The Role of Non Statin Therapies in the Management of Atherosclerotic Heart Disease. Joel Rhyner, MS, PA-C Department of Cardiology Confluence Health

Transcription

1 The Role of Non Statin Therapies in the Management of Atherosclerotic Heart Disease Joel Rhyner, MS, PA-C Department of Cardiology Confluence Health

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8 Approach to Patient Groups Who may be Considered for Additional Therapy Writing Committee et al. JACC 2016;68: American College of Cardiology Foundation

9 2016 ACC Expert Consensus Decision Pathway: Patient with Stable Clinical ASCVD without Comorbidities (one of several settings for potential use of non-statin therapies for additional LDL-C lowering) Treat with maximal tolerated statin Achieve at least 50% LDL-C reduction If this reduction is not achieved, initiate patient clinician discussion and consider non-statins: LDL-C treatment threshold 100 mg/dl Try Ezetimibe first; consider BAS if TG <300 mg/dl PCSK9 inhibitor next If treatment objective achieved, follow lipids every 3-6 months If not, reassess medication adherence and lifestyle Lloyd-Jones D et al. J Am Coll Cardiol. 2016;68:

10 Ezetimibe (Zetia) Mechanism of action: Inhibits Niemann-Pick C1 like 1 (NPC1L1) protein; reduces cholesterol absorption in small intestine. FDA-approved indication(s): As adjunct to diet to: 1) TC, LDL-C, Apo B, non HDL-C in patients with primary hyperlipidemia, alone or in combination with a statin; 2) TC, LDL-C, Apo B, non HDL-C in patients with mixed hyperlipidemia in combination with fenofibrate; 3) TC, LDL-C with HoFH, in combination with atorvastatin or simvastatin; Dose: 10 mg PO daily, with or without food. Take either 2 hours before or 4 hours after BAS if used in combination. Mean % reduction in LDL-C : Monotherapy 18%; combination therapy with statin (incremental reduction) 25%

11 Ezetimibe (Zetia) Adverse effects: Monotherapy upper respiratory tract infection, diarrhea, arthralgia, sinusitis, pain in extremity; combination with statin nasopharyngitis, myalgia, upper respiratory tract infection, arthralgia, diarrhea. Drug drug interactions: cyclosporine, fibrates, BAS CV outcomes trials: IMPROVE-IT ( Prescribing considerations: Generally well tolerated. Generic available, cost and insurance coverage vary.

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13 PCSK9 inhibitors : Mechanism of action Human monoclonal antibody to PCSK9. Binds to PCSK9 and increases the number of LDL receptors available to clear circulating LDL.

14 PCSK9 inhibitors FDA-approved indication(s): Alirocumab and evolocumab: Adjunct to diet and maximally tolerated statin therapy to treat adults with HeFH or clinical ASCVD who need more LDL-C reduction. Evolocumab: Adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with HoFH who need more LDL-C reduction.

15 PCSK9 inhibitors Alirocumab (Praluent) Evolocumab (Repatha)

16 PCSK9 inhibitors : Dose and route of administration Alirocumab initiate 75 mg subcutaneously (SQ) every 2 weeks. If more LDL reduction needed, may dose to 150 mg every 2 weeks. Alternative starting dose is 300 mg SQ every 4 weeks. Evolocumab in primary hypercholesterolemia with established clinical ASCVD or HeFH, give 140 mg SQ every 2 weeks or 420 mg SQ once monthly in abdomen, thigh, or upper arm. In HoFH, give 420 mg SQ once monthly. To administer 420 mg, give 3 (140 mg) injections consecutively within 30 minutes.

17 PCSK9 inhibitors: Mean % LDL-C reduction Alirocumab when added to maximally tolerated statin therapy, alirocumab 75 mg or 150 SQ every 2 weeks LDL-C by an additional 45% and 58%, respectively. When added to maximally tolerated statin therapy Evolocumab 140 mg every 2 weeks or 420 mg SQ every 4 weeks, LDL-C by an additional 64% and 58%, respectively.

