Vitamin D & Cognition

July 30th, 2010

I was recently asked to put together a lecture on Alzheimer’s disease that would be presented at 37 state chapter meetings.  But what happened to the other 13 states, DC & Puerto Rico?  They ran out of money!  But anyway, I digress.  I mention this b/c the editors for this program wanted evidence-based recommendations that had been vetted by major organizations.  They wanted cause & effect, not just association.  So let’s cut to the chase:  there are no randomized double blind placebo controlled studies to demonstrate that anything makes a difference in preventing or treating AD.  Well, that’s a pretty bleak statement.  But when you’re the AAN or NIH, you need concrete evidence of benefit w/o harm before you can tell millions of people to go out and do something.  In these scenarios, you’re really ruled by “First, do no harm”.  That’s their perspective.

However, if you ask our patients, myself for instance, I’ll bet that they don’t require that level of absolute proof before they’re willing to give it a go.  Along those lines, I’d like to point out a prospective study published earlier this month following 858 Italians avg 70+yo for 6yrs that demonstrated an association btwn lower 25OH vitamin D & greater cognitive decline.  And just how much is considered enough (used as the baseline reference)?  >75nmol/L or 30ng/mL.  I’m not convinced that that’s enough but that discussion requires more time for another day.

I would not be so effusive if this were the first study to demonstrate this linkage but in fact I found 2 studies from last yr & another from 2006 that came to the same conclusion: somehow vitamin D is related to cognitive function.  The problem is that none of these studies were gold-standard RCTs but rather epidemiologic observations.

But like others, while the evidence may not be the strongest, the fact that we need vitamin D for other health concerns and that the downsides to supplementation are minimal, gives me little hesitation to pause.  So while I stand to ponder the pathophysiology that would explain how vitamin D might affect cognitive function, I also remember to take my daily dose of vitamin D. 

Vitamin D & Cognition 12-06
Vitamin D & Cognition 5-09
Vitamin D & Cognition 9-09

Disclaimer:

Every effort has been made to credit appropriate sources.  Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting.  While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Cognition/Dementia, Vitamin D | No Comments »

Your TV Can Kill You!

July 29th, 2010

I admit it. Try as I do, I’m not necessarily the most timely guy around. If I were an animal, I’d be a sloth (three toe’d at that). Definitely the grasshopper rather than the ant. As for squirrels, well I’m the blind one finding the occasional nut as in today’s post.

Preceding yesterday’s treatise about sitting less, earlier this year in January, authors in Australia followed 8,800 adults avg 48-67yo for 6+yrs. Despite adjusting for the usual confounders, eg age, sex, waist circumference, and even exercise, they concluded that each add’l hour of television viewing increased all-cause mortality by 11% and CVD mortality by 18%, both statistically significant. Yes, there was a 9% increase in CA mortality but this did not reach 95% confidence interval for statistical significance.

So how much TV is too much? Unfortunately for our Madison Avenue advertisers, the cut point appears to be approximately 2hrs/d (which seems like quite a bit to me). Compared to those who watched <2hrs/d, those who watched >2 to <4hrs/d had 13% greater all-cause mortality while those who regularly sat thru 3hrs of primetime plus 1hr of nightly news plus a bit of late night talk show, in other words >4hrs/d, had 46% greater all-cause mortality. Interestingly enough, from a statistical perspective, CVD mortality didn’t reach significance for this particular analysis.

Despite this, I find it difficult to recommend more screen time since most of us are either seated or supine while watching. After all, how many of us actually engage in some form of exercise while watching TV? Clearly, not enough!

Obviously, ABC, CBS, NBC, etc, can’t be too happy. However, they can always argue that this study is, again, one of association, not of cause & effect. Still, I can’t help but believe that the preponderance of evidence points to a more active lifestyle as our ideal rather than a sedentary one.

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Exercise & Physical Activity, Mortality | No Comments »

Don’t Sit Down!

