Tuesday, December 29, 2015

Less glucose in the glucose intolerant is a good thing? Who'ulda thunk it.

In 2003, the JAMA released a paper from Chiasson, JL, et al, called: Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial.

(A little infographic-like sheet containing the major points can be found here, for a quick overview of the trial.)

Including some 1,400 people, the STOP-NIDDM trial is an international, randomized, double-blind, placebo-controlled clinical trial that, including follow-up, spanned a mean of 3.3 years. I have only briefly perused the methods and statistical analyses sections of the paper, so I have, what I would consider, only a superficial understanding of the methodology, thus far. So, take this with a grain of salt. That said, I am impressed with what I have seen, at least from the standpoint of the reporting of the data. (Any time study authors decide to include absolute risk reductions versus relative risk alone, for instance, I have to give props; and props are certainly due, on that front, here. Not to mention, all pertinent information, from what I can tell, was either offered up front, or links to such information were provided for us. Respect.)

Study question:

~ Is taking Acarbose associated with a meaningful decreased risk of cardiovascular events in persons with impaired glucose tolerance?*

*It should be noted that the original STOP-NIDDM trial, from which these data were taken, was, as the authors admit here, "not powered to answer that question." This is a secondary, retrospective analysis of the data, modified to tease out this potentially important confounding variable in order to see whether it had a significant part to play in the reduction of disease risk in the study population.

Inclusion criteria:

~ Age: 40-70 y/o,
~ BMI of 25-40,
~ Impaired glucose tolerance (IGT) (according to WHO criteria),
~ Fasting plasma glucose: 100-140 mg/dL (5.5-7.8 mmol/L)

Ultimately (after all reported dropouts), 1,368 people completed the trial and follow-up, which is pretty good. The outcome measures were kind of all over the place though, from my perspective. They claimed major cardiovascular events, including new angina, AMI, revascularization procedures, cardiovascular death, CHF, CVA, and peripheral vascular disease as primary outcomes. (Secondary outcomes were incident HTN and "rates of each type of cardiovascular event.") This does not constitute a "primary outcome." Albeit of course related, these are eight separate potential primary outcomes. For the love of God, just pick one primary outcome and study that to see if there is a legitimate association. (It is times like this that I can't help but think to myself, as cynical as it may seem, that this was intentional, as it might have been a means of using the problem of multiple comparisons to generate significant figures (to assure publication, particularly in a prestigious journal like the JAMA), where there are none. I will put that consideration on the back burner for now, I suppose...)

*Acarbose is an alpha-glucosidase inhibitor that prevents the cleavage of oligo- and polysaccharides into their single, monosaccharide sugars, during digestion.

The point of taking acarbose, clearly, is to prevent the absorption of glucose in those that do not tolerate glucose well. I follow the logic. However, it appears to beg the question: If someone does not tolerate dietary glucose, why feed them dietary glucose? Why feed someone carbohydrate just to turn around and try like hell to prevent its absorption into the extracellular fluid, because it might pose a problem in the carbohydrate intolerant individual? Does it not make sense simply to avoid ingesting said carbohydrate in the first place, and not bother taking the acarbose, at all?

I realize, I could be falling prey to a cognitive bias, here. "If a little of something is good, a lot more must be even better." However, there are other data that corroborate these findings in various ways. From a scientific perspective -- assuming these data are accurate, and I do not yet know whether or not I think they are -- I do find this intriguing, and, as I say, I think it jives rather well with much of the controlled nutritional literature I have seen on the topic. Personally, however, it strikes me as a touch illogical and futile. A little like trying to dig a massive hole using only the stick-end of your shovel.

The relative risk reduction in the acarbose group, versus those 600 some odd persons on placebo, was 49%. Note that this translated to a 2.5% absolute risk reduction. (At first glance, a 2.5% absolute risk reduction seems quite small, but, considering that many medications for cardiovascular disease translate to a much larger NNT and a much smaller absolute risk ratio, oftentimes <1%, I am actually somewhat pleased with that figure.) But, again, I just feel it would be more efficient and intelligent simply to say, "Okay, persons with IGT do not appear to tolerate glucose well, ergo, we shall see what restricting dietary glucose does," since, in the latter, they wouldn't have to play with inhibiting absorption, at all. It takes out the unnecessary middle-man.

