Clinical Dyslipidemia. Tom Ransom April 5, 2018

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1 Clinical Dyslipidemia Tom Ransom April 5, 2018

2 Disclosures Faculty/Presenter: Tom Ransom Relationships with commercial interests: Grants/research support: Research trials: Principal/Sub Investigator, CDHA, Endocrinology Research, Centre for Clinical Research. Speaker s bureau/honoraria: Consulting fees: Speaking honoraria: Sanofi, Astra Zenica, BMS, Merck, Sepracor, Pfizer, Servier, Lilly, Abbott, GSK, Novartis, Novo Nordisk. Advisory Boards: Merk & Co., Boehringer Ingelheim, AstraZeneca, Novo Nordisk. Other:

3 Outline Review the players Why treat? Key guideline updates How to treat Lifestyle Medications Discussion

4 The Players

5 Review

6 Concepts High density lipoprotein (HDL) is good apoa is good Reverse cholesterol transport Low density lipoprotein (LDL) is bad apob is bad Deposits cholesterol in arterial walls Triglycerides (TG s) are kind of bad At very high levels can cause pancreatitis Total cholesterol is a composite Ratios are useful when calculating risk for coronary artery disease (CAD) In the future we will look at subfractions of lipids e.g. oxidized LDL, small vs. large LDL etc

7 Put Simply L is for lousy H is for healthy T is for trouble maker

8 The LDL hypothesis is FAKE NEWS!!!

9 High LDL = high rate CAD Relationship between LDL cholesterol and event rate in large randomized trials (including active and placebo treatment groups)

10 Event Rate (%) Why are we trying to get LDL so low? S-placebo 2 prevention 20 4S-Rx LIPID-placebo LIPID-Rx CARE-placebo CARE-Rx HPS-placebo PROVE-IT TNT-10 mg ATV HPS-Rx PROVE-IT-PRV TNT-80 mg Mean on-treatment LDL-C level at follow-up (mmol/l) Rx=treatment Adapted from Ballantyne CM. Am J Cardiol 1998;82:3Q-12Q.

11 Evidence favouring LDL reduction for the prevention and treatment of atherosclerosis is strong and compelling Proportional reduction in event rate (% SE) Proportional reduction in event rate (% SE) A prospective meta-analysis of data from 90,056 individuals from 14 trials of statins 1 A 1 mmol/l (39 mg/dl) reduction in LDL-C was associated with a 50 23% reduction in major coronary events 50 21% reduction in major vascular events (19) 1.0 (38) 1.5 (58) Reduction in LDL-C mmol/l (mg/dl) 2.0 (77) (19) 1.0 (38) 1.5 (58) Reduction in LDL-C mmol/l (mg/dl) 2.0 (77) Adapted from Baigent C, et al, Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005;366:

12 Benefit from LDL-C reduction independent of mechanism 12

13 It s all about the LDL In the Clinic Screen Assess risk and set a target lifestyle always Max tolerated statin Other

14 CCS 2016 Guideline Update: The Management of Dyslipidemia For The Prevention of Cardiovascular Disease in the Adult

15 Who to Screen

How to Screen RECOMMENDATIONS We recommend non-fasting lipid and lipoprotein testing which can be performed in adults in whom screening is indicated as part of a comprehensive risk assessment to

16 How to Screen RECOMMENDATIONS We recommend non-fasting lipid and lipoprotein testing which can be performed in adults in whom screening is indicated as part of a comprehensive risk assessment to reduce CVD events (Strong Recommendation, High Quality Evidence). We suggest that for individuals with a history of triglyceride levels >4.5 mmol/l that lipid and lipoprotein levels be measured fasting (Conditional Recommendation, Low Quality Evidence). Practical tip: Compared to fasting lipid values, there will be minimal change with non-hdl-c, a slight decrease in LDL-C and small increase in triglyceride concentrations when individuals do not fast.

