Back in January of 2023 I reviewed claims for a purported anti-aging supplement for dogs called Leap Years. My conclusion at the time was-
Leap Years is similar to most veterinary supplements on the market: It is based on some plausible ideas with limited supporting evidence, and it is marketed with claims that go well beyond anything scientifically proven or reasonable.
In that review, I pointed out that one piece of evidence the manufacturer cited to support their claims was an unpublished clinical study conducted at the veterinary school at North Carolina State University (NCSU). That study is still has not been published in a peer-reviewed journal, but the company has recently released a report on the preprint service Bioarxiv.
This is an increasingly common practice which is supposedly intended to make important information available more quickly, but which in most cases has more public relations value than scientific value. Until a paper is put through peer-review, it has only been critically evaluated by the authors or people they have chosen, which leaves lots of opportunity for bias. Such preprints may change significantly before publication or even never be peer-reviewed and published at all.
Preprints are clearly a lower level of evidence than full published research reports, but they do at least provide more detail for anyone interested in evaluating the research and claims made using it. As you have probably already guessed, that’s what I intend to do here!
The Study
The study was a blinded, randomized, placebo-controlled clinical trial conducted in accordance with appropriate methodological guidelines, which is always nice to see. The authors do a good job of describing the methods, including the bias-control practices, progress of subjects through the trial, and the potential limitations. The one critical piece of information missing is the actual chemical compounds used in the supplement.
As discussed in my previous review, Leap Years supposedly contains an NAD+ booster, which the company states is not NMN but otherwise does not identify. This was given daily for the duration of the 6-month study period. The supplement is also claimed to contain a senolytic, which is also not identified and which was given on two consecutive days each month during the study.
The FDA is pretty clear that veterinary supplements are not covered under the limited regulatory rules for human supplements (the Dietary Supplement Health and Education Act or DSHEA). Anything marketed for animals must either be a food or a drug. Leap Years is clearly not a food, and the claims made for it very much sound like treatment claims for a veterinary drugs:
[Leap years] significantly improves owner-assessed cognitive function and may have broader effects on frailty, activity and happiness as reported by owners.
That would make it seem like the company is marketing an unlicensed veterinary drug without first demonstrating safety and efficacy, as is required. However, the FDA does not seem to have the resources or political backing to effectively enforce these rules, and the same is true for many other veterinary supplements. Legal or not, it seems to me unethical (if not unusual) to market a supplement with undisclosed ingredients and claim that it prevents or treats serious health problems in dogs. This study does nothing to address that concern.
The trial started with 67 dogs randomized to placebo, low-dose supplement, and high-dose supplement (though the authors refer to these as “low-dose” and “full-dose,” which seems an obvious attempt to avoid the potential negative connotations and anxiety that might come with claiming to provide a “high” dose of whatever the undisclosed ingredients are). Subjects dropped out at various stages of the study for a variety of reasons. The total dropout rate was a bit high (19-26% from baseline to final analysis of the data), as is to be expected with an already old population. However, the dropouts seemed roughly balanced across groups, so while this might have affected the statistical power of the study, it probably didn’t bias the results for or against any of the treatments.
The dogs were included in the study if they were at least 10 years old and had mild or moderate cognitive dysfunction as assessed by a validated tool (CADES). They also had to be cooperative for behavioral testing and not so sick or debilitated that they couldn’t complete the various evaluations of the length of the study. All of these are reasonable inclusion criteria.
There were quite a few outcomes measured, though at least these were appropriately identified as a primary outcome (which is all that is supposed to matter when one critically evaluates a study like this) and secondary outcomes (which are supposed to be viewed as potentially interesting but not probative).
The primary outcome was the change at 3 months in a validated measure of canine cognitive dysfunction (CCDR, not the same as used to test dogs for inclusion in the study). As the figure below shows, all groups improved, including those taking a placebo, which is a classic finding for non-specific effects of participating in a clinical study. Patients tend to get better due, most likely, to the increased care, attention, and monitoring they get as study subjects, even if the treatment doesn’t do anything (which is part of why having a placebo group is so important).
At 3 months, the placebo group looks better than the low-dose group, and the high-dose group looks better than both, and the authors report, “There was a significant difference between treatment groups over the three-month period (p=0.02).” However, differences in “successes” and “failures” (improvement or worsening of CCDR scores) between groups were not significant at 3 months.