One thing I think is important, and, in my opinion, is a huge confounder, is this:

a.) Almost invariably, dietary modification leads to a reduction in carbohydrates consumed, since a vast majority of the Calories eaten by the so-called "civilized" nations of the world come from this macronutrient category. Could these results have arisen out of a slight reduction in carbohydrate Calories?

b.) We know, without a doubt, that consistent exercise can improve both OGTT and insulin sensitivity. Why? Intense exercise turns the skeletal muscles into a glucose sink. (If you truly wanted to test the effectiveness of acarbose, alone, on glucose tolerance and disease risk, you would have to maintain the subjects' baseline lifestyle characteristics.)

A and B may just be study ruiners, for me. (Not necessarily for the STOP-NIDDM trial, as a whole, per se; but perhaps for these secondary, modified intention-to-treat analyses that followed.) At least, I cannot overlook the possibility that these confounders within the larger confounder couldn't have accounted for nearly all the 2.5% absolute reduction in disease outcomes.

All in all, I recommend that you check out the trial and read at least the methods and results sections, for yourself. Despite my personal annoyances, it really is an intriguing study, and you may be able to find some points of interest I have not alluded to. Enjoy!


1. Chiasson, J. L., Josse, R. G., Gomis, R., Hanefeld, M., Karasik, A., Laakso, M., & STOP-NIDDM Trial Research Group. (2003). Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. Jama290(4), 486-494.

Thursday, December 17, 2015

Sex. Critical thinking skills need not apply?

Recently, I was half-listening to a 29 year old, gay, male friend of mine -- whose name shall remain anonymous -- discuss his latest conquest, while I flipped through some notecards on cardiovascular physiology. I offered little more than a few "uh huh"s and "Oh, really?"s, until I heard him say, "And then I convinced him to top me bareback, because I'm on PrEP, so I can't get the virus."

"Excuse me?" I stopped him. "You what?"
"I'm on PrEP," he said, "So I'm protected from getting HIV, or passing it to any of my partners."
Shocked, I replied, "Where exactly did you hear that?"
"They've studied it, and it's been shown to be 100% effective at protecting against transmission of the virus."
"100%?! Who's 'they'?"
"Lots of us are doing it. Considering you are in the medical field, I'm surprised this is the first time you're hearing about it..."
I took a few breaths to steady my nerves and then said, "Okay, well, what about side effects; are you concerned about any possible side effects of taking the drug?"
"There are no side effects," he said.

That's what did me in...

There is no such thing as a drug that does not have side effects. Ibuprofen has side effects! Either he is bullshitting, or someone has actually convinced him that there are only upsides to taking this medication, and he really believes there are zero adverse events associated with its ingestion.

After a long, exasperated conversation, which ended with me sifting through an immense amount of data on pre-exposure HIV transmission prophylaxis, and finding out that this is not the first time he has done this, I hung up the phone, horrified by what I had just learned.

This isn't the first time I had learned about PrEP, or "pre-exposure prophylaxis." It is, however, the first time I've learned of anyone using it as an excuse to fool around unsafely, and the first time I've ever heard someone tell me a medication has a "proven, 100% effectiveness" record -- which, for any of you scientists and medical professionals out there, you will recognize as being totally bogus. My friend, who I truly respect and care about, honestly thinks that because he is on PrEP he cannot get HIV, and, therefore, can fool around ("raw") with his sexual partners, without protecting them or himself by wearing a condom.* And, from what he tells me, there are multiple partners across the state.

*For the time being, let's forget that HIV is not the only sexually transmitted infection that is of concern, here. My friend is a smart guy, but, clearly, he has forgotten that (even if PrEP did work as he thinks it does -- and it doesn't) there's still syphilis, genital herpes, HPV, gonococcal infections, and a myriad other STIs he could be exposing himself and others to, by engaging in this sort of practice. This really is a potential public health crisis, on many levels. For now, however, I will focus exclusively on the HIV concern. (But, if you are reading this, and this sounds like something you do, yourself, or are aware of friends, colleagues or acquaintances doing, please understand that by engaging in this behavior, you are in fact putting yourself at risk of getting and transmitting disease, including but not limited to HIV, despite whatever official or unofficial PrEP marketing has led you to believe.)

I could be false dichotomizing here, but I can think of only two reasons someone in my friend's shoes might want to take PrEP; either:

a.) They truly believe they will be 100% protected from HIV transmission. Or,
b.) They want to misuse this purported inability to transmit the virus by manipulating other, unsuspecting men (or women, in some cases) into believing they will be protected, too, so they can screw around without having to wear a condom.

