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Viagra Extends Lifespan? Firmer Methodologies Needed – SENS Research Foundation

There are similar problems in several well-publicized studies that have found an association between the use of PDE5i and reduced risk of neurodegenerative aging of the Alzheimer’s type (Alzheimer’s). One well-publicized study using Medicare claims data from 7.23 million people found that use of sildenafil was associated with a remarkable 69% reduction in the risk of Alzheimer’s!

But here again, the the authors didn’t do anything to account for the confounding personal characteristics associated with regular use of an ED medication. The authors chose to compare users of PDE5i to users of four different drugs (diltiazem, glimepiride, losartan and metformin). The rationale was that other researchers are investigating two of these drugs (losartan and metformin) as potential therapies to protect against Alzheimer’s, so the authors figured that they were comparing one candidate Alzheimer’s prophylactic against several others.

In the case of metformin, this effort is likely doomed to failure — but that isn’t the central problem with using users of these drugs as a comparison group for PDE5i. As researchers from the University of North Carolina at Chapel Hill pointed out, none of the comparison drugs are used to treat ED, and doctors aren’t currently prescribing losartan or metformin as Alzheimer’s-prevention pills. Instead, losartan and metformin are used by people with entirely different health concerns and personal characteristics from PDE5i users. Comparing PDE5i users to users of these alternative drugs therefore doesn’t get at the question of confounding — with sexual activity itself, with loneliness, or with general good health — that we discussed above. associated with lower risk of dementia, while loneliness is associated with increased risk, and regular sexual activity and sexual satisfaction are associated with slower cognitive decline. Thus, the same kind of personal confounding in PDE5i users that we discussed in the mortality study remains a likely explanation for the association between PDE5i use and reduced risk of dementia.

After a back-and-forth with the UNC Chapel Hill researchers in the letters column of the Nature Aging journal, the authors agreed to issue a correction that more accurately characterized the role that their comparison drugs played in the analysis — but they left the analysis itself standing. A later study by the same authors used slightly better comparison drugs, but still failed to grapple with the distinct personal characteristics that likely separate most PDE5i users from people who use these other drugs.

Fortunately, a group of researchers from Harvard, the National Institute on Aging (NIA), and elsewhere team came at the same question from an angle that bypasses all of these problems. This ”Drug Repurposing for Effective Alzheimer’s Medicines” (DREAM) team looked specifically at people who were using PDE5i for pulmonary hypertension (PH), not ED. Focusing on the PH indication jettisons the lifestyle baggage associated with the use of PDE5i for ED. As we’ve just discussed, men using PDE5i for ED tend to differ in critical ways from men the same age who aren’t using them. And while there are no good alternative drugs for ED whose users could be compared to PDE5i users, people with PH can choose among several classes of drugs to manage their condition. 

So by comparing people with PH who manage it with PDE5i to people with the same condition who use an entirely different class of drugs (endothelin receptor antagonists (ERAs)), the DREAM investigators could make apples-to-apples comparisons. Because all PH sufferers share the same health condition in common, any major difference in the risk of Alzheimer’s between people with PH who treat it with PDE5i versus those who treat it with ERAs is more likely to be the result of the drug itself rather than underlying differences in the kind of people who use PDE5i and those who don’t. And to further tighten up the analysis, the DREAM researchers further controlled for 76 additional confounding factors, including age, race, gender, low income, smoking, and various diseases, as well as running analyses to double-check for specific sources of methodological will-o’-the-wisps.

The result: “across four separate analytic approaches designed to address specific types of biases … we observed no evidence for a reduced risk of Alzheimer’s disease and related dementia with phosphodiesterase-5 inhibitors”.