17 Changes in Postprandial Lipids in Normal Populations Langsted A et al., Circulation Fasting and nonfasting lipid levels influence of normal food intake on lipoids, lipoproteins, apolipoproteins and cardiovascular risk prediction Cross-sectional study of fasting versus nonfasting lipid levels in Copenhagen General Population Study and Copenhagen City Heart Study Siddhu D and Naugler C. Arch Int Med Fasting time and lipid levels in a community-based population Cross-sectional study of individuals tested from 1 to 16 hours postprandially In both studies, non-hdl-c, and apo B varied little between fasting and nonfasting TG levels increased up to 20% ( mm) and LDL-C was lower by up to 10% ( mm)

18 Benefits of Non-fasting Lipids Patient convenience no need to go to lab early in the morning and fasting; no need for retesting if not fasting Reduced wait times and reduced early morning patient burden in clinical laboratories Safety prevention of hypoglycemic episodes in diabetics Enhances compliance and avoids delay in lipid screening and follow up tests Enhanced predictive value for CVD and mortality of nonfasting lipids Identification of high remnants/insulin resistance Removal of need to perform fasting blood work generally HbA1c is accepted as a diagnostic test and follow up test by CDA and ADA that does NOT have to be accompanied by a fasting glucose High fasting glucose usually results in HbA1c test

19 What s a normal LDL? No normal We have targets based on risk Your cholesterol is better than mine but I don t have diabetes so we re going to try and bash it down to under 2

20 How low should we try and get Cholesterol? Based on risk for CAD The more risk factors a patient has the more aggressive treatment should be Common risk factors include Hypertension Age Smoking status Diabetes Family history of early CAD hscrp (high sensitivity C-reactive protein)

When to Consider Pharmacological Treatment in Risk Management RECOMMENDATIONS Statin indicated conditions: We recommend management that includes statin therapy in high risk conditions including

0 mmol/l to lower the risk of CVD events and mortality (Strong Recommendation, High Quality Evidence).

21 When to Consider Pharmacological Treatment in Risk Management RECOMMENDATIONS Statin indicated conditions: We recommend management that includes statin therapy in high risk conditions including clinical atherosclerosis, abdominal aortic aneurysm, most diabetes mellitus, chronic kidney disease (age >50 years) and those with LDL-C 5.0 mmol/l to lower the risk of CVD events and mortality (Strong Recommendation, High Quality Evidence). Primary prevention: a) We recommend management that does not include statin therapy for individuals at low risk (modified FRS < 10 %) to lower the risk of CVD events (Strong Recommendation, High Quality Evidence). b) We recommend management that includes statin therapy for individuals at high risk (modified FRS 20%) to lower the risk of CVD events (Strong Recommendation, High Quality Evidence). c) We recommend management that includes statin therapy for individuals at intermediate risk (IR; modified FRS 10-19%) with LDL-C 3.5 mmol/l to lower the risk of CVD events. Statin therapy should also be considered for IR persons with LDL-C <3.5 mmol/l but with apo B 1.2 g/l or non-hdl-c 4.3 mmol/l or in men 50 and women 60 years of age with 1 CV risk factor (Strong Recommendation, High Quality Evidence). Values and preferences - This recommendation applies to individuals with an LDL-C 1.8 mmol/l. Any decision regarding pharmacological therapy for CV risk reduction in IR persons needs to include a thorough discussion of risks, benefits, and cost of treatment, alternative nonpharmacological methods for CV risk reduction and each individual s preference. The proportional risk reduction associated with statin therapy in RCTs in (IR) persons is of similar magnitude to that attained in high-risk persons. Moreover, irreversible severe side effects are very rare and availability of generic statins results in low cost of therapy. However, the absolute risk reduction is lower. Statin therapy may be considered in persons with FRS of 5%-9% with LDL-C 3.5 mmol/l or other CV risk factors as the proportional benefit from statin therapy will be similar in this group as well.

Canadian Journal of Cardiology 2016 32, 1263-1282DOI: (10.1016/j.cjca.2016.07.

Pharmacological Treatment Indications & Targets Category Consider Initiating pharmacotherapy if: Target NNT Primary Prevention High (FRS 20%) Intermediate (FRS 10-19%) LDL-C <2.

23 Pharmacological Treatment Indications & Targets Category Consider Initiating pharmacotherapy if: Target NNT Primary Prevention High (FRS 20%) Intermediate (FRS 10-19%) LDL-C <2.0 mmol/l or >50% LDL-C 3.5 mmol/l or Non-HDL-C 4.3 mmol/l or Apo B 1.2 g/l or Men 50 & women 60 yrs and 1 CV risk factor Or Apo B <0.8 g/l Statin Indicated Conditions** Clinical atherosclerosis* (CAD, CVD, PAD) Or 20 Abdominal aortic aneurysm Diabetes mellitus: 40 yrs, or >15 yrs duration & age 30 yrs (DM 1), or microvascular disease non-hdl-c <2.6 mmol/l CKD (age 50 yrs): egfr < 60 ml/min/1.73 m 2, or ACR >3 mg/mmol LDL-C 5.0 mmol/l >50% in LDL-C * consider LDL-C < 1.8 mmol/l for subjects with ACS within last 3 months;** statins indicated as initial therapy

