Comparing GLP-1 Agonists

SOURCE: Ahmann AJ, et al. Diabetes Care 2018;41:258-266.

There are more similarities than differences among the seven currently available glucagon-like peptide-1 (GLP-1) receptor agonists. The most recently FDA-approved GLP-1 receptor agonist, once-weekly semaglutide (Ozempic), was compared in a head-to-head trial to once-weekly exenatide-ER (Bydureon). In this open-label trial, adult subjects with type 2 diabetes (n = 813) taking one or more oral agents were randomized to receive either 1 mg/week of semaglutide or 2 mg/week of exenatide-ER. Subjects taking semaglutide underwent a titration from 0.25 mg/week for four weeks, then 0.5 mg/week for four weeks, and then 1.0 mg/week for the remainder of the trial; exenatide-ER subjects were started on 2.0 mg/week and maintained that dose throughout the trial. Baseline A1c was 8.3% in the exenatide group and 8.4% in the semaglutide group.

At the conclusion of the trial (56 weeks), the clinically meaningful differences in outcomes were the following: A1c was reduced by 1.5% with semaglutide vs. 0.9% with exenatide; weight declined 5.6 kg with semaglutide vs. 1.9 kg with exenatide; the fraction of subjects attaining an A1c < 7.0% was significantly greater with semaglutide (67% vs. 40%). While gastrointestinal adverse events were more common in the semaglutide treatment arm, injection site reactions were more frequent with exenatide. The efficacy advantages of semaglutide over exenatide-ER were both clinically meaningful and statistically significant. Generally, liraglutide has been regarded as the most potent GLP-1 receptor agonist. It will be interesting to see if semaglutide ultimately bests liraglutide, since both agents have demonstrated favorable cardiovascular outcomes in cardiovascular safety trials.

Rivaroxaban vs. Aspirin for Prevention of VTE

SOURCE: Anderson DR, et al. N Engl J Med 2018;378:699-707.

The combined benefits of improved efficacy and convenience of direct oral anticoagulants (i.e., apixaban, dabigatran, edoxaban, rivaroxaban) in the setting of atrial fibrillation makes them a preferred choice. For chronic anticoagulation subsequent to recurrent deep vein thrombosis or pulmonary embolism, direct oral anticoagulants are similarly attractive when compared to warfarin.

Might direct oral coagulants offer some advantage for extended venous thromboembolism (VTE) thromboprophylaxis in patients undergoing knee or hip arthroplasty who are known to suffer an increased risk of VTE in the immediate postoperative period?

Anderson et al performed a double-blind, randomized, controlled trial of knee and hip arthroplasty patients. After a run-in period of rivaroxaban 10 mg daily through postoperative day five, subjects were randomized to either continue rivaroxaban or switch from rivaroxaban to aspirin (81 mg/d). This additional VTE thromboprophylaxis continued for nine days post-knee arthroplasty (hence, 14 days total thromboprophylaxis) and 30 days post-hip arthroplasty (hence, 35 days total thromboprophylaxis).

VTE events were rare in both groups (< 1%), and there was no statistically significant difference in VTE events between aspirin and rivaroxaban, nor was there any significant difference in rates of bleeding. For now, aspirin should remain the postoperative choice for extended prophylaxis after knee and hip arthroplasty.

Inhaled Corticosteroids and Fracture Risk

SOURCE: Gonzalez AV, et al. Chest 2018;153:321-328.

Clinicians have long been reassured by reports about the safety of inhaled corticosteroids (ICS) in asthma, which assert no long-term increased fracture risk, albeit a measurable decrement in bone mineral density (BMD) may be seen. On the other hand, most of the asthmatic population is comprised of younger patients who are not near the peak age of fracture risk. The potential consequences of ICS might be better demonstrated in persons with COPD, who are typically older than the asthma population. In addition, COPD itself is a risk factor for osteoporosis, as is cigarette smoking.

Using the large database of the Quebec healthcare system, fracture rates were assessed in a cohort of 240,110 subjects. Over a five-year follow-up period, more than 19,000 fractures occurred. The mean age of patients with a fracture and the comparison control group was 75 years. Use of ICS for more than four years at a dose of ≥ 1,000 fluticasone equivalents/day was associated with a small but statistically significant 10% increase in relative risk (RR) for hip or upper extremity fracture (RR, 1.10; 95% confidence interval, 1.02-1.19). There did not appear to be any differential risk between men and women. Clinicians should strive to use the minimum ICS necessary to achieve symptomatic improvements in COPD patients.