3. Established Therapies For
Hyperlipidemia
HMG-CoA Reductase Inhibitors2
Decrease hepatic production of cholesterol via synthesis blockade
Increases density of LDL cell surface receptors in the liver which increases
uptake from the plasma
Most reduction in LDL
Ezetimibe3
Blocks cholesterol absorption in the intestines causing liver to absorb LDL from
blood stream
Niacin4
Reduces FFA release from fat tissue and increases lipoprotein lipase action
4. Established Therapies For
Hyperlipidemia
Bile Acid Resins5
Bind to bile and prevent its reabsorption, thereby depleting cholesterol stores
Used in mild hyperlipidemia with no hypertriglyceridemia
Fibrates6
Increase lipoprotein lipase activity, uptake of triglycerides from plasma, and
increased synthesis of HDL
Used mainly for hypertriglyceridemia
6. PCSK9 Inhibitors
There are three drugs in this class being developed
All are monoclonal antibodies for subcutaneous injection
Alirocumab
Currently marketed by Sanofi
Evolocumab
Will be released soon by Amgen
Bococizumab
Expected release around 2017-2018 by Pfizer
7. Alirocumab (Praluent) – Sanofi7
Stability at room Temp: 24 hours
Refrigeration and light protection required
Pre-filled glass syringes or pre-filled pens
Administered at either 75 mg or 150 mg subcutaneously q 2 weeks
Room temp for 30-40 minutes before administration
Currently FDA approved for addition to maximally tolerated statin dose for
Familial Hypercholesterolemia or those with clinical ASCVD with sub
optimal LDL-Lowering (prescribing info)
$14,600 for 1 year of therapy
8. Clinical Trials For Alirocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
Odyssey
Options I8
ASCVD and HLD uncontrolled
by atorvastatin
1)Alirocumab *
2)Ezetimibe *
3)Placebo *
4)Double atorvastatin dose
5)Switch to rosuvastatin 40
2 times >
reduction in LDL
Odyssey
Combo I9
CVD and HLD uncontrolled by
max tolerated statin dose
1) Alirocumab *
2) Placebo *
45.9 % >
reduction in LDL
Odyssey
Combo II10
CVD and HLD uncontrolled by
max tolerated statin dose
1) Alirocumab
2) Ezetimibe
29.8 % >
reduction in LDL
at week 24
9. Clinical Trials For Alirocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
NCT016444741
1
Moderate CV risk
Not on HLD therapy
1) Alirocumab
2) Ezetimibe
31 % > reduction
in LDL
Odyssey Long
Term12
(open label)
HLD currently on therapy In addition to background
therapy:
1) Alirocumab
2) Placebo
61.9 % >
reduction of LDL
1.6 % < CV
events
10. Clinical Trials For Alirocumab Awaiting
Results
Trial
Name
Patient Population Treatments
* In addition to statin
Endpoint
Odyssey FH II FH and statin treatment failure 1) Alirocumab *
2) Placebo *
% Δ in LDL
at week 24
Odyssey
Options II
HLD currently on rosuvastatin 1) Alirocumab
2) Ezetemibe
3) Placebo
% Δ
in LDL at
week 24
Odyssey High
FH
FH patients receiving therapy In addition to
background therapy:
1) Alirocumab
2) Placebo
% Δ
in LDL at
week 24
Efficacy and
Safety in CHD
and FH
High CV risk or FH uncontrolled
on current therapy
In addition to
background therapy:
1) Alirocumab
2) Placebo
% Δ
in LDL at
week 24
11. Clinical Trials For Alirocumab Awaiting
Results
Trial
Name
Patient Population Treatments
* In addition to statin
Result
Odyssey
Choice II
HLD uncontrolled by non-statin
therapy
In addition to background
therapy:
1) Alirocumab
2) Placebo
% change
in LDL at
week 24
Odyssey
MONO
Non FH HLD 1) Alirocumab
2) Placebo
% change
in LDL at
week 24
Odyssey
Choice I
Low, medium, high CV risk
With or without statin therapy
In addition to background
therapy:
1) Alirocumab
2) Placebo
% change
in LDL at
week 24
12. Clinical Trials For Alirocumab Awaiting
Results
Trial
Name
Patient Population Treatments
* In addition to statin
Result
Odyssey
Alternative
HLD and low, moderate, or
high CV risk
1) Alirocumab
2) Ezetimibe
3) Atorvastatin
4) Placebo
% change in LDL at
24 weeks
Odyssey
Escape
FH receiving apheresis 1) Alirocumab
