Statin combinations
- 1. Statin Combinations Is there a rationale ?
- 2. Statin Combinations : A key in search of a lock ! A solution in search of a problem ! • LDLC at goal, but residual risk present. • Statins at optimum dosage, but LDLC not at goal. • Statins taken, but side effects
- 4. What is the residual risk due to?
- 5. Particle number v/s Lipid level A paradigm to understand • Lipids are carried in lipoprotein particles ( like LDL, IDL, VLDL, Lp(a) etc) • Cholesterol is carried into the arterial wall within a LP particle and … • the number of LP particles determines the likelihood of cholesterol entering and lodging within an arterial wall • Now, the lipid composition of the principal atherogenic lipoproteins differs substantially amongst individuals
- 6. For example the amount of cholesterol carried by an LDL particle varies greatly between individuals and can also change in response to lipid altering Rx. A B Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty‐person/ten‐country panel Report of the thirty person/ten country panel Journal of Internal Medicine, 10 FEB 2006
- 7. Particle number v/s Lipid level • Thus, for the same amount of cholesterol measured in 2 individuals, their LP particle number may be different with different degrees of atherogenecity • Therefore, lipid levels do not automatically match lipoprotein particle levels • Hence, the total number of atherogenic particles is a more important determinant of the risk of vascular disease than the level of any of the conventional lipids (TC, TG etc)
- 8. Particle number = apo B =non HDLC Clin Lipidol, 2011 Future Medicine Ltd
- 9. Atherogenic dyslipidemia: Typical lipid profile of patients with type 2 diabetes and metabolic syndrome Cardiovasc Diabetol, 2012 BioMed Central, Ltd
- 13. How to reduce the residual risk of non HDLC ?
- 16. ACCORD LIPID study 5518 T2D at high risk for CV events started on Simvastatin at randomization Treatment group fenofibrate added at 1 month- 2765 Placebo group- 2753 Only simvastatin
- 17. For the whole group Mean LDL decreased from – 100.0 to 81.1 in Fenofibrate group – 101.1 to 80.0 in placebo group Mean HDL cholesterol levels increased from - 38.0 to 41.2 mg per deciliter in the fenofibrate group - 38.2 to 40.5 mg per deciliter in the placebo group Median plasma triglyceride levels decreased from - 164 to 122 mg per deciliter in the fenofibrate group and - 160 to 144 mg per deciliter in the placebo group.
- 20. Bezafibrate • Activates all three PPAR subtypes (alpha, gamma and delta) -> insulin resistance and atherogenic dyslipidemia • Decreases blood glucose level, HbA1C, insulin resistance and reduces the incidence of T2DM compared to placebo or other fibrates. (about 30–40% risk reduction), • Neutralizes the adverse pro-diabetic effect of statins • Significantly decreased prevalence of small, dense low density lipoproteins particles • Has important fibrinogen-related properties and antiinflammatory effects
- 21. When to start Fibrates in such selected groups of patients ? • current guidelines recommend treatment for patients with hypertriglyceridemia and low HDL cholesterol levels that persist despite statin therapy • subgroup results of ACCORD and previous trials from start in patients with type 2 diabetes who have substantial atherogenic dyslipidemia in the basal state
- 22. Is HDLC another target ?
- 24. However, failed HDLC trials : • AIM HIGH- Niacin • HPS 2 THRIVE - Niacin • Dal-OUTCOMES - dalcetrapib
- 25. But HDLC IS important • Vast epidemiological data : low HDL increases the risk of cardiovascular disease by about 40% • Coronary drug project, HATS trial • Meta-analysis of 11 randomized controlled trials, published online December 19, 2012 in the JACC: Treatment with niacin was associated with a significant 34% reduction in the composite end point of any cardiovascular disease event and a significant 25% reduction in coronary heart disease events • Problems with AIM HIGH and HPS 2 THRIVE
- 26. Present state of Low HDLC • Check nonHDLC -- Fibrates • Check Lp(a), LDLC ----- Niacin ? • Use non pharmac methods
- 27. Effects of Lifestyle Modifications on HDL-C Levels Weight reduction • For every 3 kg (7 lb) of weight loss, HDL-C levels increase 1 mg/dL Smoking cessation • HDL-C levels in smokers are 7%–20% lower than those in nonsmokers • HDL-C levels return to normal within 30–60 days after smoking cessation Exercise • Aerobic exercise (40 min, 3–4 times weekly) increases HDL-C by approximately 2.5 mg/dL
- 28. Effect of Drugs on HDL-C Levels Drug Class Effect on HDLC Amount Nicotinic acid 15%–35% Fibrates 10%–15% Estrogens 10%–15% Statins 5%–10% α-Blockers 10%–20% Alcohol 10%
- 29. What about Lp(a) ? • Lp(a) is a plasma protein composed of an LDL particle linked to apo(a), which has structural homology with plasminogen. • Lp(a) may therefore contribute to both intimal cholesterol deposition and prothrombotic potential • Genetically determined Lp(a) levels are continuously and linearly related to risk of CVD independent of lifestyle, lipid levels.