More importantly, it’s not clear if these differences would be meaningful in terms of function or quality of life even if they were statistically significant. It is not even clear that these differences are real since they are variable across time periods and do not show the expected relationship between dose and response (the placebo group should stay the same or get worse, the low-dose group should get a little better, and the full-dose group should improve more than the low-dose group).
Expanding the chart to include the data from the 6-month timepoints (reported in the supplement to the preprint) shows the lack of these relationships and suggests that there is not clear and meaningful improvement with the supplement. Even though the 3-month timepoints was reported as a prespecified endpoint, it is interesting that it is the only timepoints that seems to show a significant improvement in a treated group and not the placebo group. Despite the statistical difference reported, it is pretty clear that the primary endpoint did not show the treatment to be effective.
The secondary outcomes also failed to show any clear evidence of a beneficial effect:
- The CCDR was measured again at 6 months, and there were not changes nor differences within or between the groups
- There was no change within groups nor differences between them in activity level determined by an objective monitoring device
- There were no significant differences between the groups in the number of dogs reported to have maintained the same level of activity. The results also don’t show the kind of progressive effect with increasing dose that would be expected if there was actually a real treatment effect:
placebo 55% unchanged
low dose 62% unchanged
high dose 44% unchanged
- Similarly, no significant differences or dose response was seen in the percentage of dogs reported to have increased their activity level:
placebo 20% increased
low dose 10% increased
high dose 39% increased
- There were no statistically significant differences or dose response seen in the proportion of dogs with stable or improved frailty scores:
placebo 55% stable or improved
low dose 76.2% stable or improved
high dose 72.2% stable or improved
- A variety of cognitive function tests were run on the study dogs. These haven’t been validated to show changes over time or drug treatment effects, though they could potentially be useful for doing so. There were no significant differences and no clear sign of a dose response for these tests.
- Cylinder test- all groups improved with no differences between them
- Detour test- there was a slight decline in the full-dose group, a slight improvement in the other groups, and none of these differences were significant
- Sustained gaze test- all groups improved with no differences between them
- Gait speed- there were no changes nor differences between groups
Only a limited subset of the results was reported for owner-reported happiness in the paper, and I have not dug through the full data spreadsheet to find the rest, but the most hopeful subset reported by the authors still does not show a clear effect. - At 6 months, there were some differences in the proportion of dogs reported to get better on this measure, but these were not statistically significant, and again they don’t show a logical dose response:
placebo 24% better
low dose 47% better
high dose 35% better - At 3 months, there were some differences in the proportion of dogs reported to get worse on this measure, but these were not statistically significant:
placebo 15% worse
low dose 10% worse
high dose 0% worse
The authors also monitored for adverse effects and classified these according to appropriate standards. There were few serious adverse effects observed, and these were evenly distributed between the groups and did not suggest any dramatic safety problems with the product.
Bottom Line
This report does not count as a peer-reviewed publication, and it adds only a little to the evidence already discussed a year ago to support the product claims. However, the report is useful in that it provides more detail about how the study was conducted and what the results were. Generally, the study was designed and reported appropriately, and the level of control, for bias was pretty good. Unfortunately for the company, the results failed to show statistically significant or clearly meaningful benefits for treated dogs.
The discussion and the company website, of course, try to present the findings in at least a slightly positive light, but the final statement that the product, “can be used safely to mitigate cognitive decline in senior dogs and might have broader effects on dog health manifesting as improved happiness and reduced frailty” is certainly not supported by the actual results reported here. The best we can say is that there were no apparent signs of significant risk and there were a few non-significant findings that might turn out to be mildly beneficial at a low but significant level in a larger study or with different outcome measures.
This level of evidence is never the definitive word for or against a treatment, but that this is the best the company can come up with after over a year on the market is not encouraging. The company makes claims which seem likely to be prohibited for a veterinary supplement, and they rely on anecdote and questionable extrapolation from theoretical science and results in other species to market the product, and the release of this study does nothing to strengthen their case.
March 12, 2024- Addendum
Today Dr. Nir Barzilai announced that Dr. Sinclair was resigning from the presidency of the Academy for Health and Lifespan Research. It is nice to see some consequences for such clear, commercially motivated misuse of science. Hopefully, this will encourage Dr. Sinclair to focus more on research and less on selling unproven supplements, for dogs or humans!