2) Placebo
apheresis
requirements
normalized to
baseline schedule
Odyssey
Outcomes
Post MI taking max tolerated
rosuvastatin or atorvastatin
dose
1) Alirocumab *
2) Standard MI therapy
Time to 1st event
(CV death, MI, hosp
for UA, or ischemic
stroke)
13. Clinical Trials For Evolocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
DESCARTES13 Background therapy of:
Diet
Atorvastatin 10 mg
Atorvastatin 80 mg
Atorvastatin 80 + Zetia
In addition to
background therapy:
1) Evolocumab
2) Placebo
Diet: 55.7 % > reduction
Atorv 10: 61.6 % >
reduction
Atorv 80: 56.8 % >
reduction
Atorv 80 + zetia: 48.5 % >
reduction
14. Clinical Trials For Evolocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
GAUSS II14 Uncontrolled HLD
2 or more statin intolerances
1) Evolocumab
2) Ezetimibe
20 % > reduction in
LDL at 12 weeks
MENDEL II15 < 10 % CV risk and HLD 1) Evolocumab
2) Ezetimibe
3) Placebo
40 % > reduction
than ezetimibe
50 % > reduction
than placebo
15. Clinical Trials For Evolocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
RUTHERFORD
II16
FH and HLD
uncontrolled by current
therapy
In addition to background therapy:
1) Evolocumab
2) Placebo
60 % >
reduction in LDL
LAPLACE II17 HLD uncontrolled on
current therapy
1) Low intensity simvastatin,
atorvastatin, or rosuvastatin
2) High intensity atorvastatin or
rosuvastatin
1) Evolocumab
2) Ezetimibe
3) Placebo
40 to 50 % >
reduction in LDL
than ezetimibe
55 to 75 % >
reduction than
placebo
16. Clinical Trials For Evolocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
TESLA Part B18 FH uncontrolled on
current therapy
In addition to
background:
1) Evolocumab
2) Placebo
30.9% > reduction than
placebo
OSLER and
OSLER II19
(open label)
HLD receiving therapy In addition to
background:
1) Evolocumab
2) No change
4.4 % more AEs
0.6 % > neurocognitive AE
1.23 % less CV events
(HR = 0.47 p<.003)
17. Clinical Trials For Evolocumab Awaiting
Results
Trial Name Patient Population Treatments
* In addition to statin
Endpoint
NCT01953328 Japanese
High CV risk and HLD
1) Low intensity atorvastatin
2) High intensity atorvastatin
1) Evolocumab
2) Placebo
% change in
LDL at week 10
and 12
NCT02304484
(open label)
CVD and HLD In addition to background:
1) Evolocumab
2) No change
2 year safety
endpoints
HAUSER-RCT 10-17 years old
FH uncontrolled by statin
1) Evolocumab *
2) Placebo *
% change in
LDL at week 24
18. Clinical Trials For Evolocumab Awaiting
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
FLOREY Moderate to low CV risk
No current therapy
1) Evolocumab
2) Evolocumab + atorvastatin
3) Placebo
% change in LDL
fractional
catabolic rate at
60 days
NCT01984424 Statin intolerance history Atorvastatin run in:
1) Evolocumab *
2) Ezetimibe *
% change in LDL
at 22 and 24
weeks
GLAGOV CVD and currently on
therapy
In addition to background:
1) Evolocumab
2) Placebo
Nominal change
in % artheroma
volume at week
78
19. Clinical Trials For Evolocumab Awaiting
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
EBBINGHAUS CVD and non FH HLD
Extension of FOURIER
FOURIER study patients on
either statin plus evolocumab
or statin plus placebo
Average change
in spatial
working
memory
FOURIER CVD and non FH HLD 1) Evolocumab + statin
2) Statin
Time to 1st
event
20. Current Lipid Treatment Guidelines20
Clinical ASCVD
LDL > 190 mg/dL
DM 1 or 2 and age 40-75
ASCVD 10 y risk > 7.5 % and age 40-
75
High intensity statin unless > 75
years old or intolerant
High intensity statin unless
intolerant
High intensity statin unless 10 year
ASCVD < 7.5 %
Moderate to high intensity statin
21. Current Lipid Treatment Guidelines20
No recommendation on LDL targets
Addition of non-statin drug may be considered if baseline LDL > 190
Addition of non-statin drug in suboptimal statin response or complete
statin intolerance is considered a reasonable option
Why is there such a preference for statins?