July 28th, 2010

I hope that you’re moving or at least standing as you read this missive. Once more, physical activity makes a difference. This time, researchers followed 53,440 men & 69,776 women for 14yrs. After taking into account the usual stuff like smoking, BMI, etc, they noted a significant association btwn time spent sitting and mortality. Compared to those who spend >6hrs/d sitting (like me), those who spent <3hrs/d sitting had a significantly lower risk of all-cause mortality (mostly CV), regardless of other physical activity. Those who exceeded 24.5 metabolic equivalent (MET) hrs/wk in add'n to sitting less had an even lower mortality rate. Of course, if you're going to stand most of the day, you better adjust your ergonomics so as not to injure your back. The point of this study is that since we spend at least a third of our day at work, the more physically active we are, whether at work or play, the better off we are.

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Exercise & Physical Activity, Mortality | No Comments »

DHEA-S vs (All-Cause & CV) Mortality

July 27th, 2010

DHEA. Is it really the mother of all hormones? Clearly it’s higher up the metabolic chain, above Testosterone & Estradiol. But does it really matter? After all, there are plenty of studies demonstrating the benefit of T & E2, but the literature supporting DHEA is relatively sparse in comparison. Further evidence of its lack of power (or perhaps of politics at play) is that DHEA is available as a nutritional supplement such that its production & sale is without governmental oversight. This is in direct contradiction to T & E2, whose manufacture and prescription is closely monitored by the DEA & FDA.

So does DHEA really matter? Surprisingly, for something so “weak” that our government has abdicated control over its public availability, a study to be published in September demonstrates that low DHEA-S (steady state level) predicts all-cause & cardiovascular mortality regardless of traditional CV risk factors, CRP, T & E2, in 2,644 community dwelling Swedish men, avg 75-76yo, followed for 4+yrs.

Do understand that this is an epidemiologic study. Its conclusions are that of association. Nothing can be said about the possibility of causality, much less the direction of causality. In other words, this study tells us nothing about whether low DHEA-S caused an increase risk of death or whether an inherently higher risk of death caused a lower DHEA-S level.

However, given the few observational studies extant demonstrating some sort of association btwn higher DHEA-S and better outcomes and the rare double blind placebo controlled studies demonstrating benefit from supplementation, it would seem reasonable to supplement to the high end of the age-appropriate reference range assuming no side effects sustained. The larger question is whether to supplement everyone to a more youthful reference range w/presumably higher upper limit of normal. At the very least, we should be very careful to insure the quality of our supplement by recommending compounded supplements manufactured to specification under strict Good Manufacturing Practices.

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Mortality, Nutrition & Supplements | No Comments »

IGF-1 vs CA & Mortality

July 7th, 2010

Hot off the presses. 2 studies re GH were just released earlier today. Both support my Goldilocks theory about medicine: you want levels just right, not too high & not too low.

In one prospective cohort study, the authors followed 1,273 subjects for 11.6yrs and noted an increase in all-cause & CVD mortality in those whose IGF-1 was either in the lowest quintile (avg 7.3nmol/L) or the highest (21.4nmol/L) compared to the middle (13.5nmol/L). And notably, there was not association btwn IGF-1 & CA mortality. However, there was also a significant age differential w/avg 78.3yo in lowest quintile compared to 74.3yo in milddle & 72.0yo in highest quintile IGF-1. As I discussed during last month’s journal club, laboratory technique does matter and different equipment leads to different reference ranges, in this case 11-19nmol/L for both men & women 60-70yo. So being outside, whether too high or too low, of the age-appropriate reference range actually portends bad things!

The second study, a further (case-control) analysis of the Pfizer International Metabolic Database (KIMS) of adults receiving GH for GHD demonstrated no association btwn IGF-1 targeted to normal age-appropriate reference ranges and development of CA. Granted only 100 cases after 2yrs were matched to 325 controls but I would posit that the most interesting finding was a linkage btwn high IGFBP-3 and CA whereas previous studies had demonstrated the inverse. We’ll need to see what else comes of this in the future. But certainly, we should not fear bringing an AGHD pt’s IGF-1 into the middle of his/her age-appropriate reference range.

