1	Taking the Mystery Out of Lipid Lowering Agents Dr. Trudy Arbo Clinical Pharmacy Practice Leader NB Heart Centre, Saint John, NB
2	Learning Objectives De-mystify lipid lowering agents Understand the evidence behind the specific agents and the current practice guidelines Feel comfortable selecting a lipid-lowering agent based on patient specific factors and the best available evidence Increase awareness of potential ADR associated with lipid lowering agents and how to manage them
3	Overview Classification of Lipid lowering agents HMG-CoA inhibitors Fibrates Cholesterol Blockers Niacin Fish oils Other Evidence for use Potential ADRs and management Patient Cases (if time permits)
4	2006 Canadian Treatment Guidelines
5	Classification of Lipid lowering agents
6	Available in Canada
7	The “STATINS”
8	A Drug by any other name Atorvastatin (Lipitor^®) Simvastatin (Zocor^®) Rosuvastatin (Crestor^®) Pravastatin (Pravachol^®) Fluvastatin (Lescol^®) Lovastatin (Mevacor^®)
9	How Statins Alter Lipid Profiles Decreases LDL by 30-40% Ranges from 25% to 50% For every 1 mmol/L decrease in LDL results in approximately 19% RRR in coronary mortality Increases HDL by 3-5% Moderately lowers TG by 10% Not drug of choice for hypertriglyeridemia
10	Change in LDL from Baseline
11	Uses Primary prevention Especially in moderate to high risk patient populations Secondary prevention i.e. after a CV event High dose in Acute Coronary Syndrome
12	Mechanism of Action Inhibits the enzyme responsible for making cholesterol (HMG-CoA reductase) This results in a decreased production of mevalonic acid which reduces cholesterol produced by the liver It also may affect blood flow and arterial wall thickness Other proposed mechanisms include reducing macrophage activation and plaque rupture and altering clotting formation
13	Mechanism of Action
14	Adverse Drug Reactions Myopathy/myalgias 5% Usually described as muscle soreness, weakness NOT CRAMPING! When in doubt measure CPK Increase in LFTs 2-5 %
15	The Evidence
16	Primary Prevention Definition Treatment of patient prior to an event Based on the treatment guidelines Primary prevention trials AFCAPS (lovastatin 20 or 40 mg vs placebo) GISSI Prevention (Pravastatin 20 vs placebo) ALLHAT –LLT (Pravastatin 40 vs usual care) ASCOT-LLA (Atorvastatin 10 vs placebo) CARDS (DM pt only Atorvastatin 10 vs placebo) HPS (Simvistatin 40 vs placebo) WOSCOPS (men, Pravastatin 40 vs placebo) PROSPER (Pravastatin 40 mg vs placebo)
17	Primary Prevention of CV Disease with Statin Therapy. Arch Intern Med 2006 Patients (n=42 848 from 7 trials) 55-75 yrs old with moderate to moderately high risk of CVD (>10% but <20% 10 year CHD) 90% had no history of CV disease Pre-treatment LDL range 3.04-4.97 mmol/L Intervention and Comparator Statin therapy vs placebo Outcomes Major coronary events, major cerebrovascular events, revascularization Followed for 3.2 to 5.2 years
18	Primary Prevention of CV Disease with Statin Therapy. Arch Intern Med 2006 Statin therapy used: Atorvastatin 10 mg (2 studies) Pravastatin 40 mg (2 studies) Pravastatin 20-40 mg (1 study) Simvastatin 40 mg (1 study) Lovastatin 20-40 mg (1 study)
19	Results Mean reductions in Cholesterol Total Chol. 17.8% (9.5-21.8%) LDL-C 26.1% (16.7-33.9%) TG 10.6% (0-15.9%) HDL* 3.2% (Incr. 0.9-5%) Major Coronary Events Treatment 4.3% vs Control 5.7% (p<0.001) ARR 1.4% RRR 29.2% NNT 71
20	Results Continued Cerebrovascular events Treatment 2.1% vs Control 2.4% (p=0.02) ARR 0.3% RRR 14.4% NNT 333 Revascularization RRR 33.8% (no specific numbers given) Non-fatal MI RRR 31.7% (no specific numbers given) No significant reductions in CHD mortality, overall mortality
