Based on these results, sibutramine associated reductions in body weight gain and food intake were not associated with improvements in lifespan. However, as with most studies performed in rodents a few points merit consideration. First, the study was undertaken to assess the effect of sibutramine treatment on tumor incidence and not specifically designed as a longevity study. As such, many animals survived beyond the 2-year period of the study (Supp. Table 3
), which offers lesser power to detect effects on mortality rate than does a study with all animals followed until death. Nevertheless, power was actually quite high (see below), given the sample size and anticipated effects. Second, although rodent models are commonly used for toxicology and translation research, they are not always optimal models of cardiovascular disease (16
). Therefore, the interpretation of mortality effects using rodent models must be cautiously applied to other species, including humans, where weight loss-associated benefits on diabetes and cardiovascular disease may be realized as longevity gains. This also implies rodent models may not be ideal to reveal drug-related cardiovascular complications which have been discovered in human trials. Third, this study was performed with a single dietary composition, which may not be equivalent to the obesity-inducing diets associated with human subjects receiving sibutramine for weight loss. Since sibutramine treatment is currently prescribed for weight loss after
the establishment of obesity (while this study represents long-term sibutramine treatment prior to any established obese state), the question of whether sibutramine-associated weight loss can alleviate the morbidity and mortality associated with the obese state is not directly answered. Finally, while group housing reduces study costs, it also prevents a definitive assignment of dosage received by individual animals since food intake was measured per cage.
Despite these limitations, the comprehensive nature of the study presents several strengths. First, the large sample size and duration of study provides roughly 91% power within each species to detect a 10% difference in mortality compared to controls, even when considering the limited two-year duration of the study (see appendix). This suggests the lack of an observed lifespan benefit with sibutramine treatment is not simply due to low power. Additionally, it is clear that sibutramine was efficacious for weight control, particularly for rats. While restriction amounts from 30–40% are commonly applied in rodent longevity studies, alternative methods of dietary restriction like intermittent fasting or every other day feeding have resulted in health and longevity benefits concomitant with milder amounts of food restriction (10–15%) or body weight reduction (18
). The observed relative bodyweight and food intake reductions (~10%) of both male and female treated rats compared with controls might be expected to result in an approximately 7.3–8.4% increase in lifespan based on the relationship observed in many CR studies (with an expected relative increase of 8.6–13.3% in the SIB HI dose group) (21
). Therefore, the lack of a significant effect on lifespan in rats cannot be attributed to lack of weight-loss efficacy of sibutramine. Since there were no pair-fed groups included in the study, it is not possible to determine if an equivalent food intake reduction independent of sibutramine treatment would have resulted in lifespan extension. Had such extension been observed, as might be expected, the lack of lifespan benefit with sibutramine treatment would imply sibutramine treatment offset the potential lifespan gains. Finally, the consistent animal husbandry and care applied to toxicology studies conforming to good GLP should provide a relevant backdrop to investigate treatment-related changes in lifespan.
Suggestions for Future Research
To our knowledge, the manufacturers of sibutramine have never made a specific claim regarding longevity. Nevertheless, we think it noteworthy that we do not yet have evidence, even in an animal model, that anti-obesity drugs, and sibutramine in particular, will prolong lifespan. Whether this is indicative of a fundamental difference between the mechanisms of action of pharmacologically induced weight loss and calorie restriction might be assumed, but has not been directly tested. The hypothesized reduction in mortality rate with weight loss is a rationale for the use of anti-obesity drugs, but at present remains to be demonstrated.
Our results suggest several possibilities for future research. First, we would propose that companies marketing anti-obesity drugs also conduct full longevity studies in rodents to evaluate the effects of their drugs on lifespan. We are not suggesting that such studies be deterministic as to whether or not a drug is appropriate for marketing or use, but we do suggest they add to the available information and will be helpful in decision-making. Second, given that companies conduct two-year toxicology studies of the type we have analyzed here, the raw data from those extant studies on existing drugs should be made publicly available for analysis of the type we have done and the results published. Third, given the well known finding that caloric restriction (CR) results in increased lifespan among rodents (22
) including among rodents that have been allowed to become obese and subsequently placed on weight-loss-inducing CR (2
), further mechanistic studies investigating why a drug that causes a decrease in food intake and body weight does not cause a compelling and dose-response reduction in mortality rate seem warranted.
From a basic science perspective, these data raise an interesting question. That CR, which leads to weight loss or less weight gain, decreases mortality rate has been shown repeatedly in many studies and many species. However, the mechanism(s) of action remain unclear. It has been speculated that one mechanism may be the neurobiological cascade that underlies or follows the phenomenological experience of hunger (24
). If this were a primary mechanism, it might explain why sibutramine did not reduce mortality rate despite causing a dose-dependent reduction in food intake and body weight. That is, sibutramine reduces food intake by reducing hunger, whereas CR appears to increase hunger (24
). However, methionine restriction has also been reported to increase lifespan without requiring forced food intake reductions, with animals actually eating more, particularly per gram body weight, in many cases (26
). Whether a hunger drive is present and contributes to any longevity benefits in the methionine restriction model would also be of interest. Future research might further explore these possibilities.
With respect to clinical and public health implications, in our opinion, these data do not prove that sibutramine-induced weight loss will not improve mortality rates in humans, nor constitute evidence that sibutramine should not be used. Yet, they do temper enthusiasm for its long-term projected benefits on hard endpoints, until such benefits can be shown to accrue in other studies.