Fenofibrate

Last updated

Fenofibrate
Fenofibrate structure.svg
Clinical data
Trade names Fenoglide, Lipofen, others
AHFS/Drugs.com Monograph
MedlinePlus a601052
License data
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • UK: POM (Prescription only) [2]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding 99%
Metabolism glucuronidation
Elimination half-life 20 h
Excretion urine (60%), feces (25%)
Identifiers
  • propan-2-yl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.051.234 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H21ClO4
Molar mass 360.83 g·mol−1
3D model (JSmol)
Melting point 80 to 81 °C (176 to 178 °F)
  • O=C(c1ccc(Cl)cc1)c2ccc(OC(C(=O)OC(C)C)(C)C)cc2
  • InChI=1S/C20H21ClO4/c1-13(2)24-19(23)20(3,4)25-17-11-7-15(8-12-17)18(22)14-5-9-16(21)10-6-14/h5-13H,1-4H3 Yes check.svgY
  • Key:YMTINGFKWWXKFG-UHFFFAOYSA-N Yes check.svgY
   (verify)

Fenofibrate (sold under the brand name Tricor among others), is an oral medication of the fibrate class used to treat abnormal blood lipid levels. [3] It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. [3] [4] [5] Its use is recommended together with dietary changes. [3]

Contents

Common side effects include liver problems, breathing problems, abdominal pain, muscle problems, and nausea. [3] Serious side effects may include toxic epidermal necrolysis, rhabdomyolysis, gallstones, and pancreatitis. [3] Use during pregnancy and breastfeeding is not recommended. [6] [7] It works by multiple mechanisms. [3]

It was patented in 1969, and came into medical use in 1975. [8] It is available as a generic medication. [6] In 2022, it was the 88th most commonly prescribed medication in the United States, with more than 7 million prescriptions. [9] [10]

Medical uses

Fenofibrate is mainly used for primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate may slow the progression of diabetic retinopathy and the need for invasive treatment such as laser therapy in patients with type 2 diabetes with pre-existing retinopathy. [11] [12] [13] It was initially indicated for diabetic retinopathy in patients with type 2 diabetes and diabetic retinopathy in Australia. [14] The large scale, international FIELD and ACCORD-Eye trials found that fenofibrate therapy reduced required laser treatment for diabetic retinopathy by 1.5% over 5 years, as well as reducing progression by 3.7% over 4 years. [11] [12] [13] [15] Further studies looking at the role of fenofibrate in the progression of diabetic retinopathy as the primary outcome is warranted to understand its role in this condition. Although no statistically significant cardiovascular risk benefits were identified in these trials, benefits may accrue to add on therapy to patients with high triglyceride dyslipidaemia currently taking statin medications. [16] [17]

Fenofibrate appears to reduce the risk of below ankle amputations in patients with Type 2 diabetes without microvascular disease. [18] The FIELD study reported that fenofibrate at doses of 200 mg daily, reduced the risk for any amputation by 37% independent of glycaemic control, presence or absence of dyslipidaemia and its lipid-lowering mechanism of action. [18] [19] However, the cohort of participants who underwent amputations were more likely to have had previous cardiovascular disease (e.g. angina, myocardial infarction), longer duration of diabetes and had baseline neuropathy. [18] [19]

Fenofibrate has an off-label use as an added therapy of high blood uric acid levels in people who have gout. [20]

It is used in addition to diet to reduce elevated low-density lipoprotein cholesterol (LDL), total cholesterol, triglycerides (TG), and apolipoprotein B (apo B), and to increase high-density lipoprotein cholesterol (HDL) in adults with primary hypercholesterolemia or mixed dyslipidemia. [21]

Severe hypertriglyceridemia type IV or V

It is used in tandem with diet for treatment of adults with severe hypertriglyceridemia. Improving glycemic control in diabetics showing fasting chylomicronemia usually reduces the need for pharmacologic intervention. [21]

Statins remain the first line for treatment of blood cholesterol. AHA guidelines from 2013 did not find evidence for routine use of additional medications. [22]

Additionally, in 2016, the FDA filed "Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed Release Capsules" noting "the Agency has concluded that the totality of the scientific evidence no longer supports the conclusion that a drug-induced reduction in triglyceride levels and/or increase in HDL cholesterol levels in statin-treated patients results in a reduction in the risk of cardiovascular events. Consistent with this conclusion, FDA has determined that the benefits of niacin ER tablets and fenofibric acid DR capsules for coadministration with statins no longer outweigh the risks, and the approvals for this indication should be withdrawn." [23]

Contraindications

Fenofibrate is contraindicated in: [21]

