History of Statins

Scott M. Grundy, MD, PhD

University of Texas
Southwestern Medical Center
Dallas, Texas

COI: Consultant: Merck, Janssen

Akira Endo discovered Compactin in
1977
Penicillium citrinum Pen-51, the
fungus that produces compactin
Kaneko , Endo, et al. Eur J Biochem. 1978: 87: 313-321.
 Hypolipidemic effects of compactin in dogs.

Tsujita, Endo, et al. Atherosclerosis 1979: 21:307-313

 Akira Yamamoto's patient with familial
hypercholesterolemia first received compactin
in 1978.
 Effect of Compactin in a Patient
with Heterozygous Familial
Hypercholesterolemia

Yamamoto et al. Atherosclerosis 1980; 35: 259-266

 Compactin Treatment in Heterozygous
Familial Hypercholesterolemia

Mabuchi et al. NEJM 1981: 305: 478-482

 Discovery of Lovastatin
At the end of the 1970s other
pharmaceutical companies to begin
searching for another statin.
In July 1976, Merck Research
Laboratories, signed a confidentiality
agreement with Sankyo and obtained
samples of compactin and confidential
experimental data.
Under the direction of Alfred Albert,
Merck set out to find its own statins .
In February 1979 Albert isolated a statin
very similar to compactin, called
mevinolin (lovastatin) Alfred W. Albert
 Discontinuation of Compactin
Development
In August 1980 Sankyo discontinued the
clinical development of compactin.
The drug apparently caused lymphoma in
dogs when given in high doses
 Suspension of Development of
Lovastatin
In April 1980, Merck began preliminary
clinical studies of lovastatin
But after 5 months, in September 1980, they
discontinued the clinical trials because of
rumors that compactin caused cancers in
dogs.
For this reason Merck halted studies on
lovastatin.
 Early FDA Involvement
Following Merck's decision to
terminate clinical trials, FDA became
actively involved in maintaining
interest in the development of the
statins.
Dr. Sol Sobel at FDA took key
decisions to keep statins alive
 Dr. Sol Sobels Crucial Decision
In July 1982, Merck made lovastatin available,
under an arrangement approved by the FDA to
Roger Illingsworth of Oregon Health Sciences
University and Scott Grundy and David Billheimer of
the University of Texas Southwestern Medical
Center.
Although Merck did not have an IND at the time,
IND's were granted to Illingworth and Grundy under
a process that included Merck's agreement to allow
FDA to provide the researchers access to the Drug
Master File.
 Discovery of the LDL Receptor

Michael Brown

Brown and Goldstein 1978

Joseph Goldstein
Effects of Lovastatin on LDL Levels and Clearance

LDL-C FCR

mg/dL

+ +
Lovastatin Lovastatin

Bilheimer, Grundy, Brown, Goldstein 1983

 Roy Vageloss Crucial Decision
In March 1984, Merck submitted
an IND for lovastatin.
Thereafter, the new drug
application for lovastatin was
approved only nine months after
its submission to FDA
This was one of the shortest
approval times for a new drug Roy Vagelos
application up to that time.
 Roy Vageloss Crucial Decision
The decision to approve
cholesterol lowering agents for
marketing at this time was based
on the surrogate of lowering LDL
cholesterol (not on
cardiovascular endpoints).
This surrogate was a key
component in shortening the
review time for lovastatin, and Roy Vagelos
the drug was released for
marketing in 1987.
 Scandinavian Simvastatin
Survival Study

Secondary Prevention

2,223 Placebo

2,221 Simvastatin
Terje R. Pedersen
 4S Trial Main Results
P S Simvastatin better Placebo
Total mortality 256 182 better

CHD mortality 189 111

Major CHD event 622 431

Any CHD event 927 708

Any atheroscl. event 1,023 796

CABG or PTCA 383 252

0 0.2 0.4 0.6 0.8 1.0 1.2

Relative Risk (95% Confidence Intervals)

Scandinavian Simvastatin
Scandinavian Simvastatin Survival
Survival StudyLancet.
Study Group. Group. Lancet. 1994;344:13831389 II.1
1994;344:13831389
Major Primary Prevention Statin Trials
AFCAPS ASCOT CARDS JUPITER
Lova Atorva Atorva Rosuva
20 mg 10 mg 10 mg 20 mg
10

20
% 30
in
CHD 40 36% 37% 37%
50 44%

60
 Statin Safety
Cataracts
Liver disease
Memory loss and confusion
Myalgias ~10%
Myopathy (rare)
Diabetes (9%?)
Peripheral neuropathy (very rare)
 Statin Costs

2000 $3.00 per day

2012 $0.25 to 0.50 per day
 Potential of Statin Usage
Currently, about 40 million patients worldwide
(including about 20 million in the United
States) are being treated with statins.
This figure is dwarfed by the number of
individuals who might benefit from the drugs.
The World Health Organization suggests that
about 200 million individuals worldwide have
heart disease, stroke, or diabetes.
This suggests that statins are underused.
Horton JD, Goldstein JL, Brown MS. J Clin Invest. 2002; 109:1125-31.
Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS;
Cell Metab. 2008 Dec;8(6):512-21
 Cholesterol Homeostasis

LDL
LDL-R

Bile
Acetate Cholesterol
Acids
Potential Add-on Drugs to Statins

Statins
LDL PCSK9
Inhibitor

Bile
Acetate Cholesterol
Acids

Ezetimibe Bile Acid

Resins
 History of Statins
Biochemistry/molecular biology
Drug discovery
In vitro testing
Animal testing
Human testing (phases I, II, III)
FDA registration
Phase IV testing
Acceptance by medical community and public
 Public

Industry Government

Practice Academic