Phase III Therapeutics Lecture Lipid Lowering Drugs

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Phase III Therapeutics LectureLipid Lowering
Drugs
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Pathways of Lipid Transport Inherited
Hyperlipidemias
Familial Combined Hypertriglyceridemia
Polygenic. VERY COMMON
(ApoB)
Remnant Removcal Disease ApoE deficiency.
UNCOMMON
X
Familial HyperTriGlyceridemia LPL deficiency
etc. RARE
Familial Hyper- cholesterolemia LDL receptor
deficiency. COMMON. Heterozygotes 1500.
X HMG-coA Reductase step blocked by Statins
Familial Hypoalphalipoproteinemia (Tangiers
Disease) HDL low. RARE

• From Knopp R.H. Drug Treatment of Lipid
  Disorders. N Engl J Med 1999341498-510

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Endemic Hyperlipidemias

• 66 UK population have a Total cholesterol gt5.2
  mmol/L
• Reflects high dietary fat, obesity and genotype
• Secondary causes should be excluded but
  explains only a minority of cases

Liver or biliary disease, hypothyroidism,
diabetes, nephrotic syndrome or drug-induced
(etretinate, HAART, thiazides, OC,
glucocorticoids, ?-blockade and ciclosporin)
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Management Strategy

• Who to treat?
• Primary 10 yr risk of event ?30
• Secondary - Established IHD or CVD
• What degree of hyperlipidemia should trigger
  intervention?
• Total cholesterol gt 5mmol/L (or LDL gt3)
• What are the specific interventions
• Correct secondary causes if possible
• Dietary modification in all subjects
• Drug Rx for vast majority a statin

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Dietary Intervention

• Step II diet has lt30 of calories as fat, lt7 as
  saturated fat and lt200mg cholesterol/day.
• Can achieve a fall in LDL-C of 8-15 but
  long-term compliance a problem.
• Has useful 2ary benefits
• Weight reduction
• BP reduction
• Reduced insulin resistance
• Improve intake vitamins fresh fruit/vegetables
  (folate and antioxidants)

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General points about Statins

• They competitively and potently inhibit HMG-CoA
  reductase (in nM range) leading to 2ary
  upregulation of surface LDL receptors
• They have short half-lives (2 hours except
  atorvastatin at 14h) but effective with once
  daily administration
• All have slightly higher efficacy if given at
  night
• All except pravastatin are metabolised through
  CYP enzymes in the liver (usually 3A4) which is
  the source of important interactions
• Major side effects hepatitis (stop if ALT rises
  gt 3x ULN) and myositis

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Clinical Trials in Primary and Secondary
Prevention of IHD
LRC-CPPT Lipid Research Clinics-Coronary
Primary Prevention Trial BAS bile acid
sequestrant NR not reported AFCAPS/TexCAPS
Air Force/Texas Coronary Atherosclerosis
Prevention Study WOSCOPS West of Scotland
Coronary Prevention Study HHS Helsinki Heart
Study CDP Coronary Drug Project NA not
applicable 4S Scandinavian Simvastatin
Survival Study CARE Cholesterol and Recurrent
Events LIPID Long-Term Intervention with
Pravastatin in Ischaemic Disease PostCABG Post
Coronary Artery Bypass Graft Trial VA-HIT
Veterans Affairs High-Density Lipoprotein
Cholesterol Intervention Trial BIP Bezafibrate
Infarction Prevention Study POSCH Program on
the Surgical Control of Hyperlipidemias.
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ELIGIBILITY MRC/BHF Heart Protection Study (HPS)

• Increased risk of CHD death due to prior disease
• Myocardial infarction or other coronary heart
  disease
• Occlusive disease of non-coronary arteries or
• Diabetes mellitus or treated hypertension
• Age 40-80 years
• Total cholesterol ? 3.5 mmol/l (? 135mg/dl)
• Statin or vitamins not considered clearly
  indicated or contraindicated by patients own
  doctors
• Lancet 20023607-22

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PRIOR DISEASE at BASELINE
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TOTAL LDL CHOLESTEROLterciles at BASELINE
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SIMVASTATIN 40mg daily Muscle symptoms
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SIMVASTATIN 40mg daily Safety monitoring
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Fatal Rhabdomyolysis with Statins

• Rare probably a class effect
• Appears to be dose-dependent
• implications for superstatins
• Risk increased by combination with fibrate
• Fibrates especially for gemfibrozil/cerivastatin
• Nicotinic acid
• Protease Inhibitors (HAART therapy)
• Interacting drugs affecting metabolism through
  CYP pathway

