Clinical Briefs
Can You Make ‘Flat’ Basal Insulin ‘Flatter’?
SOURCE: Yki-Järvinen H, et al. New insulin glargine 300 units/mL vs glargine 100 units/mL in people with type 2 diabetes using oral agents and basal insulin: Glucose control and hypoglycemia in a 6-month randomized controlled trial (EDITION 2). Diabetes Care 2014;37:3235-3243.
One of the primary reasons for widespread clinician endorsement of newer basal insulins (i.e., glargine, determir) over NPH is the relative “flatness” of insulin levels with the former. The greater curve of NPH than newer basal insulins incurs greater risk for nocturnal hypoglycemia, which may become a limiting factor for insulin titration.
Glargine and detemir are generally regarded as “flat” basal insulins. Traditional glargine is supplied as 100 units/mL. Could there be an advantage to glargine 300 (300 units/mL)?
The EDITION 2 study was an open-label trial comparing traditional glargine (100 units/mL) with a new formulation of glargine (300 units/mL). The more concentrated insulin glargine-300 reportedly has smoother, more stable pharmacokinetics and pharmacodynamics than glargine-100, attributed to its extended release from the subcutaneous depot. Does glargine-300 offer any meaningful advantage?
In a 6-month trial comparing glargine-100 to glargine-300 in type 2 diabetes (n = 811), glargine-300 was similar in efficacy as far as A1c reduction goes, but there was a modest reduction in hypoglycemic events, including both severe hypoglycemia and any hypoglycemic event. Curiously, the dose of glargine-300 required for glycemic control was about 10% higher than that of glargine-100. A possible advantage of lesser hypoglycemia and smaller volume of injection with glargine-300 must be counterbalanced with the increased cost of the approximately 10% more glargine-300 needed to achieve the same degree of A1c reduction. For patients incurring problematic episodes of hypoglycemia, an insulin that provides even “flatter” plasma levels may provide an advantage.
Left Atrial Appendage Closure: Another Possible Interventional Fix for Atrial Fibrillation
SOURCE: Reddy VY, et al. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: A randomized clinical trial. JAMA 2014;312:1988-1998.
The most feared consequence of atrial fibrillation is stroke, which most commonly results from a thrombus generated in the left atrial appendage (LAA). Warfarin and novel anticoagulant agents are highly efficacious, reducing risk of stroke by as much as 66%, but warfarin requires close follow-up, and has a narrow therapeutic range. Though novel anticoagulants do not require monitoring, bleeding risk is still an important obstacle. If most atrial fibrillation-related strokes are due to thrombus formed in the LAA, might mechanical closure of the LAA prevent stroke and diminish or eliminate the need for anticoagulation?
Reddy et al report on the results of the PROTECT AF clinical trial, which randomized atrial fibrillation patients (n = 707) to LAA closure or “traditional” warfarin treatment (LAA closure patients did not receive warfarin).
The primary endpoint of the study was a composite of stroke, systemic embolism, or CV death. At a mean of 3.8 years of follow-up, LAA closure was found to be non-inferior to warfarin treatment, and the warfarin treatment group had been well managed (time in therapeutic range = 70%). LAA closure may be another reasonable option for reduction of stroke risk in atrial fibrillation.
A Glimmer of Hope for Beta-blockers in Heart Failure from Diastolic Dysfunction
SOURCE: Lund LH, et al. Association between use of ß-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA 2014;312:2008-2018.
Despite the consistent success of ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists in chronic heart failure from systolic dysfunction (s-CHF), trials of pharmacotherapy for chronic heart failure from diastolic dysfunction (d-CHF) have been disappointing. Modestly encouraging results for d-CHF were seen with candesartan (Atacand) in the CHARM-PRESERVED trial and nebivolol (Bystolic) in the SENIORS trial (for the d-CHF subgroup), but neither trial had strong enough outcomes to definitively establish a role in CHF.
Lund et al report on data obtained from national data registries in Sweden that included 19,083 patients with d-CHF (termed “heart failure with preserved ejection fraction” in this article). The registry (41,976 patients) allowed comparison of patients who had been treated with beta-blockers vs not by propensity scores. The primary outcome of the study was all-cause mortality.
Five-year survival in d-CHF was 7% higher in patients who were treated with beta-blockers. Because this data is observational in nature, it cannot definitively establish whether beta-blocker treatment reduces mortality in d-CHF, but it provides strong impetus to perform a large randomized trial to ultimately answer the question.
In this issue: flat basal insulin, another possible interventional fix for atrial fibrillation, and a glimmer of hope for beta-blockers in heart failure from diastolic dysfunction.
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