18 PCSK9 inhibitors: Adverse effects Alirocumab nasopharyngitis, injection site reactions, influenza. Evolocumab nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions. No evidence of increase in cognitive adverse effects observed in FOURIER or EBBINGHAUS

19 PCSK9 inhibitors: Drug drug interactions No clinically significant drug drug interactions identified for alirocumab or evolocumab.

20 PCSK9 inhibitors: CV outcomes trials Alirocumab ODYSSEY Outcomes (18,600 post-acs [4 52 weeks] patients on evidence-based statin therapy; Primary endpoint is CHD death, MI, ischemic stroke, or hospitalization for UA. Estimated study completion is December 2017). Evolocumab FOURIER (27,564 patients with prior MI, stroke, or PAD on atorvastatin 20 mg or equivalent; Demonstrated that addition of evolocumab reduced the primary endpoint of CV death, MI, stroke, revascularization or hospitalization for UA).

21 PCSK9 inhibitors: Considerations in prescribing Cost SQ administration Robust LDL-C reduction Refer to Cardiology/Lipid Specialist Burdensome prior authorization process

22 PCSK9 Inhibitors and Lipid / Lipoprotein Effects LDL-C is reduced about 50-60% with alirocumab or evolocumab Same % reduction in LDL-C is seen with appropriate dosing whenadded to diet alone, low and maximal dose statin or statin plus ezetimibe Patients with HeFH and nonfh respond the same HoFH patients respond about half as well, with mean reductions in LDL-C of 31% to evolocumab Other blood lipids: Decreases in Lp(a), Apo B, Non-HDL-C, Total cholesterol, triglycerides. Increase in HDL-C.

23 Bile acid sequestrants Mechanism of action: Non-absorbed, lipid-lowering polymer that binds bile acids in intestine and impedes their reabsorption. As the bile acid pool, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which conversion of cholesterol to bile acids. This causes demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG- CoA reductase, and the number of hepatic LDL receptors. These compensatory effects result in clearance of LDL-C from the blood, in turn resulting in serum LDL-C levels. Serum TG levels may or remain unchanged.

24 Bile acid sequestrants: Colesevelam 1) Adults, as adjunct to diet and exercise, to LDL-C with primary hyperlipidemia: monotherapy or in combination with statin; 2) Adults, as adjunct to diet and exercise, to improve glycemic control with type 2 diabetes mellitus; 3) Boys and post-menarchal girls, 10 to 17 years of age, with HeFH after failing an adequate trial of diet therapy (e.g., LDL-C remains 190 mg/dl; or LDL-C remains 160 mg/dl and there is a positive family history of premature CVD or 2 other CVD risk factors are present in the pediatric patient) to LDL-C levels: As monotherapy or in combination with statin. Cholestyramine, colestid: As adjunct to diet to LDL-C with primary hyperlipidemia.

25 Bile acid sequestrants: Dose and route of administration 1) Colesevelam: Tablets: 6 tablets PO once daily or 3 tablets PO twice daily; take tablets with a meal and liquid. Suspension: one 3.75-gram packet PO daily, or one gram packet PO twice daily; mixed powder with 4 8 ounces of water, fruit juice, or soft drink; take with meal g is equivalent to 6 tablets g is equivalent to 3 tablets; 2) Cholestyramine: 8 16 g/day orally divided into 2 doses; 3) Colestipol: 2 16 g/day orally given once or in divided doses.

