HARMONY: Albiglutide reduces CV risk in adults with type 2 diabetes, CVD

Issue: November 2018

Adults with type 2 diabetes and atherosclerotic disease randomly assigned to the once-weekly GLP-1 receptor agonist albiglutide experienced a 22% reduction in risk for major adverse cardiac events over 1.6 years vs. similar adults assigned to placebo, according to findings from the HARMONY-Outcomes trial presented at the European Association for the Study of Diabetes annual meeting.

Perspective from Zachary T. Bloomgarden, MD, MACE

The findings, an analysis of more than 9,400 patients across 28 countries, come after GlaxoSmithKline announced in August 2017 that it would discontinue production of albiglutide (Tanzeum) for commercial reasons.

John J.V. McMurray

“The HARMONY-Outcome trial further supports the use of evidence-based GLP-1 receptor agonists as part of a comprehensive strategy to reduce the risk of CV events in type 2 diabetes, as recommended in recent cardiology and diabetes guidelines,” John J.V. McMurray, MD, professor at the British Heart Foundation and the Cardiovascular Research Centre at the University of Glasgow, United Kingdom, told Endocrine Today. “A somewhat more controversial conclusion might be that this trial supports the view that human GLP-1-based receptor agonists, like liraglutide [Victoza, Novo Nordisk] and semaglutide [Ozempic, Novo Nordisk] give greater CV risk reduction than exendin-4-based GLP-1 receptor agonists, like lixisenatide [Adlyxin, Sanofi] and exenatide [Bydureon, Astra Zeneca]. The latter had no or less-convincing CV benefits in their respective trials.”

McMurray and colleagues analyzed data from 9,463 adults aged at least 40 years with type 2 diabetes and CVD screened between July 2015 and November 2016 (mean age, 64 years; 31% women; mean duration of diabetes, 14.1 years; mean HbA1c, 8.7%). Researchers randomly assigned patients to subcutaneous albiglutide (n = 4,731; 30-50 mg based on tolerability and glycemic response) or placebo (n = 4,732). The cohort was followed for a median of 1.5 years, with the last patient visit in March. Primary outcome was first occurrence of CV death, myocardial infarction or stroke. Secondary metabolic outcomes included time to initiation of insulin therapy, time to first occurrence of an important microvascular event, changes in HbA1c and body weight, and the proportion of patients who attained glycemic control without severe hypoglycemia.

During follow-up, researchers observed 611 primary endpoint events, including 338 (7%) in the albiglutide group and 428 (9%) in the placebo group, for event rates of 4.57 and 5.87 per 100 person-years, respectively, or a 22% reduced risk for major adverse cardiac events among the albiglutide group (HR = 0.78; 95% CI, 0.68-0.9). HRs for each component of the composite endpoint were 0.93 for CV death (95% CI, 0.73-1.19), 0.75 for MI (95% CI, 0.61-0.9) and 0.86 for stroke (95% CI, 0.66-1.14). Additionally, patients assigned albiglutide experienced a greater mean decrease in HbA1c over 16 months vs. those assigned placebo (difference, –0.52%; 95% CI, –0.58 to –0.45), as well as a greater mean reduction in body weight, whereas fewer patients in the albiglutide group initiated treatment with insulin therapy during the study, according to the researchers.

Incidence of acute pancreatitis, pancreatic cancer and medullary thyroid cancer and other serious adverse events did not differ between groups.

“The bigger picture is that if you want to reduce the risk of non-fatal and fatal CV events in patients with type 2 diabetes and established CV disease, you should consider a SGLT-2 inhibitor (which primarily acts to reduce the risk of heart failure) and an effective GLP-1 receptor agonist which will reduce the risk of athero-thrombotic events (MI and stroke),” McMurray said. “That combination will give you the best overall cardiovascular protection, added, of course, to traditional CV preventive therapies such as renin-angiotensin system blockers, statins and anti-platelet therapy.”

In a press release, John Lepore, MD, senior vice president of research and development pipeline for GlaxoSmithKline, said the HARMONY trial generated new insight about the role of the GLP-1 receptor agonist class in the management of patients with diabetes and CVD.

“GSK continued to invest in this study following a decision last year to cease all other activities on albiglutide,” Lepore said in the release. “We continue to explore opportunities to divest this medicine to a company with the right expertise and resources to realize its full potential for patients.”

In commentary published in The Lancet accompanying the study, Marion Mafham, MRCP, MD, and David Preiss, PhD, FRCPath, MRCP, both of the Nuffield Department of Population Health at the University of Oxford, United Kingdom, called the CV findings in HARMONY “an important step in the story of GLP-1 receptor agonists.”

“Given the clear cardiovascular benefit observed with albiglutide in the HARMONY Outcomes trial, GlaxoSmithKline should reconsider making it available to patients,” Mafham and Preiss wrote. – by Regina Schaffer

References:

HARMONY-Outcomes trial. Presented at: European Association for the Study of Diabetes Annual Meeting; Oct. 1-5, 2018; Berlin.

Hernandez AF, et al. Lancet. 2018;doi:10.1016/s0140-6736(18)32261-x.

Mafham M, et al. Lancet. 2018;doi:10.1016/s0140-6736(18)32261-x.

Disclosures: Hernandez reports he has received grants to his institution from AstraZeneca, GlaxoSmithKline, Luitpold Pharmaceuticals, Novartis, Merck, Portola Pharmaceuticals and Verily, and has consulted for AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Novartis and Merck. Please see the study for all other authors’ relevant financial disclosures.

Perspective

Zachary T. Bloomgarden, MD, MACE

The findings from HARMONY are of great importance in clarifying the treatment of type 2 diabetes. Prior therapeutic approaches, particularly for people with diabetes and cardiovascular disease, have been associated with hypoglycemia and weight gain, as particularly seen with sulfonylureas and insulin. It may be that GLP-1 receptor agonists have specific cardioprotective effects; however, it appears equally (or more) likely that the association of these drugs with glucose-sensitive insulin secretion (hence, less hypoglycemia) and with weight loss simply makes them better management choices.

Although less potent in glucose-lowering than the other drugs in the GLP-1 receptor agonist class, albiglutide also has somewhat fewer gastrointestinal side effects, and yet during the 1.6-years of the trial, there was a somewhat high dropout rate in this study, around 80%. We need to learn how best to explain to patients that this is the right way to treat diabetes now in advancing this different — and better — approach to treatment.

The high absolute benefit with albiglutide in HARMONY is related to the high cardiovascular risk of the study participants. It is not, then, absolutely clear that such treatment will be required for all people with type 2 diabetes; however, if one considers lifetime risk rather than risk over the short-term, it is difficult to argue that the use of GLP-1 receptor agonists should not be increasingly seen as the correct approach for all. Of course, there are other approaches. Lifestyle intervention remains crucial. People who take care of themselves, exercise, eat properly and address weight issues do much better. With findings such as the 25% reduction in myocardial infarction and marked reduction in need for insulin and of development of hypoglycemia, we are really approaching a new algorithm for diabetes management.

Zachary T. Bloomgarden, MD, MACE

Clinical professor of medicine

Icahn School of Medicine at Mount Sinai

Disclosures: Bloomgarden reports he receives consulting and advising fees from Astra Zeneca, Intarcia, Janssen, Merck, Novartis and Sanofi; speaking fees from Amgen, Astra Zeneca, Janssen and Merck; and owns stock in Allergan, Novartis and Zimer Biomet.