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.”