Hyperlipidemia

Saudi Diploma in Family Medicine Center of Post Graduate Studies in Family Medicine
Presented by: Dr. Zekeriya Aktrk zekeriya.akturk@gmail.com www.aile.net

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Top 10cause of Death in K.S.A.

Top 10cause of Death in K.S.A.

30 %

Cardiovascular diseases (CVD) are the main cause of morbidity and mortality among the Saudi population1 A significant proportion of hospital admissions is due to CVD, whether acute or chronic or to cardiac procedures including angiograms2

1-Al Balla SR,. J Trop Med Hyg 1993;96:157-62 2-Bamgboye EA, Saudi Med J 1993;13(1):8-13. ] .

Prevalence of dyslipidemia in Saudi Adults

The overall prevalence of hypercholesterolemia TC > 200 mg/ dL: 35.4% . The overall prevalence of hypertriglyceridemia TG > 150 mg/ dL) : 49.6%. HDL Values in men and women Men <40mg/dL: 74.8 % Women <50mg/dL: 81.8
Al-Nozha MM.et al. Metabolic syndrome in Saudi Arabia. Saudi Med J 2005; 26 (12): 1918-1925

Hyperlipidemia
Michele Ritter, M.D. Argy Resident February, 2007

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The story of lipids

Chylomicrons transport fats from the intestinal mucosa to the liver In the liver, the chylomicrons release triglycerides and some cholesterol and become low-density lipoproteins (LDL). LDL then carries fat and cholesterol to the bodys cells. High-density lipoproteins (HDL) carry fat and cholesterol back to the liver for excretion.
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The story of lipids (cont.)

When oxidized LDL cholesterol gets high, atheroma formation in the walls of arteries occurs, which causes atherosclerosis. HDL cholesterol is able to go and remove cholesterol from the atheroma. Atherogenic cholesterol LDL, VLDL, IDL
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Atherosclerosis

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Causes of Hyperlipidemia
Diet Hypothyroidism Nephrotic syndrome Anorexia nervosa Obstructive liver disease Obesity Diabetes mellitus Pregnancy Obstructive liver disease Acute heaptitis Systemic lupus erythematousus AIDS (protease inhibitors)

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Dietary sources of Cholesterol

Type of Fat Monounsaturated Main Source Effect on Cholesterol levels

Olives, olive oil, canola oil, peanut oil, cashews, Lowers LDL, Raises HDL almonds, peanuts and most other nuts; avocados Corn, soybean, safflower and cottonseed oil; fish Lowers LDL, Raises HDL

Polyunsaturated

Saturated

Whole milk, butter, cheese, and ice cream; red Raises both LDL and meat; chocolate; coconuts, coconut milk, coconut HDL oil , egg yolks, chicken skin Most margarines; vegetable shortening; partially Raises LDL hydrogenated vegetable oil; deep-fried chips; many fast foods; most commercial baked goods

Trans

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Hereditary Causes of Hyperlipidemia

Familial Hypercholesterolemia
Codominant genetic disorder, coccurs in heterozygous form Occurs in 1 in 500 individuals Mutation in LDL receptor, resulting in elevated levels of LDL at birth and throughout life High risk for atherosclerosis, tendon xanthomas (75% of patients), tuberous xanthomas and xanthelasmas of eyes.

Familial Combined Hyperlipidemia

Autosomal dominant Increased secretions of VLDLs

Dysbetalipoproteinemia
Affects 1 in 10,000 Results in apo E2, a binding-defective form of apoE (which usually plays important role in catabolism of chylomicron and VLDL) Increased risk for atherosclerosis, peripheral vascular disease Tuberous xanthomas, striae palmaris
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Checking lipids
Nonfasting lipid panel
measures HDL and total cholesterol

Fasting lipid panel

Measures HDL, total cholesterol and triglycerides LDL cholesterol is calculated:
LDL cholesterol = total cholesterol (HDL + triglycerides/5)

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When to check lipid panel

Two different Recommendations
Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP)
Beginning at age 20: obtain a fasting (9 to 12 hour) serum lipid profile consisting of total cholesterol, LDL, HDL and triglycerides Repeat testing every 5 years for acceptable values

