hydrochlo- Schering– Plough Pharmaceuticals high-dose statin use.3 ride) and a statin (simvastatin) compared

Denke • Coadministration of Multidrug Therapy to Achieve Lipid Goals JAOA • Supplement 7 • Vol 104 • No 9 • September 2004 • S17 Drug Class Mechanism of Action

Attenuate the activity of the hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase enzyme, a critical step Statins in the de novo synthesis of cholesterol; also stimulate the upregulation of LDL-C receptors, thus reducing circulation levels of cholesterol21

Interrupt bile acid enterohepatic recirculation by binding to bile acids in the intestine; increase hepatic formation of Bile Acid Sequestrants bile acids from cholesterol conversion; reduces circulating cholesterol cells22

Cholesterol Absorption Inhibit the intestinal absorption of cholesterol and bile Inhibitors acids by intestinal epithelial23

Influence the activity of genes involved in lipoprotein Fibrates metabolism via the peroxisome proliferator–activated receptor24

Believed to inhibit mobilization of free fatty acid from Niacin peripheral tissues, thus reducing hepatic synthesis of triglycerides25

Figure. Mechanism of action of lipid-lowering drugs. (Sources: Davignon J, et al. Can J Cardiol. 1992;8:843-86421; Knopp RH. N Engl J Med. 1999;341:498-51122; Rudel LL. Am J Manag Care. 2002;8(suppl):S33-S3523; Gervois P, et al. Clin Chem Lab Med. 2000;38:3-11.24)

with a 34% reduction in patients who complementary effects on triglyceride coadministration of statins and fibrates were treated with simvastatin alone. and LDL-C levels, and this therapy may significantly reduces both LDL-C and Although bile acid sequestrants are be useful in those patients who have triglyceride levels, but a number of safety associated with few serious adverse mixed hyperlipidemia characterized by concerns have been identified with this events, large doses may be needed for elevated triglyceride and LDL-C con- approach.7 This coadministration is asso- efficacy. As the dose is increased, patient centrations.5 In a study by Liamis et al10 ciated with an increased risk of rhab- nonadherence also increases because of to determine the safety and efficacy of domyolysis and myopathy beyond that multiple daily dosing and gastrointestinal coadministration of fibrates (fenofibrate normally observed with either drug class discomfort.5,7 In addition, triglyceride [200 mg/d] or ciprofibrate [100 mg/d]) alone; therefore, cautious consideration of levels have been shown to be increased and small doses of atorvastatin calcium the risks versus the benefits must be care- by the use of bile acid sequestrants; there- (5 mg/d), fibrate therapy resulted in a fully weighed before coadministering fore, these drugs should not be used in significant decrease in total cholesterol these agents.7 patients with the metabolic syndrome.7 and LDL-C levels. Fibrate-statin coad- ministration therapy, however, resulted Niacin and Statins Fibrates and Statins in an even further decrease, and it was Clinical trial data demonstrate that coad- The coadministration of low-dose statins well tolerated. ministration of a statin and niacin reduces and fibrates has been shown to have Clinical studies have shown that LDL-C levels by an additional 16% com-

