Evidence debates: mortality and prevention trials

Once you turn 40, it seems like half the people you know are taking a statin drug. You know, because their cholesterol is high, and to prevent heart disease down the line. It makes sense: better safe than sorry.

This is a huge triumph for preventive medicine. Statin drugs have saved (or improved) the lives of millions of people because they acted early. This is how medicine (and public health) is supposed to work.

But the devil is in the details. Like all drugs, statins have side effects. And when they are prescribed for many millions of people, the math means that millions of people will not, in fact, get any benefit from the drug. It turns out that atorvastatin (and other statin drugs) may be the most over-prescribed drugs in the history of medicine. And therein lies a Drug Story.

Sources for this episode:

[1] Akira Endo- Gairdner Gala Acceptance Speech (2017) Canada Gairdner Awards: Akira Endo, the Japanese biochemist who discovered the first statin, reflects on American dietary and lifestyle habits that inspired him to develop a solution to prevent heart disease.

[2] Influence of nicotinic acid on serum cholesterol in man (1955) Archives of Biochemistry and Biophysics: Since 1955, the B-vitamin niacin (nicotinic acid) has been used in the treatment of high cholesterol.

[3] Atherosclerotic Cardiovascular Disease Risk Estimates Using the Predicting Risk of Cardiovascular Disease Events Equations (2024) JAMA Internal Medicine: The Predicting Risk of Cardiovascular Disease Events (PREVENT) cardiovascular risk equation excludes race, adds kidney function and statin use, and suggests fewer adults may be eligible for statins compared to pooled cohort equations.

[4] It Took A Brilliant Marketing Campaign To Create The Best-Selling Drug Of All Time (2011) Business Insider: Lipitor became the best-selling drug of all time through aggressive marketing to doctors and coinciding with the FDA’s allowance of direct-to-consumer drug advertising in 1997.

[5] Learning From Our Parents’ Heart Health Mistakes (2017) The New York Times: Indigenous South Americans, the Tsimane, have low rates of coronary artery disease and healthier lifestyles compared to Americans, offering a model for prevention.

[6] CHOLESTEROL: DRUG HAILED AS TREATMENT BREAKTHROUGH (1987) The New York Times: The New York Times introduces lovastatin, a novel drug predicted to revolutionize the treatment of high cholesterol.

[7] Millions fewer people may need statins, a new study suggests. But guidelines have yet to agree (2024) STAT: The number of adults recommended for statins could drop from 45.4 million to 28.3 million based on new risk calculations.

[8] A historical perspective on the discovery of statins (2010) Proceedings of the Japan Academy: Akira Endo’s discovery of compactin from fungal cultures led to lovastatin, the first commercial statin.

[9] The Role of Lipids and Lipoproteins in Atherosclerosis (1950) Science: John Gofman discovered LDL cholesterol and its correlation with atherosclerosis through ultracentrifugation of plasma lipoproteins.

[10] Statins for Primary Cardiovascular Disease Prevention: Time to Curb Our Enthusiasm (2022) JAMA Internal Medicine: Cardiologists question the benefit of statins for individuals with low cardiovascular disease risk, citing limited evidence.

[11] History of the Framingham Heart Study (1957) Framingham Heart Study: The Framingham Heart Study identified key cardiovascular risk factors, including high cholesterol, blood pressure, smoking, obesity, diabetes, and inactivity.

[12] “For Me There Is No Substitute”: Authenticity, Uniqueness, and the Lessons of Lipitor (2010) American Medical Association Journal of Ethics: Lipitor backlash followed when it was revealed that Dr. Robert Jarvik, spokesperson in Lipitor ads, was not licensed to practice medicine and misrepresented his credentials.

[13] Lipitor a story of rags to riches (2011) Arkansas Democrat-Gazette: Lipitor achieved success by lowering LDL cholesterol more effectively than competitors, aided by expanded statin eligibility guidelines.

[14] History in medicine: the story of cholesterol, lipids and cardiology (2021) e-Journal of Cardiology Practice: Cardiology research has an extensive history: from its identification in gallstones in 1769 to Nobel Prize-winning discoveries on lipids and atherosclerosis.

[15] Discovery of Lipitor (2009) Triumph of the Heart: The Story of Statins: Despite being the fifth statin introduced, Lipitor dominated the market due to superior LDL-lowering efficacy.

[16] Counting Cholesterol (1987) The MacNeil/Lehrer NewsHour: Merck’s Mevacor became the first FDA-approved statin and cholesterol-lowering drug.

[17] Cardiovascular Disease Resulting From a Diet and Lifestyle at Odds With Our Paleolithic Genome: How to Become a 21st-Century Hunter-Gatherer (2004) Mayo Clinic Proceedings: High cholesterol may stem from a mismatch between modern diets and Paleolithic human biology.

[18] What Will the New Cardiovascular Risk Calculator Mean for Patients? (2024) Harvard Medical School: The Predicting Risk of Cardiovascular Disease Events (PREVENT) model could significantly reduce the number of statin-eligible adults.

[19] Pfizer Gets Its Deal to Buy Warner-Lambert for $90.2 Billion (2000) The New York Times: Pfizer purchased Lipitor’s manufacturer for $90.2 billion.

[20] Pharmaceutical Mycelia: A story of statins LGC Standards: Early statins derived from Penicillium and Aspergillus inhibit HMG-CoA reductase to lower cholesterol.

[21] A New Women’s Issue: Statins (2014) The New York Times Well Blog: Cardiologists raise concerns over limited evidence for statin benefits in women due to underrepresentation in trials.

[22] Statins for Primary Prevention: The Debate Is Intense, but the Data Are Weak (2016) JAMA: Researchers highlight inflated benefits of statins and incomplete adverse event data.

[23] Medical Marketing in the United States, 1997-2016 (2019) JAMA: U.S. medical marketing expenditures rose from $17.7B in 1997 to $29.9B in 2016, with limited regulation of misleading ads.

[24] Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part I (2004) Journal of Lipid Research: Nikolai Anitschkow induced vascular lesions in rabbits by feeding them cholesterol, resembling human atherosclerosis.

[25] Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans (2005) Journal of Lipid Research: Research supported lowering cholesterol through dietary changes; confirmed in the Framingham Heart Study.

[26] Primary nonadherence to statin medications: Survey of patient perspectives (2021) Preventive Medicine Reports: In this study, over half of the patients prescribed statins but not taking them never informed their prescribers, often preferring lifestyle changes or natural remedies.