18th Annual Primary Care & Cardiovascular Symposium Lipids in Primary Care Jose R Valery, MD 18th Annual Primary Care & Cardiovascular Symposium May 18, 2017

Disclosures Disclosures = None

Objectives Background Primary prevention Secondary prevention Statin monitoring Statin intolerant patients

Background Part I

Coronary Risk and Cholesterol Levels Epidemiologic studies have shown that there is a graded relationship between total cholesterol levels and atherosclerotic cardiovascular disease (ASCVD).

Data from: Stamler J, Wentworth D, Neaton JD Data from: Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screens of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 1986; 256:2823.

Data from: Pekkanen J, Linn S, Heiss G, et al Data from: Pekkanen J, Linn S, Heiss G, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990; 322:1700.

Classification of Cholesterol and Triglyceride Levels 2014 National Lipid Association (NLA) Guidelines Non-­‐HDL-­‐C (Total C -­‐ HDL-­‐C) <130 mg/dL Desirable 130-­‐159 Above Desirable 160-­‐189 Borderline High 190-­‐219 High ≥220 Very high LDL-­‐C <100 mg/dL 100-­‐129 ≥190 Very High HDL-­‐C <40 mg/dL (men) Low <50 (women) Triglycerides (VLDL-­‐C) <150 mg/dL Desirable 150-­‐199 Borderline High 200-­‐499 High ≥500 Very High J Clinical Lipidology 2014;8:473-­‐488

Intensity of Statin Therapy High Intensity Moderate Intensity Lower Intensity Lowers LDL-C ≥50% Lowers LDL-C 30-50% <30% Atorvastatin (40) 80 mg Atorvastatin (10) 20 mg Simvastatin 10 mg Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 10-20 mg Simvastatin 20-40 mg Lovastatin 20 mg Pravastatin 40 (80) mg Fluvastatin 20-40 mg Lovastatin 40 mg Pitavastatin 1 mg Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 2-4 mg

Lifestyle Changes By how much does diet lower cholesterol? United Kingdom Lipid Clinics Program study of 2508 patients showed an average reduction of 5-7% in LDL levels with dietary modification alone 2003 Jenkins et al. showed that marked dietary change can lower LDL-C by as much as 30 Percent

Lifestyle Changes BUT… So, we can lower cholesterol with diet alone, but what about CV events? The Multiple Risk Factor Intervention Trial (MRFIT) of 12,866 high-risk men dietary advice did not significantly reduce CHD mortality (1.8 versus 1.9 percent) or all-cause mortality (4.1 versus 4.0 percent) BUT… differences in achieved total cholesterol levels between the groups (generally 5 to 10 mg/dL [0.13 to 0.26 mmol/L]) were probably too small to expect significant effects on mortality.

Lifestyle Changes 7447 subjects (average age 67 yrs, 57% women): 3 groups randomized: Med Diet 1 (with extra-virgin olive oil supplements) Med Diet 2 (with mixed nuts supplements) Control Diet (advise to lower fat content) Followed for 4.8 yrs for endpoint of major CV events (MI, stroke, CV death)

Primary Prevention of Cardiovascular Disease with the Mediterranean Diet

Minimal running of 5 to 10 min/day reduced mortality from: all-cause (30%) cardiovascular disease (45%) could add 3 years of life expectancy from a 15-year follow-up of 55,137 adults at the Cooper Clinic in Dallas, Texas

J Am Coll Cardiol. 2014;64(5):482-­‐484

Primary Prevention Part 1

Primary Prevention Treatment of lipids in patient who do not have: Coronary heart disease History of myocardial infarction Angina Prior coronary revascularization Other cardiovascular disease Symptomatic carotid artery disease Peripheral vascular disease Abdominal aortic aneurysm Combinations of risk factors that result in a 10- year risk of CVD events of more than 20 percent Familial hypercholesterolemia

Nonstatin therapy in primary prevention Year Study Population Demographics Intervention Comparison Outcome 1979 WHO Cooperative Trial 10,577 pts Gender – only men Age – 46 to 55 TC – 248 to 290 HDL – 46 TG – 159 to 177 BP 121/80 – 141/90 Smokers – 36 to 56 Clofibrate Placebo Reduction in coronary events No reduction in CV mortality, Increase in mortality from non-CV causes 1984 Lipid Research Clinics Coronary Primary Prevention Trial 3806 pts Cholestyramine 1987 Helsinki Heart Study 4081 Gemfibrozil

