Abstract
With this editorial I would like to introduce myself as a new Associate Editor for Therapeutic Advances in Endocrinology and Metabolism. During my education and academic career I conducted adipose tissue research, and was an investigator in a multitude of obesity studies, either related to weight loss, or treatment of the obese hypertensive patient. Throughout the years, this work has provoked several thoughts about the treatment of the obese patient. In general, the relationship between body weight (as a more general concept) and drug treatment has two dimensions:
drugs can lead to weight loss or weight gain
body weight can influence drug action or kinetics
Being a clinical pharmacologist, I always thought about establishing a new research field termed ‘clinical pharmacology of obesity’ because we know very little about these two dimensions of drug treatment of the obese patient. Drug-induced weight gain is a well-recognized problem and the typical suspects have been identified. The mechanisms by which insulin and insulin analogues, sulfonylureas, glitazones, glucocorticoids, lithium, some antidepressants and some atypical neuroleptics increase body weight are numerous and only partially understood. Even less is known about how to prevent or counterbalance drug-induced weight gain if choosing a different drug is not an option. Metformin has a very limited efficacy when used against neuroleptic-induced weight gain [Lee and Jeong, 2011], but besides that only lifestyle changes (e.g. physical exercise and the limitation of food intake) can be suggested at present but represent a poor option for many of the affected patient groups.
Drugs to induce weight reduction have been studied extensively in the past, but failures either during the drug development period or after marketing authorization have made it clear that modes of action of a successful and safe weight-loss drug have only been defined poorly. Mammalian energy metabolism provides several ‘protective’ mechanisms against weight loss. In addition to that phenomenon, energy burning is typically associated with increased sympathetic nervous system activity and heat production. Both effects limit the success and safety of such drugs. The recent advent of brown adipose tissue research in humans fostered the idea that new drugs may possibly increase brown adipocyte formation and thus energy burning. Given the stated reasons, I doubt that this field of research will provide effective and safe drugs to reduce body weight. The reduction of food intake on the other side involves several central nervous system regulatory circuits, and unwanted side effects will very likely limit the effectiveness and safety in new drugs again. In the light of anti-obesity drug research history, regulatory authorities have become more and more reluctant to accept new drug applications for the indication of weight loss [Gadde and Allison, 2009]. The recent FDA decision to prolong the evaluation period on the phentermine/topiramate combination even after an expert panel already suggested marketing authorization exemplifies the pitfalls in weight-loss drug development beyond physiological challenges (see http://ir.vivus.com/releasedetail.cfm?ReleaseID=662825).
Perhaps we just do not ask the right questions. Perhaps we should not focus on weight loss as a treatment target and spend much more financial and scientific resources on establishing the best possible (drug) treatment for all of the diseases that require treatment in an ever-growing number of patients that are also obese. In recent years, phase II and III trials most probably, although unintentionally, include a reasonable number of obese patients. However, they are typically not analyzed as a specific subgroup. More importantly, what do we do with all the well-established drugs that were marketed 10, 15 or more years ago? They most likely have not been tested in a suitable number of obese patients under clinical study conditions. The treatment data from daily routine, on wanted and unwanted effects, are not documented in a way that allows us to establish any useful guidelines on the treatment of a certain disease with a certain drug in an obese population. The unanswered questions are numerous:
Is a given drug similarly effective in lean and obese patients?
Are specific side effects more or less severe and do they occur more or less frequently in obese rather than lean patients?
Can changes in pharmacokinetics in obese patients be better described?
Are fixed-dose regimens correct or are obese patients prone to being underdosed if they receive the same drug dose as a patient weighing 100 kg less?
Are weight (or surface)-based dose regimens dangerous because obese patients are prone to being overdosed?
How should we handle cumulative drug toxicity when an obese patient reaches the cumulative dose much earlier during the course of treatment?
We do not have good answers for these obvious questions at present [Jain et al. 2011]. Of course, not all (established) drugs need to be evaluated regarding these questions. However, those drugs with a small therapeutic window clearly deserve our attention. As an Associate Editor for Therapeutic Advances in Endocrinology and Metabolism, I will try to collect data and papers regarding these important questions in therapeutic decisions for our readership.