S18 • JAOA • Supplement 7 • Vol 104 • No 9 • September 2004 Denke • Coadministration of Multidrug Therapy to Achieve Lipid Goals pared with statin therapy alone.11 This statin was more effective than simva- monotherapy and are thus unable to course of therapy, however, may be asso- statin (10 mg/d, 20 mg/d, 40 mg/d, or achieve their LDL-C treatment goal. Addi- ciated with serious side effects as con- 80 mg/d) alone in reducing LDL-C levels tionally, ezetimibe-statin therapy may comitant use of niacin and statin is asso- (53.1% vs 38.3%). In addition, 82.4% increase the number of patients—particu- ciated with an increased risk of myopathy. of patients in whom the two agents were larly patients with diabetes mellitus, Additionally, niacin used either in coadministered achieved an LDL-C existing CHD, and the metabolic syn- monotherapy or coadministration therapy target level less than or equal to drome—reaching their NCEP lipid goals. is associated with vasodilatory side effects 100 mg/dL, compared with 42.9% of Also, aggressive lipid lowering can be chal- that are intolerable to some patients.5 This patients receiving simvastatin lenging in patients with type 2 diabetes flushing has been shown to lead to dis- monotherapy.15 mellitus who are taking multiple drugs to continuation of therapy in up to 10% of Further evidence supporting the regulate glucose metabolism. In diabetic patients taking niacin.12 Niacin has been ability of ezetimibe and simvastatin in patients currently receiving thiazolidine- shown to worsen glycemic control in helping patients to achieve their National diones, ezetimibe (10 mg/d) added to patients with diabetes mellitus and may Cholesterol Education Program (NCEP) simvastatin (20 mg/d) reduced LDL-C exacerbate gout.5,7 target levels comes from a study of 769 levels by 21% compared with diabetic patients who failed to achieve goal patients monotherapy with simvastatin New Treatment Option despite ongoing statin therapy.16 The (20 mg/d).19 in Coadministration Therapy addition of ezetimibe to statin therapy The following case presentation The recent development of the choles- resulted in an additional 21.4% reduc- illustrates the decision-making process terol absorption inhibitor ezetimibe pro- tion in LDL-C (P.001 vs statin). The in the development of a lipid-lowering vides an additional option in the treat- greater LDL-C reduction elicited by coad- treatment strategy for a typical patient ment of lipoprotein disorders.6 Ezetimibe ministration of ezetimibe and statin seen in primary care practice. is the first drug that specifically blocks allowed 71.5% of patients to achieve their absorption of intestinal cholesterol. This LDL-C goal compared with 18.9% of Illustrative Case Presentation action effectively reduces plasma LDL-C those who received statin plus placebo.16 A 51-year-old male construction worker levels, because intestinal absorption may Two recent trials confirmed this sees a primary care physician in the account for up to 50% of the cholesterol finding.17,18 The Ezetimibe Add-on to office for a physical examination. Cur- found in the circulating lipoproteins.13 Statin for Effectiveness (EASE) trial17 rently, he smokes half a pack of Ezetimibe inhibits as much as 54% of all demonstrated that coadministration of cigarettes daily, down from the four intestinal cholesterol absorption without the two agents provided a 25% greater packs he used to smoke each day. He affecting uptake of triglycerides or lipid- reduction in LDL-C than statin plus has a positive family history for CHD soluble vitamins.13 The mechanism of placebo for all CHD risk categories. The (father died of myocardial infarction in action of the statin-ezetimibe coadmin- combination also significantly increased his late 40s) but no history of hyperten- istration is attractive: the site of action the percentage of patients reaching sion in the family. His blood pressure is and its alteration of lipid metabolism for ATP III target levels compared with statin 135/90 mm Hg, his body mass index is both drugs are well characterized. Coad- alone (Table 1). Similarly, Feldman and 32, his self-reported waist circumference ministration of ezetimibe and a statin colleagues18 reported that coadministra- is 32 inches, and his fasting blood glu- reduces both intestinal cholesterol tion of ezetimibe (10 mg) and any dose of cose level is 115 mg/dL. absorption and hepatic cholesterol syn- simvastatin produced greater reductions A risk-factor analysis reveals that he thesis, resulting in a significant reduc- in LDL-C and allowed more patients at has four categorical risk factors, including tion of the plasma LDL-C level.5 high risk to achieve their ATP III target hypertension, family history, smoking, Lipid lowering with ezetimibe coad- goal (100 mg/dL after 5 weeks of and low HDL-C level, and his 10-year ministered with low-dose statins is sim- therapy (P.001) than monotherapy with risk for a CHD event is 25%. His waist ilar to that of high-dose statin simvastatin (20 mg). circumference, high triglyceride concen- monotherapy as LDL-C reductions up The safety profile for ezetimibe coad- trations, low HDL-C level, hypertension, to 55% to 60% have been demonstrated.13 ministered with a statin is similar to that and impaired fasting glucose indicate Ezetimibe (10 mg/d) plus simvastatin of statin monotherapy (Table 2), but in that he also has the metabolic syndrome. (10 mg/d) improved lipid profiles as some patients, hypersensitivity reactions, His fasting lipid levels before any effectively as simvastatin (80 mg/d). This including angioedema and rash, were intervention were as follows: coadministration therapy obviates the reported in postmarketing experience.19 Total cholesterol, 254 mg/dL; need for high statin doses.14,15 Davidson LDL-C, 156 mg/dL; et al14 demonstrated that coadministra- Patients Who May Benefit HDL-C, 32 mg/dL; tion of ezetimibe and simvastatin resulted From Coadministration Triglyceride concentration, in significantly greater reductions in LDL- of Ezetimibe and a Statin 195 mg/dL; and C (13.8%) than simvastatin alone (P.01). Patients who may benefit from coadmin- Non–HDL-C, 222 mg/dL. Similarly, Goldberg et al15 noted that istration of ezetimibe and a statin include After reviewing his risk factors and coadministration of ezetimibe and simva- those who are intolerant to high-dose statin fasting lipid profile, his physician