21	Safety Data Not all trials reported CK and LFTs level changes Of the reporting trials No significant elevations of CK or LFTs found CK elevation RR 0.51 (0.16-1.6) NS LFT increase RR 1.37 (0.9-2.09) NS Cancer rates RR 1.02 (0.92-1.13) NS
22	Secondary Prevention Definition Treatment of cholesterol after a CV event Treated as high risk Secondary Prevention Trials Pravastatin CARE, LIPID, PLAC I-II, PMSG, PROSPER, REGRESS, PREDICT Simvastatin 4S, CIS, HPS, MAAS, SCAT Lovastatin CCAIT, MARS Fluvastatin LCAS, FLARE, LIPS Atorvastatin IDEAL
23	2006 Canadian Treatment Guidelines
24	Effectiveness of Statin Therapy in Adults with Coronary Heart Disease. Arch Intern Med 2004;164:1427-1436 – Meta-analysis Patients (n= 52 782 from 19 studies) Mean age of 63, pre treatment LDL 3.85 mmol/L 20% did not have overt CHD but were high risk 23% women Intervention and Comparators Statin vs placebo 90% of patients were either on simvastatin or pravastatin Outcomes Primary outcome CHD mortality and nonfatal MI Follow up ranged from 0.3-6.1 years (15 trials at least 1 year)
25	Effectiveness of Statin Therapy in Adults with Coronary Heart Disease. Arch Intern Med 2004;164:1427-1436 – Meta-analysis Average doses used in the studies Simvastatin 27-34 mg/day Lovastatin 33-76 mg/day Fluvastatin 49 mg/day Atorvastatin 24 mg/day
26	Results CHD mortality or nonfatal MI Treatment 11% vs control 14.8% (p <0.001) ARR 3.8% RRR 25% NNT 26 CHD mortality ARR 1.4% RRR 23% NNT 71 All cause mortality Treatment 9.5% vs control 11.3% (p<0.001) ARR 1.8% RRR 16% NNT 56
27	High dose in Acute Coronary Syndromes Role Considered plaque stabilizing (pleotrophic effects) Used within 48 to 72 hours of ACS presentation Not based on lipid levels Duration of therapy Unknown
28	Early, Intensive Statin Therapy on Acute Coronary Syndrome Patients (n=17 963) From 13 trials (meta-analysis) Intervention and Comparator High dose statins (atorva 80, prava 40, fluvastatin 80, simvistatin 80) Compared to lower dose statin, placebo or usual care as per patient’s physician Therapy initiated within 14 days of event Outcome Death, recurrent MI, hospital readmission for ACS
29	Results No reduction overall cardiovascular events during first 4 months By 6^th month significant reductions overall HR* 0.76 (CI 0.7-0.84) Maintained at 24 months HR 0.81 (CI 0.77-0.87) *HR indicates hazards ratio
30	What the heck is a Hazard Ratio (HR)? Hazard of one treatment versus hazard of the other treatment If 25 skiers and 10 fall If 25 snowboarders and 15 fall Hazard ratio 0.40/0.60 0.66 or 66% 33% less likely to fall if you are skiing as compared to snowboarding OR Our example: HR of 0.76 24% less likely to have an event in treatment group as compared to the control group
31	Back to the study. . .Safety Rhabdomyolysis 3 cases reported out of 17 963 pts All on simvastatin 80 mg (from A to Z trial) Hepatitis 3.3% vs 1.1% in PROVE-IT trial Atorvastatin 80 mg vs pravastatin 40 mg 2.5% vs 0.6% in MIRICL TRIAL Atorvastatin 80 mg vs placebo Discontinuation of therapy Similar among placebo vs treatment groups
32	List of 13 Included Trials LAMIL ESTABLISH PTT LIPS RECIFE Colivicchi, et al. PROVE-IT TIMI 22 PAIS A to Z FLORIDA MIRACL PACT L-CAD
33	The “Fibrates”
34	Drugs of this class Fenofibrate Lipidil^® Lipidil Supra^® Lipidil EZ^® Gemfibrozil Lopid^® Bezafibrate Bezalip^®
35	How “FIBRATES” alter the lipid profile LDL Decrease 5 to 20% May cause a slight increase in patients with hypertriglyceridemia HDL Increase 10 to 35% Triglycerides Decrease 20 to 50%
