Richard Lehman’s journal review—14 January 2013

Richard LehmanJAMA  9 Jan 2013  Vol 309
155    We know in our bones that vitamin D is important, and we even have a rough idea of the blood levels that are needed to keep our bones healthy. Pretty well everything else about vitamin D is still subject to speculation and investigation, and so many claims have been made about it that it will take at least a decade to unravel them all (and for those who like to collect meaningless terms, vitamin D was declared “nutrient of the decade” in 2008). Somebody must have suggested that vitamin D deficiency causes osteoarthritis, and this study seeks to test that hypothesis by giving people with knee osteoarthritis extra vitamin D for 2 years at a dose sufficient to elevate 25-hydroxyvitamin D plasma levels to higher than 36 ng/mL to see if it makes any difference to knee pain or cartilage loss. It doesn’t. But true vitamin D believers will argue that this is too little too late. And so on. Expect many more vitamin D stories in reviews to come, because I actually think they are quite interesting.

NEJM  10 Jan 2013  Vol 368
100    Nearly a fifth of medical patients admitted to hospital are back in again within 30 days. The remarkable thing is that in most cases it is for something other than the condition that triggered their first admission. So for instance if you are a Medicare patient discharged with a diagnosis of “heart failure,” and readmitted within 30 days, there is only a 37% chance you will be given the same label second time round. In this ground breaking analysis, Harlan Krumholz suggests that this is because a lot of patients discharged from hospital are suffering from post hospital syndrome, a condition of generalised debility and added risk largely brought about by the hospital admission itself. Lots more research, please, and let it be done so quickly and so well that by the time my turn comes, hospitals may have become humane and health enhancing places even for crumbly old people.

107    Every Icelander has had complete genome sequencing, and 0.63% of Icelanders over 85 carry a variant form of TREM2 which is associated with a 2-4 fold increased risk of Alzheimer’s disease. This was confirmed by replication tests using case control series from the United States, Norway, the Netherlands, and Germany. It’s also confirmed by a British study. These admirable, assiduous researchers wish to believe that some day this will improve our understanding of the mechanisms of Alzheimer’s disease and how to prevent it. I hope they are right, or the medical research community would be spending an awful lot of money and effort for very little return.

128    When I did my London gynaecology job in 1976, I worked with five consultants and six registrars, all of them male. In those days the typical representative of this specialty was a haughty misogynist who performed a swift bimanual examination in the semi-public arena of the outpatient clinic, and then usually announced to some onlooker that he was listing this woman for dilatation and curettage. The duchesses he rushed off to see on Harley Street no doubt got a nicer couch and a more fawning manner. When D&C was conclusively proved to be a useless procedure, gynaecologists needed an alternative treatment for menorrhagia, and for over a decade the levonorgestrel releasing intrauterine system (levonorgestrel-IUS) has become a popular procedure with doctors. It is often less so with patients, who go through periods of worsening (or worsening of periods) before they see any benefit. I’m surprised that it has taken till now to conduct a big trial of the IUS versus medical therapy in primary care. The levonorgestrel releasing device gives better results at two years. (Note for medical linguists: the word “elute” does not yet seem to have travelled from the coronary arteries to the uterus).

138   The treatment of advanced, castration-resistant prostate cancer is a specialist area, but it’s one of potential interest to every ageing male and every generalist, since this is such a common way for men to end their days. I get the impression that progress is being made, albeit in the clunky, incremental way that we have come to accept over decades of cancer research. Last September I was unusually impressed by a trial of the novel androgen receptor blocker enzalutamide, and here is a promising new trial of the androgen synthesis inhibitor abiraterone. Initially this was a blinded trial against prednisone alone in these advanced disease patients, but it was opened up once enough evidence had come in of a halving of disease progression time with abiraterone. So what’s the next step? Probably both a trial comparing abiraterone with enzalutamide and a trial combining it with enzalutamide.

149   Vitamin D may be the vitamin to swank with this decade, but vitamin B12 was swanky ten years ago and is still important, and here is a clinical review to bring you up to date. Among British GPs, my old work partner Harold Hin has tried to sort the practical issues surrounding both these vitamins in primary care. With B12, a major problem is to know what you should measure. Serum B12 assays measure all the circulating cobalamin, but the stuff that matters is the bound vitamin, called holotranscobalamin, and if you don’t have enough of it, you produce a lot of methylmalonic acid. The problem is to know your way around the assays and what they may mean. And it is insufficient merely to try out some B12 injections on people with borderline low levels, because the red liquid has magical effects on some patients. I think most GPs will know of people who demand a shot every 3 weeks despite having attained astronomical serum B12 levels. I have often been tempted to try some myself.