In summary, these two studies support the safety of optimizing IGF-1 as a measure of GHD to the middle of the age-appropriate reference range – remember Goldilocks! The days of pushing IGF-1 to 200-300 and higher regardless of the lab’s reference range are over.

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Cancer, Growth Hormone, Mortality | No Comments »

Telomeres & CA

July 6th, 2010

Over and over again, we have to be very careful not to confuse association w/causation. However, there are times when the association is so strong and there are no downsides that I can’t help but push. For instance, I’ve posted several editorials over the last 3 years on how longer telomeres have been associated w/MVI, vitamin D, physical activity (twice), IGF-1/hGH, fish oil & diet (see Categories at right for complete listing) and vice versa. Yes, we need to be careful since conventional wisdom might posit that CA cells should have substantially longer telomeres to insure their immortal lifespan.

So it comes with a sigh of relief that authors will report tomorrow that they followed 787 subjects avg 62yo free of CA at baseline for 13+yrs and noted an increase risk of CA (mortality) w/shorter telomeres. Divided into tertiles, those in the highest/longest tertile had telomeres 3x those in the lowest/shortest tertile. Consistent w/previous studies, telomere length was also statistically associated w/physical activity and vitamin D. Two new associations w/short telomeres were DM and chronic infxn/high CRP.

What’s the take home message? Do everything you can to maintain long telomeres, not only to maximize life span but also to minimize CA risk & mortality. After all, what’s the downside to telling our patients to take a MVI, get some extra vitamin D, get/stay physically active, get some fish oil and/or eat fish, and follow a low glycemic Mediterranean diet more closely.

In case you’re wondering, there are now available commercial means to check telomere length. The bigger question is whether or not we should do so. I’ll leave that answer to people far smarter than me. I suspect that we’ll need to individualize the answer (as always do).

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Cancer, Telomeres | 1 Comment »

Rosiglitazone vs Pioglitazone: First, Do No Harm

July 4th, 2010

I trust that you’ve all celebrated a wonderful & safe Independence Day w/your family & friends. Earlier this evening as I was watching my children and many others light off fireworks, I was reminded of the phrase “Primum non nocere” oft attributed variously to Hippocrates & Galen. After all, there are safe and less safe fireworks as demonstrated unfortunately by a NY man who lost his arm to fireworks-related injury earlier today.

I mention this b/c we’ve had available to us for several years rosiglitazone and pioglitazone to control diabetes. Over the last several years, several systematic reviews and meta-analyses have reported an increase risk of adverse events associated w/rosiglitazone vs pioglitazone. Of course the manufacturer has spun these publications as inadequate w/o gold standard proof via randomized double blind placebo controlled studies.

So please realize that I make the following statement w/o prejudice or influence by direct stock ownership of (other than via mutual funds), or receipt of remuneration from, either pharmaceutical company. Whether you believe in the inherent goodness & safety of rosiglitazone, it’s difficult for me to choose a drug under suspicion without clear clinical benefit over its competitor, pioglitazone, for which there is less harm associated with its use. Granted both/all TZDs have now been associated w/incr risk of fx compared to use of a biguanide or sulfonylurea. However, all systematic reviews & meta-analyses studies point to an increase risk of negative CV outcomes in association w/rosiglitazone when compared to use of pioglitazone.

So I would suggest that should our patients require a TZD that we strongly consider pioglitazone over rosiglitazone after we discuss how to minimize an increase risk of osteoporotic fx.