36	Uses Drug of choice for hypertriglyceridemia Increases HDL As adjunct to statin therapy to reach cholesterol targets
37	Mechanism of Action The fibrates, or fibric acid derivatives, act in part to stimulate the activity of peroxisome proliferator-activated receptors (PPARs), which are involved in lipid metabolism Results in a decrease in triglyceride levels Inhibits hepatic synthesis of TG and VLDL And increase in high density lipoprotein (HDL)
38	Common Adverse Drug Reactions GI complaints 5% Nausea, abdominal pain Less with fenofibrate Myopathy 2-5% Increased risk in patients with renal dysfunction, elderly and on statin Increased LFTs 6% Renal dysfunction Increase of SCr by 8-18% May be from inhibition of prostaglandins Cholelithiasis (rare)
39	The Evidence
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41	The Evidence 6 major trials evaluating the fibrates Summary of results No affect on total mortality In some trials actually an increase! Reduction in coronary heart disease RRR 11 to 34 % NNT approximately 250 Higher incidence of cancer rates and gallstones in treatment group
42	Which Patients? Consider for Diabetic patients with isolated hypertriglyeridemia and low HDL Also for “pre-diabetic” or metabolic syndrome When statin therapy not adequately reaching target therapy Treatment of hypertriglyceridemia > 10 mmol/L should be treated to avoid pancreatitis
43	Other Considerations Drug interactions Increased risk of rhabdomyolysis when used in combination with a statin Limit dose of statin when given gemfibrozil Lovastatin 20 mg, rosuvastatin 10 mg, simvastatin 10 mg Use caution with fenofibrate risk may be slightly less with this agent Avoid using in patients with renal impairment or use under close supervision!
44	More on Rhabdomyolysis Patients at increased risk Combination of statin and fibrate Elderly patients Patients with underlying renal dysfunction Higher doses of lipid altering agents Not substantiated in the literature! Symptoms to watch for Muscle soreness, stiffness, weakness NOT cramping!
45	More on Rhabdomyolysis Incidence of hospitalized rhabdomyolysis (per 10 000 patient yrs) With statin therapy alone 0.44 With Fibrate therapy alone 2.82 In combination 5.98
46	Niacin
47	Niacin Otherwise known as Vitamin B₃ Nicotinic acid and nicotinamide Niacin decreases free fatty acid synthesis and as a result TG synthesis Also increases HDL Be wary of products claiming “no flushing” They usually do not contain nicotinic acid and are ineffective for treating hyperlipidemia
48	MOA of Nicotinic Acid
49	Affect on Lipid Profile LDL 5 to 25% reduction HDL 15 to 30% INCREASE TG 20 to 50% reduction
50	Two main forms of Niacin Regular release formulation (Niacor®): Initial: 250 mg once daily (with evening meal); Increase dose every 4-7 days Target dose is 1.5-2 g/day in 2-3 divided doses Max dose: 3 g/day (in divided doses usually TID) Only increase dose every 2 to 4 weeks after 2 g Extended release formulation (Niaspan®) Initial: 500 mg at qhs for 4 weeks Increase to 1 g at bedtime for 4 weeks Target dose is 1.5 g daily Max dose 2 g/day
51	Short vs Long acting
52	Niacin Administer with food and at HS when using long acting agent Niaspan® tablet strengths are not interchangeable with the short acting tablets When switching from immediate release tablet initiate Niaspan® at lower dose and titrate. MONITORING Blood glucose Liver function tests pretreatment and every 6-12 weeks for first year then periodically Lipid profile.
