NMT150 Primary Prevention & Cholesterol-Lowering Drugs PDF

PRIMARY PREVENTION AND DRUGS THAT LOWER CHOLESTEROL Dr. Adam Gratton NMT150 MSc ND April 6, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used positively affect lipid profiles - HMG-CoA Reductase Inhibitors -...

PRIMARY PREVENTION AND DRUGS THAT LOWER CHOLESTEROL Dr. Adam Gratton NMT150 MSc ND April 6, 2023 LECTURE COMPETENCIES Compare and contrast the mechanisms of action, indications, and adverse effects of drugs used positively affect lipid profiles - HMG-CoA Reductase Inhibitors - Bile Acid-Binding Resins - Cholesterol Absorption Inhibitors - Fibrates - Niacin Define primary prevention in terms of cardiovascular disease Describe the impact and adverse effects of the main evidence-based treatment options to reduce the risk of serious or fatal cardiovascular events PRIMARY PREVENTION Vascular disease is one of the top contributors to mortality and morbidity in Canada Many modifiable risk factors exist, yet remain undertreated Prevention requires early recognition Evidence supporting primary preventive interventions quite low compared to secondary prevention RISK ASSESSMENT/FACTORS Modifiable Non-modifiable Diabetes Diet Age Dyslipidemia Family history Hypertension Assigned male at birth Lack of physical activity Obesity Tobacco use RISK ASSESSMENT TOOLS There are many validated tools Framingham risk score is most commonly used Provides an estimate of the chance of experiencing a vascular event (coronary heart disease, cerebrovascular disease, peripheral vascular disease, heart failure) in the next 10 years Score 10 or lower – Low risk, 11 – 19 – Intermediate, 20 or higher - High A LESSON ON RISK Absolute Risk (AR) - the number of events (good or bad) in a treated (exposed) or control (non-exposed) group, divided by the number of people in that group Absolute Risk Reduction (ARR) - the AR of events in the control group minus the AR of events in the treatment group A LESSON ON RISK Number Needed to Treat (NNT) - a measurement of the impact of a medicine or therapy by estimating the number of patients that need to be treated to have an impact on one person Number Needed to Harm (NNH) - a measure of how many people need to be treated (or exposed to a risk factor) for one person to have a particular adverse effect A LESSON ON RISK https://bestpractice.bmj.com/info/toolkit/learn- ebm/how-to-calculate-risk/ PHARMACOLOGIC CHOICES Antihypertensive therapy Statin therapy Low-dose ASA ANTIHYPERTENSIVE THERAPY Myocardial infarction ARR = 0.7% NNT = 143 Stroke ARR = 1.3 % NNT= 77 With 4-5 years of therapy RR reduction ~ 20-40% for first major vascular event vs placebo Adverse effects related to the specific medications used STATIN THERAPY Cardiovascular event ARR = 1.39% NNT = 52 Myocardial infarction ARR= 0.81% NNT = 123 Stroke ARR= 0.38% NNT = 263 With 2 – 5 years of therapy Most common adverse effect is myalgia LOW DOSE ASA THERAPY Major cardiovascular event ARR = 0.41% NNT = 241 Myocardial infarction ARR = 0.28% NNT = 361 Major bleeding ARI 0.47% NNH 210 With 5 years of therapy Major bleeding is usually within the GI tract LIPID LOWERING DRUGS HMG-CoA Reductase Inhibitors Atorvastatin Bile Acid-Binding Resins Cholestyramine Cholesterol Absorption Inhibitor Ezetimibe Fibrates Fenofibrate Niacin LIPID ABSORPTION HMG-COA REDUCTASE INHIBITORS Aka statins The generic naming convention of these drugs includes “statin” at the end of the name Atorvastatin The most common cholesterol lowering drug used in clinical practice The only drug approved for primary prevention of cardiovascular disease HMG-COA REDUCTASE INHIBITORS Cholesterol synthesis involves several steps to take acetyl CoA and acetoacetyl CoA and ultimately convert them to a molecule of cholesterol. The rate-limiting step occurs early in the biosynthesis pathway where HMG-CoA is converted to mevalonate via the enzyme HMG CoA reductase Statins inhibit this enzyme and substantially slow down the biosynthesis of cholesterol HMG-COA REDUCTASE INHIBITORS Reduced cholesterol results in reduced hepatic secretion of VLDL Reduced cholesterol also stimulates transcription for LDL receptors Increased LDL receptors result in more binding of circulating LDL to increase hepatic cholesterol ATORVASTATIN The second-most potent statin available The first statin to be approved for use in 1987 although atorvastatin had been studied in Japan since the mid-70s as an isolate of the mold Monascus purpureusi aka Red Yeast which grows on rice. RYRE