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SIMVASTATIN CORONARY EVENTS REVASCULARISATION
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
(10269)
(10267)
STATIN better
PLACEBO better
Major coronary event
Non-fatal MI
357
574
Coronary death
587
707
27 SE 4
898
1212
CORONARY EVENTS
reduction
(8.7)
(11.8)
(2Plt0.00001)
Revascularisation
513
725
Coronary
Non-coronary
450
532
24 SE 4
939
1205
REVASCULARISATIONS
reduction
(9.1)
(11.7)
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN MAJOR VASCULAR EVENTS
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Vascular
event
(10269)
(10267)
STATIN better
PLACEBO better
898
1212
Major coronary
444
585
Any stroke
939
1205
Revascularisation
24 SE 3
2033
2585
ANY OF ABOVE
reduction
(19.8)
(25.2)
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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People suffering events ()
60(18)
Benefit/1000 (SE)
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SIMVASTATIN MAJOR VASCULAR EVENT by LDL TOTAL
CHOLESTEROL
SIMVASTATIN
PLACEBO
Rate ratio 95 CI
Lipid levels
at entry
(10269)
(10267)
STATIN better
PLACEBO better
LDL cholesterol (mmol/l)
598
756
(17.6)
(22.2)
lt 3.0 (116 mg/dl)
484
646
(19.0)
(25.7)
³
3.0 lt 3.5
951
1183
(22.0)
(27.2)
³
3.5 (135 mg/dl)
Total cholesterol (mmol/l)
360
472
(17.7)
(23.1)
lt 5.0 (193 mg/dl)
744
964
(18.9)
(24.5)
³
5.0 lt 6.0
929
1149
(21.6)
(26.8)
gt 6.0 (323 mg/dl)
24 SE 3
2033
2585
(19.8)
(25.2)
ALL PATIENTS
reduction
(2Plt0.00001)
0.4
0.6
0.8
1.0
1.2
1.4
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SIMVASTATIN Main conclusions

• After allowance for non-compliance, 40mg daily
  simvastatin safely reduces the risk of heart
  attack, of stroke, and of revascularisation by
  about one-third
• 5 years of statin treatment typically prevents
  these major vascular events in about
• 100 of every 1000 people with previous MI
• 80 " " " other CHD
• 70 " " " cerebrovascular disease
• 70 " " " other arterial disease
• 70 " " " diabetes (age 40)
• irrespective of cholesterol level (or age, or
  sex, or other treatments)

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Prospective Pravastatin Pooling Project Coronary
Event Rates in CARE and LIPID Patients with
Baseline LDL-C lt3.3mmol/L
Coronary Event Rate ()


Pravastatin
p.004 p (interaction) .005
Placebo
lt60
F
M






gt27
lt27
lt40
gt40
gt60
gt150
lt150
Age
Sex
HTN
Smoking
DM
BMI
HDL-C
TG
Sacks FM et al. Circulation 20021051424-1428.
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Cumulative Coronary Event Rates in Diabetic and
Nondiabetic Patients with Baseline LDL-C
lt3.3mmol/L
Placebo Diabetic Pravastatin Nondiabetic Pravastat
in Diabetic Placebo Nondiabetic
Cumulative Risk of Coronary Event or Procedure ()
Years Follow-up
Sacks FM et al. Circulation 20021051424-1428.
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Are the effects of Statins solely explained by
reduction in cholesterol ?

• Atherosclerosis can be viewed as an inflammatory
  process
• Statins could affect inflammatory process by
• 2ary effect on LDL uptake by macrophages (as
  source of CRP)
• 1ary effect on the acute phase-response
• Both scenarios suggest an exclusive focus on
  cholesterol reduction may be misplaced

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Cardiovascular Risk Prediction the role of
hs-CRP (1)

• Womens Health Survey long term effects of ASA
  vit E
• Baseline samples from 27,939 patients
• Mean age 55. 25 had HT, 12 smoked, 45 on HRT
  2.5 had DM
• Followed for mean of 8 years
• Endpoint of MI, stroke, revascularization of CV
  death

Ridker et al, NEJM 20023471557
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Cardiovascular Risk Prediction the role of
hs-CRP (2)

• CRP provides additional risk prediction to that
  provided by Framingham risk assessor across all
  LDL-C groups.

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Statins have an Effect on Inflammatory Markers
such as CRP

• CHEST study (Heart 200352-7) in 80
  dyslipidaemic patients statins (atorva, simva and
  pravastatin) reduced CRP at 1 week with further
  falls up to 12 weeks. Fall in CRP correlated
  closely with the fall in LDL-cholesterol
• PRINCE study (JAMA 20012869) primary
  prevention study of 1702 subjects randomised to
  placebo or 40mg prava and CRP followed to 24
  weeks. Prava reduced CRP by 17
• Atheroscleosis 2003166129 186 Type2 DM
  patients randomised to placebo or 10/80mg
  atorvastatin. Atorva reduced CRP by 15 47
  without significant effect on plasma IL-6

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Platelet Receptor Inhibition in Ischemic Syndrome
Management (PRISM) Statin Therapy Reduced Event
Rate
Statins discontinued
No statins
Event Rates Mortality, MI ()
Statin continued
0
1
2
3
4
7
5
30-day Follow-up Period
Heeschen C et al. Circulation 20021051446-1452.
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Current Unresolved Issues on the Use of Statins

• For secondary prevention we should treat all
  patients with established IHD but
• How soon after an event should they be started?
• Is dose-titration versus LDL-chol still
  appropriate?
• Should we simply put all patients on a high dose
  of a statin without titration in keeping with
  HPS?
• For primary prevention is the current threshold
  of 30 risk over 10 years too stringent?