Rosiglitazone vs Pioglitazone re MI, CVA & Death 6-10
Rosiglitazone vs Pioglitazone re MI, CVA & Death 6-10 (editorial)
Rosiglitazone vs CV Events 8-09
Rosiglitazone vs CV Outcomes (RECORD) 6-09
Rosiglitazone vs CV Outcomes in Elderly DM 11-08

TZD vs Fx Risk in T2DM 2-10
TZD vs Fx Risk in Older T2DM 8-09
TZD vs Fx Risk in T2DM 1-09
TZD vs Fx Risk in T2DM 1-09 (editorial)

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Heart Disease, Heart Failure, Osteoporosis & Fractures, T2DM | No Comments »

Is TOM the male equivalent of WHI?

June 30th, 2010

Wow! I’ve commented multiple times on how our view of various supplements & foodstuffs depends upon the prevailing study, alternating good w/bad w/good again. However, I never expected to see a negative study regarding testosterone supplementation.

TOM is the Testosterone in Older Men w/Mobility Limitations trial, a randomized placebo controlled double blind study that enrolled 209 community dwelling men avg 74yo from 9/05 to 12/09 when it was stopped prematurely b/c excess adverse events. To qualify, these men had to be >65yo w/Total T 100-350ng/dL or calculated Free T <50ng/mL who had difficulty walking 2 blocks on level surface or climbing 10 steps. They were allowed to have many common comorbidities but excluded if these were considered severe or uncontrolled.

They were randomized to placebo gel or 100mg transdermal T gel applied daily x 12wks followed by 12wks’ observation off regimen. The dose was adjusted up to 15mg if repeat levels were less than 500ng/dL and down to 5mg if repeat levels were greater than 1000ng/dL. In other words, the authors took men w/avg Total T 250+/-57ng/dL & Free T 48+/-12pg/mL and achieved avg Total T 574+/-403ng/dL in those randomized to T gel after adjustment to achieve target range. Those randomized to placebo ended up w/292+/-160ng/dL.

Despite equivalent CV risk profiles, those randomized to T gel sustained more CV and other adverse events at 6, 12, 18, 24, and 36wks post-randomization. Now, the statistics are beyond me so I’ve attached the appendix for your review. But several points come to mind. First, I should point out that some of those randomized to T gel ended up w/less Total T than they started with if you look at the SD+/-403ng/dL. Perhaps the men who had adverse events were those who had lower Total T levels although I couldn’t discern this from the study or its appendix.

Second, the authors wanted 252 men for the study but enrollment was stopped prematurely when the trial was stopped (obviously). Third, only 176 men were available for efficacy analysis after completing 12wks therapy. Fourth, while the study size was larger than others in the past, TOM is still considered small and the number of adverse events was small. Similar to an article/editorial published 2d ago re JUPITER, studies that are stopped early tend to overestimate treatment differences. Moreover, due to the diversity of the adverse events, the lack of a consistent pattern in said events, and the overall small number of events, the authors did not exclude chance as an explanation.

Why do I consider TOM to be the male equivalent of WHI? Not only b/c of its negative findings but b/c we’re usually offering T to men <65yo w/less severe mobility issues. So do these findings, if real, really apply to our typical demographic?

Lastly, I would also direct your attention to similar study published earlier this year of older hypogonadal frail men who received significant improvement in body composition, QoL & physical fxn from T gel w/o adverse events – see my 1/11/10 post for details.

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Heart Disease, Testosterone | 3 Comments »

Stroke: What Can We Do to Prevent One?

June 28th, 2010

What’s the worse thing that’s going to happen sometime in our lifetime? Besides taxes, I mean! I hate to be morbid and depressing but I figure we all have to die at some point since no one’s conquered immortality as much as some might argue that we’ll soon be able to replace worn out organs like we currently do w/our clothes. From my perspective, one of the worse things is to have a stroke (I’m hoping that if I become demented I won’t know about it!) which would impact both me and my family (while dementia would really only impact my family as far as I’m concerned).

