Case Studies in Lipid Management

Transcription

1 Case Studies in Lipid Management Jeffrey Boord, MD, MPH Advances in Cardiovascular Medicine Kingston, Jamaica December 6, 2012 VanderbiltHeart.com

2 Case 1- Adult with severe hypercholesterolemia 37 year old female with hypercholesterolemia, tobacco use, presents with chest pain and dyspnea. Cardiac catheterizalon reveals 3 vessel CAD requiring CABG FasLng lipid profile at baseline: Chol (mg/dl)- 350, TRG- 100, HDL- 50, LDL- 280

3 The palent is started on simvastaln 40 mg daily, and returns to your office 6 weeks later for follow up. Labs: cholesterol 239, HDL 45, trig. 120, LDL 170 mg/dl What do you do next?

4 StaLn and AdjuncLve Therapy vs StaLn TitraLon 6% 6% 6% Statin at starting dose 1st 2nd 3rd 3-STEP TITRATION Doubling 18% Statin at starting dose + GI-acting drug or niacin 1-STEP COADMINISTRATION % Reduction in LDL-C Adapted from: Bays H, et al. Expert Opin Pharmacother. 2003;4:

5 CombinaLon therapy with stalns for LDL reduclon Drug Pros Cons Bile Acid Resins Nonsystemic Cheap (generics) Good synergy with statins GI intolerance Impairs absorption of meds (except colesevelam) Can increase TRG Niacin Ezetimibe Raises HDL, lowers LDL, and lowers TRG Long acting preparations available Cheap (OTC preparations) Good synergy with statins Well tolerated Minimal systemic exposure/ drug interact. Flushing, glucose intolerance, itching?slight increase in myopathy risk with statin Potential liver toxicity (rare) Expensive Limited data- unproven benefit for CV events

6 Case 58 year old male with CAD s/p MI 5 years ago, hypertension, obesity, and impaired faslng glucose, presents for evalualon Weight 223 pounds, BMI 34 Current medicalons- ASA, atenolol, lisinopril, HCTZ Baseline lipid profile Cholesterol 216 mg/dl HDL 25 Triglycerides 489 Non- HDL Cholesterol 191 Direct LDL 97

7 In addilon to lifestyle measures, which of the following agents would you prescribe? 1. A staln 2. A fibrate (gemfibrozil or fenofibrate) 3. Niacin 4. Nothing, because his direct LDL is <100

8 Part 2 Lipid profile ager 8 weeks on pravastaln 40 mg Cholesterol 152 mg/dl, HDL 23, Triglycerides 349, LDL 59 non- HDL cholesterol 129 What do you do next? 1. ConLnue with pravastaln 40 mg daily 2. Convert to atorvastaln 80 mg daily 3. Add a fibrate (fenofibrate) 4. Add fish oil 5. Add niacin

9 Key Fibrate Clinical Trials Trial Subjects Fibrate Primary end point Primary end point entire cohort (p value) Metabolic subgroups Primary end point subgroups (p value) HHS Non-HDL-C >201 Gemfibrozil MI/sudden cardiac death 3.4% (0.02) Triglyceride >204, LDL-C/ HDL-C>5 71% (0.005) VA-HIT FIELD ACCORD Lipid CHD, HDL-C 39 T2DM receiving statin T2DM + CVD or 2 CV risk factors receiving simvastatin Gemfibrozil Fenofibrate Fenofibrate Non-fatal MI/CHD death Non-fatal MI/CHD death Non-fatal MI/non-fatal stroke/cv death 22% (0.006) 11% (0.16) 8% (0.32) Diabetes Triglyceride 204, HDL-C <43 32% (0.004) 27% (0.005) Triglyceride 204, HDL-C 32% (0.06) 34 Adapted from: Watts and Karpe, Heart 2011;97:

10 Fish Oil PreparaLons Capsules available containing >1000 mg omega- 3 fajy acids, including: Eicosapentaenoic acid (EPA) Docosahexaenoic acid (DHA) TG benefits usually associated with combined dose of EPA + DHA of 2-4 g/d (equivalent to 6-9 capsules/d of most OTC preparalons) Side effects include fishy agertaste and dyspepsia May be improved by refrigeralon prior to administralon May impair platelet aggregalon and increase bleeding Lme No significant increase in risk of bleeding in clinical trials with ASA or Warfarin Flaxseed Oil is an alternalve source of omega- 3 FA PrescripLon fish oil (Lovaza)- dose 2-4 capsules/day Bays HE, et al. Expert Opin Pharmacother. 2003;4: Kris-Etherton PM, et al. Circulation. 2002;106:

11 Pearls for combinalon therapy Avoid fibrates in moderate to severe renal insufficiency (Cr > or CrCl<45 ml/min) Gemfibrozil inhibits glucuronidalon- increases levels of all stalns except fluvastaln Fenofibrate does not appear to inhibit staln glucuronidalon to degree that gemfibrozil does Can use lower dose fenofibrate (45 mg, 96 mg) Fenofibrate can cause an increase in serum crealnine level, good idea to check baseline and post- inilalon Cr levels Use the lowest dose of staln needed to get to LDL goal when using staln+fibrate therapy When adding a second agent for trigs consider fish oil or niacin instead of a fibrate for palents at increased risk for toxicity

12 Case- Refractory Hypertriglyceridemia 45 year old female with type 2 diabetes, asthma, arthrils, migraines, presents to clinic for evalualon of high triglycerides. She was hospitalized 3 months prior with pancrealls with a triglyceride level of 2500 mg/dl. She has been on gemfibrozil 600 mg BID for several years. She recently had simvastaln added to her regimen. She has been post- menopausal s/p TAH/BSO for cervical cancer 16 years ago, with no history of recurrence. MedicaLons: SH Amitriptyline Smokes 1 ppd Conjugated Estrogens mg qd Celecoxib Gemfibrozil 600 mg bid FH SimvastaLn 10 mg qd brother- hypertrig. Glyburide 5 mg bid Father- DM and CAD Meoormin 1000 mg bid Lipid profile: Cholesterol 319, TRG 1406, HDL 53 HbA1c= 7.9%

13 Suspect a Secondary Cause if: New onset or progressive hyperlipidemia in palent without a family history of dyslipidemia Worsening lipid profile in palent with primary hyperlipidemia without change in lifestyle or drug adherence Refractory hyperlipidemia Acute exacerbalon in palent with previously mild hyperlipidemia Remember- A common cause of poor lipid control is medica:on noncompliance Common Secondary Causes: Drugs: Diet: Steroids Cyclosporine, sirolimus, tacrolimus Oral estrogens ReLnoids Alcoholism high fat diet/weight gain Diseases: NephroLc syndrome hypothyroidism Disorders of Metabolism: Uncontrolled Diabetes Pregnancy Adapted From: Stone, NJ Med Clin NA 1994:78:117

14 Case 59 year old female with severe hyperlipidemia, CAD with prior MI, carold stenosis, CHF, type 2 diabetes presents for evalualon Cholesterol 270, HDL 35, triglycerides 440, direct LDL 167 mg/dl CreaLnine 1.5, est. GFR 47 ml/min She reports a prior intolerance to stalns that caused severe myalgia VanderbiltHeart.com

15 StaLns and myopathy The great majority of palents that have myopathy have myalgia without CPK elevalon. History is key to diagnosis Many other condilons can mimic symptoms ajributed to staln associated myopathy (neuropathy, PAD, severe vitamin D deficiency, polymyalgia rheumalca, arthrils) Most severe myopathy from stalns occurs in palents at increased risk for the condilon Incidence of severe myopathy (myalgia with CPK >10 ULN) is about % with staln monotherapy in large clinical trial databases, incidence of rhabdomyolysis requiring hospitalizalon is 4.4 out of every 100,000 people/year* * Graham DJ, et al JAMA. 2004;292:

16 Risk Factors for StaLn- Associated Myopathy: Drug Metabolism and InteracLons Concomitant meds: Fibrates Nico:nic acid (rarely) Cyclosporine Azole an:fungals Itraconazole, ketoconazole Macrolide an:bio:cs Erythromycin, clarithromycin HIV protease inhibitors Nefazodone (an:depressant) Verapamil/dil:azem Amiodarone Large quan::es of grapefruit juice (>1 qt/d) Alcohol abuse Drug Metabolism pathway T ½ (h) Renal excretion (%) Atorvastatin CYP3A Fluvastatin, Fluvastatin XL CYP2C (4.7 XL) Lovastatin CYP3A Pravastatin sulfation Rosuvastatin CYP2C Simvastatin CYP3A Pitavastatin Minor CYP2C9 Pasternak RC et al. J Am Coll Cardiol. 2002;40: Table adapted from: Bolego, C et al. Curr Opin Lipidol 2002, 13: Yee, LL et al. Clin Ther 2011, 33:

17 My approach to staln- associated myopathy Careful medicalon and symptom history Any underlying condilons that may mimic or exacerbate myopathy symptoms? Have non- staln agents been tried? Has the palent tried a different preparalon and/or alternate day dosing? VanderbiltHeart.com

18 ACC/AHA/NHLBI Clinical Advisory on the use and safety of stalns RouLne monitoring of CK is of lijle value in the absence of clinical signs and symptoms in palents on staln therapy ATP- III guidelines do recommend measurement of baseline CK, because asymptomalc baseline elevalons of CK are common Obtain a CK and TSH in palents with muscle symptoms that are suggeslve of myopathy If a palent experiences muscle symptoms with either no or a moderate (3-10x ULN) elevalon of CK, follow the palent s CK and muscle symptoms unll situalon declares itself Some asymptomalc palents can have moderate (3-10x ULN) elevalons in CK. Such palents can usually be treated with a staln without harm. However, careful clinical monitoring and more frequent CK measurements are indicated Pasternak RC et al. J Am Coll Cardiol. 2002;40:

19 Novel therapeu:c agents for LDL reduc:on in development Mipomersen- anlsense oligonucleolde inhibitor of apo B100 Lomitapide- oral inhibitor of microsomal transfer protein PCSK9 Inhibitors monoclonal anlbody or anlsense oligonucleolde leading to increased LDL- receptor aclvity Nat Rev Cardiol 2011;8: Pharmacol & Ther 2012;135: 31-43

20 Case 47 year old male with a history of hypertension, obesity, impaired faslng glucose presents to your clinic Cholesterol: 289, HDL 31, Trig 320, LDL 194 mg/dl FasLng glucose 118 mg/dl AST 97 (4-40), ALT 104 (4-50), bili 1.0, Alk Phos 160 (70-190) How should his dyslipidemia be managed? VanderbiltHeart.com

21 StaLns and Hepatotoxicity High dose therapy carries slightly higher risk of transaminase elevalon, but any staln can cause tranaminase elevalon (or significant liver injury- very rarely) Many palents with abnormal transaminases on therapy have underlying nonalcoholic fajy liver disease (NAFLD)- this is not a contraindicalon to therapy PaLents with NAFLD have increased CVD mortality, and thus are more likely to benefit from stalns Generally speaking, compensated chronic liver disease/cirrhosis is not a contraindicalon to staln therapy. StaLns should be avoided in palents with decompensated cirrhosis and acute liver failure Though roulne liver enzyme monitoring is recommended in the prescribing informalon for stalns, there is no clear evidence that this actually improves palent safety NLA Statin Safety Task Force Liver Expert Panel, Am J Cardiol 2006;97 (suppl): 77C-81C