Trimetazidine (
IUPAC
The International Union of Pure and Applied Chemistry (IUPAC ) is an international federation of National Adhering Organizations working for the advancement of the chemical sciences, especially by developing nomenclature and terminology. It is ...
: 1-(2,3,4-trimethoxybenzyl)piperazine) is a drug sold under many brand names for
angina pectoris
Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.
Angina is typically the result of part ...
(chest pain associated with impaired blood flow to the heart). Trimetazidine is described as the first
cytoprotective anti-
ischemic
Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
agent developed and marketed by
Laboratoires Servier
Servier Laboratories (French: Laboratoires Servier, often abbreviated to Servier) is an international pharmaceutical company governed by a non-profit foundation, with its headquarters in France (Suresnes).
The consolidated turnover for the 2018 ...
(France). It is an anti-ischemic (antianginal) metabolic agent of the
fatty acid oxidation inhibitor class, meaning that it improves the heart muscle's ability to use glucose as a fuel by inhibiting its use of
fatty acid metabolism
Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processe ...
. It has become controversial for its use as a
performance-enhancing drug
Performance-enhancing substances (PESs), also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans.
Many substances, such as anabolic steroids, can be used to improve at ...
, with several scandals involving its use erupting at successive
Olympic games
The modern Olympic Games (Olympics; ) are the world's preeminent international Olympic sports, sporting events. They feature summer and winter sports competitions in which thousands of athletes from around the world participate in a Multi-s ...
.
Medical uses
Trimetazidine is usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for
tinnitus
Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
and dizziness. It is taken twice a day. In 2012, the
European Medicines Agency
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
(EMA) finished a review of benefits and risks of trimetazidine and recommended restricting use of trimetazidine-containing medicines to just as an additional treatment of angina pectoris in cases of inadequate control by or intolerance to
first-line antianginal therapies.
Controlled studies in angina patients have shown that trimetazidine increases
coronary flow reserve
Coronary flow reserve (CFR) is the maximum increase in blood flow through the coronary arteries above the normal resting volume. Its measurement is often used in medicine to assist in the treatment of conditions affecting the coronary arteries and ...
(thereby delaying the onset of ischemia associated with exercise), limits rapid swings in
blood pressure
Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...
without any significant variations in
heart rate
Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of
nitrates
Nitrate is a polyatomic ion with the chemical formula . Salts containing this ion are called nitrates. Nitrates are common components of fertilizers and explosives. Almost all inorganic nitrates are soluble in water. An example of an insol ...
.
However, a 2020
placebo-controlled,
randomized trial
In science, randomized experiments are the experiments that allow the greatest reliability and validity of statistical estimates of treatment effects. Randomization-based inference is especially important in experimental design and in survey sampl ...
in over 6000 patients who had recently had a
percutaneous coronary intervention
Percutaneous coronary intervention (PCI) is a minimally invasive non-surgical procedure used to treat stenosis, narrowing of the coronary artery, coronary arteries of the heart found in coronary artery disease. The procedure is used to place and ...
or heart surgery found that adding trimetazidine to typical anti-anginal therapies alone led to no significant difference in
cardiac death
Clinical death is the medical term for cessation of blood circulation and breathing, the two criteria necessary to sustain the lives of human beings and of many other organisms. It occurs when the heart stops beating in a regular rhythm, a conditio ...
, hospital admission for a
cardiac event, recurrence or persistence of angina, or the need for repeat
coronary angiography Coronary () may, as shorthand in English, be used to mean:
* Coronary circulation, the system of arteries and veins in mammals
** Coronary artery disease
** Coronary occlusion
** A myocardial infarction, a heart attack
As adjective
* Referring to ...
.
This study therefore calls into question the clinical utility of trimetazidine in the treatment of angina.
It improves
left ventricular function in diabetic patients with
coronary heart disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...
. Recently, it has been shown to be effective in patients with
heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF ...
of different etiologies.
As of 2023, it is in clinical trials to determine if it is effective in treating
bipolar depression
Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that each last from days to weeks, and in some cases months. If the elevated m ...
.
Use as a performance-enhancing drug
Although trimetazidine was already developed for medical use in the 1970s, it only became listed in the
World Anti-Doping Agency
The World Anti-Doping Agency (WADA; , AMA) is an international organization co-founded by the governments of over 140 nations along with the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against d ...