United States Preventative Services Task Force

Women aged 45 years and older, and men ages 35 years and older undergo screening with a total and HDL cholesterol every 5 years. If total cholesterol > 200 or HDL <40, then a fasting panel should be obtained Cholesterol screening should begin at 20 years in patients with a history of multiple cardiovascular risk factors, diabetes, or family history of either elevated cholesteral levels or premature cardiovascular disease.
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Goals for Lipids

LDL
< 100 Optimal 100-129 Near optimal 130-159 Borderline 160-189 High 190 Very High

HDL
< 40 Low 60 High

Serum Triglycerides
< 150 normal 150-199 Borderline 200-499 High 500 Very High

Total Cholesterol
< 200 Desirable 200-239 Borderline 240 High

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Determining Cholesterol Goal (LDL!)

Look at JNC 7 Risk Factors
Cigarette smoking Hypertension (BP 140/90 or on anti-hypertensives) Low HDL cholesterol (< 40 mg/dL) Family History of premature coronary heart disease (CHD) (CHD in first-degree male relative <55 or CHD in first-degree female relative < 65) Age (men 45, women 55)

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Determining Goal LDL

CHD and CHD Risk Equivalents:
Peripheral Vascular Disease Cerebral Vascular Accident Diabetes Mellitus

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LDL Goals
0-1 Risk Factors:
LDL goal is 160 If LDL 160: Initiate TLC (therapeutic lifestyle changes) If LDL 190: Initiate pharmaceutical treatment

2 + Risk Factors
LDL goal is 130 If LDL 130: Initiate TLC If LDL 160: Initiate pharmaceutical treatment

CHD or CHD Risk Equivalent

LDL goal is 100 (or 70) If LDL 100: Initiate TLC and pharmaceutical treatment
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Treatment of Hyperlipidemia
Lifestyle modification
Low-cholesterol diet Exercise

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Medications for Hyperlipidemia

Drug Class
HMG CoA reductase inhibitors Cholesterol absorption inhibitor Nicotinic Acid

Agents
Lovastatin Pravastatin Ezetimibe

Effects (% change)
LDL (18-55), HDL (5-15) Triglycerides (7-30) LDL( 14-18), HDL (1-3) Triglyceride (2) LDL (15-30), HDL (15-35) Triglyceride (20-50)

Side Effects
Myopathy, increased liver enzymes Headache, GI distress Flushing, Hyperglycemia, Hyperuricemia, GI distress, hepatotoxicity Dyspepsia, gallstones, myopathy

Fibric Acids

Gemfibrozil Fenofibrate Cholestyramine

LDL (5-20), HDL (10-20) Triglyceride (20-50) LDL HDL No change in triglycerides

Bile Acid sequestrants

GI distress, constipation, decreased absorption of other drugs

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Case # 1
A 55-year-old woman without symptoms of CAD seeks assessment and advice for routine health maintenance. Her blood pressure is 135/85 mm Hg. She does not smoke or have diabetes and has been postmenopausal for 3 years. Her BMI is 24. Lipoprotein analysis shows a total cholesterol level of 240 mg/dL, an HDL level of 55 mg/dL, a triglyceride level of 85 mg/dL and a LDL level is 180 mg/dL. The patient has no family history of premature CAD.
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Case # 1 (cont.)
What is the goal LDL in this woman? What would you do if exercise/diet change do not improve cholesterol after 3 months? How would your management change if she complained of claudication with walking?

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Case # 2
A 40- year-old man without significant past medical history comes in for a routine annual exam. He has no complaints but is worried because his father had a heart attack at the age of 45. He is a current smoker and has a 23-pack year history of tobacco use. A fasting lipid panel reveals a LDL 170 mg/dL and an HDL of 35 mg/dL. Serum Triglycerides were 140 mg/dL. Serum chemistries including liver panel are all normal.
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Case # 2 (cont.)
What is this patients goal LDL? Would you start medication, and if so, what?