Denke • Coadministration of Multidrug Therapy to Achieve Lipid Goals JAOA • Supplement 7 • Vol 104 • No 9 • September 2004 • S19 reduction from baseline); Table 1 Triglyceride concentration, Patients Achieving Adult Treatment Panel III 110 mg/dL (37% reduction from base- Low-Density Lipoprotein Cholesterol Goal* line); LDL-C, 129 mg/dL (4% reduction Patients Receiving Patients Receiving from baseline); Placebo Plus Ezetimibe Plus HDL-C, 41 mg/dL (21% reduction Variable Statin, % Statin, % from baseline); Non–HDL-C, 151 mg/dL (32% reduc- Total 20.6 71.0 tion from baseline); and Glucose, 121 mg/dL (5% increase CHD or CHD Risk Equivalent 17.3 69.5 over baseline). Statin plus ezetimibe: 2 Risk Factors 32.2 75.1 Total cholesterol, 168 mg/dL (25% reduction from baseline); 2 Risk Factors 52.4 90.7 Triglyceride concentration, 145 mg/dL (17% reduction from base- *Coadministration of ezetimibe with statin versus coadministration of placebo and statin (n4888). All line); patients not at goal at baseline. Statins used: atorvastatin calcium, 40%; simvastatin, 31%; pravastatin LDL-C, 104 mg/dL (17% reduction sodium, 24%; fluvastatin sodium, 7%; lovastatin, 4%. (Source: Pearson T, et al. Ezetimibe added to statin therapy reduces LDL-C and improves goal attainment in patients with hypercholesterolemia. Abstract from baseline); presented at: 2004 Scientific Session of the American College of Cardiology. March 7-10, 2004; New Orleans, HDL-C, 35 mg/dL (3% increase over La.) †P.001 versus placebo plus statin. baseline); Non–HDL-C, 133 mg/dL (40% reduc- tion from baseline); and develops a treatment strategy to reduce indicated? What should this therapy Glucose, 115 mg/dL (baseline). the patient’s risk by initiating therapeutic include? Thus, the combination of ezetimibe lifestyle changes (TLC) and drug therapy. The estimated benefits of next-dose and a statin would achieve the greatest Treatment goals for this patient include statin or combination therapy are as fol- reductions in the triglyceride concentra- achieving an LDL-C level of less than lows: tion and the LDL-C and non–HDL-C 100 mg/dL and a non–HDL-C level of Increase statin dose: levels. A statin plus niacin is estimated to less than 130 mg/dL. Total cholesterol, 191 mg/dL (25% achieve the greatest reduction in triglyc- Recommended lifestyle changes reduction from baseline); eride concentration and greatest increase include a diet that obtains less than 7% Triglyceride concentration, in HDL-C level and an increase in blood of calories from saturated fat and an 160 mg/dL (9% reduction from base- glucose level. intake of dietary cholesterol of less than line); 200 mg/d. The caloric restriction should LDL-C, 124 mg/dL (7% reduction Comment be designed to help him lose weight, but from baseline); Coadministration of a statin and another minimally, the patient should be encour- HDL-C, 35 mg/dL (3% increase over agent can provide greater LDL-C low- aged not to gain more weight. In addi- baseline); ering than with either agent used as tion, a realistic physical activity program Non–HDL-C, 156 mg/dL (30% reduc- monotherapy. Despite this advantage, should be designed and implemented. tion from baseline); and acceptance of coadministration therapy Glucose, 115 mg/dL (baseline). has been appropriately slowed owing to Intermediate Outcomes Statin plus fibric acid: safety concerns and inconvenience, par- The patient lost 10 pounds in the 3 Total cholesterol, 202 mg/dL (8% ticularly when niacin, bile acid seques- months since initiation of TLC and statin reduction from baseline); trants, and fibrates were the drugs to con- therapy. Triglyceride concentration, sider for coadministration with a statin. Three months posttreatment, his 130 mg/dL (26% reduction from base- The advent of ezetimibe has changed the lipid levels were as follows: line); outlook on coadministration therapy for Total cholesterol, 220 mg/dL (13% LDL-C, 138 mg/dL (3% increase over lipid lowering. The coadministration of reduction); baseline); ezetimibe (10 mg/d) and simvastatin LDL-C, 134 mg/dL (14% reduction); HDL-C, 38 mg/dL (12% increase over (10 mg/d) has been shown to reduce HDL-C, 34 mg/dL (6% increase); baseline); LDL-C as effectively as monotherapy Triglyceride concentration, Non–HDL-C, 164 mg/dL (26% reduc- with simvastatin (80 mg/d) and has been 175 mg/dL (10% reduction); and tion from baseline); and well tolerated. These data suggest that Non–HDL-C, 186 mg/dL (16% reduc- Glucose, 115 mg/dL (baseline). this combination is a safe and effective tion). Statin plus niacin: addition to the choices of lipid-modifying Is more aggressive drug therapy Total cholesterol, 192 mg/dL (13% modes of therapy.