(WADA) prohibited substances list under the category of "hormone and metabolic modulators" in 2014, and its use is prohibited at all times "in- and out-of-competition."
In 2014, Chinese Olympic champion swimmer
Sun Yang
Sun Yang (; ; born 1 December 1991) is a Chinese Swimming at the Summer Olympics, Olympic and former List of world records in swimming, world-record-holding competitive Swimming (sport), swimmer. In 2012, Sun became the first Chinese athlete ...
tested positive for trimetazidine, which had been newly banned four months earlier and classified as a prohibited stimulant by WADA; Sun Yang and his doctor claim that they were not made aware of the changes to the use of the drug, for which he had a prescription. He was subsequently banned by the
Chinese Swimming Association
The Chinese Swimming Association () is the national federation which oversees aquatic sports in China. It is a national non-governmental, nonprofit sports organization which oversees competition in Swimming (sport), swimming, Diving (sport), divin ...
for three months.
In January 2015, WADA reclassified and downgraded trimetazidine from a "stimulant" to a "modulator of cardiac metabolism."
In 2018, U.S. swimmer
Madisyn Cox was banned from competition for six months after a urine sample tested positive for trimetazidine.
FINA
World Aquatics, formerly known as FINA (; ), is the international federation recognised by the International Olympic Committee (IOC) for administering international competitions in List of water sports, water sports. It is one of several interna ...
initially reduced her suspension from four years to two years because of Cox's testimony that she did not knowingly ingest the drug. Upon analysis of both opened and sealed bottles of Cooper Complete Elite Athletic multivitamins, the
Court of Arbitration for Sport
The Court of Arbitration for Sport (CAS; , TAS) is an international body established in 1984 to settle disputes related to sport through arbitration. Its headquarters are in Lausanne, Switzerland, and its courts are located in New York City, Sy ...
(CAS) determined that the multivitamins were the source, and reduced Cox's suspension to six months. The suspension expired on September 3, 2018.
23 Chinese swimmers tested positive by China Anti-Doping Agency for the drug in 2021, and reported to WADA, this case was reviewed by WADA in June and July 2021. The United States Anti-Doping Agency (USADA) contacted WADA in 2020 (before the positive TMZ cases arose) and 2023 with respect to allegations (from an unspecified source) of doping cover-ups within Chinese swimming. These allegations were unsubstantiated and WADA advised that the threshold to open an investigation was not met.
In February 2022, the medal ceremony for the figure skating team event at the Olympics originally scheduled for Tuesday, 8 February, was delayed over what
International Olympic Committee
The International Olympic Committee (IOC; , CIO) is the international, non-governmental, sports governing body of the modern Olympic Games. Founded in 1894 by Pierre de Coubertin and Demetrios Vikelas, it is based i ...
(IOC) spokesperson Mark Adams described as a situation that required "legal consultation" with the
International Skating Union
The International Skating Union (ISU) is the international sport governing body, governing body for competitive ice skating disciplines, including figure skating, synchronized skating, speed skating, and short track speed skating. It was founded ...
(ISU). Several media outlets reported on Wednesday that the issue was over a December 2021 test for trimetazidine by the Russian Olympic Committee's
Kamila Valieva, whose result was released on February 11. The results are pending investigation. Valieva was cleared by the
Russian Anti-Doping Agency
The Russian Anti-Doping Agency (RUSADA; ), established in January 2008, is the Russian National Anti-Doping Organisation (NADO), affiliated with (but suspended from, since 2015) the World Anti-Doping Agency (WADA).
History
It was established un ...
(
RUSADA) on February 9, a day after positive results of a test held in December 2021 were released. The IOC, WADA, and ISU appealed RUSADA's decision. On February 14, the Court of Arbitration for Sport ruled that Valieva would be allowed to compete in the women's single event, deciding that preventing her from competing "would cause her irreparable harm in the circumstances", though her gold medal in the team event was still under consideration. The favorable decision from the court was made in part due to her age, as minor athletes are subject to different rules from adult athletes.
The IOC announced that the medal ceremony would not take place until the investigation was over and there was a concrete decision whether to strip Russia of their medals.