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Fibrates

• ? FA oxidation in muscle and liver and
  lipogenesis in the liver
• Most effective at reducing VLDL (TG) smaller ?
  in LDL-chol but useful ? in HDL-chol
• Act as PPAR? ligands (cf glitazones) - reduced
  expression of Apo C11 is key to ? VLDL catabolism
• Main side effects
• GI intolerance
• 1-2 increase in the incidence of gallstones

• Important interactions
• increased risk of myositis on a statin
• reduction in dose requirements (30) for
  patients on warfarin

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Nicotinic Acid

• 1ary effect is reduced FA mobilization from the
  periphery ? ? hepatic VLDL synthesis

• Is the agent with largest impact on HDL, and the
  only agent that lowers Lp(a) (by 30)
• Usually employed in combination with fibrate,
  resin or statin this avoids side effects of
  higher doses
• Major side effects
• Flushing prostaglandin mediated
• Skin drying GI intolerance

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Anion-Exchange Resins

• Sequester bile acids (BA) in the gut hence
  blocking enterohepatic cycling of BA e.g.
  cholestyramine and colestipol
• 2ary effect on cholesterol synthesis actually ?
  VLDL and hyperTG may limit use
• Usually used in combination with a statin
• Major side effect not palatable and constipate
• Important interactions bind polar drugs such as
  warfarin, digoxin, thyroxine and statins ?give 1
  hr before resin

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Super Statins

• New Superstatins
• Rosuvastatin launched 2003, Pitavastatin
  expected 2005
• Super is an exaggeration
• Do we really need them?
• No doubt that reduction in ischaemic end-points
  is a class-effect
• Proven safety should probably be the major
  concern following cerivastatin withdrawal
• Older statins going generic i.e. costs likely to
  fall

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Does the intensity of Lipid reduction matter?

• PROVE IT-TIMI 22 Trial (NEJM 2004 3501495)
• designed as a non-inferiority study of the two
  agents
• 4162 patients within 10 days of an ACS were
  randomized to pravastatin 40mg/d or atorvastatin
  80mg/d
• followed up for mean of 24 months
• Atorvastatin limb produced a 16 reduction in
  primary end point events
• LDL-cholesterol was 1.6 mmol/l vs 2.46 in
  pravastatin limb

Note early separation of event curves vs. 12-18 m
delay in 2ary prevention trials does this still
reflect differences in the pleiotropic actions of
the 2 statins?
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The Z phase of the A to Z Trial intense vs
leisurely simvastatin, SS

• Patients with ACS randomised to either SS 40mg/d
  for 1/12 then 80mg/d OR placebo for 4/12 then SS
  20mg/d
• No difference in 1ary end point (composite CV
  death, non-fatal MI, ACS or need for revasc) in
  first 4/12
• Differences only obvious after 6-8/12
• Only 10 episodes of myopathy (9 in intense limb)

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Newer Therapies - Ezetimibe

• Novel inhibitor of intestinal cholesterol
  transporter (? SR-B1)
• Rapidly metabolised to glucuronide (EZEG) which
  has 400x the potency of EZE and prolongs action
  by enterohepatic cycling
• No important adverse effects OR significant drug
  interactions
• Effective in mild/moderate HC as monotherapy or
  in combination with statins for moderate/severe
  HC where it acts synergistically
• Unlike resins does not raise TG - actually falls
  and again synergism with a statin

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Emerging Therapy - Torcetrapib

• Novel inhibitor of cholesteryl ester transfer
  protein, (CETP), that is normally responsible for
  transfer of these esters from HDL to Apo-B1 gt
  fall in HDL-cholesterol content and particle size.

• small rise in HDL with atorvastatin 20mg/d
• much larger and dose-dependent rise with
  Torcetrapib

NEJM 20043501505
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Important points

• Hyperlipidemia is common and a major risk factor
  for IHD and stroke
• Intervention with a statin is highly effective
  and can reduce risk by 1/3rd
• Statins are safe but still under prescribed even
  to high risk groups (e.g. diabetics)
• HPS has still to impact on guidelines and
  clarification needed on the dogma of
  dose-titration
• Prescription of statins is likely to expand
  substantially driven by appearance of generics
  and OTC sales?

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Further Materials
Slides are available at www-clinpharm.medschl.cam.
ac.uk

• Knopp R.H. Drug Treatment of Lipid Disorders. N
  Engl J Med 1999341498-510
• Munford R. S. Statins and the Acute-Phase
  Response. N Engl J Med 2001 3442016-2018
• Frenette P. S. Locking a Leukocyte Integrin with
  Statins. N Engl J Med 2001 3451419-1421
• Chapter 25 of Bennett P.N. Brown M.J. Clinical
  Pharmacology, Churchill-Livingstone 2003