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Case # 3
A 65 year-old woman with medical history of Type II diabetes, obesity, and hypertension comes to your office for the first time. She has been told her cholesterol was elevated in the past and states that she has been following a low cholesterol diet for the past 6 months after seeing a dietician. She had a normal exercise stress test last year prior to knee replacement surgery and has never had symptoms of CHD. A fasting lipid profile was performed and revealed a LDL 130, HDL 30 and a total triglyceride of 300. Her Hgba1c is 6.5%.
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Case # 3 (cont.)
What is this patients goal LDL? What medication would you consider starting in this patient? What labs would you want to monitor in this patient?

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HYPERLIPIDEMIA

Brian V. Reamy, MD, Colonel, USAF, MC Chair Department of Family Medicine Uniformed Services University
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Why Bother?
Optimum treatment of lipids helps in the primary & secondary prevention of ASCVD; still our nations #1 killer

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Why Bother?
ASCVD has been #1 cause of death every year since 1900 with exception of 1918. 50% of CVD diagnoses and 15% of CVD deaths are in patients < 65 years of age Many young adults have 2 or more risk factors that go unrecognized and untreated.

HUGE opportunity to prevent disease!!

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NCEP/ATP III 15 May 2001

www.nhlbi.nih.gov LDL goals lowered Raised acceptable HDL to 40 Lowered TG goal to 150 Risk Factor assessment enhanced with the 10-yr Framingham risk calculator Added the Metabolic Syndrome to Tx
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NCEP/ATP III 9 Steps

Step 1: Obtain, complete & fasting lipids. Interpret: LDL < 100mg/dl optimal LDL 100-129 near optimal LDL 130-159 borderline high LDL 160-189 high LDL >190 very high (mg/dl x 0.0259mmol/l = SI units)
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NCEP/ATP III
Step 2: Identify if patient has CAD or equivalent (PAD, DM, AAA, Carotid) Step 3: Risk factor assessment (HTN, FHx, Tob, Age & Sex, HDL<40 or >60) Step 4: If 2 or more risk factors; do Framingham 10-yr risk assessment.

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Framingham Ten Year Risk

Men Women

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Framingham Ten Year Risk

0

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Framingham Ten Year Risk

0 3 0
Non-Smoker

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Framingham Ten Year Risk

0 3 0 1
HDL = 43

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Framingham Ten Year Risk

0 3 0 1 0 4
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SBP = 119, untreated

Framingham Ten Year Risk

0 3 0 1 0 4
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NCEP/ATP III Step 5

Risk CategoryLDL Goal Start T.L.C. Start Drug Treatment >100mg/dl >100 129mg/dl >130 160mg/dl >160 40 / 29 190mg/dl

CHD/10yr risk>20% (high) 2+RF or 10yr<20% (Medium)

<100mg/dl

<130mg/dl

>130mg/dl

0-1 risk <160mg/dl factors (low)

>160mg/dl

NCEP/ATP III Step 6

Initiate Therapeutic Lifestyle Changes (TLC)
AHA Step 2 diet Soluble fiber 10-25gm/day Plant sterols/Sitostanol (Benecol, Take Control margarines) - lower LDL 10% Increased exercise Weight management
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NCEP/ATP III Step 7

Add drug therapy simultaneously to TLC in patients with CHD or equivalent. Add drugs after 3 months if TLC not effective in other risk categories. Best unbiased source for review of drug treatment: The Medical Letter: Choice of lipid regulating drugs 43:2001,pp43-48 and 2003;1;77-79.
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Drugs Step 7 (cont.)

Resins- (cholestyramine,colestid, colesevelam): lower LDL; adjunct to statins; GI side effects/malabsorption issues Niacin- miracle agent, cheap & moves every parameter in the right direction. But, side effects problematic. NIASPAN easier to tolerate. Need slow dose titration and pre-med with ASA. Caution with Diabetes; can worsen glycemic control if HBA1C >7.5 at baseline. Most potent agent at increasing HDL.
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Drugs Step 7 (cont)

Fibrates (fenofibrate, gemfibrozil) lower TG and raise HDL. Can combine with statins but caution re: hepatic side effects. Cutting statin dose by is good rule. *Fenofibrate qd & less side effects, >$$ If combining w/ a statin use fenofibrate; gemfibrozil has > rates of rhabdomyolysis
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Newer Drugs Step 7 (cont.)