S20 • JAOA • Supplement 7 • Vol 104 • No 9 • September 2004 Denke • Coadministration of Multidrug Therapy to Achieve Lipid Goals Table 2 Safety of Ezetimibe Plus Simvastatin Versus Statin Monotherapy*

Ezetimibe, 10 mg, Placebo Ezetimibe, 10 mg All Statins* Plus All Statins (n=259) (n=262) (n=936) (n=925)

Body as a Whole: General Disorders □ Chest pain, % 1.2 3.4 2.0 1.8 □ Dizziness, % 1.2 2.7 1.4 1.8 □ Fatigue, % 1.9 1.9 1.4 2.8 □ Headache, % 5.4 8.0 7.3 6.3

Gastrointestinal Disorders □ Abdominal pain, % 2.3 2.7 3.1 3.5 □ Diarrhea, % 1.5 3.4 2.9 2.8

Infection □ Pharyngitis, % 1.9 3.1 2.5 2.3 □ Sinusitis, % 1.9 4.6 3.6 3.5 □ Upper Respiratory Tract Infection, % 10.8 13.0 13.6 11.8

Musculoskeletal Disorders □ Arthralgia, % 2.3 3.8 4.3 3.4 □ Back pain, % 3.5 3.4 3.7 4.3 □ Myalgia, % 4.6 5.0 4.1 4.5

*Adapted from Zetia (ezetimibe) package insert. North Wales, Pa: Merck/Schering–Plough Pharmaceuticals; 2003.

References 8. Tikkanen MJ. Statins: within-group comparisons, hypercholesterolemia. J Am Coll Cardiol. statin escape, and combination therapy. Curr Opin 2002;40:2125-2134. 1. The Third Report of the National Cholesterol Lipidol. 1996;7:385-388. Education Program (NCEP) Expert Panel on Detec- 15. Goldberg AC, Capece R, Sapre A, et al. Effi- tion, Evaluation, and Treatment of High Blood 9. Knapp HH, Schrott H, Ma P, Knopp R, Chin B, cacy of ezetimibe 10 mg/day with multiple doses of Cholesterol in Adults (Adult Treatment Panel III). Gaziano JM, Donovan JM, et al. Efficacy and safety simvastatin in patients with primary hypercholes- National Cholesterol Education Program. National of combination simvastatin and colesevelam in terolemia. Abstract presented at: 2004 Scientific Heart, Lung, and Blood Institute. National Insti- patients with primary hypercholesterolemia. Am Sessions of the American College of Cardiology. tutes of Health. NIH Publication No. 02-5215, J Med. 2001;110:352-360. March 7-10, 2004; New Orleans, La. September 2002. 10. Liamis G, Kakafika A, Bairaktari E, Miltiadous 16. Gagne C, Bays HE, Weiss SR, Mata P, Quinto K, 2. Worz CR, Bottoroff M. Treating dyslipidemic G, Tsimihodimos V, Goudevenos J, et al. Combined Melino M, et al; Ezetimibe Study Group. Efficacy patients with lipid-modifying and combination treatment with fibrates and small doses of atorva- and safety of ezetimibe added to ongoing statin therapies. Pharmacotherapy. 2003;23:625-637. statin in patients with mixed hyperlipidemia. Curr therapy for treatment of patients with primary Med Res Opin. 2002;18:125-128. hypercholesterolemia. Am J Cardiol. 2002;90:1084- 3. Pearson TA, Laurora I, Chu H, Kafonek S. The 1091. Lipid Treatment Assessment Project (L-TAP): a mul- 11. Davignon J, Roederer G, Montigny M, Hayden ticenter survey to evaluate the percentages of dys- MR, Tan MH, Connelly PW, al. Comparative efficacy 17. Pearson T, Denke M, McBride P, Battisti W, lipidemic patients receiving lipid-lowering therapy and safety of pravastatin, nicotinic acid and the Brady W, Palmisano J. Ezetimibe added to statin and achieving low-density lipoprotein cholesterol two combined in patients with hypercholes- therapy reduces LDL-C and improves goal attain- goals. Arch Intern Med. 2000:160:459-467. terolemia. Am J Cardiol. 1994;73:339-345. ment in patients with hypercholesterolemia. Abstract presented at: 2004 Scientific Session of 4. Neal PC, Jones PH. Lipid-lowering: can ezetimibe 12. Kashyap ML, McGovern ME, Berra K, Guyton JR, the American College of Cardiology. March 7-10, help close the treatment gap? Cleve Clin J Med. Kwiterovich PO, Harper WL, et al. Long-term safety 2004; New Orleans, La. 2003;70:777-783. and efficacy of a once-daily niacin/lovastatin for- mulation for patients with dyslipidemia. Am J Car- 18. Feldman T, Koren M, Insull W Jr, McKenney J, 5. Denke MA. Combination therapy. J Manag Care diol. 2002;89:672-678. Schrott H, Lewin A, et al. Treatment of high-risk Pharm. 2003;9:17-19. patients with ezetimibe plus simvastatin co-admin- 13. Sudhop T, von Bergman K. Cholesterol absorp- istration versus simvastatin alone to attain National 6. Genest J, Pedersen TR. Prevention of cardiovas- tion inhibitors for the treatment of hypercholes- Cholesterol Education Program Adult Treatment cular ischemic events: high-risk and secondary pre- terolemia. Drugs. 2002;62:2333-2347. Panel III low-density lipoprotein cholesterol goals. vention. Circulation. 2003;107:2059-2065. Am J Cardiol. 2004;93:1481-1486. 14. Davidson MH, McGarry T, Bettis R, Melani L, 7. Kastelein J. What future for combination ther- Lipka LJ, LeBeaut AP, et al. Ezetimibe coadminis- 19. Zetia (ezetimibe). Package insert. North Wales, apies? Int J Clin Pract Suppl. 2003:134:45-50. tered with simvastatin in patients with primary Pa: Merck/Schering-Plough Pharmaceuticals; 2003.