Why are there no longer LDL targets?
22. The Actual Evidence
Statin drugs are the only class with actual mortality and morbidity benefits
studied in randomized controlled trials
No RCT evidence that adjuncts to statin therapy add clinical benefit
Actually evidence to the contrary:
AIM HIGH: niacin added to statin when LDL < 80 mg/dL provides no benefit23
ACCORD: adding fenofibrate to statin in patients with DM provides no benefit22
Focus Shift from LDL lowering to mortality and morbidity benefit
No evidence for target LDL levels in terms of ASCVD event risk reduction
High intensity statin therapy ( > 50 % LDL reduction) provides more clinical
benefit than moderate intensity therapy ( 30-50 % LDL reduction)27
23. IMPROVE-IT21
High Risk Patients within 10
days of ACS
Placebo + Simvastatin 40 mg
Ezetimibe 10 mg +
Simvasatatin 40 mg
Time to first event
(CV death, MI, hospitalization for UA, coronary artery revascularization > 30 days post
randomization, or stroke)
24. Implications of IMPROVE-IT21
Ezetimibe + moderate intensity simvastatin produces modest ASCVD event
rate reduction
6.4 % RRR (HR 0.936 p < 0.016)
Evidence that lowering LDL, not statin intensity, should be the goal
Further reduction of LDL beyond statins should be implemented
So can we expect PCSK9 inhibitors to show real clinical benefit based on
the results of IMPROVE-IT?
25. Problems With IMPROVE-IT
Ezetimibe also reduced expression of thrombomodulin, platelet
endothelial cell adhesion molecule, and vitronectin receptor24
Also improved multiple indices of platelet reactivity24
Conclusion that LDL reduction mediates ezetimibe ASCVD risk reduction is
confounded
No evidence that these results extend to other lipid lowering agents
No evidence that addition to high intensity statin is also beneficial
26. How Much Did We IMPROVE-IT?
Addition of ezetimibe reduced the risk of any endpoint, but did not reduce
deaths.
Results were mainly driven by reduction in MI and stroke rates
The Average cost of MI in medicare patients is about 20,000 dollars (30 day
total treatment)25
The average cost of a stroke over a patient lifetime has been estimated as
about 100,000 dollars (all subtypes averaged)26
Assuming these are the only two events that occurred (probably most
expensive scenario):
in one year, 1 in 350 patients (NNT) treated with simvastatin but no Zetia would cost
an average of 60,000 dollars to healthcare
In contrast, treating 350 patients for a year with Zetia would cost ($250/30
days * 12 month/year * 350 patients) about 1 million dollars. (good Rx)
This is a very expensive price for society to pay for such a small benefit
27. IMPROVE-IT and PCSK9 Inhibitors
IMPROVE-IT does not necessarily ensure the clinical benefit of PCSK9I’s
PCSK9 inhibitors cost $12,000 more per patient-year
Given previous assumptions, for PCSK9 inhibitors to be cost neutral the NNT
would need to be 4 (compared to 350 for zetia)
Even assuming $500,000/event cost, the NNT would need to be 33
Increasing statin intensity has a NNT/year of about 50, so PCSK9I’s achieving
an NNT of 33 is unlikely6
Health plan reactions will probably include:
Negotiating lower prices from manufacturers in exchange for exclusivity
Limiting beneficiary access through high coinsurance
raising premiums for all members
Involved prior auth process including proof of adequate exercise, adequate trial of
two statins, adequate trial of moderate statin with zetia, laboratory tested statin
intolerance.