Nonstatin therapy in primary prevention Year Study Population Demographics Intervention Comparison Outcome 1979 WHO Cooperative Trial 10,577 pts Gender – only men Age – 46 to 55 TC – 248 to 290 HDL – 46 TG – 159 to 177 BP 121/80 – 141/90 Smokers – 36 to 56 Clofibrate Placebo Reduction in coronary events No reduction in CV mortality, Increase in mortality from non-CV causes 1984 Lipid Research Clinics Coronary Primary Prevention Trial 3806 pts Cholestyramine 1987 Helsinki Heart Study 4081 Gemfibrozil

Effect of early clinical trials on mortality Year Study Demographics Intervention Comparison Outcome 1995 West of Scotland Coronary Prevention Study (WOSCOPS) 6595 pts Men Age 45 to 64 TC > 252 LDL > 155 Pravastatin 40mg/day Placebo 26% ↓ LDL CV death ↓ 32 % Total mortality ↓ 22% No difference in non CV death 2001 Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS trial) 6605 pts (997 women) LDL 150 TC 221 Lovastatin 20-40 mg/day 25% ↓ LDL Risk of first acute CV event ↓ 37 % No decrease in total mortality 2003 The Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) 10305 pts (1942 women) LDL 131 TC 213 Atorvastatin 10mg/day 35% ↓ LDL CV events ↓ 36% WOSCOPS – Treatment effect was the same regardless of the baseline lipid concentration and the reduction in the LDL-C concentration, 30% reduction in the risk of developing diabetes diabetes

Effect of early clinical trials on mortality Year Study Demographics Intervention Comparison Outcome 2007 The Measuring Effects on Intima-Media Thickness (METEOR) 984 pts Men 45 to 70 Women 55 to 70 TC > 252 LDL 120 to 190 Rosuvastatin 40mg/day Placebo 49% ↓ LDL Stabilized intima-media thickness but not done to study clinical outcomes 2008 The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) 17802 pts Men > 50 Women > 60 LDL < 130 Rosuvastatin 20mg/day 50% ↓ LDL Risk of first acute CV event ↓ 44 % 20 % ↓ in total mortality No difference in non CV death Slightly higher rate of diabetes in treatment arm 2016 The Heart Outcomes Prevention Evaluation (HOPE)-3 12708 pts Intermediate risk Rosuvastatin 10mg/day CV events/mortality ↓ 23% WOSCOPS – Treatment effect was the same regardless of the baseline lipid concentration and the reduction in the LDL-C concentration, 30% reduction in the risk of developing diabetes diabetes

Effect of early clinical trials on mortality Year Study Demographics Intervention Comparison Outcome 2007 The Measuring Effects on Intima-Media Thickness (METEOR) 984 pts Men 45 to 70 Women 55 to 70 TC > 252 LDL 120 to 190 Rosuvastatin 40mg/day Placebo 49% ↓ LDL Stabilized intima-media thickness but not done to study clinical outcomes 2008 The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) 17802 pts Men > 50 Women > 60 LDL < 130 Rosuvastatin 20mg/day 50% ↓ LDL Risk of first acute CV event ↓ 44 % 20 % ↓ in total mortality No difference in non CV death Slightly higher rate of diabetes in treatment arm 2016 The Heart Outcomes Prevention Evaluation (HOPE)-3 12708 pts Intermediate risk Rosuvastatin 10mg/day CV events/mortality ↓ 23% WOSCOPS – Treatment effect was the same regardless of the baseline lipid concentration and the reduction in the LDL-C concentration, 30% reduction in the risk of developing diabetes diabetes

So, who do I treat with statins? These studies show a cardiovascular benefit of around 20-30% statin therapy. Absolute risk reduction will be larger in higher risk patients.

Calculating Risk ACC/AHA Pooled Cohort Calculator 2013 -Diabetes is a yes/no question. -Does not consider family history

Calculating Risk Framingham (2008) -Does not consider family history -May underestimate risk

Calculating Risk Reynolds -Diabetes is a yes/no question -Does consider family history and can include high sensitivity CRP

Guidelines ACC/AHA makes the following recommendations for adults ages 40 to 75 without known cardiovascular disease (CVD) and low-density lipoprotein cholesterol LDL between 70 and 189

Guidelines In those without diabetes If 10-year CVD risk ≥7.5%: moderate-to-high intensity statin therapy. It is reasonable to offer treatment with moderate intensity statin therapy to those with an estimated 10-year CVD risk between 5.0 and 7.5 percent

Summary There is a graded relationship between cholesterol levels and risk of atherosclerotic cardiovascular disease Diet and exercise are effective. Recommending a specific diet such as the mediterranean diet may be more effective than simply advising the patient to eat a “low cholesterol” diet. For primary prevention, calculate a patient’s 10- year risk of ASCVD at least every 5 years using one of the available calculators together with your clinical judgement.

