New Pharmacologic Direction for Parkinson’s Disease

SOURCE: Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: A randomised, double-blind, placebo-controlled trial. Lancet 2017;390:1664-1675

Most clinicians are used to thinking about dopamine modulation when considering treatments for Parkinson’s disease. Unfortunately, none of the current treatments can be designated as disease-modifying, even though such treatment provides transient symptomatic relief.

Current use of a glucagon-like peptide-1 receptor agonist (GLP-1RA) is limited to the management of type 2 diabetes. From where did the idea emerge that GLP-1RA might benefit Parkinson’s patients?

The authors of studies about Parkinson’s based on animal models have noted that a GLP-1RA not only crosses the blood-brain barrier, but produces sufficient neuroprotective and neurorestorative effects to improve motor function and memory. Investigators who conducted a subsequent open-label, one-year pilot trial of exenatide in humans with Parkinson’s disease found favorable effects that endured for an additional 12 months post-treatment.

Based on these early successes, Athauda et al performed a randomized, double-blind, placebo-controlled trial of exenatide administered in weekly, subcutaneous, 2 mg doses (n = 62) for 48 weeks added to whatever current regimen study participants were receiving. The primary outcome was the motor performance subscale of a Parkinson’s disease rating scale, measured 12 weeks after discontinuing exenatide treatment. Motor function improvements were demonstrated in exenatide-treated patients, whereas investigators noted deterioration in placebo patients. Larger, longer-term studies will be needed before GLP-1RA treatment could be confirmed as an appropriate consideration for Parkinson’s patients.

CV Benefits of GLP-1RA Treatment in Type 2 Diabetes

SOURCE: Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228-1239.

Only in the last several years have randomized, clinical trials confirmed a cardiovascular (CV) benefit from glycemic control. To date, sodium-glucose cotransporter 2 (SGLT-2) inhibitors (canagliflozin, empagliflozin), glucagon-like peptide-1 receptor agonist (GLP-1RA; liraglutide, semaglutide), and bromocriptine have demonstrated CV risk reduction convincingly.

Among the SGLT-2 inhibitor and GLP-1RA classes of pharmacotherapy, there appears to be much more similarity than not. Should clinicians consider these salubrious CV effects a class effect? That is, should all members of the class be anticipated to experience similarly favorable CV outcomes?

The authors of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial randomized type 2 diabetics (n = 14,752) to either 2 mg of the GLP-1RA exenatide or placebo added to whatever ongoing diabetes regimen they already were receiving. The mean baseline A1c was 8.0%, and > 70% of participants presented with pre-existing CV disease.

After 3.2 years (mean) of intervention, exenatide failed to demonstrate a statistically significant improvement in the composite CV endpoint vs. placebo. Although all the answers are not known, the EXSCEL trial suggests there might be important differences among the class of GLP-1RA in reference to cardiovascular outcomes. Is it a class effect? Maybe not.

Morphine in Dyspneic Acute Heart Failure

SOURCE: Miró Ò, Gil V, Martín-Sánchez FJ, et al. Morphine use in the ED and outcomes of patients with acute heart failure: A propensity score-matching analysis based on the EAHFE Registry. Chest 2017;152:821-832.

Patients who experience acute heart failure (aHF) often are burdened with distressing dyspnea and its concomitant heightening of anxiety. Historically, clinicians have used morphine in these situations.

These decisions have been based on physiologic effects, such as preload and afterload reduction, as well as putative central nervous system effects, including reduced anxiety, breathlessness, and pain.

Unfortunately, morphine use in such settings is neither adequately supported nor refuted by clinical trial data.

Miró et al reviewed the data on a large population of aHF patients between 2011 and 2014 (n = 6,516). Investigators compared persons who received IV morphine within three hours of admission to an emergency department to those who did not.

From this larger population of aHF patients, a subgroup who could be matched for a wide variety of other variables was selected for analysis (n = 550). Patients treated with morphine demonstrated a hazard ratio for 30-day mortality of 1.66.

The authors suggested that based on these data, clinicians should avoid morphine use in aHF patients.