Trimetazidine

Trimetazidine is usually prescribed as a long-term treatment of angina pectoris, and in some countries (including France) for tinnitus and dizziness. It is taken twice a day. In 2012, the European Medicines Agency (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 (thereby delaying the onset of ischemia associated with exercise), limits rapid swings in blood pressure without any significant variations in heart rate, significantly decreases the frequency of angina attacks, and leads to a significant decrease in the use of nitrates.{{Citation needed|date=April 2024}}

However, a 2020 placebo-controlled, randomized trial in over 6000 patients who had recently had a percutaneous coronary intervention or heart surgery found that adding trimetazidine to typical anti-anginal therapies alone led to no significant difference in cardiac death, hospital admission for a cardiac event, recurrence or persistence of angina, or the need for repeat coronary angiography.{{cite journal | vauthors = Ferrari R, Ford I, Fox K, Challeton JP, Correges A, Tendera M, Widimský P, Danchin N | title = Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial | journal = The Lancet | volume = 396 | issue = 10254 | pages = 830–838 | date = September 2020 | pmid = 32877651 | doi = 10.1016/S0140-6736(20)31790-6 | hdl = 10044/1/82242 | s2cid = 221365071 | url = https://eprints.gla.ac.uk/223528/2/223528Supp.pdf }} 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.{{Citation needed|date=April 2024}} Recently, it has been shown to be effective in patients with heart failure of different etiologies.{{cite journal |vauthors=Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, Calori G, Alfieri O, Margonato A | title = A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure | journal = J. Am. Coll. Cardiol. | volume = 48 | issue = 5 | pages = 992–998 |date=September 2006 | pmid = 16949492 | doi = 10.1016/j.jacc.2006.03.060 | doi-access = | s2cid = 46184701 }}{{cite journal |vauthors=Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, Juhani Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J | title = Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy | journal = Circulation | volume = 118 | issue = 12 | pages = 1250–1258 |date=September 2008 | pmid = 18765391 | doi = 10.1161/CIRCULATIONAHA.108.778019 | doi-access = | s2cid = 23580702 }}

As of 2023, it is in clinical trials to determine if it is effective in treating bipolar depression.{{cite journal | vauthors = Khanra S, Reddy P, Giménez-Palomo A, Park CH, Panizzutti B, McCallum M, Arumugham SS, Umesh S, Debnath M, Das B, Venkatasubramanian G, Ashton M, Turner A, Dean OM, Walder K, Vieta E, Yatham LN, Pacchiarotti I, Reddy YC, Goyal N, Kesavan M, Colomer L, Berk M, Kim JH | title = Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine | journal = Molecular Psychiatry | volume = 28 | issue = 8 | pages = 3231–3242 | date = August 2023 | pmid = 37386057 | doi = 10.1038/s41380-023-02134-8 | doi-access = free | pmc = 10618096 }}

Although trimetazidine was already developed for medical use in the 1970s, it only became listed in the World Anti-Doping Agency (WADA) prohibited substances list under the category of "hormone and metabolic modulators" in 2014,{{cite news | vauthors = Ritchie H, Ramsay G |title=Trimetazidine: Drug banned by WADA makes 'your heart work more efficiently' |url=https://www.cnn.com/2022/02/10/sport/trimetazidine-banned-drug-explainer-spt-intl/index.html |access-date=10 February 2022 |work=CNN |agency=CNN |date=10 February 2022}}{{Cite web|url=https://cen.acs.org/analytical-chemistry/forensic-science/trimetazidine-banned-Olympic-competition/100/web/2022/02|access-date=2022-02-19|website=cen.acs.org|title=What is trimetazidine and why is it banned in Olympic competition?|date=17 February 2022|author=Howes, Laura|quote=Trimetazidine (TMZ) is the generic name for the chemical that acts as a vasodilator and was discovered over 50 years ago (1970s). TMZ is commonly prescribed in Europe and Russia where it is taken as a pill or in delayed-release tablets to treat angina as well as vertigo, tinnitus, and certain visual disturbances. Since 2014, WADA has classed TMZ as a prohibited substance.}} and its use is prohibited at all times "in- and out-of-competition."{{cite web |title=World Anti-Doping Code International Standard Prohibited List |url=https://www.wada-ama.org/sites/default/files/2022-01/2022list_final_en_0.pdf |publisher=World Anti-Doping Agency |date=1 January 2022}}

In 2014, Chinese Olympic champion swimmer Sun Yang 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 for three months.{{Cite web|date=2020-03-19|title=Chinese swimmer Sun Yang is being falsely punished|url=https://www.sportsintegrityinitiative.com/chinese-swimmer-sun-yang-is-being-falsely-punished/|access-date=2022-02-19|website=Sports Integrity Initiative|language=en-GB}}

In January 2015, WADA reclassified and downgraded trimetazidine from a "stimulant" to a "modulator of cardiac metabolism."{{cite news |title=Sun Yang, el chico malo de la natación que gana todo pero al que nadie quiere |url=https://es.sports.yahoo.com/fotos/sun-yang-el-chico-malo-de-la-natacion-china-que-ha-generado-un-escandalo-en-el-mundial-113723023/photo-trimetazidine-photo-bsip-uig-via-104018948.html |publisher=yahoo.es |date=22 July 2019}}{{Cite web | vauthors = Selthoffer S |url=https://www.swimmingworldmagazine.com/news/sun-yang-doping-case/|title = The Sun Yang Doping Case: Chapter Two of an Olympic Champion | work = Swimming World |date = 2 December 2014}}

In 2018, U.S. swimmer Madisyn Cox was banned from competition for six months after a urine sample tested positive for trimetazidine. FINA initially reduced her suspension from four years to two years because of Cox's testimony that she did not knowingly ingest the drug.{{cite web |title=FINA reduces doping ban for world champ Madisyn Cox |url=https://www.cbc.ca/sports/olympics/aquatics/fina-american-madisyn-cox-doping-ban-reduced-1.4808729 |website=CBC |access-date=2018-09-03 |date=2018-09-03}} Upon analysis of both opened and sealed bottles of Cooper Complete Elite Athletic multivitamins, the Court of Arbitration for Sport (CAS) determined that the multivitamins were the source, and reduced Cox's suspension to six months. The suspension expired on September 3, 2018.{{cite web | vauthors = Gibbs R |title=Madisyn Cox's Suspension Reduced to Six Months after Trimetazidine Detected in Multivitamin |url=https://swimswam.com/madisyn-coxs-suspension-reduced-to-six-months-after-trimetazidine-detected-in-multivitamin/ |website=SwimSwam |access-date=2018-09-03 |date=2018-08-31}}

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. {{Cite web |date=2024-04-20 |title=WADA statement on case of 23 swimmers from China |url=https://www.wada-ama.org/en/news/wada-statement-case-23-swimmers-china |access-date=2024-08-01 |website=World Anti Doping Agency |language=en}}

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 (IOC) spokesperson Mark Adams described as a situation that required "legal consultation" with the International Skating Union (ISU).{{Cite web|date=9 February 2022|title=Olympic medals in team figure skating delayed by legal issue|url=https://apnews.com/article/winter-olympics-figure-skating-sports-international-olympic-committee-court-of-arbitration-for-sport-c49077705737be8a7d41a2847c2f355b|access-date=9 February 2022|website=AP News|language=en}} 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,{{Cite news| vauthors = Tétrault-Farber G, Axon I, Grohmann K |date=9 February 2022|title=Figure skating-Russian media say teen star tested positive for banned drug|language=en|work=Reuters|url=https://www.reuters.com/lifestyle/sports/figure-skating-medals-ceremony-delayed-over-legal-consultation-2022-02-09/|access-date=9 February 2022}}{{cite web |url= https://www.usatoday.com/story/sports/olympics/beijing/2022/02/09/olympic-figure-skating-team-medals-delayed-russian-drug-test/6717526001/|title=Positive drug test by Russian Kamila Valieva has forced a delay of Olympic team medals ceremony| vauthors = Brennan C |author-link=Christine Brennan|website=USA Today|date=9 February 2022}} whose result was released on February 11. The results are pending investigation.{{Cite web | vauthors = Thompson A |url=https://www.bbc.com/sport/winter-olympics/60329120 |title=Valieva failed drugs test confirmed|date=February 11, 2022|website=BBC Sport}} Valieva was cleared by the Russian Anti-Doping Agency (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.{{Cite web | vauthors = Ritchie H, Watson A, Regan H |url=https://www.cnn.com/2022/02/10/sport/kamila-valieva-roc-drugs-test-olympics-spt-intl-hnk/index.html|title=Russian anti-doping agency allowed Kamila Valieva to compete in Olympics despite failed drug test|website=CNN|date=11 February 2022 }} 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.{{Cite web | vauthors = Ellingworth J, Dunbar G |date=2022-02-14|title=Russian skater Kamila Valieva cleared to compete at Olympics|url=https://apnews.com/article/winter-olympics-kamila-valieva-doping-decision-0dd063b5092681697525b69cd0c7212d|access-date=2022-02-14|website=AP NEWS|language=en}}{{cite web|url=https://www.tas-cas.org/fileadmin/user_upload/CAS_Ad_Hoc_Media_Release_Beijing_8.pdf |title=CAS Ad Hoc Media Release}}

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.{{cite web | url = https://olympics.com/ioc/news/ioc-eb-decides-no-medal-ceremonies-following-cas-decision-on-the-case-of-roc-skater | title = IOC EB decides no medal ceremonies following CAS decision on the case of ROC skater | work = International Olympic Committee }}

Popular Science 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 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 aid."{{Cite web | vauthors = Kiefer P |url=https://www.popsci.com/health/kamila-valieva-trimetazidine/|title=Kamila Valieva's 'doping' drug probably doesn't give athletes an edge|date=February 16, 2022 | work = PopSci}} 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.{{cite journal | vauthors = Burke MG, Faber K | title = A plea for thresholds, i.e., maximal allowed levels for prohibited substances, to prevent questionable doping convictions | journal = Science & Justice | volume = 52 | issue = 3 | pages = 199–201 | date = September 2012 | pmid = 22841145 | doi = 10.1016/j.scijus.2012.02.002 }}

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, 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."{{cite web | vauthors = Longman J, Kolata G, Tumin R | date = 11 February 2022 | url = https://www.nytimes.com/2022/02/11/sports/olympics/trimetazidine-doping-kamila-valieva.html | title = What Is Trimetazidine, and Would It Have Helped Kamila Valieva of Russia? | work = The New York Times }}

Aaron Baggish, director of the Cardiovascular Performance Program at Massachusetts General Hospital 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."{{Cite news | vauthors = Garcia-Roberts G, Abutaleb Y |access-date=2022-02-14|id=0190-8286|newspaper=Washington Post|title=What to know about Trimetazidine, the drug at the center of the Olympic doping case|url=https://www.washingtonpost.com/sports/olympics/2022/02/11/trimetazidine-valieva-olympics-doping/|archivedate=2022-02-11 |archive-url= https://web.archive.org/web/20220211233100/https://www.washingtonpost.com/sports/olympics/2022/02/11/trimetazidine-valieva-olympics-doping/}}

Besides trimetazidine, Valieva also admitted taking hypoxen 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.{{Cite web |title=Why Would a 15-Year-Old Star Figure Skater Take Heart Medicine? |url=https://www.vice.com/en/article/epxmmn/russian-figure-skater-kamila-valieva-doping-heart-medicine-why |access-date=2022-05-27 |website=www.vice.com |date=17 February 2022 |language=en}}

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.{{Cite tweet |user=aiu_athletics |number=1548331706435850243 |url=https://twitter.com/aiu_athletics/status/1548331706435850243 |access-date=2023-05-27 |url-status=live |archive-url=https://web.archive.org/web/20220716154217/https://twitter.com/aiu_athletics/status/1548331706435850243 |archive-date=2022-07-16 |title=The AIU has provisionally suspended… |language=en}}

Iga Swiatek, 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.{{cite web| url=https://www.itia.tennis/news/sanctions/polish-tennis-player-iga-swiatek-accepts-one-month-suspension-under-tennis-anti-doping-programme/| title=Polish tennis player Iga Świątek accepts one-month suspension under Tennis Anti-Doping Programme| date=November 28, 2024| archive-url=https://web.archive.org/web/20241128145411/https://www.itia.tennis/news/sanctions/polish-tennis-player-iga-swiatek-accepts-one-month-suspension-under-tennis-anti-doping-programme/| archive-date=November 28, 2024| access-date=January 1, 2025| url-status=live}} The WADA subsequently announced that they would make no further inquiries into the matter due to Swiatek's explanation being "plausible".Associated Press (January 20, 2025) [https://www.tennis.com/news/articles/world-anti-doping-agency-will-not-appeal-iga-swiatek-plausible-drug-case-ruling World Anti-Doping Agency will not appeal Iga Swiatek's "plausible" drug-case ruling] Tennis Magazine

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.{{cite journal |vauthors=Ciapponi A, Pizarro R, Harrison J | veditors = Ciapponi A | title = Trimetazidine for stable angina | journal = Cochrane Database Syst Rev | volume =2017 | issue = 3 | pages = CD003614 | year = 2017 | pmid = 16235330 | doi = 10.1002/14651858.CD003614.pub3 | pmc = 6464521 }} {{Retracted|intentional=yes}}|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.{{cite journal | vauthors = Fragasso G, Rosano G, Baek SH, Sisakian H, Di Napoli P, Alberti L, Calori G, Kang SM, Sahakyan L, Sanosyan A, Vitale C, Marazzi G, Margonato A, Belardinelli R | title = Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study | journal = International Journal of Cardiology | volume = 163 | issue = 3 | pages = 320–325 | date = March 2013 | pmid = 23073279 | doi = 10.1016/j.ijcard.2012.09.123 }}

The EMA recommends that doctors no longer prescribe trimetazidine for the treatment of patients with tinnitus, vertigo, or disturbances in vision.{{cite web | url = http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/06/WC500129070.pdf | title = European Medicines Agency recommends restricting use of trimetazidine-containing medicines | work = Press release | date = 2012-06-12 | publisher = European Medicines Agency | access-date = 2012-06-24 | archive-date = 2013-04-06 | archive-url = https://web.archive.org/web/20130406224454/http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/06/WC500129070.pdf | url-status = dead }} The recent EMA evaluation also revealed rare cases (3.6/1,000,000 patient years) of parkinsonian (or extrapyramidal) symptoms (such as tremor, rigidity, akinesia, hypertonia), gait instability, restless leg syndrome, 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.

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 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.{{cite journal |vauthors=Kantor PF, Lucien A, Kozak R, Lopaschuk GD | title = The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase | journal = Circ. Res. | volume = 86 | issue = 5 | pages = 580–588 |date=March 2000 | pmid = 10720420 | doi = 10.1161/01.RES.86.5.580 | doi-access = free }} 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.{{cite journal |vauthors=Stanley WC, Marzilli M | title = Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine | journal = Fundam Clin Pharmacol | volume = 17 | issue = 2 | pages = 133–145 |date=April 2003 | pmid = 12667223 | doi = 10.1046/j.1472-8206.2003.00154.x | s2cid = 10407498 }}

Notes

{{Reflist}}

Further reading

{{refbegin}}

• {{cite journal |vauthors=Sellier P, Broustet JP | title = Assessment of anti-ischemic and antianginal effect at trough plasma concentration and safety of trimetazidine MR 35 mg in patients with stable angina pectoris: a multicenter, double-blind, placebo-controlled study | journal = Am J Cardiovasc Drugs | volume = 3 | issue = 5 | pages = 361–369 | year = 2003 | pmid = 14728070 | doi = 10.2165/00129784-200303050-00007 | s2cid = 68895472 }}
• {{cite journal |vauthors=Génissel P, Chodjania Y, Demolis JL, Ragueneau I, Jaillon P | title = Assessment of the sustained release properties of a new oral formulation of trimetazidine in pigs and dogs and confirmation in healthy human volunteers | journal = Eur J Drug Metab Pharmacokinet | volume = 29 | issue = 1 | pages = 61–68 | year = 2004 | pmid = 15151172 | doi = 10.1007/BF03190575 | s2cid = 10455129 }}

{{refend}}

{{Piperazines}}

Category:Antianginals

Category:Benzylpiperazines

Category:1-Piperazinyl compounds

Category:Phenol ethers

Category:Laboratoires Servier

Category:World Anti-Doping Agency prohibited substances