Truly disgusted with both possibilities -- as A implies a total lack of critical thinking on our part, as consumers, and B implies an intention to mislead another for ones own sexual gratification (which feels a lot like a sick form of rape, to me) -- I wanted to conduct a small poll with a few of my other gay friends, to see if they have heard of PrEP, take it, or know someone else who takes it, and their reasons for doing so.

Three of five people (none of whom knew I had spoken with anyone else regarding this topic, as far as I am aware) explicitly told me that they know of many people who are On PrEP because it "protects them from getting the virus," and at least two gay men who use the medication as an excuse to "fuck around bareback" -- which just means to have intercourse (anal, or otherwise) without a condom.

The CDC website, to which I've linked above, provides links to the four main clinical trials on pre-exposure prophylaxis. I would like to take a quick look at them, now. (In no particular order.)

I would like to make something clear: although I am currently at arms with the popular conception of PrEP, I'm not entirely against it -- HIV and, therefore, AIDS is a debilitating, life-changing (and eventually ending) disease process, and the scientific and medical communities at large are working very hard, and spending many billions of dollars per annum, to find ways to protect against and possibly rid people of the disease. I commend that! What I have an issue with is marketing it to people disingenuously, or convincing gay men that it will reduce their risk of transmission by "over 90%." (Is it really that hard to believe that men, regardless of sexual orientation, who are told they are nearly 100% protected won't round that number up to 100% and tell their partner(s), "Hey, it's cool if we mess around raw, now, because I'm on this new medication!"*)

*Obviously, if this is happening (and I know that it is), there's not just a critical thinking pandemic on the side of these drug-takers, but also with respect to those who are allowing themselves to be convinced of this nonsense. Wake up, people. Don't blindly trust everything you see or hear. Just because he bats his beautiful lashes at you while he says it does not make it true.

Getting back to the point, this study included roughly 1,200 participants, and followed them for a median of 1.1 years, which is pretty good. I have a few issues with it, however.

First, as the title implies, these people were reportedly all heterosexual. As the route of transmission, vaginally, is not the same, as rectally, because the nature of the epithelium of the rectum allows for a much greater absorption of seminal proteins from the ejaculate, and because the pH of the fluids in the vaginal canal are more acidic and, therefore, protein denaturing, we should not expect rates of HIV transmission in heterosexual persons to be representative of similar gay populations. As the outcome measures in this study looked at heterosexual men and women, we cannot extrapolate the results of this trial to homosexual men, who are engaging in unprotected anal intercourse.

It is important to consider that, even though these 1,200 study subjects were free of HIV at the start of the trial, 36 of them tested positive for HIV before the end of the trial. 10 of these subjects were in the intervention group, receiving the antiretroviral therapy. That means that ~28% of the newly HIV infected persons were on the drug. The authors go on to state:

"With the exclusion of 3 participants who were HIV-infected at the time of enrollment, the overall protective efficacy of TDF–FTC [the antiretroviral drug] in the modified intention-to-treat analysis (comprising 1216 participants) was 62.2%."

I wonder, if my friend had heard that the drug was reportedly 62.2% effective in a trial on heterosexual men and women, whether he would still have jumped as quickly onto it as he seemed to. After all, 62.2% isn't bad, but it's certainly not 90%, let alone 100%.

Lastly, the trial boasts a randomized, double-blind, placebo-controlled design, at the start, but, for whatever reason -- and I have my suspicions -- the trial did not proceed as designed until the very end. Retention and adherence issues abound, this study converted to an observational trial, by default, which is, unfortunately, insufficient to tease out imperative causes and effects. There were also some significant adverse events in both groups, with far more nausea and vomiting in the group receiving medication. The CDC makes it clear on their website that this is a possibility of taking PrEP, but states (as did the trial authors) that these symptoms appeared to subside after a few months of consistent treatment. Whether that's true or not, they did not mention that bone mineral densities were substantially decreased in the group receiving the medication versus those receiving placebo. So much for "no side effects."

Already, we are faced with the same concern as the last trial. The outcomes of a trial on heterosexual intercourse (presumably vaginal) -- and, in this case, on HIV-1-serodiscordant couples, who are presumably committed to one another and not having sexual relationships with other persons -- cannot be extrapolated to homosexual men or anal intercourse. Individual study designs attempting to answer these specific questions must be conducted, before we can have any reliable answers pertinent to them. Otherwise, we are just guessing, which would not only be a disservice to homosexual men (cis- or trans), and other persons who engage in anal sex, it would be scientifically disingenuous.