''
Popular Science
Popular science (also called pop-science or popsci) is an interpretation of science intended for a general audience. While science journalism focuses on recent scientific developments, popular science is more broad ranging. It may be written ...
'' published an overview of scientific research about the potential for the use of trimetazidine as a performance enhancing drug for athletes. The author of the article concluded in its headline that "there's no hard proof that it would improve a figure skater's performance". Scott Powers, a physiologist at the
University of Florida
The University of Florida (Florida or UF) is a public university, public land-grant university, land-grant research university in Gainesville, Florida, United States. It is a senior member of the State University System of Florida and a preem ...
who studies the effects of exercise on the heart explained how trimetazidine was included in WADA list. "I've been involved in roundtables with the International Olympic Committee, and I think their policy is: When in doubt, ban the drug," says Scott Powers. "I guess they're just trying to err on the possibility that this drug may be an
ergogenic
Performance-enhancing substances (PESs), also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans.
Many substances, such as anabolic steroids, can be used to improve at ...
aid."
Doping expert Klaas Faber referred to "grossly inconsistent anti-doping rules" in Sun Yang's case. Faber has pointed out for years the necessity to establish thresholds for trimetazidine detected so as to avoid any inadvertent positive doping cases. Faber has detailed some of these observations published in the journal ''
Science & Justice
''Science & Justice'' is a peer-reviewed scientific journal of forensics published by Elsevier on behalf of the Forensic Science Society and the International Society for Forensic Genetics. The journal was established in 1960 as the ''Journal of t ...
''.
On the efficacy of the drug on figure skating and Valieva in particular, heart expert Benjamin J. Levine, a professor of exercise science at the
University of Texas Southwestern Medical School
The University of Texas Southwestern Medical Center (UT Southwestern or UTSW) is a Public university, public Academic health science centre, academic health science center in Dallas, Texas. With approximately 23,000 employees, more than 3,000 ...
, said "The chance that trimetazidine would improve her performance, in my opinion, is zero. The heart has plenty of blood. And the heart is so good at using different fuels."
Aaron Baggish, director of the Cardiovascular Performance Program at
Massachusetts General Hospital
Massachusetts General Hospital (Mass General or MGH) is a teaching hospital located in the West End neighborhood of Boston, Massachusetts. It is the original and largest clinical education and research facility of Harvard Medical School/Harvar ...
said "In theory, trimetazidine could aid endurance athletes who have to generate high cardiac output, such as cyclists, rowers and long-distance runners, but would be unlikely to have a direct impact on a figure skater's performance, where there is less demand on the heart."
Besides trimetazidine, Valieva also admitted taking
hypoxen
Sodium polydihydroxyphenylene thiosulfonate (гипоксен, Hypoxen) is under laboratory studies in Russia as a potential regulator of cell metabolism. It is purported to affect mitochondrial function, though this has not been proven in any ...
and
L-carnitine supplements in her forms, neither of which is a banned substance; nevertheless, the combination of these two substances with trimetazidine raised suspicions over a potential deliberate attempt to enhance performance. Some experts believe that the combination of the three substances can reduce fatigue and increased endurance during intense exercises.
Lawrence Cherono, winner of several major marathons, tested positive for trimetazidine and was suspended just one day before slated to run the marathon at the
2022 World Athletics Championships
The 2022 World Athletics Championships was the eighteenth edition of the World Athletics Championships. It was held at Hayward Field in Eugene, Oregon, United States, from July 15–24, 2022, with the country hosting that competition for the ...
.
Iga Swiatek IGA or IgA may refer to:
Businesses and organizations
* IGA (supermarkets) (initially Independent Grocers Alliance), a name used by many independent supermarkets throughout the world
** IGA (Australian supermarket group), the local Australian va ...
, at the time the top-ranked women's tennis player, tested positive for trimetazidine in September 2024 and was provisionally suspended for one month, missing several tournaments, after accepting a ruling of "No Significant Fault or Negligence," because she consumed it through a contaminated melatonin supplement. The WADA subsequently announced that they would make no further inquiries into the matter due to Swiatek's explanation being "plausible".
Associated Press
The Associated Press (AP) is an American not-for-profit organization, not-for-profit news agency headquartered in New York City.
Founded in 1846, it operates as a cooperative, unincorporated association, and produces news reports that are dist ...
(January 20, 2025
World Anti-Doping Agency will not appeal Iga Swiatek's "plausible" drug-case ruling
''Tennis Magazine
''Tennis'' is a U.S. print sports magazine devoted to the sport of tennis. It is published eight months per year, and operates a website, Tennis.com.
History
The magazine was established in May 1965, published out of Chicago with a regional foc ...
''
Adverse effects
Trimetazidine has been treated as a drug with a high safety and tolerability profile.
[
Information is scarce about trimetazidine's effect on mortality, cardiovascular events, or quality of life. Long-term randomized, controlled trials comparing trimetazidine against standard antianginal agents using clinically important outcomes would be justifiable.][ , This review ''series'' was withdrawn because the authors did not opt to continue updating it; the journal has not "withdrawn" it in the usual sense] A 2013 international multicentre retrospective cohort study has indeed shown that in patients with heart failure of different etiologies the addition of trimetazidine on conventional optimal therapy can improve mortality and morbidity.
The EMA recommends that doctors no longer prescribe trimetazidine for the treatment of patients with tinnitus
Tinnitus is a condition when a person hears a ringing sound or a different variety of sound when no corresponding external sound is present and other people cannot hear it. Nearly everyone experiences faint "normal tinnitus" in a completely ...
, vertigo
Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...
, or disturbances in vision. The recent EMA evaluation also revealed rare cases (3.6/1,000,000 patient years) of parkinsonian
Parkinsonism is a clinical syndrome characterized by tremor, bradykinesia (slowed movements), rigidity, and postural instability.
Both hypokinetic features (bradykinesia and akinesia) and hyperkinetic features (cogwheel rigidity and tremors ...
(or extrapyramidal) symptoms (such as tremor, rigidity, akinesia, hypertonia), gait instability, restless leg syndrome
Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...
, and other related movement disorders; most patients recovered within 4 months after treatment discontinuation, so doctors are advised not to prescribe the medicine either to patients with Parkinson disease, parkinsonian symptoms, tremors, restless leg syndrome, or other related movement disorders, or to patients with severe renal impairment. Parkinson’s-like symptoms may increase the risk for falls, as it was observed in a case-control study.
Mechanism of action
The mechanism of action of trimetazidine involves its effect on cellular energy metabolism, specifically the metabolism of fatty acids and glucose.
One of the primary ways that cells generate energy is through the process of oxidation, where molecules such as fatty acids or glucose are broken down to produce ATP (adenosine triphosphate), the main energy currency of cells. In a healthy cell both fatty acids and glucose can be oxidized to produce ATP.
However, in certain situations such as ischemia (reduced blood flow) or hypoxia (reduced oxygen supply), the cell's ability to generate energy becomes compromised. In these conditions the cell may experience a shortage of oxygen, which is necessary for the complete oxidation of fatty acids. This can lead to a decrease in ATP production, affecting the cell's ability to maintain its normal functions.
Trimetazidine works by inhibiting a specific enzyme called long-chain 3-ketoacyl-CoA thiolase, which is involved in the beta-oxidation
In biochemistry and metabolism, beta oxidation (also β-oxidation) is the Catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl ...
process of fatty acids. By blocking this enzyme, trimetazidine reduces the oxidation of fatty acids and promotes the oxidation of glucose instead. Glucose oxidation requires less oxygen consumption compared to the beta-oxidation of fatty acids. Therefore, by enhancing glucose oxidation and reducing the reliance on fatty acid metabolism, trimetazidine helps optimize cellular energy production in conditions where oxygen supply is limited.
By preserving energy metabolism and promoting glucose oxidation, trimetazidine prevents a decrease in intracellular ATP levels. This is important because ATP is essential for various cellular processes, including the functioning of ionic pumps and the maintenance of transmembrane sodium-potassium flow. By ensuring adequate ATP levels, trimetazidine helps to maintain cellular homeostasis, or the balance of different ions and molecules within the cell.
References
Notes
Further reading
*
*
{{Piperazines
Antianginals
Benzylpiperazines
1-Piperazinyl compounds
Phenol ethers
Laboratoires Servier
World Anti-Doping Agency prohibited substances