Lipitor – The World’s All-Time Best Selling Drug

pills drugs on banknote money

Since the 1950s, pharmaceutical companies have raced to discover and develop billion-dollar blockbuster drugs. In the face of stiff competition, only a handful are able to remain relevant over the course of many years; Rituxan, Advair and Humira are several that come to mind. But which of these can lay claim to being the best selling drug of all time? With millions of prescriptions every year since 1996, Pfizer’s anti-cholesterol drug atorvastatin (Lipitor) is still going strong over 20 years later.

Pfizer’s atorvastatin (trade name Lipitor) entered the game late, with several similar ‘statins’ already on the market. But despite fierce competition, it quickly established itself to be the most effective and potent of its class. Although Lipitor’s patent expired in 2011, it is still the most prescribed anti-cholesterol medication in the world. In 15 years (1996 – 2011) of market dominance, Lipitor raked in USD 125 billion in sales, becoming the best-selling drug in the history of the pharmaceutical industry. This is the story of how the king of blockbuster drugs came to be.

Health Effects of Cholesterol

Cholesterols, being essential components of cell membranes, are an important class of lipids. Our body also needs cholesterol to produce certain hormones, vitamins and bile; all useful chemicals that we need to function. Contrary to popular belief, we actually need a fair amount of cholesterol in our blood to remain healthy! We are able to produce the majority of cholesterol within our liver, with only a fraction coming from our diet.

The ongoing large scale Framingham Heart Study (since 1948!) provides conclusive evidence that cholesterol plays a major role in coronary artery diseases. In short, too much Low-Density Lipoprotein (LDL) – or too little High-Density Lipoprotein (HDL) – in our blood puts us at higher risk of heart attacks and strokes, among other heart diseases.

As mentioned earlier, our bodies produce most of the cholesterol we need. A key step in LDL biosynthesis involves a certain enzyme, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase. As you might guess, it’s responsible for reducing HMG-CoA, an important precursor in the cholesterol synthetic pathway. Once this was known, the next step was to design an inhibitor capable of blocking HMG-CoA reductase.

brown goldstein nobel prize physiology medicine 1985 cholesterol metabolism
The Nobel Prize in Physiology or Medicine 1985 was awarded jointly to Michael S. Brown and Joseph L. Goldstein “for their discoveries concerning the regulation of cholesterol metabolism.”


Statins Enter the Market

In 1971, Japanese biochemist Akira Endo got to work on a medicinal chemistry program, assaying microbial strains for their ability to inhibit lipid production. 6000 compounds and 2 years later, he had his active compound – mevastatin2. Mevastatin was shown to be effective in inhibiting LDL cholesterol production in animal trials, but certain tumors started to arise in dogs treated with it. Hence, it never made it to market.

Despite this setback, cholesterol-lowering ‘statins’ were still important areas of drug development for many pharmaceutical companies. A breakthrough finally arrived when in 1978, Alfred Alberts and Julie Chen of Merck & Co. discovered a compound with extremely potent HMG-CoA reductase activity3. It was moved into animal and subsequent human clinical trials, with lovastatin (Mevacor) hitting the shelves in 1987 – the first statin on the market.

Not satisfied with their success in this area, Merck continued to invest in statin research. In 1992, their second statin, simvastatin – 2.5 times more potent than lovastatin – was approved for use by the FDA. Marketed with the trade name Zocor, it was a blockbuster success, racking up peak sales of $5 billion in 2003. A year later, Merck combined simvastatin with fellow pharmaceutical company Schering-Plough’s ezetimibe (another cholesterol-lowering drug) to produce Vytorin, another huge market success.

chemical structure of lovastatin simvastatin pravastatin fluvastatin
Chemical structure of several statin-class drugs. (From left, clockwise) Lovastatin, simvastatin, pravastatin, fluvastatin

Atorvastatin: Pfizer’s Johnny-Come-Lately

Medicinal chemist Bruce Roth, working for Warner-Lambert/Parke-Davis (now Pfizer) in the 1980s, synthesized atorvastatin. The drug was designed by borrowing attributes of prior statins, in classic ‘me-too’ drug design fashion. Roth made several changes to the structure of lovastatin, optimizing its chemical structure in the hope of creating a more effective drug.

chemical structure comparison between lovastatin and atorvastatin
Comparison of lovastatin (left) and atorvastatin (right) chemical structures. Notice the new pyrrole (5 membered N heterocycle) on atorvastatin, with the lactone (6 membered cyclic ester) on lovastatin opened up. Other changes include a fluorine atom at the para position to prevent oxidation by CYP450 enzymes.

Atorvastatin delivered positive results in pre-clinical trials, lowering cholesterol levels in animals with comparable efficacy to lovastatin. But by the mid-1990s, pharmaceutical companies had flooded the market with their own versions of statins and other LDL cholesterol-lowering drugs; atorvastatin would become the 5th statin on the market. Despite this, Parke-Davis pushed the drug through to human clinical trials, to incredible results. Atorvastatin performed significantly better than any statin that was available on the market at the time.

In 1997, atorvastatin was marketed and sold by Pfizer as Lipitor, with annual sales estimated to be around $300 million. This amount was actually rather meager by pharmaceutical industry standards, as Lipitor would enter an already saturated market as a ‘Johnny-come-lately’ drug. But fueled by its remarkable efficacy, sales skyrocketed to the billion-dollar mark before the turn of the year.

lipitor atorvastatin 40mg label
Lipitor 40 mg drug label


Lipitor’s Legacy

By 2005, Lipitor was bringing in peak annual sales revenues of $12.9 billion. Pfizer continued to make huge profits off their best-selling blockbuster, as well as other drug combinations that included atorvastatin. Numerous head-to-head studies funded by rival pharmaceutical companies were carried out, attempting to prove their statins were just as good, if not better. None of them succeeded, but instead served to cement Lipitor’s status as the best-in-class LDL cholesterol-lowering drug available. Even today, its incredible safety and efficacy profile is reflected in its sheer volume of prescriptions; almost 100 million people in the U.S. alone take atorvastatin. That’s almost one-third of its entire population!

Bruce Roth medicinal chemist inventor of lipitor atorvastatin
Somewhat ironically, Bruce Roth – the scientist who invented Lipitor – takes the drug himself to lower his cholesterol levels

For the 15 years that atorvastatin was under Pfizer’s patent, it raked in over $125 billion in sales, becoming the world’s best-selling drug of all time. Once the patent had expired, manufacturers quickly flooded the market with generic versions of atorvastatin under other trade names, craving a share of the lucrative market. Since manufacturers could now acquire the rights to produce atorvastatin, illegal and even counterfeit versions of Lipitor began to appear, driven by the public’s willingness to pay a premium for the drug bearing the original trade name.

Trapibs the Future of Cardiovascular Drugs?

Although statins continue to dominate the cardiovascular drug market, there is still ongoing research into other mechanisms to improve patient outcomes in this area. Just as high LDL levels increase the risk of heart diseases, low HDL levels (the good cholesterol) do the same. Exercise, stress relief, as well as reducing tobacco and alcohol intake are just some ways that individuals can increase their HDL cholesterol levels.

A potential target for HDL-increasing drugs is the cholesteryl ester transfer protein (CETP). The protein converts HDL cholesterol to LDL cholesterol, hence CETP inhibitors should lead to an increase in our blood HDL levels4. Pharmaceutical companies made significant advances in CETP inhibitor discovery and development, including Pfizer (torcetrapib), Merck (anacetrapib), Roche (dalcetrapib) and Eli Lilly (evacetrapib). Although these ‘trapib’ class of drugs showed early promise, they quickly fell by the wayside. Adverse reactions and low efficacy led to every single project being terminated, some as recently as 2017.

Although these expensive setbacks were huge blows to the pharmaceutical industry, they were able to provide valuable lessons regarding trapib pharmacology as well as CETP inhibition as a whole. In the future, perhaps one of these will give rise to a successful drug candidate that can emulate the success of atorvastatin – paving the way for another generation of best-selling blockbuster drugs.

Reference

  1. Li, J. J. (2006). Laughing Gas, Viagra, and Lipitor: The Human Stories Behind the Drugs We Use. Oxford University Press.
  2. Bellosta, S., Paoletti, R., & Corsini, A. (2002). History and development of HMG-CoA reductase inhibitors. In HMG-CoA Reductase Inhibitors (pp. 1-17). Birkhäuser, Basel.
  3. Greenspan, M. D., Yudkovitz, J. B., Lo, C. Y., Chen, J. S., Alberts, A. W., Hunt, V. M., … & Chiang, Y. C. (1987). Inhibition of hydroxymethylglutaryl-coenzyme A synthase by L-659,699. Proceedings of the National Academy of Sciences84(21), 7488-7492.
  4. Farrer S. (2018). Beyond Statins: Emerging Evidence for HDL-Increasing Therapies and Diet in Treating Cardiovascular Disease. Advances in preventive medicine2018, 6024747. doi:10.1155/2018/6024747

2 Responses

  1. scott L says:

    Perhaps in the future there might be a safe and effective drug that will both have a CETP inhibiting and HMG-CoA reductase inhibiting function incorporated. That way, I will doubly protected with lowered HDL and higher LDL cholesterol hahaha. Sean, do you know the extent that genetics play a role in how your body produces cholesterol? I know lots of people still eat healthy but are cursed with bad cholesterol readings (me specifically) LMAO.

    • Sean says:

      Lipitor (atorvastatin) itself is actually very safe, with few side effects – that’s a key contributor to its blockbuster success. Some scientists joke that our drinking water should be laced with atorvastatin to improve the health of the population! Genetics definitely plays a role in controlling cholesterol levels (and practically every physiological process) but it is difficult to pinpoint a specific target, as there are likely to be a multitude of genes controlling it – each with complementary and contradictory effects. You may like to read about our article on genes and how they work: https://theskepticalchemist.com/body-spaceship-genes-crew/

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