JUPITER trial

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The JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial) was a clinical trial aimed at evaluating whether statins reduce heart attacks and strokes in people with normal cholesterol levels.

Contents

Study rationale

JUPITER was a randomized double-blind placebo-controlled study investigating the use of rosuvastatin in the primary prevention of cardiovascular disease. The trial focused on patients with normal low-density lipoprotein (LDL) cholesterol levels but increased levels of high-sensitivity C-reactive protein (hs-CRP). JUPITER was the first clinical trial to indicate that statin therapy may provide benefit to patients with low-to-normal LDL levels and no known cardiovascular disease. [1] [2] The trial, which began in 2003, was directed by Paul Ridker of Brigham and Women’s Hospital. [3]

Because half of all vascular events occur in patients with normal or low levels of LDL cholesterol, JUPITER was designed to determine whether hs-CRP testing could identify these patients, and whether statin therapy could prevent cardiovascular events among them. [4] Elevated hs-CRP levels are thought to be a biomarker of inflammation, and have been associated with an increased risk of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death. [4]

Study details

The trial analyzed 17,802 patients without evidence of heart disease but with high CRP levels. In 2008, results presented at the American Heart Association meeting and published in the New England Journal of Medicine (NEJM) found that patients with low-to-normal LDL cholesterol receiving rosuvastatin had a lower rate of major cardiovascular events. Compared to patients taking a placebo, patients given rosuvastatin had reductions in LDL and CRP levels, and a reduction of 0.2% to 0.6% in their absolute risk of heart attack, stroke, and death at one year. [5] [6] [7] The study's authors estimated that the number needed to treat with rosuvastatin to prevent one cardiovascular event was 95 over two years, extrapolated to 25 over five years. The trial was stopped early, after just 1.9 years median duration, by the study's Independent Data Monitoring Board, because the interim results met the study's predefined stopping criteria (it had been predetermined that it would be unethical to continue the study once it became clear that the patients in one arm of the study had a significantly higher cardiovascular risk than the other arm's patients). [1] [8]

The trial was sponsored by AstraZeneca, the marketer of Crestor (rosuvastatin). [3] The company saw an increase in its share of the U.S. statin drug market following the November 2008 NEJM publication. [9]

Adverse events

Reports of serious adverse events within JUPITER were equally distributed between the study's rosuvastatin and placebo arms. There were no significant differences between the treatment groups with respect to muscle pain, muscle weakness, hepatic function, or renal function; however, the researchers noted small but statistically significant increases in the rate of physician-reported diabetes and glycated hemoglobin values in the rosuvastatin group, an effect that has also been seen in studies with other statins. [5] [8] Those latter findings, along with concerns over the safety of very low LDL levels, rosuvastatin's higher cost compared to generic statins, and the validity of biomarkers used in the diagnosis of cardiovascular disease, have been cited by those urging caution before expanding indications for statin treatment. [10] [11] [12] [13]

Criticism of the trial

In 2010, Dr. Michel de Lorgeril, et al., published "a critical reappraisal" of the JUPITER Trial in the Archives of Internal Medicine . The article's authors critiqued what they saw as flaws in the trial, pointing out that the cardiovascular mortality rate and the case-fatality rate for myocardial infarction were much lower than they expected. They also raised concerns about conflict of interest in the trial design and leadership: nine of 14 authors of the main report had financial ties to the sponsor, AstraZeneca, and the lead investigator held the patent for the C-reactive protein test, whose use in screening would be promoted by the results as reported. [14] They also argued that the trial's premature termination may have distorted the results, and raised concerns that AstraZeneca scientists had controlled and managed the raw data. They concluded that, "The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors." [14]

In addition, some prior and some subsequent studies have contrasted with the JUPITER trial results. On the role of C-reactive protein, a 2009 study employing Mendelian randomization, published in the Journal of the American Medical Association suggested that CRP does not play a causal role in cardiovascular disease; the results may argue against CRP's use as a marker of cardiovascular disease risk or for identifying subjects for statin therapy as in JUPITER, and more strongly argue against using CRP as a therapeutic target per se. [15] The discordant results of this subsequent study provoked debate over the role and value of CRP as a biomarker and possible therapeutic target in heart disease. [16]

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol, a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membranes. When chemically isolated, it is a yellowish crystalline solid.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.

<span class="mw-page-title-main">C-reactive protein</span> Mammalian protein found in Homo sapiens

C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells in order to activate the complement system via C1q.

<span class="mw-page-title-main">Hypercholesterolemia</span> High levels of cholesterol in the blood

Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia, hyperlipoproteinemia, and dyslipidemia.

Dyslipidemia is an abnormal amount of lipids in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). ASCVD includes coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Rosuvastatin</span> Statin medication

Rosuvastatin, sold under the brand name Crestor among others, is a statin medication, used to prevent cardiovascular disease in those at high risk and treat abnormal lipids. It is recommended to be used together with dietary changes, exercise, and weight loss. It is taken by mouth.

In clinical trials, a surrogate endpoint is a measure of effect of a specific treatment that may correlate with a real clinical endpoint but does not necessarily have a guaranteed relationship. The National Institutes of Health (USA) defines surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint".

Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Paul Ridker</span> Cardiovascular epidemiologist and biomedical researcher

Paul M. Ridker is a cardiovascular epidemiologist and biomedical researcher. He is currently the Eugene Braunwald Professor of Medicine at Harvard University and Brigham and Women's Hospital, where he directs the Center for Cardiovascular Disease Prevention. Ridker also holds an appointment as Professor in the Department of Epidemiology at the Harvard T.H. Chan School of Public Health.

<span class="mw-page-title-main">Pitavastatin</span> Chemical compound

Pitavastatin is a member of the blood cholesterol lowering medication class of statins.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein, in the blood and early cardiovascular disease. The most common mutations diminish the number of functional LDL receptors in the liver. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

The discovery of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, called statins, was a breakthrough in the prevention of hypercholesterolemia and related diseases. Hypercholesterolemia is considered to be one of the major risk factors for atherosclerosis which often leads to cardiovascular, cerebrovascular and peripheral vascular diseases. The statins inhibit cholesterol synthesis in the body and that leads to reduction in blood cholesterol levels, which is thought to reduce the risk of atherosclerosis and diseases caused by it.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

The AURORA trial was a randomized, double-blind, placebo-controlled study investigating the use of rosuvastatin in the prevention of cardiovascular disease among patients undergoing chronic hemodialysis.

Bococizumab is a drug that was in development by Pfizer targeting PCSK9 to reduce LDL cholesterol. Pfizer withdrew the drug from development in November 2016, determining that it was "not likely to provide value to patients, physicians or shareholders."

Inclisiran, sold under the brand name Leqvio, is a medication for the treatment of people with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk-equivalents, and heterozygous familial hypercholesterolemia (HeFH). It is a small interfering RNA (siRNA) that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein PCSK9.

The BaleDoneen Method is a risk assessment and treatment protocol aimed at preventing heart attack and stroke. The method also seeks to prevent or reduce the effects of type 2 diabetes. The method was developed by Bradley Field Bale and Amy Doneen.

References

  1. 1 2 "JUPITER: Using hsCRP to identify primary prevention patients who may benefit from statin therapy", Endocrine Today, 25 November 2008
  2. ↑ Myat, Aung; Gershlick, A. H.; Gershlick, Tony (2012). Landmark Papers in Cardiovascular Medicine. Oxford University Press. p. 35. ISBN   978-0-19-959476-4.
  3. 1 2 JUPITER trial information page, Brigham and Women’s Hospital
  4. 1 2 Ridker PM; Jupiter Study, Group (November 2003). "Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER trial". Circulation. 108 (19): 2292–7. doi: 10.1161/01.CIR.0000100688.17280.E6 . PMID   14609996.
  5. 1 2 Ridker PM, Danielson E, Fonseca FA, et al. (November 2008). "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein". N. Engl. J. Med. 359 (21): 2195–207. doi: 10.1056/NEJMoa0807646 . PMID   18997196.
  6. ↑ "To combat plaques, research targets inflammation-fighting statins" [ dead link ], Los Angeles Times , 8 December 2008
  7. ↑ "Treating elevated C-reactive protein with a statin", Endocrine Today, 1 December 2008
  8. 1 2 Paul M Ridker, MD, MPH (May 2009). "The JUPITER Trial: Results, Controversies, and Implications for Prevention". Circulation: Cardiovascular Quality and Outcomes. 2009, 2 (3): 279–285. doi:10.1161/CIRCOUTCOMES.109.868299. PMID   20031849. S2CID   2271425.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ "Astra's Crestor gets sales boost after positive data", Reuters, 24 November 2008
  10. ↑ Hlatky MA (November 2008). "Expanding the orbit of primary prevention--moving beyond JUPITER". N. Engl. J. Med. 359 (21): 2280–2. doi:10.1056/NEJMe0808320. PMID   18997195.
  11. ↑ "Dramatic JUPITER Findings Fail to Sway Prescribing Behavior, Poll Shows", press release, MarketWatch, 25 November 2008
  12. ↑ Shishehbor MH, Hazen SL (January 2009). "JUPITER to Earth: A statin helps people with normal LDL-C and high hs-CRP, but what does it mean?". Cleve Clin J Med. 76 (1): 37–44. doi:10.3949/ccjm.75a.08105. PMC   2836530 . PMID   19122109.
  13. ↑ Mora S, Musunuru K, Blumenthal RS (February 2009). "The Clinical Utility of High-Sensitivity C-Reactive Protein in Cardiovascular Disease and the Potential Implication of JUPITER on Current Practice Guidelines". Clin. Chem. 55 (2): 219–28. doi: 10.1373/clinchem.2008.109728 . PMID   19095730.
  14. 1 2 de Lorgeril, M (2010). "Cholesterol Lowering, Cardiovascular Diseases, and the Rosuvastatin-JUPITER Controversy: A Critical Reappraisal" (PDF). Arch Intern Med. 170 (12): 1032–1036. doi: 10.1001/archinternmed.2010.184 . PMID   20585068.
  15. ↑ Elliott P, et al. (2009). "Genetic Loci Associated With C-Reactive Protein Levels and Risk of Coronary Heart Disease". JAMA. 302 (1): 37–48. doi:10.1001/jama.2009.954. PMC   2803020 . PMID   19567438.
  16. ↑ Kolata, Gina (June 30, 2009). "Study Dismisses Protein's Role in Heart Disease". New York Times . Retrieved July 1, 2009.
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