Denke • Coadministration of Multidrug Therapy to Achieve Lipid Goals JAOA • Supplement 7 • Vol 104 • No 9 • September 2004 • S21 20. Gaudiani L, Lewin A, Meneghini L, et al. Effi- 21. Davignon J, Montigny M, Dufour R. MMG- 23. Rudel LL. Preclinical and clinical pharmacology cacy and safety of ezetimibe coadministered with CoA reductase inhibitors: a look back and a look of a new class of lipid management agents. Am simvastatin versus simvastatin alone in thiazo- ahead. Can J Cardiol. 1992;8:843-864. J Manag Care. 2002;8(suppl):S33-S35. lidinedione-treated patients with type-2 diabetes. Abstract presented at: 2004 Scientific Sessions of the 22. Knopp RH. Drug treatment of lipid disorders. 24. Gervois P, Torra IP, Fruchart JC, Staels P. Reg- American College of Cardiology. March 7-10, 2004; N Engl J Med. 1999;341:498-511. ulation of lipid and lipoprotein metabolism by New Orleans, La. PPAR activators. Clin Chem Lab Med. 2000;38:3-11.

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The new 3-year continuing medical uing Medical Education, American education cycle of the American Osteo- Osteopathic Association, 142 E Ontario pathic Association (AOA) began Jan- St, Chicago, IL 60611-2864. uary 1, 2004. One way to earn CME AOA members who do not com- credit for this CME cycle is through plete the quizzes can still obtain one- the reading of AOA publications. half hour of Category 2-B credit for Nearly every of issue of JAOA— each issue of the JAOA and each sup- the Journal of the American Osteopathic plement by informing the AOA Divi- Association and all supplements to the sion of Continuing Medical Education JAOA carry CME quizzes. AOA mem- of the issues they read. Members can bers can earn 2 hours of Category 1-B obtain the same credit for reading The CME credit for each quiz they com- DO, The Whole Patient, and other med- plete and submit to the AOA Division ical publications. of Continuing Medical Education. For more information on earning AOA members can complete these CME credit by reading medical jour- quizzes electronically on DO-Online, nals, AOA members can call (800) 621- which is located at www.do-online.org 1773, Ext 8262, or (312) 202-8262; they AOA members can also fill in the quiz can send e-mail to drodgers @aoa- answers directly on the forms located net.org; or they can fax questions to inside the JAOA and its supplements. (312) 202-8200. In addition, AOA mem- They should then mail the completed bers can write to the AOA Division of quiz forms to the Division of Contin- Continuing Medical Education.

S22 • JAOA • Supplement 7 • Vol 104 • No 9 • September 2004 Denke • Coadministration of Multidrug Therapy to Achieve Lipid Goals