24 Currently this is how we predict risk for CAD

25 Cardiovascular Age Tables / Diabetes: NO

26 Cardiovascular Age Tables / Diabetes: YES

27 Diabetes is a CAD equivalent Haffner N Engl J Med 1998

29 You can never predict for the individual

30 Treatment Strategies Lifestyle (diet and exercise) are always recommended If the above dose not work and the patient is not at target then pharmacotherapy should be considered

31 Fat Treatment Options: Diet Decrease saturated and trans fatty acids Increase mono unsaturated and omega 3 fatty acids Carbohydrate Decrease simple sugars and increase complex carbohydrates especially soluble fibre Protein No significant effects Total calories Eat less to lose weight Functional foods Almonds, soy, oats, psyllium, plant sterols, garlic, etc

32 The Simian Diet It works but is not practical It lowered my LDL by almost 50% to well below 2 Jenkins DJ. Metabolism 2001

33 What about fish oil, i.e. Omega 3 fatty acids?

35 ?Plant Sterols?

36 A plant s version of cholesterol hcs.osu.edu/hcs300/biochem3.htm

37 Lots to choose from

38 Plant Sterols Becel now has a plant sterol version Centrum multivitamins now come with plant sterols Used regularly you can expect around a 6% reduction in LDL and a relatively neutral effect on HDL Mechanism of action similar to that of ezetimibe

39 Why are people nuts about nuts? Mukuddem-Petersen, J Nutr 2005

40 Nuts Tree nuts are preferential over ground nuts Numerous studies have shown them to be weight neutral Most of the literature looks at almonds Again expect about a 6% reduction in LDL when your patient snack on almonds regularly

41 Too little too late?

42 A psyllium based cereal can lower your cholesterol by 4% Anderson J. Amer J Clin Nutrition 2000

43 So What? We have a bunch of little interventions with small effects on lipids Each functional food or supplement has usually been studied in isolation The question arose Are the effects additive Hence the Portfolio Diet Soy, Almonds, Viscous Fibre and Plant Sterols

44 Normal Healthy Diet Breakfast Bran flakes cereal Skim milk Blueberries Fat-free vanilla yogurt Double-fruit jam Portfolio Diet Breakfast Hot oat-bran cereal Soy beverage Blueberries Sugar and psyllium Oat-bran bread Test margarine Double-fruit jam Snack Bran muffin Control light margarine Fresh fruit Snack Almonds Soy beverage Fresh fruit Jenkins DJ. Eur J Clin Nutr. 2005

45 The Portfolio Diet did almost as well as the statin control portfolio Statin (20 mg lovastatin ) Jenkins DJ. Eur J Clin Nutr. 2005

46 Pharmacotherapy Statins Fibrates Niacin Bile acid binding resins Cholesterol absorption inhibitors PCSK9 inhibitors

48 Pharmacotherapy Statins -HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase) inhibitors Block rate limiting step in cholesterol synthesis Excellent for lowering LDL HDL and TG neutral

49 RULE OF SIX LDL-C: % Change From Baseline Mean % Reduction in LDL-C from Baseline Dose, mg Rosuvastatin (n = ) Atorvastatin (n = ) Pravastatin (n = ) Simvastatin (n = ) Jones, PH, Davidson, MH, et al. Am J Card. Vol. 92, July 15, 2003.

CHD Risk Reduction with Statin Therapy Relative Risk Reduction (%) Endpoints +20 0 5 10 15 20 25 30 35 Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events 40 45 50

50 CHD Risk Reduction with Statin Therapy Relative Risk Reduction (%) Endpoints Major coronary events Coronary deaths Cardiovascular deaths Noncardiovascular events Total mortality Strokes Intermittent claudication Angina La Rosa JC et al. JAMA 1999;282: Crouse JR III et al. Arch Intern Med 1997;157: Pedersen TR et al. Am J Cardiol 1998;81: Slide Source Lipids Online Slide Library