Adverse effects

The most common adverse events (>3% of patients with coadministered statins) are [24]

Precautions

When fenofibrate and a statin are given as combination therapy, it is recommended that fenofibrate be given in the morning and the statin at night, so that the peak dosages do not overlap. [25]

Musculoskeletal

Hepatotoxicity

Nephrotoxicity

Biliary

Coagulation/Bleeding

Overdose

"There is no specific treatment for overdose with fenofibric acid delayed-release capsules. General supportive care is indicated, including monitoring of vital signs and observation of clinical status". Additionally, hemodialysis should not be considered as an overdose treatment option because fenofibrate heavily binds to plasma proteins and does not dialyze well. [24]

Interactions

These drug interactions with fenofibrate are considered major and may need therapy modifications:

Mechanism of action

"In summary, enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL underlie the hypotriglyceridemic effect of fibrates, whereas their effect on HDL metabolism is associated with changes in HDL apolipoprotein expression." [29]

Fenofibrate is a fibrate derivative, a prodrug comprising fenofibric acid linked to an isopropyl ester. It lowers lipid levels by activating peroxisome proliferator-activated receptor alpha (PPARα). PPARα activates lipoprotein lipase and reduces apoprotein CIII, which increases lipolysis and elimination of triglyceride-rich particles from plasma. [29]

PPARα also increases apoproteins AI and AII, reduces VLDL- and LDL-containing apoprotein B, and increases HDL-containing apoprotein AI and AII.

Formulations

Fenofibrate is available in several formulations and is sold under several brand names, including:

The formulations may differ in terms of pharmacokinetic properties, particularly bioavailability; some must be taken with meals, whereas others may be taken without regard to food. [30]

The choline salt of fenofibrate is available in the United States, sold as Trilipix, and may be taken without regard to meals. [24] [31]

Environmental presence

Fenofibric acid was one of the 12 compounds identified in sludge samples taken from 12 wastewater treatment plants in California that were associated with estrogenic activity in in vitro. [32]

History

Fenofibrate was first synthesized in 1974, as a derivative of clofibrate, and was initially offered in France. It was initially known as procetofen, and was later renamed fenofibrate to comply with World Health Organization International Nonproprietary Name guidelines. [33]

Fenofibrate was developed by Groupe Fournier SA of France.

Society and culture

In the United States, Tricor was reformulated in 2005. This reformulation was controversial, seen as an attempt to stifle competition from generic equivalents, [34] and was the subject of antitrust litigation by Teva. [34]

Related Research Articles

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. HDL particles enlarge while circulating in the blood, aggregating more fat molecules 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 has been associated with the progression of atherosclerosis.

<span class="mw-page-title-main">Diabetic retinopathy</span> Diabetes-induced damage to the retina of the eye

Diabetic retinopathy, is a medical condition in which damage occurs to the retina due to diabetes. It is a leading cause of blindness in developed countries and one of the lead causes of sight loss in the world, even though there are many new therapies and improved treatments for helping people live with diabetes.

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

Statins are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins, such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

<span class="mw-page-title-main">Fibrate</span> Class of chemical compounds

In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid. They are used for a range of metabolic disorders, mainly hypercholesterolemia, and are therefore hypolipidemic agents.

<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 a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases, which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for cardiovascular disease, abnormal levels do not 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.

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

Atorvastatin 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">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Pravastatin</span> Cholesterol lowering medication in the statin class

Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It is suggested to be used together with diet changes, exercise, and weight loss. It is taken by mouth.

<span class="mw-page-title-main">Hypertriglyceridemia</span> High triglyceride blood levels

Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and high triglyceride levels are associated with atherosclerosis, even in the absence of hypercholesterolemia and predispose to cardiovascular disease.

<span class="mw-page-title-main">Gemfibrozil</span> Medication

Gemfibrozil, sold under the brand name Lopid among others, is a medication used to treat abnormal blood lipid levels. It is generally less preferred than statins. Use is recommended together with dietary changes and exercise. It is unclear if it changes the risk of heart disease. It is taken by mouth.

<span class="mw-page-title-main">Ezetimibe</span> Medication used to treat high cholesterol

Ezetimibe, sold under the brand name Zetia among others, is a medication used to treat high blood cholesterol and certain other lipid abnormalities. Generally it is used together with dietary changes and a statin. Alone, it is less preferred than a statin. It is taken by mouth. It is also available in the fixed-dose combinations ezetimibe/simvastatin, ezetimibe/atorvastatin, ezetimibe/rosuvastatin, and ezetimibe/bempedoic acid.

Hyperlipidemia is abnormally high 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">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 cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. 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.