Summary Once you calculate the 10 year risk, weigh risks and benefits of statin therapy with your patient. RRR with moderate intensity statin therapy in primary prevention is around 20-30%, the larger the absolute risk, the larger the impact. Recommend treatment who have a high absolute risk (>5 - 7.5%)

Thank You! Questions? Email: valery.jose@mayo.edu

Guidelines Guidelines for lipid management for primary prevention of CVD from the United Kingdom's National Institute for Health and Clinical Excellence (NICE): For patients with an estimated 10-year CVD risk ≥10 percent based on known risk factors, use a risk calculator to more formally assess risk Patients should be informed about the absolute risks and benefits of 10 years of therapy Other CVD risk factors should be optimized if possible Patients with a 10-year risk of CVD of 10 percent or more should be offered statin therapy

Secondary prevention Part 2

Question 4 Which of the following statements is true? Statins can reverse atherosclerosis Statins can slow progression of atherosclerosis Non statins can reverse atherosclerosis Statins lead to changes in existing atheromatous lesions that stabilize them to prevent plaque rupture All of the above are true

Question 4 Which of the following statements is true? Statins can reverse atherosclerosis Statins can slow progression of atherosclerosis Non statins can reverse atherosclerosis Statins lead to changes in existing atheromatous lesions that stabilize them to prevent plaque rupture All of the above are true

Studies Showing Improvement in Atherosclerosis

Effect of early clinical trials on mortality Study Demographics Intervention Comparison Outcome CLAS Trial 188pts s/p CABG Colestipol 30g/d + nicotinic acid 3-12g/d Placebo Regression of atherosclerosis Slowed progression REGRESS Trial 885 male pts Pravastatin 40mg/d LCAS 429 pts w/CHD Fluvastatin BECAIT Trial 92 male pts h/o MI Bezafibrate GAIN Trial 131 pts Atorvastatin Reduced progression Increased plaque stability (from lipid rich to fibrous/calcified) REVERSAL Trial 654 pts Atorvastatin 80 Pravastatin 40 Atorvastatin better at halting progression ARBITER 2 Study Niacin Halted progression ASTEROID Trial 507 pts w/CAD Rosuvastatin 40d Historic cohort Showed regression of lesions SATURN Trial 1039 pts Rosuvastatin 40 Similar effects on atherosclerotic lesions WOSCOPS – Treatment effect was the same regardless of the baseline lipid concentration and the reduction in the LDL-C concentration, 30% reduction in the risk of developing diabetes diabetes

Studies showing improvement in clinical outcomes

Effect of early clinical trials on mortality Study Demographics Intervention Comparison Outcome 4S 4444 pts w/CHD Simvastatin 20-40/d Placebo Mortality ↓ 25% CHD Death ↓ 42% No ∆ in non-CV death LIPID Trial 9014 pts w/CHD Pravastatin 40mg/d Mortality ↓ 21.4% CHD Death ↓ 23% TNT Trial 10000 pts Atorvastatin 10 w/goal LDL < 100 Atorvastatin 80 w/goal LDL < 75 No reduction in overall mortality SEARCH Trial 12064 pts Simvastatin 80 Simvastatin 20 No difference in primary outcome 7x higher myopathy in high dose group CARE Trial 4159 pts Pravastatin 40 Mortality ↓ 30% ACCORD 5518 pts w/T2DM Fenofibrate + simvastatin Simvastatin No difference in primary endpoint or mortality ASPEN Trial 2410 pts w/T2DM Atorvastatin 10 No change although many patient in “placebo” group started on statin during study IMPROVE IT 18144 pts w/ACS w/I 10 days Simvastatin + ezetimibe MI ↓ 13%, no change in mortality WOSCOPS – Treatment effect was the same regardless of the baseline lipid concentration and the reduction in the LDL-C concentration, 30% reduction in the risk of developing diabetes diabetes

Meta Analyses: statins in patients with CHD 17,617 patients in the 4S, CARE, and LIPID trials: major coronary events ↓ 30% cardiovascular mortality ↓ 27% all-cause mortality ↓ 23% no effect on non cardiovascular mortality risk reduction was similar for men and women and for older adults and middle-aged persons. 25,000 subjects (34 trials) four years of cholesterol-lowering therapy would prevent one death for every 110 patients treated one CHD death for every 96 patients treated one cardiovascular death for every 117.