26 Bile acid Sequestrants: Mean % LDL reduction Colesevelam: Monotherapy 15% (6 tablets daily); combination with low- to moderate-intensity statin additional 10% to 16% reduction in LDL-C (data from simvastatin 10 mg, atorvastatin 10 mg). Cholestyramine: Monotherapy 10.4% vs placebo. Colestipol: In dose-ranging RCT with monotherapy, doses of 5 g, 10 g, and 15 g resulted in 16.3%, 22.8%, and 27.2% reduction in LDL-C, respectively

27 Bile acid Sequestrants Adverse effects: Constipation, dyspepsia, and nausea. Postmarketing reports with colesevelam include seizure activity or phenytoin levels in patients receiving phenytoin, INR in patients receiving warfarin, TSH in patients receiving thyroid hormone replacement therapy, bowel obstruction, dysphagia, esophageal obstruction, fecal impaction, hypertriglyceridemia, pancreatitis, and increased transaminases Drug drug interactions: Drugs with potential interaction should be taken at least 1 hour before or 4 hours after BAS to avoid impeding their absorption.

28 Bile acid Sequestrants CV outcomes trials: LRC-CPPT (3,806 asymptomatic middle-aged men with primary hypercholesterolemia randomized to cholestyramine resin and versus placebo for an average of 7.4 years). Cholestyramine group experienced a 19% reduction in risk (p < 0.05) of the primary endpoint definite CHD death and/or definite nonfatal MI

29 Considerations in prescribing Bile Acid Sequestrants Pill burden Inconvenience in preparation of oral suspension preparations/taste/texture GI side effects Exacerbation of hypertriglyceridemia Colesevelam lowers HbA1c 0.5% in diabetes Limited CV outcomes data. Cost/Insurance Coverage

30 Plant Based Food Guide

31 Plant Based A plant-based vegetarian diet is associated with total cholesterol that s 29.2 mg/dl lower in observational studies. In clinical trials, a plant-based diet lowers total cholesterol by 12.5 mg/dl. In observational studies, a plant-based vegetarian diet is associated with a 22.9 mg/dl reduction in LDL cholesterol and a 3.6 mg/dl reduction in HDL cholesterol, compared to control groups following an omnivorous diet.

32 Plant Based Diet A plant-based vegetarian diet is not associated with statistically significant changes in triglyceride levels in observational studies or in clinical trials. Vegetarian diets and lower cholesterol levels may be due to the association a plant-based diet has with a lower body weight, a reduced intake of saturated fat, and an increased intake of plant foods, like vegetables, fruits, legumes, nuts, and whole grains, which are naturally rich in components such as soluble fiber, soy protein, and plant sterols.

33 Ketogenic Diet Ketogenic diets increase the concentrations of heart-healthy HDL cholesterol more than low-fat, high-carb diets. Lowering carbohydrate consumption in healthy individuals also leads to higher levels of HDL cholesterol. Low-carb, high-fat diets decrease LDL particle concentration (LDL- P) and increase the size of LDL cholesterol. Ketogenic diets decrease the amount of harmful VLDL cholesterol in the blood.

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35 Ketogenic Diet Replacing carbs with the fats that are commonly consumed on the ketogenic diet improve total-to-hdl cholesterol ratio. By replacing carbohydrates with stearic acid, lauric acid, monounsaturated fats, and polyunsaturated fats, total-to- HDL cholesterol ratio improves.

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38 DASH vs Mediterranean

39 DASH Diet Benefits Decreases cancer risk: A recent review found that people following the DASH diet had a lower risk of some cancers, including colorectal and breast cancer. Lowers metabolic syndrome risk: Some studies have shown that the DASH diet reduces your risk of developing metabolic syndrome by up to 81%. Lowers diabetes risk: Following the DASH diet has been linked to a lower risk of developing type 2 diabetes. Some studies have also shown that it can improve insulin resistance. Decreases heart disease risk: One recent review showed that in women, following a DASH-like diet was associated with a 20% lower risk of heart disease and a 29% lower risk of stroke.