<span class="mw-page-title-main">Lipoprotein lipase deficiency</span> Genetic disorder in fat handling

Lipoprotein lipase deficiency is a genetic disorder in which a person has a defective gene for lipoprotein lipase, which leads to very high triglycerides, which in turn causes stomach pain and deposits of fat under the skin, and which can lead to problems with the pancreas and liver, which in turn can lead to diabetes. The disorder only occurs if a child acquires the defective gene from both parents. It is managed by restricting fat in diet to less than 20 g/day.

<span class="mw-page-title-main">Colesevelam</span> Pharmaceutical drug

Colesevelam is a bile acid sequestrant administered orally. It was developed by GelTex Pharmaceuticals and later acquired by Genzyme. It is marketed in the US by Daiichi Sankyo under the brand name Welchol and elsewhere by Genzyme as Cholestagel. In Canada, it is marketed by Valeant as Lodalis.

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

Saroglitazar is a drug for the treatment of type 2 diabetes mellitus, dyslipidemia, NASH and NAFLD It is approved for use in India by the Drug Controller General of India. Saroglitazar is indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, saroglitazar has demonstrated reduction of triglycerides (TG), LDL cholesterol, VLDL cholesterol, non-HDL cholesterol and an increase in HDL cholesterol a characteristic hallmark of atherogenic diabetic dyslipidemia (ADD). It has also shown anti-diabetic medication properties by reducing the fasting plasma glucose and HBA1c in diabetes patients.

Cardiovascular agents are drugs used to treat diseases associated with the heart or blood vessels. These medications are available for purchase only with a physician’s prescription. They include, but are not limited to, drugs that target hypertension (antihypertensives), hyperlipidemia (antihyperlipidemics) and blood clotting (blood-thinners) to reduce the risk of cardiovascular diseases.