28. Recommended Use of PCSK9I’s
Based on current guidelines, available evidence, and economic
considerations:
Patients with FH or ASCVD and statin resistance (on max dose) for additional
LDL lowering is a reasonable strategy.
Discuss with patient costs vs uncertain clinical benefit
In FH patients to avoid apheresis
2nd line to addition of ezetimibe for statin intolerant patients
No evidence to support use of PCSK9I’s as monotherapy or for arbitrary
reduction of statin dose
In complete statin intolerance, PCSK9I monotherapy should be considered only after
careful risk assessment and patient preference
29. Sources
Clinicaltrials.gov
All trials with no published data
1Xue-Qiao Zhao. Pathogenesis of atherosclerosis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 25, 2013.)
2Zocor® [package insert]. Whitehouse Station, NJ: Merck and Co. Inc; 1999.
3Zetia® [package insert]. Whitehouse Station, NJ: Merck and Co, Inc; 2001.
4Niaspan® [package insert]. North Chicago, IL: AbbVie Inc; 2015
5Questran® [package insert]. Spring Valley, NY: Par Pharm Co Inc; 2013.
6Tricor® [package insert]. North Chicago, IL: AbbVie Inc; 2013.
7Praluent® [package insert]. Bridgewater, NJ: Sanofi-Aventis LLC; 2015.
8Bays H1, Gaudet D1, Weiss R1, et al. Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. J Clin
Endocrinol Metab. 2015 Aug;100(8):3140-8. doi: 10.1210/jc.2015-1520. Epub 2015 Jun 1.
9Kereiakes DJ1, Robinson JG2, Cannon CP3, Lorenzato C4, Pordy R5, Chaudhari U6, Colhoun HM7. Efficacy and safety of the proprotein convertase subtilisin/kexin type
9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015 Jun;169(6):906-
915.e13. doi: 10.1016/j.ahj.2015.03.004. Epub 2015 Mar 13.
10Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM. Efficacy and safety of alirocumab in high cardiovascular risk patients
with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015
May 14;36(19):1186-94. doi: 10.1093/eurheartj/ehv028. Epub 2015 Feb 16.
11Eli M. Rotha, Marja-Riitta Taskinenb, Henry N. Ginsbergc, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with
hypercholesterolemia: Results of a 24 week, double-blind, randomized Phase 3 trial. International Journal of Cardiology. Sept 14; 176(1): 55-61.
12Jennifer G. Robinson, M.D., M.P.H., Michel Farnier, M.D., Ph.D., Michel Krempf, M.D, et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular
Events. The new England journal of medicine. april 16, 2015: 372(16).
13Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi:
10.1056/NEJMoa1316222. Epub 2014 Mar 29.
14Stroes E1, Colquhoun D2, Sullivan D3, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-
controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2541-8. doi: 10.1016/j.jacc.2014.03.019. Epub 2014 Mar 30.
30. Sources
15Koren MJ1, Lundqvist P2, Bolognese M3, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of
evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2531-40. doi: 10.1016/j.jacc.2014.03.018. Epub 2014 Mar 29.
16Raal FJ1, Stein EA2, Dufour R3, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised,
double-blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):331-40. doi: 10.1016/S0140-6736(14)61399-4. Epub 2014 Oct 1
17Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients
with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014 May 14;311(18):1870-82. doi: 10.1001/jama.2014.4030.
18Raal FJ1, Honarpour N2, Blom DJ3, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-
blind, placebo-controlled trial. Lancet. 2015 Jan 24;385(9965):341-50. doi: 10.1016/S0140-6736(14)61374-X. Epub 2014 Oct 1.
19Sabatine MS1, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr
16;372(16):1500-9. doi: 10.1056/NEJMoa1500858. Epub 2015 Mar 15.
