We have identified 25 anti-obesity medications that were withdrawn after marketing between 1964 and 2009, 23 of which had centrally acting mechanisms via monoamine neurotransmitters. The evidence for withdrawal in about 80% of cases was anecdotal reports. Cardiovascular and psychiatric adverse drug reactions and drug abuse and dependence together accounted for 83% of the withdrawals. In 28% of cases, deaths were attributed to the products. Among the centrally acting agents, re-uptake inhibitors were more likely to be withdrawn because of cardiotoxicity, while the neurotransmitter releasers were more likely to be withdrawn because of drug abuse and dependence. When compared with our overall corpus of 462 medicinal products withdrawn from the market after 1950 [17], there was no significant difference in the proportion of case reports being used as evidence for withdrawal. The median interval to first reports of adverse reactions and first withdrawals was longer with the anti-obesity products (11 versus 3 years), but this is likely due to the smaller proportion of anti-obesity product approvals after 1976 compared with the overall data (the median interval to withdrawal for the products withdrawn since 1995 was 3 years). Furthermore, the intervals to withdrawal with more recent product launch are also consistent with the trend observed in the overall corpus.
The use of case reports as evidence for making withdrawal decisions in a majority of instances corroborates our previous findings that formal studies are seldom conducted when adverse drug reactions are suspected [18]. In addition, the fact that most of the withdrawn products were centrally acting anorectics suggests that use of this class of products in the treatment of obesity is associated with a negative benefit-to-harm balance over time (see Table 3 and Additional file 3). Furthermore, the discrepancy in withdrawal patterns across regulatory authorities indicates a lack of uniformity in harms assessment by different drug regulators, and also contributes to discrepancies in patterns of marketing authorizations of this class of products.
Table 3 Profile of centrally acting anti-obesity products withdrawn because of associated deaths over the last 50 years That the delays to reports of adverse reactions with time were shortened, albeit inconsistently, suggests an influence of better methods for detection of adverse drug reactions, improved transparency in the report of adverse drug events by trials investigators, or a combination of the two. However, the speed with which withdrawals occurred following reports of suspected adverse reactions with more recently launched drugs arouses suspicion of selective reporting of harms in the pre-marketing phase. The shorter intervals to withdrawals when deaths are reported suggest that regulatory authorities are quicker at making withdrawal decisions in these circumstances.
Comparison with existing literature
Our findings are consistent with other published reports. A previous review reported that most anti-obesity treatments have been withdrawn from the market because of concerns about adverse reactions [14]. Two other reviews concluded that cardiovascular and psychiatric adverse reactions are major concerns with psychoactive anti-obesity drugs that have recently gained marketing approval from licensing authorities [19, 20]. A recent analysis of serious adverse reactions reported to the EudraVigilance database also showed that cardiac and psychiatric disorders were the most common adverse reactions attributed to anti-obesity medicinal products [21]. The authors of another report concluded that lower doses of multiple chemical entities targeting different mechanistic pathways should be a priority in future drug development [1].
Strengths and limitations
To our knowledge, this is the first review that has systematically identified anti-obesity medicinal products withdrawn from the market because of adverse drug reactions. We comprehensively searched various sources of information in order to identify anti-obesity medicinal products that have been withdrawn, we accounted for the levels of evidence used in making withdrawal decisions, extracted data on the intervals between launch, adverse reactions reports, and withdrawals, and explored the trends in withdrawal over time. We also used statistical methods to explore and compare the patterns of withdrawal. However, we recognize some limitations. We may not have identified all countries in which products were withdrawn, and we do not have complete information about where all the products were marketed; indeed it is possible that some products were withdrawn in a few countries because those were the only places where they were marketed. In addition, we do not have information on the time lapse between the actual occurrence of an adverse reaction and the date the reaction appeared in the published literature, though we do not consider that such delays would have significantly influenced our findings. Finally, the intervals between launch, first adverse reaction reports, and first withdrawals were computed irrespective of where products were first introduced or where adverse reactions were first observed; however, some products were withdrawn in some countries because of adverse reactions reported in others irrespective of whether the product was first marketed in such countries.
Implications for drug therapy
Apart from two products (cyclovalone and iodinated casein), the products identified in the review had actions involving 5-hydroxytryptamine (5HT, serotonin). While agonist activity at 5HT2A receptors can cause psychiatric dysfunction [22], stimulation of 5HT2B receptors is associated with cardiac abnormalities, largely valvulopathies [23].The unfavourable benefit-to-harm balance of this class of products therefore appears to have led to the development of new chemical entities that target other mechanistic pathways. These include leptin sensitizers, glucagon-like peptide 1 (GLP-1) receptor agonists, islet amyloid polypeptide (IAPP), and neuropeptide Y [24]. Of note, several medicinal products with similar mechanisms of action to the withdrawn psychotropic anti-obesity medications have been successfully used for treating other medical conditions, and they have not been withdrawn from the market. This may be because in those conditions their mechanisms of action are specifically targeted against abnormal pathways. For example, several analogues of amphetamine are available for treating attention deficit hyperactivity disorder (ADHD) and narcolepsy [25, 26].
