Significant reduction in myocardial infarctions; will drug be brought back to market?
BERLIN -- The GLP-1 receptor agonist albiglutide (Tanzeum) -- withdrawn from the market in 2017 -- was superior for reducing cardiovascular events in people with type 2 diabetes, researchers reported here.
In the Harmony Outcomes trial, adults with type 2 diabetes with established cardiovascular disease given a weekly injection of albiglutide had a significant reduction in the primary composite outcome -- stroke, myocardial infarction (MI), or cardiovascular (CV) death -- when compared with placebo (HR 0.78, 95% CI 0.68-0.90, P<0.0001 for noninferiority, P=0.0006 for superiority).
Over the median 1.5-year follow-up period of the trial, only 7% (n=338) of the patients who were given albiglutide in addition to their standard care experienced one of these major adverse cardiovascular events compared with 9% (n=428) patients who did not receive the GLP-1 receptor agonist, reported Stefano Del Prato, MD, of the University of Pisa in Italy, and colleagues.
The findings were presented at the annual meeting of the European Association for the Study of Diabetes (EASD) and simultaneously published in The Lancet.
This overall reduction in major adverse cardiovascular events (MACE) was largely driven by a reduction in fatal or non-fatal MI risk:
- MI outcomes: HR 0.75 (95% CI 0.61-0.90, P=0.003)
- CV death: HR 0.93 (95% CI 0.73-1.19, P=0.578)
- Fatal or nonfatal stroke: HR 0.86 (95% CI 0.66-1.14, P=0.3000)
Although the only significant benefit seen was in regards to MI risk reduction, the researchers suggested that a longer follow-up period may have lent itself to a significant reduction in CV death, as was seen with liraglutide in the 3.8-year long LEADER trial.
These findings weren't particularly surprising to the study investigators, they said, given the prior cardiovascular outcome trials in humans that have looked at the benefit of GLP-1 RAs, Del Prato told MedPage Today. He recommended that this class of agents should therefore be a component to a comprehensive diabetes management plan aimed at reducing MACE risk.
"A 2% absolute and 22% relative risk reduction in the primary composite endpoint of three-point MACE that was driven by significant reduction in nonfatal MI with CV death and nonfatal stroke leaning in favor of albiglutide on the background of optimal cardioprotective therapy is quite impressive," he told MedPage Today.
This trial took place across 610 international centers and recruited adults over the age of 40 with type 2 diabetes with an HbA1c over 7% and established coronary, cerebrovascular, or peripheral arterial circulation disease between 2015 and 2016. The 4,731 patients, randomized in a 1:1 ratio, received albiglutide, while 4,732 patients received placebo. The starting dose of albiglutide was 30 mg and was later increased up to 50 mg depending upon patient tolerability and glycemic goal.
Not surprisingly, patients who received albiglutide also saw a significant drop in their HbA1c (difference from placebo at 16 months -0.52%, -0.58 to -0.45) and body weight (-0.83 kg, -1.06 to -0.60) when compared with placebo. There was also a slight decrease in systolic blood pressure seen with albiglutide treatment over 16 months of treatment (-0.67 mm Hg, -1.40 to 0.06).
Although the specific underlying mechanisms accounting for the cardiovascular benefit with albiglutide is still uncertain, Del Prato suggested that it is more than likely that this benefit wasn't solely attributed to the glucose-lowering effect, or the benefit with body weight and blood pressure.
"What can be hypothesized is an anti-atherogenic effect and/or a direct effect on the cardiovascular system. The former is in line with the time required for the risk curve to separate and the second with a number of mechanisms observed in pre-clinical studies," he suggested.
Albiglutide treatment was also generally safe without any differences in serious adverse events between the two groups, including for acute pancreatitis (10 in albiglutide versus seven placebo), pancreatic cancer (six versus five), and for medullary thyroid carcinoma (0 versus 0).
However, following FDA approval back in 2014, maker GlaxoSmithKline later pulled albiglutide from the market in 2017 due to poor sales following the addition of a warning on the label for risk of anaphylactic reactions -- adding to the previous boxed warning for thyroid c-cell tumors.
"The fact this is only the second GLP-1 RA to yield clear-cut cardioprotective benefits in this cohort should question the wisdom of that decision," commented Kaul. "I am curious to know if the patients who signed up for this trial were made aware during the consent process about the possibility of withdrawing the drug for marketing reasons. This raises questions about the ethical obligations of the sponsor, the Data and Safety Monitoring Board and the investigators. The safety concerns raised by the FDA last year regarding anaphylactic reactions -- also raised for liraglutide and semaglutide -- are not borne out in this trial, although the exposure was arguably limited."
Kaul emphasized that the robustness of this data is sufficient to meet the FDA's criteria for efficacy, but noted that a longer follow-up period would have been preferred in terms of safety concerns. "Whether the sponsor would be incentivized by these data to resuscitate this drug remains the $64,000 question."
The trial was funded by GlaxoSmithKline.
Hernandez reported grants to his institution from AstraZeneca, GlaxoSmithKline, Luitpold Pharmaceuticals, Novartis, Merck, Portola Pharmaceuticals, and Verily, and he has been a consultant for AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Novartis, and Merck.
Del Prato reported grants to his institution from AstraZeneca, Boehringer Ingelheim, Merck, and Novartis; he reports honoraria for presentations from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck, Novartis, Novo Nordisk, and Takeda Pharmaceuticals; and he reports participation in advisory boards for Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Merck, Mundipharma, Novartis Pharmaceuticals, Novo Nordisk, Sanofi, Servier, and Takeda Pharmaceuticals.
Source Reference: Hernandez A, et al “Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial” Lancet 2018; DOI: 10.1016/S0140-6736(18)32261-X.
Read the original article on Medpage Today: Heart Benefit Seen with GLP-1 RA Albiglutide