20Neil J. Stone, Jennifer G. Robinson, Alice H. Lichtenstein, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic
Cardiovascular Risk in Adults. Circulation. 2014;129:S46-S48.
21Virani SS1, Akeroyd JM2, Nambi V3, Maddox TM4, Gillette MA5, Michael Ho P4, Rumsfeld J4, Petersen LA2, Ballantyne CM6. Implications for Ezetimibe Therapy Use
Based on IMPROVE-IT Criteria. Am J Med. 2015 Jun 10. pii: S0002-9343(15)00511-2. doi: 10.1016/j.amjmed.2015.05.027.
22DiNicolantonio JJ1, Chatterjee S2, Lavie CJ3, Bangalore S4, O'Keefe JH5. Ezetimibe Plus Moderate-dose Simvastatin After Acute Coronary Syndrome: What Are We
IMPROVEing On? Am J Med. 2015 Aug;128(8):914.e1-4. doi: 10.1016/j.amjmed.2015.01.034. Epub 2015 Feb 27.
23Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec
15;365(24):2255-67. doi: 10.1056/NEJMoa1107579. Epub 2011 Nov 15.
24Miller M1, DiNicolantonio JJ, Can M, Grice R, Damoulakis A, Serebruany VL. The effects of ezetimibe/simvastatin versus simvastatin monotherapy on platelet and
inflammatory biomarkers in patients with metabolic syndrome. Cardiology. 2013;125(2):74-7. doi: 10.1159/000347134. Epub 2013 May 7.
25Kim N1, Bernheim SM, Ott LS, Han L, Spivack SB, Xu X, Volpe M, Liu A, Krumholz HM. An administrative claims measure of payments made for Medicare patients for a
30-day episode of care for acute myocardial infarction. Med Care. 2015 Jun;53(6):542-9.
26Taylor TN1, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996 Sep;27(9):1459-66.
27van der Harst P, Voors AA, van Veldhuisen DJ. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Aug
12;351(7):714-7.
Editor's Notes
I am going to be presenting on the much anticipated PCSK9 inhibitors; the touted game changers in the field of lipid disorder. In order to fully understand the impact of these agents, we must understand the full picture of why we treat hyperlipidemia and how our understanding of cholesterol modifying therapies has evolved over time.
Lets begin with a basic overview of how hyperlipidemia leads to serious health complications: endothelial dysfunction occurs due to many factors, including high blood glucose, smoking, and oxidized LDL particles. LDL begins to enter the endothelium and activate resident macrophages to produce chemokines and inflammation. Macrophages cells collect under the intima and become foam cells as they scavenge LDL particles. This process leads to necrosis and apoptosis with even more inflammatory consequences. Smooth muscle cells and ECM begin to abnormally proliferate. The luminal exterior becomes fibrous and the internal portions of this mass become necrotic and calcified. As the mass becomes larger, it occludes blood flow, or disrupts the coagulation resistant luminal epithelium layer, causing clot formation and downstream ischemia. These two events lead to clinical events including angina pain, myocardial infarction, and stroke. The development of these sequalae are most related to elevated levels of low density lipoprotein particles, which is why LDL has been the target of most pharmaceutical therapies to date.
Early in our investigation into atherosclerosis and CVD, etiologic studies demonstrated that LDL levels were the most consistent predictors of CVD, but other cholesterol levels, such as HDL and triglycerides were also deemed important. Therefore, many medications were developed to treat patients with abnormal lipid levels, particularly high LDL levels, in an attempt to prevent atherosclerosis and clinically evident CVD. Statins or HMG CoA inhibitors have become the most successful of these drugs. They work by inhibiting cholesterol synthesis in the liver, increasing LDL receptor density on the liver cells, and thereby reducing LDL levels in the blood. Ezetemibe blocks cholesterol absorption from the intestines, again reducing levels in the blood stream both directly and through liver absorption. Niacin increases lipoprotein lipase action, increasing fat storage in HDLs and uptake of triglycerides into tissues.
