October 7th, 2013

Selections from Richard Lehman’s Literature Review: October 7th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

NEJM  3 Oct 2013  Vol 369

Saxagliptin and CV Outcomes in Patients with Type 2 Diabetes (pg. 1317): We definitely need better drugs to provide better outcomes in type 2 diabetes. But the pharmaceutical industry argues that so long as they can reduce HbA1c, their new products should be licensed for use on millions of people, and the hard outcomes can be collected later. And so it has been with dipeptidyl peptidase 4 (DPP-4) inhibitors saxagliptin and alogliptin. These drugs have been prescribed to hundreds of thousands of patients who were never told, “Actually, we have no idea what this stuff may do to you in the long term, but it will probably lower your blood sugar in the short term.” Well, now we know a bit more, because saxagliptin has been tested on 16 492 people with diabetes who are at high cardiovascular risk. In just over two years, it made no difference to their cardiovascular outcomes except admissions for heart failure, which were higher in the saxagliptin group. Moreover, the incidence of hypoglycaemia was higher than expected, in a group of drugs which is supposed to be relatively free of this risk. And the reduction in HbA1c was a measly 0.3%.

Alogliptin after ACS in Patients with Type 2 Diabetes (pg. 1327): At the same time, the rival agent alogliptin was undergoing a randomised double-blinded trial against placebo in diabetic patients who had recently had myocardial infarction. Good: the open-label methodology of the RECORD trial of rosiglitazone was not repeated here, even though the manufacturer had tight control over both the data collection and the write-up of this paper. A total of 5380 patients were followed up for 18 months and there was no difference in cardiovascular events. Nor was there an excess of pancreatic events in this and the previous trial, but it is too soon to relax vigilance: any increase in cancer would take much longer to show up.

The CV Safety of Diabetes Drugs — Insights from the Rosiglitazone Experience (pg. 1285): There is no ordinary editorial about these trials in the NEJM, but instead a Perspective at the beginning of the journal which is free for all to access, “The Cardiovascular Safety of Diabetes Drugs — Insights from the Rosiglitazone Experience.” Two of the three authors declare payments from NovoNordisk. They say that, “It is disappointing that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. Thus the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.” Indeed; we’ve known that for five years. Nice to see the message is getting through. But earlier in the same piece they say that the new trials (and the RECORD trial!) show that the FDA is creating unnecessary work for itself and industry by insisting on trials to demonstrate cardiovascular safety before licensing drugs for diabetes. Pardon? The FDA “safety” margin indicates that diabetes drugs could be licensed if they show less than an 80% increase in CV events—is that too tight? For drugs that are meant to reduce CV risk in a high risk condition? Words fail me. What on earth are these drugs meant to achieve then? The answer comes in the saxagliptin paper: “Numerous studies, even those involving patients with advanced cardiovascular disease, have shown that improved glycemic control reduces microvascular complications.” But is this actually true? The evidence relating glycaemic control to real microvascular end-points, such as serious visual loss and end-stage renal failure, is very patchy, and involves numbers-needed-to-treat running into hundreds, with confidence intervals reaching infinity. The whole treat-the-sugar paradigm is wrong.

JAMA  2 Oct 2013  Vol 310

Menopausal HT and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials (pg. 1353):  The Women’s Health Initiative is often cited as the prime example of a big randomised trial which demonstrated harm after the observational evidence had suggested benefit. Women randomised to receive conjugated equine oestrogens (CEE) had worse cardiovascular and cancer outcomes than those randomised to placebo. Red-faced doctors (myself included) had to eat our encouraging words and advise droves of patients to come off hormone replacement therapy. A lot of the ladies then had red faces as their flushes returned, and nobody was very happy. And half of them were not taking CEE anyway, but oestradiol-based preparations, which for all we know may have a quite different balance of harms and benefits. Here, free to the world, is a follow-up report from the WHI. “Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.” Methinks they generalise too much. How about a rerun of WHI using different a different oestrogen? Or a risk/benefit chart so women can decide for themselves?

BMJ  5 Oct 2013  Vol 247

Effect of Smoking on Comparative Efficacy of Antiplatelet Agents: Clopidogrel was a massive earner for its manufacturer while its patent lasted, but like so many drugs which have cost health systems billions in long-term treatment, it may not actually do that much for most people who take it. A meta-analysis of nine trials in patients with established cardiovascular disease, the effect of clopidogrel was highly dependent on smoking status. Those who smoked showed a 25% reduction in a composite outcome of cardiovascular death, myocardial infarction or stroke, compared with a reduction of 8% in non-smokers. This may also apply to the newer agents ticagrelor and prasugrel, though with less certainty.

Association Between BMI and CV Disease Mortality in East Asians and South Asians: It has been said that the recommended limits of body mass index should be set lower for people of South Asian origin, because they store fat differently. But this study which pooled data from 20 prospective cohort studies was able to look at 3893 deaths in people from India and Bangladesh and was only able to identify a significant rise in cardiovascular deaths at a BMI level of 35 and above. This contrasts with people from further east (China, Taiwan, Singapore, Japan, and Korea) where the rise begins at a BMI of 25. In the “Far East” people really do seem to carry the “thrifty genotype.”

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