Statin Combinations Is there a rationale ?

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

What is the residual risk due to?

Particle number v/s Lipid levelA 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

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.

Report of the thirty person/ten country panel Journal of Internal Medicine, 10 FEB 2006

A

B

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty person/ten country panel‐ ‐

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)

Particle number = apo B =non HDLC

Clin Lipidol, 2011 Future Medicine Ltd

Atherogenic dyslipidemia: Typical lipid profile of patients with type 2 diabetes and metabolic

syndrome

Cardiovasc Diabetol, 2012 BioMed Central, Ltd

How to reduce the residual risk of non HDLC ?

ACCORD LIPID study

5518 T2D at high risk for CV events started on Simvastatin at randomization

Treatment group Placebo group- 2753fenofibrate added Only simvastatinat 1 month- 2765

For the whole group Mean LDL decreased from– 100.0 to 81.1 in Fenofibrate group– 101.1 to 80.0 in placebo groupMean 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 groupMedian 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.

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 anti-inflammatory effects

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

Is HDLC another target ?

However, failed HDLC trials :

• AIM HIGH- Niacin

• HPS 2 THRIVE - Niacin

• Dal-OUTCOMES - dalcetrapib

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

Present state of Low HDLC

• Check nonHDLC -- Fibrates

• Check Lp(a), LDLC ----- Niacin ?

• Use non pharmac methods

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

Effect of Drugs on HDL-C Levels

Drug ClassDrug Class Effect on HDLCEffect on HDLC AmountAmount

Nicotinic acidNicotinic acid 15%–35%15%–35%

FibratesFibrates 10%–15%10%–15%

EstrogensEstrogens 10%–15%10%–15%

StatinsStatins 5%–10%5%–10%

α-Blockersα-Blockers 10%–20%10%–20%

AlcoholAlcohol 10%10%

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.

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)

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

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

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.

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 .

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

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

Approach to statin intolerance

Start with low doses of more potent statins• Intermittent dosing• Gradual up-titration

Trial of multiple statinsOther therapies• Statin + co-enzymes Q10• Statin + ezetimibe• Bile acid resin + niacin

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.

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

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 mipomersen sodium (? Outcome studies)

• When myalgia : Co Q

…. 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 ?