Ezetimibe (Zetia)- new class that inhibits the intestinal absorption of cholesterol. Lowers LDL 17%, TG 6%, increases HDL by 1.3%. Combined with a statin increases effects of statin by 10-15% w/o side effects. VERY well tolerated at 10mg/d.

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Newer Drugs Step 7 (cont)

Lovastatin + Niacin (Advicor)- in fixed combos 20/500, 20/750, 20/1000. Increase dose monthly up to max 40/2000. Max dose w/ LDL decrease 45%, TG 42%, and HDL increase by 41%. Causes less flushing and hepatic effects than any niacin formulation. Greater risk of myopathy than a statin alone.
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Newer Drugs Step 7

Simvastatin(10/20/40/80) + Ezetimibe 10mg: VYTORIN OMACOR: concentrated omega-3s; 4 capsules = 12 OTC fish oil capsules Can interfere with clotting times; caution in folks on warfarin
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Drugs Step 7 (cont.)

Statins- All w/ anti-inflammatory effects. None safe in pregnancy. All are more potent by 10-15% with evening dosing. - muscle pain = 1-5% - hepatitis (transaminases>3x nl.) = 0.5% - rhabdomyolysis = rare; incidence rates per million Rxs: pravastatin0.04, lovastatin0.19 atorvastatin 0.04, simvastatin 0.12. (cerivistatin was 16-80x these rates!!)
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Drugs Step 7 (cont.)

Atorvastatin great LDL & TG lowering Lovastatin: take w/ food; generic version Pravastatin: least drug interactions due to different elimination pathway; take on empty stomach Simvastatin: lots of prevention data, potent Fluvastatin: less potent; poor prevention data Rosuvastatin: most potent; 5 - 40 mg (CRESTOR); may raise HDL a bit more & lower TG. Caution w/ CrCl<30cc/min and in Asian subpopulations at higher doses.
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Statin Pearls
Elevated transaminases on statins; (unless reaching 3x normal), are not a reason to stop the statin they are are a reason to watch closely. Statin side effects are often agent specific, not always class specific. Unexplained myalgias may occur on statins without CK elevation. Try a different statin.

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Statin Pearls
Rhabdomyolysis is uncommon unless CK is elevated to 10 x normal. Usually occurs in patients with multiple co-morbidities. Unless you enjoy driving yourself nuts; do not check CK serially in patients on statins. Remember vigorous yard work will bump your CK! Some think a baseline CK may be helpful. But what about the PROVE-IT study? (NEJM 8 April 2004)
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PROVE-IT Trial
Designed to PROVE that 80mg atorvastatin was no better than 40 mg pravastatin in secondary prevention. But, atorvastatin was superior as early as 30 days of therapy. In just 24 mths the atorvastatin group (meanLDL=62) had 16% less of all CV events. 28% less mortality than pravastatin group (meanLDL=95)
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PROVE-IT Trial
WOW! Evidence from mammalian species had shown that atherogenesis stops & reverses at an LDL <80 now some clinical outcome data.

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NCEP Update 13 July 2004

Circulation 13 July 2004:227-239 Added the results of PROVE-IT, HPS, PROSPER, ALLHAT, ASCOT Confirmed ATP-III and added that in very high risk an LDL goal <70 was optional For patients at moderately high risk = 10-20% Framingham risk; LDL <100 new goal Felt that drug treatment should aim for at least a 30-40% LDL reduction.
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Updated ATP-III Guidelines

RISK HIGH >20% 10yr Mod. High 10-20% Moderate <10% 10yr LOW LDL <70mg/dl Optional <100mg/dl Optional <130mg/dl <160mg/dl TLC >100mg/dl >130mg/dl >130mg/dl >160mg/dl DRUGS >100mg/dl or <100mg >130mg/dl or 100-130 >160mg/dl >190mg/dl
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TNT Study Treat to New Targets

