Treatment with GLP-1RA results in reduction of MACE in type 2 diabetes patients with established CVD
Albiglutide was superior to placebo with respect to MACE in T2DM patients in the Harmony Outcomes trial without differences in serious adverse events.
Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trialLiterature - Hernandez AF, Green JB, Janmohamed S et al. - The Lancet 2018, doi: 10.1016/S0140-6736(18)32261-X
Introduction and methods
Effects of members of the GLP-1RA class on CV outcomes in trials with T2DM patients have been inconsistent. Liraglutide and semaglutide (structural homology to native GLP-1) reduced MACE, whereas lixisenatide and exenatide (exendin-4 based) did not [1-4]. Besides differences in chemical structure, there are differences in duration of action, patient populations that were studied and trials had different design, size and follow-up.
Albiglutide is a GLP-1RA with structural homology to endogenous human GLP-1 and long-acting (injected once-weekly) [5,6].
The efficacy and safety of albiglutide was assessed in Harmony Outcomes trial. It was a double-blind, randomized, placebo-controlled, event-driven trial, that enrolled T2DM patients ≥40 years with established coronary, cerebrovascular disease or PAD. Among other criteria, those with eGFR <30 ml/min/1.73² and current use of GLP-1RA were excluded. Patients were assigned in a 1:1 ratio to receive subcutaneous injections of albiglutide or placebo once a week.
Primary outcome was the first occurrence of any component of the composite of CV death, non-fatal MI and non-fatal stroke. Secondary outcomes were 4 point MACE (primary outcome plus urgent revascularization for unstable angina), individual components of primary outcome, composite of CV death or HF hospitalization. Safety outcomes were change in blood pressure and heart rate, change in eGFR, and adverse events of special interest.
Between July 1, 2015 and Nov 24, 2016, 9463 patients were enrolled. The study had a median follow-up of 1.6 years (IQR 1.3-2.0).
Main results
- Primary outcome of MACE was reduced in the albiglutide group vs placebo group (HR 0.78; 95%CI:0.68-0.90, P<0.0001 for non-inferiority, and P=0.0006 for superiority).
- HRs for each component of composite were 0.93 (95%CI: 0.73-1.19) for CV death, 0.75 (0,61-0.90) for MI and 0.86 (0.66-1.14) for stroke. HR for death from any cause was 0.95 (95%CI:0.79-1.16).
- Mean glycated hemoglobin was more decreased in albiglutide group compared to placebo group.
- Number of injection site reactions was greater in albiglutide group than in placebo group (86 vs 29) with similar number of patients with suspected hypersensitivity reactions (45 vs 48). Severe hypoglycemia was less common in albiglutide group vs placebo group (31 vs 55). Other serious adverse events were not different between groups.
- There were no large difference at 16 months in mean systolic BP, heart rate and eGFR between albiglutide group and placebo group.
Conclusion
Injection of once-weekly albiglutide resulted in a 22% reduction of MACE compared to placebo in T2DM patients with established CVD, without any safety concerns. These results contribute to the evidence that certain GLP-1RAs provide CV benefit in T2DM patients with CVD.
Editorial comment
In their editorial comment, Mafham and Preiss mention that in 2017 GSK announced to withdraw albiglutide from the market for commercial reasons, before the evidence of CV efficacy and safety of this agent. The authors continue to summarize the results of the Harmony Outcomes trial and also list the results of trials with other GLP-1RAs. As also mentioned by Hernandez et al, the structures of albiglutide, liraglutide and semaglutide are based on human GLP-1, whereas exenatide and lixisenatide are exendin-4 based. These structural differences could translate into the observed different outcomes, however, small directly comparative trials do not suggest this association between structure of drugs and effects on CV risk factors and poor adherence in EXSCEL and ELIXA could explain the discrepancy in findings. Mafham and Preiss also note that the duration of some trials was short (<2 years) leading to perhaps unreliable results. They conclude that ‘international guidelines should reflect the increasing weight of evidence that supports the use of GLP-1 receptor agonists in patients with diabetes and cardiovascular disease’ but also recognize that more studies are needed in patients with diabetes, but without vascular disease and vice versa. Finally, they write: ‘given the clear cardiovascular benefit observed with albiglutide in the Harmony Outcomes trial, GlaxoSmithKline should reconsider making it available to patients.’
References
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2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375: 1834–44.
3. Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373: 2247–57.
4. 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: 1228–39.
5. Tahrani AA, Barnett AH, Bailey CJ. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus. Nat Rev Endocrinol 2016; 12: 566–92.
6. Fisher M, Petrie MC, Ambery PD, Donaldson J, Ye J, McMurray JJ. Cardiovascular safety of albiglutide in the Harmony programme: a meta-analysis. Lancet Diabetes Endocrinol 2015; 3: 697-703.
7. Mafham M, Preiss D. HARMONY or discord in cardiovascular outcome trials of GLP-1 receptor agonists? Lancet. 2018;392:1489-1490.