Richard Lehman’s journal review—7 September 2015

richard_lehmanNEJM  3 Sep 2015  Vol 373

895   The cool new look is beige and fat. Understanding beige fat may be the beginning of the end of obesity in humans. Or it may disappear and be forgotten as soon as the next panacea offers itself on the pharma catwalk. The NEJM clearly thinks it is important, since it has made the full text of the study free and more importantly the editorial, which explains the basic genomics and how changes in fat type might govern metabolism. It’s not an especially easy read, but now that the nights are drawing in I commend it to your attention. In large genomewide association studies, the strongest genetic signal related to body weight has been in the FTO locus. Now, although this locus appears to have nothing directly to do with cellular protein synthesis, twiddling with some of its alleles in mice seems to change white adipocytes into beige ones or the other way round, with profound effects on how much energy is stored or lost as heat. “The creation of a knock-in mouse with high-risk FTO alleles should facilitate the determination of the contribution of these gene variants to obesity.” About 5% of mouse research ever leads to anything applicable to humans, and then any intervention has to be tested through stages 1-3, each taking a year or two (or ten if you want a reasonable idea of safety). Don’t watch this space. Leave it to the gene gnomes and the lab rats for a while yet.

908   The NEJM seems in an impatient mood this week. There are no randomised trials in its pages, just a couple of small early phase studies of imetelstat, a telomerase inhibitor. I once read that telomeres are to strands of DNA like the shiny things at the end of shoelaces: they stop them unravelling. Since that moment I have affected to understand telomeres. You mess with them at your peril. In a study of 33 patients with myelofibrosis, “imetelstat was found to be active . . . but also had the potential to cause clinically significant myelosuppression.”

In the next trial, there were just 18 participants, although it classes itself as a phase 2 trial. They all had essential thrombocythaemia. “Rapid and durable hematologic and molecular responses were observed in patients with essential thrombocythemia who received imetelstat. (Funded by Geron).” So are these trials meant to help the fast tracking of Geron’s product on a “treat now, worry about harms later” basis? I don’t know. Watch this space if you’re a haematologist or a pharmascold.

929   Had the late Oliver Sacks been a cardiologist rather than a neurologist, he would undoubtedly have written about takotsubo cardiomyopathy, a condition in which the heart balloons out acutely and stops pumping properly. It has all the right elements for a Sacks chapter: it’s a poorly understood, dramatic, slightly freakish, stress related, and in some cases seemingly psychogenic condition, replete with possibilities for mind-body theorising and ingenious suggestions for interventions. The International Takotsubo Registry, a consortium of 26 centres in Europe and the United States, has succeeded in collecting 1750 patients with the diagnosis, with a mean age of 67. It does not bode well for those who have it. During long term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year.

JAMA  1 Sep 2015  Vol 314

884   Here’s a little test of clinical knowledge and logic. Consider the following statement: “In diabetes, the presence of albuminuria predicts progression to renal failure; therefore a drug which reduces albuminuria is likely to reduce renal failure in diabetes.” I’ve invented this statement because it seems to be the rationale behind a series of trials of mineralocorticoid receptor blockers in diabetes. But almost nothing in it is true and its logic is upside down. Albuminuria in people with type 2 diabetes (itself a dubious category) is highly variable and is rarely a precursor for end stage renal disease. Reduction of albuminuria is not a valid surrogate for anything. For example, in a previous trial in people with T2DM and microalbuminuria, the mineralocorticoid receptor blocker olmesartan reduced albumin excretion but worsened cardiovascular outcomes. This trial of finerenone was different in that it recruited people with much higher albumin output and worse renal function who were already on an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. You may have guessed from its name that finerenone, like spironolactone and eplerenone, is an aldosterone antagonist. Compared with placebo, this drug achieved a dose related improvement in the urinary albumin-creatinine ratio over a 90 day period. Was this trial useful? Was it even ethical to try this agent on 823 people at 148 sites in 23 countries, with just 94 in the placebo group, given the inability of this design to answer any clinically significant question? Why do journal editors even print this stuff? And is it ethical to sell reprints to the manufacturer, knowing they will be used for promotion?

895    The winter evenings would have to get very long indeed before I wanted to read a paper with the title Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. Population genomics chases fuzzy diagnostic category. Like watching paint dry, only without the useful outcome of something with dry paint on it. It’s free to all who want to read it.

OL   Q: What’s the similarity between a Vienna Philharmonic concert and a cardiology conference? A: You will see an awful lot of scores. Q: And what’s the difference? A: In the first everyone plays from the same scores so you get beautiful music, while at the other everyone shouts about their individual score so you just get noise. For heart failure alone, there’s a scores of scores. You can read my rather dreary chapter about them when our book “Heart Failure and Palliative Care” re-emerges as a new edition in a few weeks’ time. The CHA2DS2-VASc score came too late for inclusion in our masterpiece, but let’s not worry. As the authors say, “Predictive accuracy was modest, and the clinical utility of the CHA2DS2-VASc score in patients with HF remains to be determined.” Just like all the others then.

