ShortCuts-This Week in the Journals

September 29, 2008

250px-centralpark_20040520_121402_1_1504.jpgCommentary by Michael Tanner MD, Section Editor, Clinical Correlations

Stormy SEAS for Vytorin

This week the New England Journal published the Simvastatin and Ezetimibe in Aortic Stenosis  (SEAS) trial, whose findings had already been widely publicized in July.  The study compared ezetimibe 10/simvastatin 40 mg to placebo in 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. Why a trial of lipid lowering in aortic stenosis, a classically surgical disease?  Because hyperlipidemia has been suggested as a risk factor and some data suggest that statins may have a beneficial effect on calcific aortic stenosis.  SEAS found that ezetimibe/simvastatin did not reduce aortic-valve or ischemic events in patients with AS.  The combination (marketed as Vytorin by Merck) did reduce LDL cholesterol by an impressive 61%–from 140 to 53 mg/dL-over the 4 years of follow-up.  There were also fewer CABG procedures in the treatment group.  An unanticipated and unwelcome finding was that incident cancers were more frequent in the ezetimibe/simvastatin arm as compared with placebo (11.1% vs. 7.5%, p=0.01).  Combined analysis of the ongoing IMPROVE-IT and SHARP trials of ezetimibe/simvastatin do not support the cancer association.  This is the second major negative trial of ezetimibe/simvastatin this year.   The ENHANCE trial published in the NEJM in March found that simvastatin plus ezetimibe was no better than simvastatin alone at slowing the progression of carotid stenosis.   Carotid intima media thickness and aortic stenosis, however, are not the endpoints that concern us most when prescribing lipid-lowering drugs to our patients.  For me, these two trials do not spell the end of Vytorin, which is unquestionably a potent lowerer of LDL.  A large clinical end-point trial comparing simvastatin with ezetimibe/simvastatin in patients with hyperlipidemia should answer important morbidity and mortality questions in 2012.  Meanwhile, the Medical Letter recommends ezetimibe, niacin, or a bile acid sequestrant as drug number two in patients failing statins.

Premixed insulin analogues

Let’s say you have a type 2 diabetic taking two shots a day of Novolin 70/30 (70%NPH/30% regular).   You of course want the very best for her that insurance will allow.  Should you switch her from premixed human insulin to one of the premixed insulin analogues?  The Annals features a systematic review of the three commercially available insulin analogue mixtures:

70% insulin aspart protamine/30% insulin aspart (NovoLog Mix 70/30-Novo Nordisk)

75% insulin lispro protamine/25% insulin lispro (Humalog Mix 75/25–Lilly)

50% insulin lispro protamine/50% insulin lispro (Humalog Mix 50/50–Lilly)

The review makes many comparisons; I will just summarize how the analogues compare with glargine (Lantus) and the human insulin blends with regard to five surrogate endpoints:

Postprandial glucose level: analogues are better than glargine or premixed human insulin

Hemoglobin A1c level: better than glargine, similar to premixed human insulin

Fasting glucose level, weight: not as good as glargine, similar to premixed human insulin

Hypoglycemia: not as good as glargine or premixed human insulin

So, by switching your diabetic lady from Novolin 70/30 to Novolog Mix 70/30 you can expect similar A1c levels and improved postprandial glucose levels but with increased risk of hypoglycemia at twice the cost  ($95 versus $46 for a 10-milliliter, 1,000-unit vial).   


The LEAD-3 (Mono) study published early online by the Lancet is a head-to-head, unblinded trial of the new once-daily GLP-1 analogue liraglutide versus the oral sulfonylurea glimepiride.   The study randomized 746 type 2 diabetics to monotherapy with once-daily subcutaneous liraglutide 1.2 or 1.8 mg or once-daily oral glimepiride 8 milligrams.  Starting from an A1c of 8.3%, the liraglutide groups wound up with A1c reductions of 0.84% and 1.14%, respectively, over the course of the 52-week trial. Both liraglutide groups lost a little over 2 kilograms.  Liraglutide was superior to glimepiride in terms of A1c, weight loss, hypoglycemia, and blood pressure.  Liraglutide is similar to exenatide (Byetta): they are both injected incretin mimetics that work by stimulating insulin release, suppressing glucagon release, and inhibiting gastric emptying. The incidence of nausea in the liraglutide groups was 27% and 29%, less than the 36-51% reported in the exenatide trials.  Liraglutide will face competition from exenatide and exenatide LAR, the once-weekly version of Byetta, which is expected to come out in 2009.


