Statin combinations aim to address residual cardiovascular risk from atherogenic dyslipidemia. While lowering LDL cholesterol is important, the number of lipoprotein particles is a stronger determinant of risk. Fibrates may help when triglycerides are high and HDL is low despite statins. Ezetimibe can lower LDL further when at maximum statin dose. Niacin reduces non-HDL cholesterol and Lp(a), but failed outcome trials question its benefit. Lifestyle changes and drugs like aspirin and clopidogrel may provide additional benefits when added to statins. Ongoing research evaluates new agents for refractory hypercholesterolemia and statin intolerance.

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 ?