Ann Intern Med  1 Sep 2015  Vol 163

347    In case you needed more evidence, a northern Danish population case-control study shows that long term, continuous use of low dose aspirin and long term use of nonaspirin NSAIDs were associated with reduced colorectal cancer risk. But as usual they were unable to control for over the counter use. There seems to be some relation between the cyclooxygenase-2 selectivity of NSAIDs and their protective effect.

373   In the forthcoming hit lists of useless procedures that should be abandoned on the principle of Choosing Wisely, I hope the Academy of Medical Royal Colleges will include epidural corticosteroid injections for radiculopathy. A meta-analysis of the English language literature shows that these “were associated with immediate reductions in pain and function” (they mean reduction in pain and improvement in function), but at such a low level and for such a short time that they were clinically meaningless.

Lancet  5 Sep 2015  Vol 386

964   I’ve been fascinated by bariatric surgery ever since its first trials in type 2 diabetes. This Italian open-label trial recruited 60 people with T2DM and a BMI of 35 or more aged 30-60 and randomised them to bariatric surgery or medical treatment, and the article reports the five year follow-up. Outcomes—including cardiovascular events—were far better in those who had the surgery, which was either Roux-en-Y gastric bypass or biliopancreatic diversion. But to me the fascinating thing about all these trials is that improvement in glycaemia—often resulting in the “cure” of diabetes—did not correlate with the degree of weight loss following surgery. There is something else going on, and something very important to our understanding of what “T2DM” is all about.

OL   I seem to have taken a tetchy tone in the reviews this week, so let me make up by declaring that there has never been a more promising time in history for the health of human beings. And medical science can take some of the credit—a lot of it, in fact. Look at this gigantic survey of global, regional, and national disability adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990–2013. Overwhelmingly, the picture is positive. But it is never simple: “The notion of an epidemiological transition—in which increasing sociodemographic status brings structured change in disease burden—is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status.” And as people live longer, the demand for healthcare does not diminish. Also I can’t help putting in a final bit of tetch—the picture would be even better were it not for the follies of Bush-Blair geopolitics, which have combined with Islamist fanaticism to kill or displace millions of helpless people. And we urgently need to address the avoidable ignorance that is still rife within the science and practice of medicine.

The BMJ  5 Sep 2015  Vol

Of all the medical journals, I think The BMJ has the best record of tackling avoidable ignorance head on. Sometimes it does this in its research section, more often in its generally excellent education and debate features. Here’s some research about mental illness, challenging behaviour, and psychotropic drug prescribing in people with intellectual disability. In my decades as a GP, I was often astonished and humbled at the seemingly inexhaustible kindness and patience shown by the carers of these people, who often worked far beyond the hours for which they were paid (usually at or below the national minimum wage). This UK population based cohort study shows that “The proportion of people with intellectual disability who have been treated with psychotropic drugs far exceeds the proportion with recorded mental illness. Antipsychotics are often prescribed to people without recorded severe mental illness but who have a record of challenging behaviour.” I know that this is not a good thing. Sometimes it even amounts to abuse. But sometimes it amounts to a compromise forced by the reality of what can best be done for individuals given the level of care available. Sadly, this is not a simple issue.

My mother died of ovarian cancer, which probably started at the age that I am now. It wasn’t  diagnosed until it was causing ascites and urinary tract obstruction. I don’t in the least blame anyone for that, because if she had any earlier symptoms she would have put them aside in the effort of looking after my dad who was dying of heart failure. This excellent clinical review states that “In 80% of women the disease will be advanced at presentation, with a low five year survival rate; the all stage five year survival in the United Kingdom is 46%. This low survival rate in the UK has been recognised in the International Cancer Benchmarking Partnership and has been attributed at least partly to less timely diagnosis.” I remain to be convinced that earlier diagnosis is widely feasible, or that it will really make any difference to length of survival, other than through lead-time bias. But then I am a tetchy old codger.

Plant of the Week: Scabiosa columbaria var. ochroleuca

This is a lovely, late flowering perennial, which should be rife in every garden. I say rife because it spreads eagerly by seeding and every seedling comes true, carrying classy cut leaves and pale straw-yellow flowers, which are loved by bees. It is utterly hardy, it flowers for weeks, and if you don’t want its lovely offspring, you can easily pot them up and give them away. It is like a miniature and rather more beautiful version of Cephalaria gigantea, the great bee intoxicating yellow cornflower of late spring.

And if that doesn’t recommend it to you, nothing will.