Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors

Key Points

  • Studies in the 1950s and 1960s led to the formulation of the lipid hypothesis, which proposed that elevated low-density lipoprotein (LDL) cholesterol was causally related to coronary heart disease (CHD) and that reducing it would reduce the risk of myocardial infarction and other coronary events.

  • 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, was an attractive target in the search for drugs to reduce plasma cholesterol concentrations.

  • Compactin and lovastatin, natural products with a powerful inhibitory effect on HMG-CoA reductase, were discovered in the 1970s, and taken into clinical development as potential drugs for lowering LDL cholesterol.

  • However, in 1980, trials with compactin were suspended for undisclosed reasons (rumoured to be related to serious animal toxicity). Because of the close structural similarity between compactin and lovastatin, clinical studies with lovastatin were also suspended, and additional animal safety studies initiated.

  • In 1982 some small-scale clinical investigations of lovastatin in very high-risk patients were undertaken, in which dramatic reductions in LDL cholesterol were observed, with very few adverse effects. After the additional animal safety studies with lovastatin revealed no toxicity of the type thought to be associated with compactin, clinical studies resumed.

  • Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987.

  • Lovastatin at its maximal recommended dose of 80 mg daily produced a mean reduction in LDL cholesterol of 40%, a far greater reduction than could be obtained with any of the treatments available at the time. Equally important, the drug produced very few adverse effects, was easy for patients to take, and so was rapidly accepted by prescribers and patients. The only important adverse effect is myopathy/rhabdomyolysis. This is rare and occurs with all HMG-CoA reductase inhibitors.

  • Several other HMG-CoA reductase inhibitors, now widely known as statins, subsequently became available for prescription: simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and rosuvastatin.

  • The mechanism of the reduction in LDL cholesterol by statins is now known not to be simply reduction in cholesterol biosynthesis. Induction of the LDL receptor is crucial to their effectiveness.

  • Although the basic lipid hypothesis had been validated by the late 1980s, the movement towards treating hypercholesterolaemia was questioned because overviews of trials of treatments from the pre-statin era suggested that although CHD events might be reduced, survival was not improved.

  • However, large-scale, long-term trials published during the last decade, such as the Scandinavian Simvastatin Survival Study (4S, 1994), The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID, 1998) and the Heart Protection Study (HPS, 2002) with simvastatin, have now provided unequivocal evidence of a reduction in all-cause mortality.

  • In 2001, cerivastatin was withdrawn by its manufacturer due to an excessive risk of rhabdomyolysis.

  • In HPS the risk of serious cardiovascular events was reduced by simvastatin regardless of LDL-cholesterol level.


In the 1950s and 1960s, it became apparent that elevated concentrations of plasma cholesterol were a major risk factor for the development of coronary heart disease, which led to the search for drugs that could reduce plasma cholesterol. One possibility was to reduce cholesterol biosynthesis, and the rate-limiting enzyme in the cholesterol biosynthetic pathway, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, was a natural target. Here, I describe the discovery and development of lovastatin — the first approved inhibitor of HMG-CoA reductase — and the clinical trials that have provided the evidence for the ability of drugs in this class to reduce the morbidity and mortality associated with cardiovascular disease.

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Figure 1: The cholesterol biosynthesis pathway.
Figure 2: Plasma cholesterol changes in the Phase IIb studies of lovastatin.
Figure 3: Structures of the statins.


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I am indebted to the following individuals for their careful review and helpful comments: D. Bilheimer, R. Collins, C. Newman, D. Steinberg, S.Wright and J. Vega.

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Cytochrome P450 3A4

HMG-Co A reductase

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familial hypercholesterolaemia

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Popularly known as a heart attack, this is the death of part of the heart muscle due to sudden loss of blood supply. Typically, the loss of this supply is caused by a complete blockage of a coronary artery containing athersclerotic plaque by a blood clot.


(CHD). A condition in which the main arteries supplying the heart contain atherosclerotic plaque, which can cause myocardial infarction (see above) or angina pectoris, in which cardiac blood flow is reduced, leading to heart pain on exercise. Atherosclerotic plaque contains macrophages and cholesterol.


Framingham is a Massachusetts town considered representative of the United States population, and the epidemiology of cardiovascular disease still continues to be studied there after more than half a century.


(FH). This is an autosomal dominant condition characterized by a defective allele coding for the low-density lipoprotein (LDL) receptor, which causes gross elevations of plasma LDL cholesterol.


An agent that is useful for diseases too rare to provide more than minimal commercial potential is known as an orphan drug.

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Tobert, J. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov 2, 517–526 (2003). https://doi.org/10.1038/nrd1112

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