From a variety of large epidemiological studies, HIV appears to be the most difficult sexually transmitted infection to transmit sexually, among non-promiscuous, heterosexual men and women.[3] That, of course, does not mean it doesn't happen; it certainly does. But, when compared to the incidence of syphilis and chlamydia, for example, it is significantly less. However, this is just another reason to question whether these results would translate to homosexual men. The incidence of HIV infection in homosexual persons is notably higher than in heterosexual persons -- I read somewhere that it is something in the ball park of 2% as compared with 0.4%, respectively; but, please don't quote me on that. Let's say that these results are ~67% effective, as the authors suggest; would anyone want to wager that the same exact number would result in a study of serodiscordant homosexual male couples?*

*Yet again, this study reports the efficacy of PrEP to be roughly 67%. Not bad. In fact, it's pretty damn impressive! But certainly not 90-100% protection.

In this trial, statistically significant adverse effects associated with once daily ingestion of the antiretroviral drug (TDF-FTC), as compared to placebo, were neutropenia, gastrointestinal upset and general fatigue.

Interestingly, and importantly, in my opinion, there were accounts of antiretroviral resistance in the intervention group. This means that the HIV virus, in infected individuals, had mutated in such a way, as a result of receiving PrEP therapy, that it may have effectively rendered any future antiviral therapy useless.

Lastly, of those individuals who began the trial free of HIV infection, who subsequently became seropositive, by the end of the trial, 31% of them had detectable levels of the drug in their plasma samples. This means that at least these people had been consistently taking the medication, enough to have built up a meaningful amount in their system, and still became infected, regardless. (Thus continuing to serve as evidence that a proposed 90% efficacy rating is utter horse shit.)

Consistently and habitually sticking "dirty" needle in ones arm, and thus injecting HIV directly into ones bloodstream is, once again, a very different route of transmission than having unprotected anal intercourse... And, in this trial, the reduction in HIV transmission was only 49%.* (At this point, I have absolutely no idea where anyone is getting this >90% reduction in transmission rates nonsense?)

*Now, I do not wish to demean this figure, per se. 49% reduction is pretty good, all things considered. There is an enormous difference, however, between 50% and 90%. Also, let me reiterate: the outcome measure in question matters. Habitual intravenous drug users =/= habitual recipients of anal sex.

Finally, we get to the one and only study that matters, for our purposes. The only one that actually examined the results of homosexual men, partaking in consistent anal intercourse, taking this prophylactic chemotherapeutic antiviral therapy.

The enrolled cohort was roughly 2,500 persons, from 11 different countries, and they were followed for a median of 1.2 years. Those numbers are highly promising, considering the quality of data we are looking for. Then again, it is very important to remember that this is only one trial.

Out of the 2,500 persons enrolled in the trial who continued evaluation until the end, 110, or approximately 4%, of the initially seronegative men tested positive for emergent HIV infection. 36 were in the intervention arm. The authors conducted a modified intention-to-treat analysis and here is what they concluded:

"...representing a relative reduction of 44% in incidence in the modified intention-to-treat population."

44%. Now, of course, that's just a modified analysis of a specific subgroup, post hoc. But, isn't this the population we should be concerned with? Brand new, emergent cases of HIV, despite being on the drug and having adequate blood levels of it in their system. This concerns me.

Also important to consider is that every individual who participated in this trial was also hit, fresh from the start, with biobehavioral counseling, which included risk reduction techniques and condoms. The authors go on to state, in the results, that the "total numbers of sexual partners with whom the respondent had receptive anal intercourse decreased, and the percentage of those partners who used a condom increased after subjects enrolled in the study." (Emphasis, mine.)

Don't we now have to ask ourselves whether the positive outcomes we are so eagerly attributing to the use of PrEP might not also have had something to do with the increased condom use? Would it not be inappropriate to realize this confounding variable and then brush it off as a triviality?

We know that HIV transmission doesn't come about as easily as we are often led to believe -- it was "just" 4% in this particular trial -- otherwise the international HIV epidemic would be unfathomable, right now, instead of remaining at the decade-long lull we have gotten accustomed to. We also know that the false positive and false negative rates of rapid and even western blot tests are quite common in the infectious disease literature. So, there are certainly a great deal of possible confounding factors to consider, here; certainly far more than I could possibly conceive of right now. But, one thing we know for sure is that condom use is already a well-established, powerfully effective preventive measure to protect against the emergent acquisition of HIV infection in previously seronegative individuals.