There were no new approvals of anti-obesity medications during the 20 years from 1976 to 1995. It is unclear what caused this hiatus; however, we observed a steep increase in the number of scientific publications relating obesity prevalence and treatment after the hiatus (PubMed trend; Additional file 4). The resurgence of new approval applications after the hiatus was not associated with a major shift in the development of drugs that affect neurotransmitters, but it is notable that no new drugs that cause neurotransmitter release have been marketed since 1974. This is consistent with the fact that of the nine medicinal products currently available for obesity management, all six (78%) that exert their weight reducing actions through centrally acting mechanisms act via neurotransmitter release, rather than inhibition of re-uptake (see Table 4). This suggests that drug developers have largely abandoned the use of chemical entities that inhibit re-uptake in favour of releasing agents. However, the lack of long-term data on the safety of these products, especially with the more recent approvals, is of great concern. Indeed, psychiatric and cardiovascular adverse events have been reported as major concerns of recently approved products with centrally acting mechanisms [19].
Table 4 Anti-obesity drugs currently approved for use in at least one country Modest reduction in body weight has beneficial effects on short-term (≤1 year) cardiovascular profile [27]. However, whether the weight losses generated by anti-obesity medicinal products have beneficial effects on long-term cardiovascular outcome is unclear, largely because the follow-up duration of most clinical trials is not long enough to assess these benefits beyond the weight losses achieved [28]; indeed, one large long-term study (n = 5145; median follow-up of 9.6 years) showed that weight reduction did not reduce the risk of adverse cardiovascular events in obese and overweight adults with type 2 diabetes [29]. In addition, the benefit of aggressive weight reduction in overweight and obese patients with cardiovascular decompensation (e.g. patients with heart failure) has been questioned, because this group of patients survives for a longer period at higher body weights [30]. Furthermore, more than one-third of the centrally acting products included in our review were withdrawn because their use was associated with adverse cardiovascular outcomes that are the health risks the use of the products were intended to reduce — an “obesity treatment paradox”.
Implications for future harms assessment and policy
Although there have been revisions to regulatory guidance for the assessment of harms in anti-obesity drug trials [31, 32], there are uncertainties about the extent to which these guidelines are applied when assessing trial results for new weight loss products whose actions are through central mechanisms. For example, lorcaserin, a 5HT2C receptor agonist, was approved by the FDA based on the results of three pivotal trials [33–35], with discontinuation rates of 45%, 50%, and 34%, with mean differences in weight loss of only 3–3.6%. Although two of the three trials met the FDA guidance for effectiveness (“The proportion of subjects who lose greater than or equal to 5 percent of baseline body weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant”) [32], the analysis was based on the per-protocol population for completers. Furthermore, the trials failed to meet the FDA’s guidance for products for weight management, which sets clinical significance at 1 year as 5% weight loss with at least 80% power. Indeed, the FDA noted that baseline psychiatric history was limited in the clinical trials, discontinuations owing to nervous system and psychiatric disorders were higher with lorcaserin than with placebo, and the trials were not powered to detect cardiovascular adverse events [36]; these same concerns influenced the decision of the EMA in declining the product’s approval application [37]. In addition, transcripts from the FDA showed that although members of the voting panel approved the product, many had concerns about cardiovascular harms [38]; it is of further concern that the post-marketing surveillance of the product is behind schedule [39].
Similarly, the approval of naltrexone plus bupropion (Contrave, Mysimba) by the FDA and EMA has been questioned by some authors because of the potential for severe harms that appear to outweigh the benefits [40, 41]. In a recent large randomized trial there was a significantly increased risk of psychiatric disorders, and the cardiovascular profile of the product is uncertain [42]. These questionable approvals by regulatory authorities lend credence to the argument that an independent group of experts should be given responsibility for assessing harms [43]. The re-introduction of amfepramone (diethylpropion) and phentermine in Europe, based on a long-standing legal action, unrelated to new information on benefits or harms, is another case in point [44, 45].
The herbal weight loss medication Ephedra spp., which has agonist activity at 5HT and dopamine receptors and showed evidence of beneficial effects on body weight, was banned by the FDA in 2004 because of an increased risk of cardiovascular and psychiatric adverse reactions [46, 47]. That regulatory authorities removed this product from the market yet granted its “conventional analogues” marketing licences arouses suspicion of regulatory bias [48].
In addition to the above, several of the products that have been withdrawn by regulatory authorities are now marketed as non-prescription formulations, alone, or in combination over the counter, or via the Internet [49]. Indeed, there have been many reports of suspected adverse reactions attributed to such products [7, 50, 51]. There should be tougher legislative action against the promoting and marketing of such products.