Diabetic Patients Is diabetes a “cardiovascular risk” equivalent? this averages events across patients with widely differing risks of CHD Issues that affect risk with DM include age, sex, other CV risk factors, duration of DM, and whether the patient has type 1 or type 2 DM. > 1.5 million adults followed for 10 years lower rate of new CHD events in patients with DM than in those with a prior CHD event (12.2 versus 22.5 events per 1000 person-years) the risk of events was similar to that with prior CHD only in patients who had DM for more than 10 years.

Diabetic Patients The following patients with DM have a similar risk those with known CVD: Men > 40 with type 2 DM and any other CHD risk factor, or over age 50 with or without other CHD risk factors Women > 45 with type 2 DM and any other CHD risk factor, or over age 55 with or without other CHD risk factors Men or women of any age who have had DM (type 1 or type 2) for more than 20 years if they have another risk factor or more than 25 years without another risk factor A meta-analysis of 18,686 pts with diabetes in 14 randomized trials of statins (n = 18,686) found that relative benefits appeared unrelated to the baseline LDL-C [29].

Secondary Prevention Guidelines All patients should be counseled to exercise, eat a prudent diet, and lose weight as appropriate. Patients with ACS should be treated aggressively with atorvastatin 80 mg daily (avoid “tapering up”) In patients with CVD treat with an intensive dose of a statin independent of the baseline LDL-C LDL-C goal in secondary prevention is controversial.

STATIN MONITORING Part III

Question 5 Which of the following statins have the largest impact on LDL? Atorvastatin Pravastatin Rosuvastatin Simvastatin

Question 5 Which of the following statins have the largest impact on LDL? Atorvastatin Pravastatin Rosuvastatin Simvastatin

Statin Pearls Largest drop in LDL: Rosuvastatin, atorvastatin, and simvastatin. ESRD: use atorvastatin or fluvastatin. No dose adjustment req’d. Chronic liver disease: Abstain from alcohol and use low dose pravastatin. Fewer pharmacokinetic drug interactions are likely to occur with: pravastatin, fluvastatin, rosuvastatin, and pitavastatin (Not CYP3A4) Pravastatin and fluvastatin appear less likely to cause muscle toxicity than other statins. Check baseline aminotransferase levels and CK levels prior to initiating statin therapy routine monitoring not necessary. Check a TSH level prior to initiating statin therapy.

STATIN INTOLERANT PATIENTS Part IV

Statins and Muscles Myalgias and myopathy occur with a frequency of 2 to 11 percent. Severe myonecrosis and clinical rhabdomyolysis are rare (0.5 percent and less than 0.1 percent, respectively). Patients can experience statin-induced myalgias without an elevation in serum creatine kinase (CK) concentration. Risk is increased when taking statin that is extensively metabolized by cytochrome P450 3A4 (lovastatin, simvastatin, atorvastatin) .

Statins and Muscles Pravastatin, fluvastatin, rosuvastatin, and pitavastatin are preferred when concurrent therapy with a strong inhibitor of CYP3A4 cannot be avoided. Grapefruit juice inhibits CYP3A4; however, daily consumption of eight ounces or less of grapefruit juice, or one-half of a grapefruit or less, is unlikely to increase the risk of an adverse interaction or muscle injury. Patients on gemfibrozil who need a statin, treat with pravastatin or fluvastatin. However, patients who require combined therapy with a statin (including pravastatin or fluvastatin) and a fibrate, it is suggested to use fenofibrate rather than gemfibrozil.

Statins and Muscles Enhanced susceptibility to statin-associated myopathy occurs in patients with acute or chronic renal failure, obstructive liver disease, and hypothyroidism. Muscle symptoms usually begin within weeks to months after starting statins. Myalgias, weakness, and serum CK concentrations usually return to normal over days to weeks after drug discontinuation. Some patients can have muscle symptoms from statin therapy without an elevation in serum CK, and it can then be difficult to be certain whether muscle symptoms are due to statin therapy.