51 Statin Adverse Events Common side effects - Headache Myalgia Fatigue - GI intolerance Flu-like symptoms Increase in liver enzymes Occurs in 0.5 to 2.5% of cases in dose-dependent manner Serious liver problems are exceedingly rare Manage by reducing statin dose or discontinue until levels return to normal Myopathy Occurs in 0.2 to 0.4% of patients Rare cases of rhabdomyolysis Reduce by Cautiously using statins in patients with impaired renal function Using the lowest effective dose Cautiously combining statins with fibrates Avoiding drug interactions Careful monitoring of symptoms Presence of muscle toxicity requires the discontinuation of the statin

52 Fibrates Excellent for lowering TG s and good at raising HDL Data for preventing CAD is weak Benefits seen in patients who start with low HDL and high TG s

53 Fibric Acid Derivatives Indications: Mechanism of Action: Adjunctive therapy to diet Hypertriglyceridemia, Combined hyperlipidemia with low HDL-C who do not respond to nicotinic acid Increase peripheral lipolysis and decrease hepatic TG production Efficacy: Decrease TG 25 50% LDL-C decreases, remains the same, or increases Increase HDL-C 15 25% in hypertriglyceridemia Side Effects: Contraindications: Intervention Trials: GI upset (8%), cholelithiasis, myositis, abn LFTs Hepatic or renal dysfunction Pre-existing gallbladder disease Modest effects on decreasing CAD at best

54 Clinical Features of Nicotinic Acid Products available (daily dose) Immediate-release, 2 4 g/d Extended-release (Niaspan ), 1 2 g/d OTC products, sustained-release, 2 g/d Best agent to raise HDL-C Reduces coronary events (Coronary Drug Project) Adverse effects Flushing, itching, headache (immediate-release, Niaspan ) Hepatotoxicity, GI (sustained-release) Activation of peptic ulcer Hyperglycemia and reduced insulin sensitivity Contraindications Active liver disease or unexplained LFT elevations Peptic ulcer disease

55 Nicotinic Acid: Mechanism of Action Mobilization of FFA TG synthesis Liver Apo B VLDL VLDL secretion VLDL LD L Serum VLDL results in reduced lipolysis to LDL Serum LDL HDL Circulation Hepatocyte Systemic Circulation Decreases hepatic production of VLDL and of apo B

56 Decreasing Flushing Avoid alcohol Avoid spicey foods Take just before bed ASA 325mg 30 minutes prior Titrate up slowly It will get better

57 Effect of Niacin on Lipoproteins 35% 25% 12.5% Baseline LDL-C with Niaspan HDL-C with crystalline niacin HDL-C with Niaspan -15% TG with Niaspan LDL-C with crystalline niacin -30% TG with crystalline niacin 0 1 g/d 2 g/d 3 g/d Adapted from Knopp RH. N Engl J Med 1999;341: Massachusetts Medical Society. All rights reserved.

cholesterol stores and increase in clearance of cholesterol from the blood decrease in delivery of

58 Ezetimibe: Mechanism of Action Cholesterol synthesis Intestine Ezetimibe acts at the brush border of the small intestine and inhibits the absorption of cholesterol This results in: reduction in hepatic cholesterol stores and increase in clearance of cholesterol from the blood decrease in delivery of intestinal cholesterol to the liver Ezetimibe inhibited 54% of all intestinal cholesterol absorption

Enterohepatic Recirculation Terminal Ileum BA Excretion Reabsorption

59 Bile Acid Resins: Mechanism of Action Gall Bladder Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion Bile Acid Enterohepatic Recirculation Terminal Ileum BA Excretion Reabsorption of bile acids LDL Receptors Liver VLDL and LDL removal Net Effect: LDL-C

Change in LDL-C 0% -5% Effect of Colesevelam on LDL-C (N=494 patients with baseline LDL-C of 130 220 mg/dl and TG <300 mg/dl; after 24 weeks of therapy)

60 Change in LDL-C 0% -5% Effect of Colesevelam on LDL-C (N=494 patients with baseline LDL-C of mg/dl and TG <300 mg/dl; after 24 weeks of therapy) Placebo 3.8 g/d 4.5 g/d 0% -10% -15% -20% 15% 18% Davidson MH et al. Expert Opin Investig Drugs 2000;9: Reprinted with permission from Ashley Publications.