NEJM 7 April 2005: Prospective trial at lowering LDL well below 100mg/dl in adults with CHD (secondary prevention) 10,001 patients; 2 groups for 4.9 years with mean LDL = 99mg/dl before study
10 mg atorvastatin (mean LDL=101mg/dl) 80 mg atorvastain (mean LDL=77mg/dl)
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TNT - Results
Side Effects: increased LFTs in 0.2% of patients on low dose and 1.2% on high dose. No change in rhabdomyolysis risk. Results: Relative risk reduction of 22% and absolute risk reduction of 2.2% in major cardiovascular events for group with LDL <80 versus group with LDL=101. More evidence to lower our LDL goals
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NCEP/ATP III Step 8

Identify Metabolic Syndrome: (3 of 5)
SBP>130, FBS>110, TG>150, HDL<40 in men and <50 in women, waist>40men, 35women

Aggressively:
Treat underlying causes of overweight and physical inactivity. Treat HTN, use ASA for CHD patients
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NCEP/ATP III Step 9

Treat elevated TG (>150mg/dl)
First lower LDL; if TG still >200 consider adding/increasing drug therapy But, if TG >500mg/dl, first lower triglycerides to prevent pancreatitis. When they are <500 then return to LDL lowering Treat HDL <40 after lowering LDL.

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CASES
All real cases. No perfect answers. All present real Family Practice dilemmas. Will use the evidence to help formulate a best answer. Use cases to convey cutting edge info.

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Case # 4 Middle-of the Road

45 year old woman who on a routine lipid screen has the following values: TC = 203 HDL=48 TG = 155 LDL = 124 PMHx: negative, smoker Meds: daily vitamin FHx: MI in F age 60, M age 64 PE: 65 130lbs P=72 BP=118/68
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Case #4 Middle of the Road

Risk Factors: 2 ; Framingham = 5% risk NCEP/ATP III says that she is at her LDL goal; e.g. <130 But, concerns remain: FHx, Smoking, HDL is <50 & TG >150; both less than ideal. What do you do with this middle-of-theroad risk profile?
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Case# 4 Middle of the Road

Consider a new idea: measure her hs-CRP Facts: CRP is a marker of inflammation. ASCVD is a disease of inflammation Multiple prospective epidemiological (vs. interventional studies) have shown that CRP can predict MI,CVA, PAD, sudden cardiac death.
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Case #4 Middle of the Road

Hs-CRP assays are now widely available; can check non-fasting, anytime of day. < 1mg/l = low risk 1-3mg/l = moderate risk >3mg/l = high risk >10mg/l = invalid for cardiac risk prediction;consider 1 inflammatory disease, trauma, serious infection.
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Case #4 Middle of the Road

PRINCE (PRavastatin INflammation/Crp Evaluation trial; JAMA 2001:286;64-70. And other trials have proven that Statins lower CRP 15-25% within 6 weeks of initiation. Weight loss, exercise and smoking cessation also lower CRP.
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Case # 4 Middle of the Road

CARE & AFCAPS/TEXCAPS both suggest that the benefit of statin therapy among those with low LDL but high CRP may be as large as those with overt hyperlipidemia. How to answer this ? 2003: 15,000 patients with LDL<130 but CRP above 2.0mg/l (JUPITER). All will be put on CRESTOR for prevention. What will happen?
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Case # 4 Middle of the Road

What does this mean for our patient? CRP is most useful in those judged at intermediate risk and in primary prevention. Review; 45 yr old woman with an LDL<130 but +FHX and other borderline riskseg a 5% Framingham risk HOW about checking an hs-CRP to further assess her risk ?
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Case # 4 Middle of the Road

CRP = 3.2mg/l HIGH risk Studies have proven she is in fact at risk; more than her LDL would tell us. What to do? Smoking cessation will lower CRP Statins will lower her CRP But, no prospective proof that this will change her outcome. It is your call, Doctor!
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Other Novel Risk Factors

EBCT (coronary Ca++ score) Lp (a) lipoprotein, Apo B, LDL particle size Homocysteine Plasma Adiponectin

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EBCT/Coronary Ca++ scores

Coronary Ca++ occurs due to ASCVD Normal score=0-10; 11-100 = mild disease, 101400 = non-obstructive disease, >400 = obstructive Significant false positives and poor data in women and younger patients It may not provide incremental information above that obtained with conventional risk factor assessment; it is an alternative.
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EBCT
Like with hs-CRP, it is not very useful in low risk or very high risk patients. It significantly correlates w/ cheaper hs-CRP. Best used in intermediate risk folks where it might change treatment approach. In patients w/ intermediate risk an EBCT score >80 has a sensitivity of 85% and a specificity of 75% for the risk of events.
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EBCT/Coronary Ca++ Scores