Clinical practice guidelines for the management of impacted cerumen appear in the September issue of Otolaryngology–Head and Neck Surgery. Impacted cerumen is responsible for about 12 million patient visits and leads to 8 million removal procedures in the U.S. per year.  Earwax can hinder visualization of the tympanic membrane and lead to pain, hearing loss, and skeevy earbuds.  The guidelines state that acceptable interventions for wax removal include cerumenolytic agents, irrigation, and manual removal by a skilled practitioner.  Expert opinion recommends against the use of cotton-tipped swabs at home, “although the evidence against it is sparse.”

One comment on “ShortCuts-This Week in the Journals

  • Avatar of Marilyn Mann
    Marilyn Mann on

    Hi Dr. Tanner,

    I am not a physician, but I have been following the ezetimibe controversy because my teenage daughter, who has heterozygous familial hypercholesterolemia, was on it at one point (she’s now on atorvastatin). I hope you don’t mind my commenting on your blog.

    There was another editorial on SEAS published in the NEJM, by Thomas Fleming of the University of Washington. Here’s the link:

    Dr. Fleming is a well-known biostatistician, very respected. His interpretation of the data from IMPROVE-IT and SHARP is that a link to increased cancer mortality cannot be ruled out. Here are the last three paragraphs from his editorial:

    “Given the possibility that simvastatin–ezetimibe could have an effect on the rate of cancer-related deaths through a cancer-promoter mechanism, separate analyses should be performed for the end point of cancer-related mortality. Unfortunately, these two trials indicate an increase in the number of cancer-related deaths associated with active treatment, as compared with control therapy (97 vs. 72 deaths; approximate hazard ratio, 1.34; 95% CI, 0.98 to 1.84), indicating an increase in risk of 34%. Given this confidence interval, investigators cannot exclude a relative increase of as much as 84% in the risk of cancer-related death associated with the use of simvastatin–ezetimibe. Hence, there are clinically important increases in the risk of cancer-related death that are not ruled out by these data.

    The analyses of the IMPROVE-IT and SHARP trials raise additional important concerns. The interim nature of the data from these trials is problematic. As is frequently discussed,2,9 there is a serious risk of misinterpreting interim data as well as disturbing the integrity of ongoing trials through the release of interim data. Hence, access to interim data from ongoing trials such as IMPROVE-IT and SHARP should be restricted to data monitoring committees. Furthermore, without full access to peer-reviewed summaries of these data, it is not possible to determine the extent to which the two trials meet the list of above-mentioned performance standards for safety trials.

    Additional data are needed to adequately address the signal that simvastatin–ezetimibe is associated with an increased risk of death from cancer. Such data should be provided by completed randomized trials that have been prospectively designed and conducted to meet the performance standards for safety trials. Such confirmation is especially important in the case of agents, such as ezetimibe, for which there are safety signals of major illness or death and evidence of efficacy that is limited to documented effects on a biomarker.”

    Another analysis of SEAS that may interest you was published last week in Circulation: Cardiovascular Quality and Outcomes. Allen J. Taylor and Steven E. Nissen, Preliminary Observations From Preliminary Trial Results: Have We Finally Had Enough? Here’s the link:

    As discussed in the two editorials in the NEJM and in the paper by Taylor and Nissen, there is a biologically plausible explanation for the apparent increase in cancer risk with ezetimibe. Ezetimibe inhibits the absorption of phytosterols. There is some evidence that phytosterols have anti-cancer effects. The most recent review article is by Bradford and Awad, Phytosterols as anticancer compounds. Here’s the link:

    Best regards,

    Marilyn Mann

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