- 30. When to check for Lp(a) ? • premature cardiovascular disease esp not explained by routine lipid parameters or RF • existing heart or vascular disease, especially with normal or only mildly elevated lipids. • recurrent cardiovascular disease despite statin treatment • family history of premature cardiovascular disease • family history of elevated lipoprotein (a) • familial hypercholesterolaemia, esp low HDL-C • Patients with a moderate or high risk of cardiovascular disease (2010 European Atherosclerosis Society Consensus Panel)
- 31. Lp(a) Cut points – Desirable: < 14 mg/dL (< 35 nmol/l) – Borderline risk: 14 - 30 mg/dL (35 - 75 nmol/l) – High risk: 31 - 50 mg/dL (75 - 125 nmol/l) – Very high risk: > 50 mg/dL (> 125 nmol/l) – If the level is elevated, treatment should be initiated with a goal of bringing the level below 50 mg/dL – most studies and meta-analyses show an increase in CVD risk starting at Lp(a) >25 mg/dl
- 33. Available Rx for high Lp(a) • Niacin and estrogens lower Lp(a) up to 30% • Aspirin • Statins either have no effect or increase Lp(a) levels Thyromimetics • Cholesterol-ester-transfer protein (CETP inhibitors) • Anti-sense oligonucleopeptides to apoB -Mipomersen • Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors. • L-carnitine (2 g/day) may also reduce lipoprotein a levels • • Gingko biloba may be beneficial, but has not been clinically verified Coenzyme Q-10 and pine bark extract have been suggested as beneficial, but neither has been proven in clinical trials
- 34. Statins at optimum dosage, but LDLC not at goal. Statin combinations with Ezetimibe: • Combo with Atorvastatin- Liptruzet – now FDA approved -2013 • Available as a once-daily tablet containing 10 mg of ezetimibe combined with 10, 20, 40, or 80 mg of atorvastatin.
- 35. Outcome studies with Ezetimibe ? • ENHANCE- Simvastatin-Ezetimibe combination (80+20)-Vytorin, did not result in a significant difference in changes in intima-media thickness (IMT) compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein • IMPROVE-IT-Outcomes in ACS with ezetimibe/simvastatin combination expected to be completed in 2013 .
- 36. Statins at optimum dosage, but LDLC not at goal: Other options o Colesevelam o Niacin, Fibrates o Plant stanols and sterols approximately 2 g/day reduces LDL-C by approximately 10% o Monoclonal antibody to PCSK9 AMG 145 (Amgen) o Lomitapide and mipomersen sodium
- 37. Statins taken, but side effects • Statin myopathy (AHA/ACC/NHLBI) Myalgia: Pain with normal CPK Myositis: Pain with incerased CPK (1 to10- fold normal) Rhabdomyolysis: Increased CPK >= 10- fold normal +/- renal disease
- 38. Approach to statin intolerance Start with low doses of more potent statins • Intermittent dosing • Gradual up-titration Trial of multiple statins Other therapies • Statin + co-enzymes Q10 • Statin + ezetimibe • Bile acid resin + niacin
- 39. Statin-Aspirin Combo “REGARDS”: a cross-sectional analysis • • • • Participants : neither agent (n = 7,718) aspirin only (n = 3,673) statin only (n = 1,898) both agents (n = 3,008) • • • • Results: Estimated mean CRP was 2.78 mg/L for subjects taking neither 2.73 mg/L with aspirin only 2.29 mg/L with statins only 2.03 mg/L for subjects taking both agents The association was larger among those who had been taking aspirin for >5 years and among participants with self-reported CVD.
- 40. Statin-Clopidogrel Combo • A secondary analysis of “CHARISMA” trial: There was no evidence of an interaction clinically with concomitant clopidogrel and CYP3A4-MET statin administration in 10,078 subjects • A single center, small randomized, pharmacodynamic study in Italy : Adding Atorvastatin to Clopidogrel Reduces High On-Treatment Platelet Reactivity-JACC Interv Feb 21, 2013
- 41. Conclusion: When & what would I add to a statin ? • When basal TG >200, basal HDLC <35 & non HDLC abN –ath dyslipid : Fibrates (esp Beza for low HDLC) • When HDLC < 30 with abN Lp(a) and not at goal LDLC :Niacin • When LDLC refractory to highest statin dose : Ezitimibe, Colesevelam monoclonal antibody to PCSK9 AMG145 (Amgen) lomitapide and mipomerse n sodium (? Outcome studies) • When myalgia : Co Q
- 42. …. When & what would I add to a statin ? • High TG and intolerance to Fibrates : Omega 3 FA • Diabetic retinopathy, PAD ± Ath DysL, statin induced diab : Feno or Bezafibrate • To reduce CRP: Aspirin • To reduce high platelet reactivity : Clopidogrel ?
Editor's Notes
- #6: because the number of particles within any lipoprotein fraction determines the likelihood of any member of that class entering and lodging within an arterial wall
- #35: for the treatment of elevated LDL-cholesterol levels in patients with primary or mixed hyperlipidemia as an adjunct to dietary changes, as well as for reducing cholesterol levels in patients with homozygous familial hypercholesterolemia
- #41: Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration