The news of Maria Sharapova’s failed drug test at the Australian Open tennis championships in January thrust a little-known drug–meldonium–into the spotlight. Almost unheard of outside of Russia, where it is approved for use in cardiovascular disease, the properties of meldonium offer an insight into the mind of a tennis superstar and the team that surrounds her.
While objectively, having found a banned substance in her blood, she is guilty there is debate as to the seriousness of the infringement: Is it an honest mistake or an attempt to gain some kind of unfair advantage? Sharapova herself has made the case for the former, saying she has been taking the drug since 2006 as a medical treatment for pre-diabetes. And her former coach, Nick Bollettieri, also believes it was “an honest mistake.”
Certainly, meldonium does improve the body’s handling of glucose, both in animal models and in humans. So, superficially at least, Sharapova’s explanation makes sense. But you don’t have to scratch far below the surface to reveal facts that at best stretch the believability of such an account to the limit, and at worst are clear evidence of a different rationale for taking meldonium.
First of all, even in Russia, where meldonium is an approved drug, the label is for improved exercise tolerance in ischemic heart disease. Although it is not approved for use in the U.S. or in Europe, it is used quite extensively in Russia and neighboring countries among patients with coronary heart disease to reduce debilitating angina attacks. Even in Russia, though, it is hardly a first-line therapy for treating pre-diabetes–in Russia, as in the U.S. and much of the rest of the world, clinicians concerned about development of diabetes would reach for metformin (a drug with a similar safety profile to meldonium, and which is above all an equally low-cost option). In the absence of specific indications to the contrary, it seems certain that Sharapova would have found herself on metformin rather than meldronate, were she not an athlete.
On the same lines, Grindeks, the Latvian drug company that makes meldonium, told the Associated Press, “Depending on the patient’s health condition, treatment course of meldonium preparations may vary from four to six weeks. Treatment courses can be repeated twice or thrice a year,” which contrasts with the ten years Sharapova has been taking the drug.
Equally implausible, though, is the claim that she had pre-diabetes from 2006 that required treatment with an agent such as meldonium. While teenagers do develop diabetes, it is overwhelmingly type 1 diabetes, which usually arises as a result of autoimmune destruction of the insulin-producing cells in the pancreas. Type 2 diabetes, by contrast, is almost exclusively a disease of middle age, when the body becomes resistant to the effects of the insulin produced by the pancreas. Not only is it very unusual in a teenager, but the risk factors for developing type 2 diabetes are principally lack of exercise and high body mass index–hardly the profile of an 18-year-old reaching the top of an elite sport such as tennis.
This matters, because meldonium would be completely ineffective as a treatment for type 1 diabetes–it is only in the insulin-resistant form of the disease that the effects of this drug could have any beneficial effect at all.
Of course, without access to private medical notes its impossible to be certain of the diagnosis of any individual. Similarly, the individual factors that could have led to the choice of meldonium as the treatment will almost certainly never be known. But the proposition that an otherwise healthy, fit 18-year-old was developing insulin resistance that required treatment (of any kind, let alone with meldonium) is stretching biological plausibility to its very limits.
Then there is the flip side: the real benefits of meldonium. The published clinical studies show a quite remarkable effect on exercise tolerance in patients with ischemic heart disease–as much as a 50% increase in the duration the individual can remain pain-free while on a treadmill. This effect is associated with increased blood flow to the heart, and while the molecular mechanisms that lead to such an effect remain the subject of debate, it seems very likely–even in the absence of compelling study data–that meldonium will increase exercise tolerance in healthy people without ischemic heart disease.
The World Anti-Doping Agency certainly thought so–after monitoring the situation for more than a year, they moved in September last year to add meldonium to the banned list because the weight of evidence clearly suggests it has performance-enhancing effects in endurance sports. While unproven (at least in the public domain), it seems virtually certain that benefit would extend to tennis.
Once you recognize the implausibility of the clinical justification for use of meldonium, and couple that with a thorough review of the clinical studies that support increased exercise tolerance among individuals taking meldonium, a rather different picture emerges to the one painted by Sharapova. We have an athlete taking an agent that is almost certain to be performance-enhancing–whether or not there was any requirement for its effects on insulin resistance–who has continued, whether accidentally or deliberately we will likely never know, to take it after it had been added to the list of banned substances. From this perspective there is little room for sympathy, and few if any mitigating circumstances. Her claims of innocence seem as implausible as a diagnosis of type 2 diabetes in a teenage tennis champion.
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