Naturally, it would be completely unethical to divide people up into two groups, as one would need to do to find "the answer" to this outcome question, where one group got the drug, and no condoms, while the other group got condoms, but no drug.... Clearly, this trial couldn't even be done. But, to make the sorts of claims made about PrEP, now, this is precisely what we would need to see conducted, and it just serves to remind us that there may be innumerable factors at play, here, that we are unaware of. From my perspective, it would be unwise to jump to any premature conclusions, considering the evidence of the efficacy of this treatment is still in its infancy, and the answers we need have not yet been fully elucidated.

Lastly, statistically significant alterations in serum creatinine and phosphorous levels changed, as a result of taking PrEP in many of the studies conducted, thus far. Among other concerns, including, but not limited to, significant negative changes to glomerular filtration rates -- even in previously healthy persons -- should, if not serve as cause for concern, at least be considered among the list of potential downsides of taking this new medication.

I should like to say, I am not "anti-PrEP," per se. I am anti-manipulative marketing tactics. I am anti-non-scientific statements like:

Take this wonderful drug. There are no side effects, and you'll never have to worry about getting sick again!

which are not only unsupported by the data, but are also wholly intellectually absurd. Will I also get to ride into work on Monday morning on a rainbow? C'mon...



1. Do not manipulate others into having bareback sex with you by telling them you "can't" get HIV. You absolutely can. PrEP is not a cure or a pill with magical properties. (If you are not morally concerned about hurting another person, at least understand that you're not necessarily getting a "free ride" either.)

2. Do not let others manipulate you into having bareback sex with them, by believing that just because they're on PrEP that they "can't give you HIV." Viral transmission rates may be lower, but they are not zero, and you can still become infected.

3. Think critically, before putting any drug into your body. There's no such thing as a medication with 100% efficacy and 0 side effects. (Indeed, there aren't any that have either 100% efficacy or 0 side effects. Even Tylenol can cause severe hepatotoxicity at doses on the high end of normal, and PrEP drugs are chemotherapeutic, just like those given to persons already seropositive for HIV. Ergo, It is reasonable to at least anticipate the possibility of similar long-term adverse events from chronic PrEP treatment.)

4. Wear a condom. (Even if you choose to take PrEP; which is your right as a healthcare consumer.) Even the CDC, which, in my opinion, inappropriately and prematurely provides young homosexual men with the hope that if they "just take this little pill" they'll save themselves years of heartache and eventually-fatal autoimmune disease, state that the only way to virtually ensure protection from HIV infection is to couple PrEP with the regular use of a condom, during any and all sexual penetration.

5. Wear a condom, regardless. Even if PrEP worked the way people seem to think -- and it doesn't -- it will not protect you from contracting other STIs, like HPV, genital herpes, chlamydia, gonorrhea and more. If you don't want your junk to fall off, or go insane from neurosyphilis, never let anyone put any of their body parts inside of yours (or vice versa), unless it is protected.

6. Get tested, make your partner get tested, too, and don't be afraid to ask about previous sexual relationships. (This is an incredibly serious public health concern, and ought to be treated as such.)

NOTE: I am not trying to dissuade the use of PrEP, per se. I am trying to help the men and women in my community and elsewhere understand that not all of the wonderful things they have been told about this medication are quite so wonderful, and to suggest they simply open their minds and think critically before embracing something as "the truth." In other words, I am not against PrEP; I am against people using it to manipulate other, innocent and ignorant people into potentially giving up their lives for 12 minutes of pleasure.


1. Thigpen, Michael C., et al. "Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana." New England Journal of Medicine 367.5 (2012): 423-434.
2. Baeten, Jared M., et al. "Antiretroviral prophylaxis for HIV prevention in heterosexual men and women." New England Journal of Medicine 367.5 (2012): 399-410.
3. Padian, Nancy S., et al. "Heterosexual transmission of human immunodeficiency virus (HIV) in northern California: results from a ten-year study." American journal of epidemiology 146.4 (1997): 350-357.
4. Choopanya, Kachit, et al. "Antiretroviral prophylaxis for HIV infection in injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, double-blind, placebo-controlled phase 3 trial." The Lancet381.9883 (2013): 2083-2090.
5. Grant, Robert M., et al. "Preexposure chemoprophylaxis for HIV prevention in men who have sex with men." New England Journal of Medicine 363.27 (2010): 2587-2599.