40 Dietary Approaches to Stop Hypertension (DASH) It's a diet that's often recommended to people who want to prevent or treat hypertension (high blood pressure) and reduce their risk of heart disease. The DASH diet focuses on fruits, vegetables, whole grains and lean meats. The diet was designed after researchers noticed that high blood pressure was much less common in those who followed a plant-based diet, such as vegans and vegetarians, than in meat eaters. This led researchers to design a diet that provided liberal amounts of the nutrients that appeared to protect people against high blood pressure. The result was the DASH diet, which is high in fruits and vegetables and contains some lean protein sources like chicken, fish and beans. The diet is low in red meat, salt, added sugars and fat.

41 Modified DASH Diet Up to 8 servings (1/2 cup) of whole grains (not products made from flour) At least 5 vegetables At least 5 fruits Up to 3 servings of live-culture yogurt or cheese (optional) 2-3 servings of seafood per week Beans or legumes daily (no limit) A few handfuls of nuts or snack seeds daily A few tablespoons of olive oil daily(optional) Avoid: added sugars and other refined carbohydrates, limit red meat consumption

42 DASH Diet Sample Menu Breakfast: 1 cup (90 grams) of oatmeal with 1 cup (240 ml) of skim milk and 1/2 cup (75 grams) of raspberries. 1/2 cup (120 ml) of fresh orange juice. Snack: 1 medium banana. Lunch: Salad made with 4.5 ounces (130 grams) of grilled tuna, 1 boiled egg, 2 cups of green salad, 1/2 cup (38 grams) of cherry tomatoes, 2 tablespoons of low-fat salad dressing and 2 slices of whole wheat toast. Snack: 1/2 cup (30 grams) of fruit and 1 cup (285 grams) of low-fat yogurt. Dinner: 3 ounces (85 grams) of pork fillet with 1 cup (150 grams) of mixed vegetables and 1 cup (190 grams) of brown rice

43 Mediterranean Diet Do s Use olive oil abundantly for cooking, and for seasoning dishes ( Eat 2 or more servings of vegetables every day, with at least one serving fresh in a salad Eat at least 2-3 daily servings of fresh fruit ( including natural juices ) Eat at least 3 servings per week of legumes Eat at least 3 servings of fish or seafood, including at least one serving of fatty fish Eat at least one weekly serving of nuts or seeds Eat white meat (chicken, rabbit) instead of red meat, burgers, sausages, or processed meat Cook at least twice weekly with a sauce of tomato, onion, and garlic, which should be made by simmering these ingredients in olive oil. Use this as dressing for vegetables, pasta, rice, and other dishes. Eat two main meals of the day seated at the table; each should last at least 20 minutes Use wine as main alcohol, drink 1-3 glasses per day Consume the following foods as desired: nuts, eggs, fish, seafood, low-fat cheese, dark chocolate, and wholegrain cereals.

44 Mediterranean Diet Don ts: Limit or avoid cream, butter, margarine cold meats, pâté, duck carbonated or sweet beverages pastries, cakes, donuts, cookies, puddings, custards, especially if industrially produced fries and potato chips Aim for less than one serving per week of cured ham, red meat, and fatty cheeses.

45 Soluble/Viscous fiber Mechanism of action: Trapping of cholesterol and bile acids in the small intestine, resulting in absorption/reabsorption. FDA-approved claims: Soluble fiber as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease. Dose and route of administration: Food source must be low in saturated fat and cholesterol, and include 1 or more of the following whole oat or barley foods: 1) oat bran, 2) rolled oats, 3) whole oat flour, 4) whole grain barley or dry milled barley.

46 Soluble/Viscous fiber Mean % LDL-D reduction: With intake of g/day, mean TC and LDL-C levels were relative to control by 9.7 and 11.6 mg/dl, respectively. Adverse effects: Few safety concerns.

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56 Who/When To Refer? Baseline LDL-C 190 mg/dl (HeFH or HoFH) Very high risk for ASCVD and LDL-C>100 mg/dl, despite being on maximally tolerated statin therapy Complex lipid disorders (High TG, Low HDL) Statin intolerance or multiple lipid medication intolerances Telemedicine an option!