Statins are recommended as a first-line therapy for the management of lipid disorders, particularly elevations in low-density lipoprotein cholesterol. In the 1950s and 1960s, it became obvious that elevated concentrations of plasma cholesterol represent a major risk factor for the development of heart disease, which led to the quest for drugs that could reduce it.

Since lovastatin had been commercialized, six statins – including two semi-synthetic statins (known as simvastatin and pravastatin) and four synthetic statins (fluvastatin, rosuvastatin and pitavastatin and atorvastatin) – have been introduced to the market. The most popular statin today is atorvastatin.

The discovery of statins

While working at the Sankyo Company in 1976, the Japanese biochemist Akira Endo isolated a factor from the fungus Penicillium citrinum which he identified as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase). This substance, which he named compactin or mevastatin, was the first statin to be administered to humans.

Compactin was shown to lower plasma cholesterol in the dog, rabbit and monkey. Nevertheless, some researchers stayed skeptical as compactin did not lower plasma cholesterol in the rat, which was subsequently demonstrated to result from massive induction of HMG-CoA reductase in rat liver by inhibitors of the enzyme.

Clinical studies of compactin in Japan ensued soon after that, as well as experimental studies around the world. In 1978, Alfred Alberts with his colleagues at Merck Research Laboratories discovered a potent inhibitor of HMG-CoA reductase in a fermentation broth of Aspergillus terreus, which was named lovastatin, mevinolin or monacolin K. Conicidentally, Akira Endo independently identified a same compound within a year of Alberts’ discovery.

After animal safety studies have shown no adverse effects, Merck began clinical trials of lovastatin in April 1980. Still, promising start was interrupted because the trials with structurally similar compactin were stopped by Sankyo Company in September 1980, supposedly due to serious animal toxicity.

But since additional animal safety studies with lovastatin revealed no toxicity issues believed to be associated with compactin, in 1983 Merck decided to re-initiate the clinical development programme, initially only in patients at very high risk of myocardial infarction.

The experience with lovastatin inspired efforts to chemically modify natural statins to make even more effective derivatives. Researchers at Merck synthesized a side-chain ester analog from lovastatin (known as simvastatin) with a 2.5-fold better activity in inhibiting HMG-CoA reductase activity.

Investigators at Warner-Lambert synthesized a substituted H-pyrrole compound known as atorvastatin. This drug was approximately 3-4 times more potent in rat models when compared to lovastatin. Several other statins – including crilvastatin, nisvastatin and cerivastatin – have been synthesized by different pharmaceutical companies.

Entering the clinical use

On September 1, 1987 lovastatin became the first statin to be approved in the USA by the Food and Drug Administration (FDA). This agent is responsible for the revolution in the treatment of hypercholesterolemia, initially achieving peak annual sales of more than $1 billion US.

Simvastatin, an aforementioned side-chain ester analog of lovastatin, was approved for marketing in Sweden in 1988, with subsequent worldwide distribution. This drug was followed by pravastatin in 1991, fluvastatin in 1994, atorvastatin in 1997, cerivastatin in 1998, and rosuvastatin in 2003.

In 2012, the FDA introduced certain changes to the safety information on the labels of statins, which included a small increased risk of higher blood sugar levels and eventual type 2 diabetes diagnosis. Furthermore, the statin labels now also reports potential cognitive effects such as confusion and memory loss experienced by some patients.