Level 1 [likely reliable] evidence

Treatment goals for patients with type 2 diabetes (T2D) traditionally focus on reducing glycated hemoglobin (HbA1c). With the advent of a number of new options, however, clinicians can now select agents shown to improve patient-oriented outcomes rather than just HbA1c. Several trials have examined cardiovascular outcomes in glucagon-like peptide-1 (GLP-1) agonists. The LEADER1 trial showed that liraglutide could reduce myocardial infarctions (MIs) and all-cause mortality in patients with T2D who had increased cardiovascular (CV) risk, and the SUSTAIN-62 trial demonstrated lower rates of nonfatal MI and stroke in similar patients treated with semaglutide. Now, a recent multicenter study examined albiglutide in a double-blinded, randomized, placebo-controlled trial with more than 9000 patients with T2D. Patients had a mean HbA1c of 8.7%, and 70% had known CV disease.3 More than 75% in each group were taking a biguanide and were receiving therapy for CV disease, including aspirin and a statin. The primary composite outcome was major CV events, which consisted of MI, stroke, and CV death. The investigators powered the trial for noninferiority, with plans for superiority analysis if the noninferiority margin was met. 

Over an average of 18 months of follow-up, there were fewer major CV events in the albiglutide group than in the placebo group, which met the noninferiority margin allowing for superiority analysis for the primary outcome (4.6 events per 100 person-years in albiglutide group vs 5.9 events per 100 person-years in the placebo group, hazard ratio 0.78, number needed to treat = 50 over 1.6 years). This was primarily driven by a single component of the composite outcome, nonfatal and fatal MI. There was no difference in the secondary outcome of death from any cause or CV death. Patients in the albiglutide group had greater weight loss (1.5 lb) and a lower likelihood of beginning insulin therapy. In each group, approximately one-quarter of participants discontinued the weekly injections, although only 2% had injection-site reactions. Rates of hypoglycemia were lower in the placebo group than in the albiglutide group.

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This trial demonstrates albiglutide to be safe for patients with T2D and CV disease. It is worth noting that the drug has been withdrawn from the US market, although this was not for safety reasons. Also, GLP-1 agonists have black box warnings regarding concerns about thyroid cancer risk. Albiglutide is available in other countries, and this trial may serve as an impetus for its reintroduction in the United States, particularly if follow-up results show a survival advantage with albiglutide. This trial did not find a survival benefit, but a duration of only 18 months is likely too short to reliably determine if a difference in survival exists or not.

Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Massachusetts, and assistant clinical professor in family medicine, University of Massachusetts Medical School, Worcester.

DynaMed is a database that provides evidence-based information on more than 3000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.

References

  1. Marso SP, Daniels GH, Brown-Frandsen K, et al; for the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322.
  2. Marso SP, Bain SC, Consoli A, et al; for the SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.
  3. Hernandez AF, Green JB, Janmohamed S; for the Harmony Outcomes committee and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392:1519-1529.