Lancet  12 Jan 2013  Vol 381
117   A once weekly injection to control blood sugar levels and help you lose weight—what’s not to like, if you are an overweight patient with type 2 diabetes? Well, the complete absence of long term data about safety and benefit, for a start. And then there’s the cost, hidden from NHS patients but a real consideration nonetheless. And the fact that this trial shows that once weekly exenatide produces a lesser drop in HbA1c than daily liraglutide. This is perhaps a mild embarrassment for the manufacturers of exenatide, Eli Lilly and Amylin, who sponsored this trial (they have since fallen out with each other)—but my guess is that The Lancet will still make a lot of money from selling reprints for use by drug reps who will emphasise the smallness of the difference in comparison with the greater convenience of once weekly administration. Perhaps they will even sell some copies to Novo Nordisk who sell liraglutide. This study is a classic illustration of all that is wrong with current drug trials. “The sponsors of the study took part in study design; protocol development; data collection, review, and analysis; and writing of the report.” They went to 105 sites in 19 countries to collect fewer than a thousand patients with the very common condition of inadequately controlled type 2 diabetes: a bad way to conduct a tight trial but a good way to put your drug into the hands of lots of opinion leading clinicians. It was an open label study and lasted 26 weeks in a condition where treatment is commonly life long. The fact is that no drugs in this class should ever have been licensed for use in patients: outside this cosy short term study, there are signals of thyroid and pancreatic cancer risk both from animal and human studies of GLP-1 agonists, and there is no current evidence that they reduce any of the long term effects of diabetes. Nothing has been learnt from the case of rosiglitazone (Avandia). We are still letting down patients with diabetes by giving them drugs we know far too little about.

133   By contrast, the summary of this paper from the Million Women Study tells you all you need to know about the drug of addiction which brings in the largest amount of tax revenue: “Among UK women, two thirds of all deaths of smokers in their 50s, 60s, and 70s are caused by smoking; smokers lose at least 10 years of lifespan. Although the hazards of smoking until age 40 years and then stopping are substantial, the hazards of continuing are ten times greater. Stopping before age 40 years (and preferably well before age 40 years) avoids more than 90% of the excess mortality caused by continuing smoking; stopping before age 30 years avoids more than 97% of it.” We should do all we can to encourage smoking: not only does it bring in revenue for the NHS, but it could also massively reduce the number of elderly women blocking beds that could be used to bring visitors into the UK for lucrative elective surgery.

153   And in men, smoking causes not only death but erectile dysfunction, and so may help to stop the spread of sexually transmitted diseases. Here is a very comprehensive review. The coming of the phosphodiesterase inhibitors has not solved all the problems of this condition, and I think that as Viagra comes off patent this year, pharmaceutical companies will need to stiffen their resolve to find better drugs and maintain market penetration. There is even an ongoing trial of zotarolimus–eluting stents for pudendal artery stenosis. (Note for medical linguists: this shows that although the word “elute” may not have reached the uterus, it is coming perilously close to the male genitals).

BMJ  12 Jan 2013  Vol 346
A magnificent editorial led by Iain Chalmers calls for all trials to be registered and the results published. Look back over more than 20 years and you’ll find several magnificent pieces by Iain Chalmers calling for all trials to be registered and the results published. It is amazing and scandalous that in 2012 people can still do human experiments and then fail to disclose the results. So much so that I can’t fully believe it myself: yet it’s not just true but applies to half of trials here and now. Make it a thing of the past by signing the petition at

And even when randomized trials are reported in reputable journals, all you will get is a tiny selection of the data—though this no longer applies to the BMJ and to the open access journals.

“I had an excellent repast—the best repast possible—which consisted simply of boiled eggs and bread and butter. It was the quality of these simple ingredients that made the occasion memorable. The eggs were so good that I am ashamed to say how many of them I consumed ….It might seem that an egg which has succeeded in being fresh has done all that can be reasonably expected of it.” Henry James here expresses himself soundly on the question of eggs, though many would argue that scrambled eggs are even better, since they incorporate larger amounts of butter. Nor should one’s egg consumption be confined to those of the hen. Most birds and fish produce eggs which are perfectly delicious, and seagull eggs combine the qualities of both. As for the fabled eggs of the sea-urchin, however, these are not eggs at all, but the delicious gonads of the spiny creatures. By contrast, the eggs of snails and slugs, while attractive, are for the most part insipid and earthy. Why anyone should be troubled by the consumption of eggs as a medical issue, I cannot imagine, but this dose-response meta-analysis of the subject simply reinforces my advice to eat lots of eggs. They do not increase your risk of stroke or coronary disease, but even if they did, it would simply be a good reason to eat as many as you can while you still have the chance.

Plant of the Week: Daphne bholua Jacqueline Postill

My annual hymn of praise to this goddess among plants must be shorter than usual this year. The specimen that used to reach above our heads and sent waves of heavenly fragrance over our front path has, alas, died as a result of wounds from three winters ago. We now have a small replacement in a more sheltered passage at the back of the house. The big shrub would generally break flower before Christmas and go on flowering till late March. Her little successor is just coming into flower now.

This is by far the best shrub for winter scent and beauty, but there are a number of smaller daphne hybrids which also manage to produce fragrant flowers in mid winter. In our garden, both “Eternal Fragrance” and “Beulah Cross” are sporting a few scented petals among their shapely domes of evergreen leaf.