Bile acid resins bind to bile and cause its excretion out of the body. This depletes cholesterol stores and impairs the digestion and absorption of fats. Fibrates increase lipoprotein lipase activity like niacin, and are used mainly in the treatment of hypertriglyceridemia.
The PCSK9 inhibitors have a unique mechanism of action. Normally, PCSK9 (proprotein convertase subtilisin/kexin 9) binds to LDL receptors as LDL causes receptor mediated endocytosis. This ultimately leads to the degradation of the LDL receptor in the resulting lysosome. PCSK9 inhibitors prevent this process from occurring, allowing LDL receptors to be recycled to the cell surface. This effectively achieves the same end as statins…increase LDL receptor density.
Alirocumab is newly on the market. Some notable features for clinicians are its room temperature stability for 24 hours and requirement for refrigeration and protection from light. It comes in prefilled pens or syringes at 75 and 150 mg doses to be given twice weekly. It garnered FDA approval for addition to max tolerated statin dose in FH and ASCVD patients with sub-optimal LDL lowering.
Now that we have introduced the PCSK9 inhibitors, lets discuss the evidence we have seen to date in clinical trials.
Several important studies for Alirocumab have published results.
Options I compared the addition alirocumab to atorvastatin 20 or 40 mg to the addition of ezetimibe or placebo, the doubling of the atorvastatin dose, or the switching to rosuvastatin 40 mg. Alirocumab reduced LDL by at least twice as much as all comparators. (44.1 % and 54 % reduction for 20 and 40 mg atorvastatin respectively)
COMBO 1 and 2 basically demonstrated that in addition to statins, Alirocumab produces additional reduction in LDL by 45 % compared to placebo and 30 % compared to ezetimibe.
Another RCT demonstrated alirocumab monotherapy to be superior in LDL reduction than ezetimibe monotherapy (by 31 %) in patients with moderate CV risk.
The biggest study, arguably, was Odyssey long term, which in addition to showing that alirocumab was far superior to placebo in reducing LDLs when added to background therapy, also demonstrated 1.6 % less pooled CV events when safety data were analyzed.
This is a list of RCTs which we can expect to have results for over the coming years. Important results include the exact LDL lowering effects in familial hypercholesterolemia patients
patients with various background therapies.
And as a monotherapy in various levels of Cardiovascular risk. Two important studies awaiting results are ESCAPE, looking at reduction in the usage of apheresis in FH patients, and OUTCOMES, which will formally assess the effect on CV events.
Evolocumab has several important Phase three RCTs with published results as well.
DESCARTES demonstrated vast superiority over placebo when added to diet, low or high intensity atorvastatin, and high intensity atorvastatin plus ezetimibe
GAUSS II demonstrated that evolocumab was superior to ezetimibe in reducing LDL as early as week 12 in those who were intolerant to two or more statins
MENDEL II demonstrated superior LDL lowering than ezetimibe and placebo in patients with < 10 % CVD risk
RUTHERFORD II affirmed the superiority of evolocumab to placebo in reducing LDL in patients with FH inadequately controlled by current therapy
LEPLACE II compared addition of evolocumab, ezetimibe or placebo to patients randomized to baseline statin therapies of various agents and intensities. Across all statins and intensities, evolocumab produced greater reductions in LDL than ezetimibe or placebo
TESLA part B showed that addition of evolocumab was better than no change in therapy in patients with familial hypercholesterolemia
Arguably the most impactful studies were OSLER I and II, which found that evolocumab was well tolerated, other than slight concern over neurocognitive side effects. More importantly, an analysis of the safety data showed a 1.23 % lower rate of any CV event in the evolocumab group.
We are still awaiting the publishing of data from many trials.
This data will include long term safety profiles, efiicacy in addition to statins in treating adolescents with familial hypercholesterolemia
60 day efficacy of monotherapy vs combo therapy with statin and placebo in lower risk patients,
efficacy vs ezetimibe when added to statin in statin intolerant patients,
And Relative reduction in artheroma volume in CVD patients on background lipid therapy
we are waiting for two notable studies:
EBBINGHAUS will assess the difference between treatment and control with respect to changes in special working memory, which is the only major safety concern of PCSK9 inhibitors
FOURIER is formally assessing rate of CV events in CVD patients taking statin with or without evolocumab. (CV death, MI, hosp for UA, stroke, or coronary revascularization)
Now that we have an overview of the body of evidence supporting PCSK9 inhibitors, lets look at the current treatment guidelines and the evidence backing them.