61 Clinical Features of BARs Products available: Cholestyramine (Questran), 4 16 g/d Colestipol (Colestid), 5 20 g/d Colesevelam (WelChol) 625 mg tablets, 6 7 tablets/d Reduce coronary events (LRC-CPPT) Adverse effects GI intolerance: constipation, bloating, abdominal pain, flatulence Lack systemic toxicity Drug interactions (colestipol and cholestyramine) Bind other negatively charged drugs Impede the absorption of drugs and/or fat-soluble vitamins Must give other drugs 1 hour before or 4 6 hours after

Percent Change 30 20 10 0-10 -20-30 -40-50 -60 Statin + Fibrate Simva + Gemfibrozil 230 332 LDL-C 39% TG 50% 16% HDL-C 38 Prava/Simva +

62 Percent Change Statin + Fibrate Simva + Gemfibrozil LDL-C 39% TG 50% 16% HDL-C 38 Prava/Simva + Fenofibrate 166 LDL-C 28% 191 TG 41% 22% HDL-C 34 Da Col PG et al. Curr Ther Res Clin Exp 1973;53: Ellen RL et al. Am J Cardiol 1998;81:60B-65B.

63 Steps to Minimize the Risk of Muscle Toxicity with Fibrate Statin Combination Therapy Use statin alone for non-hdl-c goals Use fish oils or niacin rather than fibrates Keep the doses of the statin and fibrate low Dose the fibrate in the AM and the statin in the PM Avoid (or cautiously use) combo in renal impairment Assure no interactions Teach the patient to recognize muscle symptoms Discontinue therapy if muscle symptoms are present and CK is >10 times the upper limit of normal

64 Triple-Drug Regimen Lovastatin 40 mg/d Niaspan g/d Colestipol 20 g/d Baseline (mg/dl) 8 months (mg/dl) Change (%) LDL-C % HDL-C % LDL-C/HDL-C ratio % Brown BG et al. Am J Cardiol 1997;80:

66 Pharmacotherapy (LDL Cholesterol): Minority of patients will require combination therapy Ezetimibe (inhibits cholesterol absorption) Additional LDL-C reductions of up to 20% Bile acid sequestrants (inhibits bile acid reabsorption) Additional LDL-C reductions of 10-15% Niacin Additional LDL-C reductions of up to 20% Combinations are generally safe Clinical outcome trials underway

67 Optional Secondary Targets when LDL-C at Target Test Cut-point Intervention TC/HDL-C >4.0 Fibrate Niacin Non HDL-C >3.5 mmol/l Fibrate Niacin Apo B/AI >0.8 Ezetimibe Niacin Triglycerides >1.7 mmol/l Fibrate Niacin hscrp >2.0 mg/l Ezetimibe Statin Adjusting lipid-lowering therapy to optimize one or more of these secondary targets may be considered in the high risk patient, after achieving a target LDL-C or ApoB, but the clinical advantages of this approach, with respect to patient outcomes, remain to be proven. Genest J et al: Can J Cardiol 2009; 25(10):

68 Statin treatment in other populations End-Stage Heart Failure (LVEF < 30%) GISSI-HF CORONA End-Stage Renal Disease- (Hemodialysis patients) 4-D AURORA Statin therapy did not reduce mortality or morbidity Clinical judgment must be applied when treating these end-stage patients. Patients on dialysis awaiting renal transplantation may still benefit from statin therapy. Kjekshus J et al; Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007; 357: CCS Lipid Guidelines 2009 Tavazzi L et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI_HF trial): A randomized, double-blind, placebo-controlles trial. Lancet 2008; 372: Wanner C et al. German Diabetes and Dialysis Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005; 353: Felström BC et al. AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009; 360:

PCSK9 inhibition Anderson TJ, Gregoire J et al.

Inhibition of ApoB synthesis Anderson TJ, Gregoire J et al.

76 Important Take Home Points Evidence favouring LDL reduction for the prevention and treatment of atherosclerosis is strong and compelling New guidelines recommend a more aggressive approach to management of both high and medium risk patients Target LDL-C<2.0 mmol/l or 50% reduction Many Canadian high risk patients are not achieving LDL-C Goals on statin monotherapy Need for combination therapy (ezetimibe, resins, niacin, PCSKi s) Don t forget about diet

77 My lipid clinic is my favorite clinic Tom Ransom Fax:

Update in Lipid Management. Rameshkumar Raman M.D. Endocrine Associates of The Quad Cities

Update in Lipid Management. Rameshkumar Raman M.D. Endocrine Associates of The Quad Cities Update in Lipid Management Rameshkumar Raman M.D. Endocrine Associates of The Quad Cities Low-Density Lipoprotein (LDL) Consists of Multiple Distinct Subclasses Differing in Size and Lipid Content* Association