So what can we do to prevent strokes, both ischemic & hemorrhagic? The authors of INTERSTROKE, a 22 country case-control study, closely analyzed 2,337 patients w/ischemic CVA, 663 w/hemorrhagic CVA, and 3,000 controls. Not surprisingly, the same issues that we discuss w/our patients regularly also impact CVA risk, eg HTN, smoking, waist-to-hip ratio, nutrition, physical activity & DM, amongst others. Excess EtOH consumption, stress/depression, cardiac issues, and ApoB:ApoA were also associated w/CVA risk.

Interestingly, while WHR was correlated to CVA risk, body mass index didn’t matter. Cardiac issues included atrial fibrillation (as expected), previous MI, rheumatic valvular disease & prosthetic valve replacement (the latter 2 being associated w/thromboembolic phenomenon if not adequately anticoagulated).

In summary, these 10 factors, all essentially under our control, accounted for 90% CVA risk. By focusing our efforts on reducing blood pressure & smoking while promoting low glycemic nutrition & regular physical activity, we could make tremendous strides towards maximizing our independence and functionality as we age.

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in 1o Prevention, CVA & TIA | No Comments »

Estrogen & Progesterone in Menopausse

June 22nd, 2010

You’ve come a long way, baby! Prior to July 2002, primary care physicians & gynecologists were ready to put CEE+MPA in the water for perimenopausal & postmenopausal women. Moreover, besides choosing btwn cyclic vs continuous regimens, there was really no individualization of dose. Every women was given 0.625mg CEE +/- MPA. As we’re all too aware, with the publication of WHI, we turned our collective backs on all the observational studies extant and essentially threw out the baby along w/the bath water even tho WHI studied a different group of women than those for whom we normally give hormone (replacement) therapy.

So here we are, just a month shy of the 8th anniversary of WHI, and reason has returned to our colleagues as demonstrated by this prepublication release of the Endocrine Society’s scientific statement on postmenopausal hormone therapy. As we know, level A evidence demonstrates that HT improves vasomotor instability & urogenital s/sxs. It also improves bone mass and decreases colon CA risk. Level A evidence only supports increase in mammographic density but no increase risk of breast CA. And physiologic amounts of transdermal testosterone improves sexual function. HT increases risk of thromboembolic events (but don’t forget to look over my 2/13/08 & 2/20/08 posts) and doesn’t improve cognition when initiated after 60yo while E alone w/o P increases risk of endometrial CA. So yes, we have to take the bad along w/the good.

Level B evidence shows that E as well as E+P is associated w/decr risk of T2DM plus less wt gain. E appears to protect against OA while improving QoL. Cyclic E+P has lower risk of endometrial CA compared to E alone but not nearly as low as continuous E+P. HT is associated w/40% lower mortality when started in women <60yo or within 10yrs of menopause onset. Basic science, animal models & observation studies all point towards HT preventing CAD & reducing CV events. Contradictory results in WHI resulted from starting HT in older women too many yrs after menopause onset! Level B evidence does demonstrate increase risk of breast CA from E but it’s complicated (read the complete statement for details). Starting E at surgical menopause improves memory but after 65yo increases risk of dementia (window of opportunity theory). Standard dose HT may increase CVA risk but again review my 5/8/08 post comparing oral to transdermal E especially b/c level C evidence shows low dose HT does not increase CVA risk.

Is the data clearcut? No, it never is. However, this statement gives a reasonably balanced interpretation of the evidence as it currently exists and is worthy of your time to review. Hopefully, you can then offer your patients & colleagues a more balanced and scientifically rigorous recommendation.

Disclaimer:

Every effort has been made to credit appropriate sources. Readers’ comments and opinions are welcomed and topic suggestions may be submitted for consideration. Given the significant amount of literature available, your topic, if chosen, may appear online within a reasonable time frame as I cannot guarantee immediate posting. While I am a Senior Institute Physician at the Cenegenics Medical Institute, my editorials and newsletter posts reflect my personally deranged views on studies and research, which may or may not reflect Cenegenics Medical Institute’s.

Posted in Estrogen +/- Progestogen, Women | No Comments »

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