According to the most recent AHA/ guidelines, its all about statins. There are four main groups which have proven benefits in morbidity and mortality when receiving statin therapy: clinical CVD, high baseline LDLs, older patients with diabetes, and > 7.5% ASCVD 10 year risk. The only decisions to make are 1) whether to initiate a statin or not and 2) at what intensity?
(high intensity > 50% reduction in LDLs moderate intensity 30 – 50 %)
The new treatment guidelines also trash the established standard of treating patients to a target LDL level. Furthermore, the addition of other cholesterol medications to statins to achieve further reduction of LDL is considered unnecessary. It is only recommended in patients with very high baseline LDLs. Even patients who cannot tolerate max doses of statins are merely instructed to maintain whatever dose of statin they can tolerate. The addition of other therapies is relegated to the status of “reasonable option”.
If we ignore the established practice of many years, and look at the strongest RCT evidence to date, we see that Statin drugs are the only class of drug with proven mortality and morbidity benefits.
For a long time, no evidence even existed that addition of other therapies to statins added any benefit beyond LDL lowering.
In fact Niacin added to statins and fenofibrate added to statins actually failed to show any clinical benefit beyond lipid profile changes
This strict reevaluation of evidence led experts to conclude that the only evidence based therapy for improving patient outcomes is to give statins to those groups that benefit most. All other therapies are generally considered optional because there is uncertainty in their actual benefit.
The expert panel also found no evidence to support treating patients to specific goals of LDL. They only found evidence that reducing LDLs 30-50 % with statin therapy provided benefit to certain groups, and reducing LDLs more than 50 % with statin therapy provided incremental benefit for some groups.
The more statin rather than lower LDL theory was relatively untested until an RCT looking at outcomes in patients taking Vytorin was released in 2015. Patients post ACS were randomized to receive either simvastatin 40 mg alone or with ezetimibe in addition to standard post MI therapy. Time to first CV event was measured as the primary result
The study found that the addition of ezetimibe to moderate intensity simvastatin produced a 6.4 % relative rate reduction in CV events
To many, this was game changing news because it was evidence that lowering LDL more was the appropriate goal, not maximizing statin intensity. Some believe this means additional lipid lowering therapy should always be added to statins unless contraindicated or the patient is below 70 mg/dL
Before we jump to conclusions, lets talk about several shortcoming of IMPROVE-IT
Ezetimibe was also shown to affect several inflammation and platelet reactivity indices, which may mediate its clinical benefit. It is far from conclusive that lower LDL is the reason ezetimibe was effective, and therefore inconclusive that LDL lowering by other agents will produce similar effects.
There is also a lack of evidence to show that ezetimibe has similar effects when added onto high intensity statin, or whether or not it would be preferable to increase statin intensity vs add ezetimibe
In addition to the shortcomings of what the study did not find,
What it did find is not all too impressive.
Mortality was not decreased, only Mis and strokes
Only 1 in 350 patients treated per year would be spared a stroke or MI. This strategy will probably be implemented in higher risk patients willing and able to pay for more therapy.
From a cost effectiveness standpoint, it would cost approximately a million dollars to treat 350 patients for a year with zetia, compared to an average of 60,000 dollars for the 1 patient that would otherwise have had a stroke or MI.
Nevertheless, this is good news that some patients can benefit from nonstatin therapy. Particularly those unable to reach high intensity statin therapy.
IMPROVE-IT does not necessarily improve the likelihood that PCSK9 inhibitors will reduce adverse CV events.
In addition, PCSK9 inhibitors cost a great deal more than Zetia…12,000 dollars a year more.
The NNT would need to be astounding for this drug to be the least bit exciting to health plans. If 1 in 4 patients