produces a number of statin-like compounds, including the drug lovastatin, which is less potent than other statins INDICATIONS Lowering LDL-C Primary prevention of CVD Statins, in general, lower LDL-C by 20-60% and increase HDL-C by 5-15%  ADVERSE EFFECTS The most serious adverse effect is rhabdomyolysis (potentially fatal skeletal muscle toxicity) - 0.2% of all patients taking a statin will experience this - Myalgia and myositis may also be caused by statins The potential for muscle-related adverse effects increases with dose Additional factors: Being assigned female at birth, renal and hepatic disease, hypothyroidism, and use of CYP3A4 inhibitors Muscle-related side effects resolve with discontinuation of the medication Common adverse effects are GI related ABSORPTION INHIBITION Dietary lipids are absorbed as small micelles into enterocytes via a transporter called Niemann-Pick C1-Like 1 (aka NPC1L1) among others (step 3b in previous image on slide 9) Mechanistically, drugs that prevent the function of transport proteins, bind dietary lipids and prevent incorporation into micelles or compete with lipids for micelle carriage could all reduce absorption ABSORPTION INHIBITION Transport protein inhibition - Specifically NPC1L1 - Ezetimibe Binding dietary lipids preventing incorporation into micelles - Cholestyramine EZETIMIBE Currently a class unto itself Inhibits NPC1L1 and prevents absorption of cholesterol from the intestinal lumen This inhibits the absorption of cholesterol from the diet as well as cholesterol secreted as bile Reduced cholesterol increases LDL receptors and takes LDL-C out of circulation Administered as a prodrug which needs to be metabolized to the active form ezetimibe-glucuronide which localizes to the small intestine EZETIMIBE Adverse effects are uncommon and it has a low potential for drug interactions Because it is a prodrug, moderate to severe hepatic impairment substantially decreases its effect Magnitude of benefit – reduces LDL-C by 14-25% and increases HDL-C by 1% CHOLESTYRAMINE A bile acid-binding resin – a high molecular weight polymer that can bind bile acids Binding to bile acids prevents reabsorption in the small intestine and forces the excretion of cholesterol This also forces the liver to create new bile acids using cholesterol already in the body Decreased cholesterol then increases LDL receptors and use of LDL-C by the liver CHOLESTYRAMINE Completely unabsorbed and works entirely within the digestive tract Adverse effects include: constipation, fecal impaction, rash, decreased absorption of fat-soluble vitamins Magnitude of benefit – reduces LDL-C by 10-30% and increases HDL-C by 3-10% CHOLESTYRAMINE Drug interactions Has the capacity to bind other drugs like digoxin, thyroxin, and warfarin Decreases absorption of ezetimibe FIBRATES Whereas the rest of the drugs discussed are indicated for hypercholesterolemia, fibrates, as a class, have a more modest effect at reducing LDL-C Better suited for increasing HDL-C and reducing triglycerides - Diabetic dyslipidemias - Benefit seems to be best in diabetic populations FENOFIBRATE Activator of PPAR-α (peroxisome proliferator activated receptor) Activation of PPAR-α increases lipolysis and elimination of triglyceride-rich particles from plasma Activation also changes lipoprotein ratios – increase apoprotein AI and AII which increases HDL and reduces apolipoprotein B which reduces VLDL and LDL FENOFIBRATE Magnitude of benefit – lowers LDL-C by 5-20%, increases HDL-C by 10-35% More potent at lowering triglycerides by 20-50% FENOFIBRATE Adverse Effects Can cause myopathy and rhabdomyolysis like statins, especially when the two are combined Can also cause decreased platelets and white blood cells, allergic reactions, and cholelithiasis Contraindicated in patients with hepatic dysfunction and pre- existing gall bladder disease NIACIN Has the broadest spectrum of lipid-altering effects of any agent Dose required is quite large 1.5-4 g/d Given the flushing response (erythema and pruritus) to mg doses it is not routinely used Works by inhibiting lipolysis in adipose tissue which results in reduced formation and secretion of hepatic VLDL (which is a precursor to LDL) May also cause liver damage and hepatitis, hyperuricemia, and gout, and aggravate peptic ulcers SAMPLE QUESTION Which of the following drugs can cause rhabdomyolysis as an adverse effect? A. Niacin and cholestyramine B. Cholestyramine and fenofibrate C. Fenofibrate and atorvastatin D. Atorvastatin and niacin