Statins and Muscles Clinical judgment is necessary in interpreting elevated CK levels in patients on statins. CK elevations can be related to hypothyroidism or muscle injury during sports Routine monitoring of CK levels is not recommended. It is useful to obtain a baseline CK level for reference. In patients who develop evidence of muscle toxicity while on statin therapy, we assess for drug interactions, and if none are noted, we check vitamin D and thyroid function status.

Statins and Muscles Pravastatin and fluvastatin appear to have much less intrinsic muscle toxicity than other statins. Thus, in patients who have developed statin myopathy (other than rhabdomyolysis) on a statin other than pravastatin or fluvastatin, we suggest switching to one of those two medications once symptoms have resolved off statin therapy. In patients who are unable to tolerate daily dosing of pravastatin or fluvastatin, it is suggested to try alternate-day or less frequent dosing of statin therapy. There is no convincing outcomes data regarding the use of CoQ10 for treatment or prevention of statin myopathy.

Statin Intolerant Patients In primary prevention No lipid-lowering therapy should be administered. Potential interventions include lifestyle modification and, in higher-risk patients, antiplatelet therapy. In the highest-risk patients (10-year risk of events of approximately 20 percent or more), if statin myopathy has been carefully assessed and statin therapy is not possible, treatment with a PCSK9 inhibitor may be an option.

Statin Intolerant Patients In secondary prevention Standard-risk patients with CVD who do not tolerate a statin: Consider treatment with another class of lipid-lowering therapy In higher-risk patients who do not tolerate any statin regimen: Consider treatment with a proprotein convertase subtilisin kexin 9 antibody (PCSK9-ab).

Targets of Therapy - Triglycerides . . n (a' -:::.-:..-:- - ... . ' . , ' Targets of Therapy - Triglycerides An elevated triglyceride level is not a target of therapy per se, except when very high (severe; 500 mg/dl ). When triglycerides are between 200-499 mg/dl, the targets of therapy are non-HDL-C and LDL-C. When the triglyceride concentration is very high ( 500 mg/dl, and especially if 1000 mg/dl), reducing the concentration to <500 mg/dl to prevent pancreatitis becomes the primary goal of therapy. 20 www lipid org

What is PCSK9 ?Answer: Proprotein convertase subtilisin/ kexin 9 Antibody to PCSK9 PCSK9 regulates the number of LDL receptors on the cell surface. PCSK9 inhibitors result in more LDL receptors recycled to cell surface.

PCSK9 Inhibitors Alirocumab ‘Praluent’ ODYSSEY Long Term PCSK9 Inhibitors Evolocumab ‘Repatha’ OSLER Trial

Both Published March 15, 2015 NEJM ODYSSEY Long Term Both Published March 15, 2015 NEJM (~60% ↓ LDL-­‐C) OSLER Trials

CV Events in Long Term PCSK9 Trials (Post hoc analysis…exploratory) CV Events Reduced ~50% J Am Coll Cardiol. 2015;65(24):2638-2651. doi:10.1016/j.jacc.2015.05.001

Adverse Side Effects of PCSK9 Inhibitors Injec\on site reac\ons (erythema, pruritus, swelling tenderness) Nasopharyngi\s Possible neurocogni\ve adverse reac\ons Confusion Memory impairment

(2015) FDA Approved Indica0ons for An0-­‐PCSK9 Monoclonal An0bodies in Addi0on to Diet and Maximally Tolerated Sta0n Therapy for Additional LDL-­‐C Lowering Clinical ASCVD* Heterozygous FH Homozygous FH Evolocumab (Repatha) + Alirocumab (Praluent) -­‐ *Clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revasculariza\on, stroke, TIA, or PAD ACC Expert consensus (May, 2016): eze\mibe should be the first-­‐line and PCSK9 inhibitors second-­‐line choice for high risk ASCVD pa\ents who con\nue to have high LDL-­‐C despite maximally tolerated sta\n therapy

Willingness-­‐ to pay threshold $5,404 / year Willingness-­‐ to pay threshold $3,166 / year

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Aspirin for Primary Prevention New 2016 USPSTF RecommendaHon Adults 50-­‐59 years with ≥ 10-yr CVD risk Return

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References UpToDate articles: Primary & Secondary Prevention of ASCVD, Frank G. Yanowitz, MD