53	The Evidence Secondary Prevention Study of 1119 pts No difference in mortality between the groups Reduction of recurrent MI Placebo 12.2% vs Niaspan 8.9% RRR 27% ARR 3.3% NNT 30 New studies on the horizon evaluating primary prevention and secondary prevention
54	Ezetimibe (Ezetrol^®)
55	Ezetimibe Selective cholesterol absorption inhibitor Decreases intestinal absorption of cholesterol Similar effect to bile acid sequestering agent Available in 10 mg tablets Usual dose: 10 mg daily ADR rate of 1-2%
56	Affect on Lipid Profile LDL 19% reduction (15-25%) HDL 5% increase TG 11% reduction
57	Uses Patients intolerant to statins In combination with other lipid lowering agents to achieve lipid targets Fibrates + ezetimibe Statins + ezetimibe Similar effect to bile acid sequestering agents, with much less ADRs
58	The Evidence To date, there are no clinical trials evaluating clinically relevant endpoints Only surrogate endpoints of lipid levels NOT morbidity or mortality Studies on the horizon ASAPS extended 2007 Using Ezetemibe added to simvastatin measuring CIMT SHARP 2010 Renal failure patients IMPROVE IT 2008 Acute Coronary Syndrome SEAS Aortic stenosis
59	Combination Therapy with Statin
60	Bile Acid Sequestering Resins
61	Bile Acid Sequestering Resins Binds to bile acids which are used by liver to produce cholesterol This stimulates the liver to produce more bile acids which uses up stored cholesterol May cause an increase in TG levels Examples: Cholestyramine, colestipol
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63	Side effects 20-40% of patients will experience ADR from bile acid sequestering resins Usually GI nausea, bloating, cramping, and an increase in liver enzymes Not widely used in clinical practice for this reason
64	Affect on Lipid profile LDL 15-30% reduction (in general 12%) HDL 3-5% increase TG No change or INCREASED in some patients! 19% reduction (RRR) in coronary events No effect on mortality
65	A word about Fish Oils Omega 3- Fatty Acid Lipid profile Decrease TG by 10 to 33% Slight increase in LDL and HDL Doses Range from 1 to 6 g per day Observational, epidemiological studies have shown a reduction in morbidity and mortality but not with RCT trials Potential increased risk of bleeding 3 to 9%
66	Bringing it all together
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68	2006 Canadian Treatment Guidelines
69	Case 1
70	Bill 75 year old male PMHx Angina Hypertension Family history of MI (father, age 50) Framingham risk 10 year CHD 20% Lifestyle Avid golfer Moderately active Good diet
71	Lipid profile Total Cholesterol 5. 58 mmol/L LDL 3.41 mmol/L HDL 1.68 mmol/L TG 1.07 mmol/L Ratio 3.3 mmo/L Do we treat? With what agent? Monitoring parameters?
72	Case 2
73	Larry PMHx Previous MI HTN Smoker Lifestyle Late nights Little to no physical activity Poor diet
74	Lipid Profile Total Cholesterol 7.93 mmol/L LDL 6.08 HDL 1.45 TG 0.87 Ratio 4.19 What is our target LDL? What would you treat with and at what dose? Monitoring parameters?
75	6 Months later Lipid profile Total Chol 4.54 LDL 2.5 HDL 1.1 TG 2.1 Ratio 4.12 What would you do?
76	References Wilt TJ, et al. Effectiveness of Statin Therapy in Adults with CHD. Arch Intern Med 2004;164:1427-36. Pedersen TR, et al. High dose atorvastatin vs usual dose simvastatin for secondary prevention after MI (IDEAL). JAMA 2005;294:2437-45. LaRosa JC, et al. Effect on Statins on Risk of Coronary disease: a meta-analysis. JAMA 1999;282:2340-2346. Knopp RH. Drug Treatment of Lipid Disorders. N Engl J Med 1999;341:498-511. Field study investigators. Effects of long-term fenofibrate therapy on CV events in 9795 people with type 2 DM (FIELD study). Lancet 2005;366:1849-1861. Knopp RH, et al. Effects of ezetimibe on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003;24:729-741. www.jr2.ox.ac.uk/bandolier/band121/b121-2.html
77	References con’t Thavendiranathan P, et al. Primary prevention of Cardiovascular diseases with statin therapy: a meta-analysis of RCT. Arch Intern Med 2006;166:2307-13. LIPID study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57. Deedwania P, et al. Reduction of LDL-C in patients with coronary heart disease and metabolic syndrome: analysis of the treating to new targets study. Lancet 2006;368:919-928. Heart Protection Study Collaborative Group. HPS of cholesterol lowering with simvastatin in 20 536 high risk individuals: a randomized placebo controlled trial. Lancet 2003;360:7-22. Hullen E, et al. The effect of early, intensive statin therapy on acute coronary syndrome: A meta-analysis of randomized controlled trials. Arch Intern Med 2006;166:1814-21.