Back on a complex affair with Professor Jean-François Bergmann, Head of the Department of Internal Medicine at Lariboisière Hospital, Paris and Professor of Therapeutics at Paris Diderot University. Former Vice-Chairman of the Marketing Authorization Board (MA), he is certainly one of the most knowledgeable about Levothyrox, a drug that is said to be anything and everything. He decrypts the truth from the false.
A few months ago, I made some assumptions to try to explain the "Levothyrox case": it seemed to me that there were no pharmacological arguments to think that Mannitol, in the new formula of Levothyrox , can explain the symptoms described. These seemed to me more likely due to the effect "nocebo" of the molecule, amplified by relays of social networks and the hype of this sad story.
Since then, the National Agency for the Safety of Medicinal Products (ANSM) has published, at the end of January, its second pharmacovigilance report analyzing all the reports of adverse effects reported when taking the new Levothyrox formula: more than 12,000 notifications were analyzed and reported in 0.75% of patients taking this drug.
A majority of mild side effects
Three-quarters of the adverse events were mild. Patients aged 55 years old were women in 90% of cases and reported an average of five adverse events each. Asthenia was reported in 78% of cases, headache in 45%, muscular disorders in 58%, insomnia in 43%, digestive disorders in 60%, alopecia in 60% and dizziness in more than 95% of the subjects. For 1745 cases it was possible to analyze the evolution of the TSH assay: it was normal in 2/3 of the cases, raised rather in favor of hypothyroidism in 24% of cases and therefore low in favor hyperthyroidism in 10% of cases.
Relativiser the frequency of side effects
If the vast majority of notifications took place between July and November 2017, it is remarkable to note that more than 1500 patients reported the onset of the disorders in the first quarter of 2017, that is to say before the marketing of the new form of Levothyrox!
It is surprising that only 10 deaths were reported because if we follow 2,600,000 French people (those taking Levothyrox) for three months, at least 5,000 deaths should have been reported. This means that the reports of adverse effects are only a very biased reflection of the disorders observed.
A variable correlation with respect to the hormonal balance
Many patients have complained of an imbalance in their treatment with the arrival of the new form of Levothyrox. It should be noted, however, that 2/3 of them kept a normal TSH while the subjective disorders were proven. The new form of Levothyrox was supposed to be more stable for tablets approaching the expiration date.
We could then consider that the new Levothyrox kept more activity and therefore had a higher risk of hyperthyroidism. In fact, hypothyroidism was the most common and once again the disturbances in the therapeutic effect were observed only in 1/3 of the subjects which proves that for the majority of patients reporting adverse effects these were not related to an imbalance in their substitution therapy.
Usual side effects
The reported symptoms were extremely diverse, impossible to objectively confirm by specific tests and sometimes mixed in the same patient signs in favor of hypothyroidism and signs in favor of hyperthyroidism! None of the reported deaths could be related to these adverse effects.
The data from the literature reported in the ANSM report are extremely interesting since we cite in particular the CONTROL study of Mac Millan and collaborators in 2016, which analyzed more than one year more than 900 patients always taking the same formulation. of levothyroxine.
In the year, 23.4% of these patients had an imbalance in their therapy and had to change their dosage of levothyroxine and there was even 8% of them who had to make two modifications during the course of the year. year. We are finally very close to the figures observed in patients who reported the adverse effects related to the new formulation of Levothyrox. The possible thyroid imbalances are finally not more frequent with the new form of Levothyrox than was found by Mac Millan in his follow-up of patients who have always used the same drug.
What to think of all this?
It is now established that the new Levothyrox does not cause significantly more imbalance in thyroid function than the natural history of patients still taking the same presentation of levothyroxine. The notifications were extremely numerous, as in a galloping epidemic, but there was no serious adverse effect attributable. Had there been an iatrogenic physiopathological mechanism specific to the new formulation of Levothyrox, the alleged adverse effects would have been much more stereotyped, while the multiplicity and variety of reported symptoms makes it unlikely that a specific pharmacological action that can explain all this symptomatology and all these phenotypes so different from one subject to another.
Now what to do?
The victims have sought compensation but it will be very difficult for them to win the case since no pathophysiological causality has been established between the new form of Levothyrox and the symptoms observed. Would new studies help to better understand the observed phenomena?
It seems to me quite useless to repeat the bioequivalence study carried out in 204 volunteers proving the perfect similarity between the new and the old Levothyrox formula.
This study is methodologically very solid, duplicate or remake with prolonged treatments in patients would give the same pharmacokinetic equivalence, would be vain and ethically questionable. In addition, the fact that patients reporting adverse effects have 2/3 of them normal TSH proves that these adverse effects are independent of the pharmacodynamic activity of the new formulation of Levothyrox.
Should studies be done to find out if the excipient Mannitol can give such undesirable effects? But let's not forget that this product is found in many food additives, in many drugs and has never led to such events. It is pharmacologically impossible for 60 mg of a vehicle as well known as this to cause such important disorders.
Should we analyze and explore further the reported symptoms? But these are subjective and have never been accompanied by abnormalities in imaging, biology or physiology, particularly at the cerebral, digestive, muscular or cutaneous level.
Should we redo epidemiological studies? But we now have fairly accurate data on large numbers and only a comparison, from the basics of Social Security, would find out if there have been significantly more thyroid imbalances in 2017 than in 2016 or 2018 ( but it will be necessary to be wary of a bias to assays more frequent in 2017 contemporaneous with "the affair": the more one makes dosages of TSH, the more one is likely to find falsely abnormal).
Can we close the debate?
So finally, the only way to really close the debate would be to suggest to a few hundred patients who complained of adverse effects when taking the new formulation of Levothyrox, to enter a prospective randomized controlled trial double-blind where half of them would receive the old Levothyrox and the other half the new Levothyrox without, of course, knowing which treatment group they would be in. It would then measure the incidence of signs of intolerance and it would then be possible to affirm with obvious causal relationship whether or not there is an increase in adverse effects with the new Levothyrox.
But who will have the courage or the folly to do this study and who would agree to participate? Even if this study were done and would show the incidence of identical adverse effects, it is not certain that the "Levothyrox case" would be extinguished. The dozens of well-run controlled trials proving the lack of effectiveness of homeopathy do not prevent millions of patients from still believing in it and there are situations where scientific demonstrations are not enough to alter a belief.
I am absolutely convinced that these sufferings are real, I remain convinced that they are not related to the new formulation of Levothyrox, I think that other tests, studies or investigations will not be enough to change the convictions of some but I remain optimistic: the symptoms will disappear as they came and the treatment with levothyroxine will remain easy for some, chaotic and fraught with pitfalls for others. It is up to us doctors to explain all this to patients as best as possible, to accompany them, to reassure them with empathy and compassion, but without giving way to a disproportionate pseudoscience.