References

  1. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. ↑ "Fenofibrate 267mg Capsules - Summary of Product Characteristics (SmPC)". (emc). 12 February 2020. Retrieved 13 April 2020.
  3. 1 2 3 4 5 6 "Fenofibric Acid/Fenofibrate Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  4. ↑ Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA, Linz P, et al. (April 2010). "Effects of combination lipid therapy in type 2 diabetes mellitus". The New England Journal of Medicine. 362 (17): 1563–1574. doi:10.1056/NEJMoa1001282. PMC   2879499 . PMID   20228404.{{cite journal}}: CS1 maint: overridden setting (link)
  5. ↑ Kim NH, Han KH, Choi J, Lee J, Kim SG (September 2019). "Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study". BMJ. 366: l5125. doi:10.1136/bmj.l5125. PMC   6763755 . PMID   31562117. S2CID   203580658.
  6. 1 2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 198. ISBN   9780857113382.
  7. ↑ "Fenofibrate Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
  8. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 474. ISBN   9783527607495.
  9. ↑ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  10. ↑ "Fenofibrate Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
  11. 1 2 Wong TY, Simó R, Mitchell P (July 2012). "Fenofibrate - a potential systemic treatment for diabetic retinopathy?". American Journal of Ophthalmology. 154 (1): 6–12. doi:10.1016/j.ajo.2012.03.013. PMID   22709833.
  12. 1 2 Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM, Moffitt MS, et al. (November 2007). "Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial". Lancet. 370 (9600): 1687–1697. doi:10.1016/S0140-6736(07)61607-9. PMID   17988728. S2CID   30479730.{{cite journal}}: CS1 maint: overridden setting (link)
  13. 1 2 Chew EY, Davis MD, Danis RP, Lovato JF, Perdue LH, Greven C, et al. (December 2014). "The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study". Ophthalmology. 121 (12): 2443–2451. doi:10.1016/j.ophtha.2014.07.019. PMC   4252767 . PMID   25172198.{{cite journal}}: CS1 maint: overridden setting (link)
  14. ↑ "Australian Public Assessment Report for fenofibrate". TGA. Archived from the original on 29 June 2015. Retrieved 27 June 2015.
  15. ↑ Fazio S (June 2009). "More clinical lessons from the FIELD study". Cardiovascular Drugs and Therapy. 23 (3): 235–241. doi:10.1007/s10557-008-6160-5. PMID   19160032. S2CID   7987660.
  16. ↑ Elam MB, Ginsberg HN, Lovato LC, Corson M, Largay J, Leiter LA, et al. (April 2017). "Association of Fenofibrate Therapy With Long-term Cardiovascular Risk in Statin-Treated Patients With Type 2 Diabetes". JAMA Cardiology. 2 (4): 370–380. doi:10.1001/jamacardio.2016.4828. PMC   5470410 . PMID   28030716.{{cite journal}}: CS1 maint: overridden setting (link)
  17. ↑ Kim NH, Han KH, Choi J, Lee J, Kim SG (September 2019). "Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study". BMJ. 366: l5125. doi:10.1136/bmj.l5125. PMC   6763755 . PMID   31562117.
  18. 1 2 3 Rajamani K, Colman PG, Li LP, Best JD, Voysey M, D'Emden MC, et al. (May 2009). "Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial". Lancet. 373 (9677): 1780–1788. doi:10.1016/S0140-6736(09)60698-X. PMC   2687887 . PMID   19465233.{{cite journal}}: CS1 maint: overridden setting (link)
  19. 1 2 Steiner G (October 2009). "How can we improve the management of vascular risk in type 2 diabetes: insights from FIELD". Cardiovascular Drugs and Therapy. 23 (5): 403–408. doi:10.1007/s10557-009-6190-7. PMID   19757004. S2CID   12747599.
  20. ↑ Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. (October 2012). "2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia". Arthritis Care & Research. 64 (10): 1431–1446. doi:10.1002/acr.21772. PMC   3683400 . PMID   23024028.{{cite journal}}: CS1 maint: overridden setting (link)
  21. 1 2 3 "TRICOR (fenofibrate) Package Insert" (PDF). Abbot Laboratories. October 2010.
  22. ↑ Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. (June 2014). "2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Circulation. 129 (25 Suppl 2): S1-45. doi: 10.1161/01.cir.0000437738.63853.7a . PMID   24222016.{{cite journal}}: CS1 maint: overridden setting (link)
  23. ↑ "AbbVie Inc. et al; Withdrawal of Approval of Indications Related to the Coadministration With Statins in Applications for Niacin Extended-Release Tablets and Fenofibric Acid Delayed- Release Capsules" (PDF). Food and Drug Administration. 18 April 2016.
  24. 1 2 3 4 5 6 7 8 9 10 Fenofibric Acid FDA Label Prescribing Information "FDA Label Information" (PDF). FDA.
  25. ↑ Wierzbicki AS, Mikhailidis DP, Wray R, Schacter M, Cramb R, Simpson WG, et al. (2003). "Statin-fibrate combination: therapy for hyperlipidemia: a review". Current Medical Research and Opinion. 19 (3): 155–168. doi:10.1185/030079903125001668. PMID   12814127. S2CID   35948128.
  26. ↑ Product Information: TriCor(TM), fenofibrate. Abbott Laboratories, North Chicago, IL, 1998.
  27. ↑ Product Information: Sandimmune(R) oral capsules, oral solution, intravenous injection, cyclosporine oral capsules, oral solution, intravenous injection. Novartis Pharmaceuticals Corporation, East Hanover, NJ, 2010.
  28. ↑ Product Information: TRICOR(R) oral tablets, fenofibrate oral tablets. Abbott Laboratories, North Chicago, IL, 2007.
  29. 1 2 Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC (November 1998). "Mechanism of action of fibrates on lipid and lipoprotein metabolism". Circulation. 98 (19): 2088–2093. CiteSeerX   10.1.1.1004.321 . doi:10.1161/01.cir.98.19.2088. PMID   9808609. S2CID   5858864.
  30. ↑ Ling H, Luoma JT, Hilleman D (April 2013). "A Review of Currently Available Fenofibrate and Fenofibric Acid Formulations". Cardiology Research. 4 (2): 47–55. doi:10.4021/cr270w. PMC   5358213 . PMID   28352420.
  31. ↑ Alagona P (May 2010). "Fenofibric acid: a new fibrate approved for use in combination with statin for the treatment of mixed dyslipidemia". Vascular Health and Risk Management. 6: 351–362. doi: 10.2147/vhrm.s6714 . PMC   2879297 . PMID   20531954.
  32. ↑ Black GP, He G, Denison MS, Young TM (May 2021). "Using Estrogenic Activity and Nontargeted Chemical Analysis to Identify Contaminants in Sewage Sludge". Environmental Science & Technology. 55 (10): 6729–6739. Bibcode:2021EnST...55.6729B. doi:10.1021/acs.est.0c07846. PMC   8378343 . PMID   33909413.
  33. ↑ Lalloyer F, Staels B (May 2010). "Fibrates, glitazones, and peroxisome proliferator-activated receptors". Arteriosclerosis, Thrombosis, and Vascular Biology. 30 (5): 894–899. doi:10.1161/ATVBAHA.108.179689. PMC   2997800 . PMID   20393155.
  34. 1 2 "Abbott's request to dismiss the antitrust charge over Tricor was rejected". FDANews, Drug Daily Bulletin. 1 June 2006.
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