USPSTF: Feb 2004; D recommendation for adults at low risk. absence of evidence that detection ultimately results in improved health outcomes, and because false positive tests are likely to cause harm I recommendation for those at high risk

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Homocysteine
High plasma homocysteine may be directly related to atherosclerosis development. Homocysteine may enhance inflammation & thrombosis. There may be no causal association between elevated homocysteine and CV disease risk. New Evidence!!
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Homocysteine
NEJM; 13 April 2006; 2 studies re: homocysteine lowering #1: Secondary prevention: 5522 patients: placebo vs 2,5mg Folate+B6+B12: did not reduce the risk of cardiovascular event, more pts in Tx had unstable angina. #2: 3749 pts post-MI: treatment with Bvitamins did not lower risk of recurrent CV disease. A harmful effect of B-vitamin Tx was suggested.

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Lipid Sub-fractions & other markers

Lipoprotein a, Apolipoprotein B, LDL particle size
All have predictive value for CHD, indeed LDL particle size is more precise than LDL alone. But not widely available, expensive, less reproducible and still no outcome studies.

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Case # 5 The Unreachable Goal

60 yr old male returns to see you 3 months after a 4vCABG. He feels great. At his last visit with his CT surgeon he was told; follow-up with your family doctor to get your cholesterol in control PMHX: HTN x 20 yrs, BPH, ED, mild OA MEDS: ASA, Metoprolol 50 mg po bid, Viagra, Simvastatin 20 mg po qd FHX: F with CVA at 68
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Case # 5 The Unreachable Goal

PE: 70 160lbs P=60 BP=124/76 Cor: RRR, no m/r/g, no jvd, healed median sternotomy scar Ext: no edema Lungs: slight dec. breath sounds TC=180, HDL=42 TG=100 LDL=118

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Case # 5 The Unreachable Goal

Risk Assessment = he has CHD; 2 prev. Goal LDL is <100 per ATP III (<70-80 TNT trial data and ATP update) At this level atherogenesis seems to arrest At an LDL of 80 in mammalian species atherogenesis reverses. Also the PROVEIT trial shows that an LDL of 62 was superior to an LDL of 95.
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Case #5 The Unreachable Goal

You decide to increase the simvastatin to 40mg po qd. 6 weeks later; TC= 170 TG=105 HDL=42 LDL=107 What do you do?

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Case # 5 The Unreachable Goal

Many options: 1)increase simvastatin to 80 mg or change to atorvastatin or rosuvastatin. PROBLEM: inc risk of side effects and less LDL lowering effect as you inc statin doses. For every doubling of dose, LDL decreases by only 6 %. A threefold higher dose by 12% and a fourfold increase lowers LDL cholesterol by only 18%. 80 / 29

Case # 5 The Unreachable Goal

2.) Add Ezetimibe 10 mg po qd: less chance of side effects; should help to reach goal LDL easily. 3.) Intensify diet; Ornish Plan; add soluble fiber, add soy, add omega-3 fatty acids. 4.) Be satisfied and await more trials

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Summary
8 Points to make you strong 1) 1 & 2 prevention of ASCVD are possible! 2) NCEP/ATP III at www.nhlbi.nih.gov is useful. 3) The key step is risk assessment & then tailoring treatment to individual risk.
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Summary 8 Points
3) Better medication options are a help: Ezetimibe, Advicor, new statins and a cleaner understanding of statin side effects 4)Attack the metabolic syndrome!! A multi-modal treatment plan is best. 5) Dont ignore a chance for prevention because your patient is >70 or <35.
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Summary 8 Points
6) hs-CRP is a powerful new tool to predict risk; especially in those at intermediate risk. But, we need prospective proof that lowering it will help reduce ASCVD endpoints. 7) Try to get to goal; anticipate new ATPIV guidelines.
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Thanks for your Attention!

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