by François Boissier at the ADA meeting

NEW ORLEANS, June 14 (APM) - Novo Nordisk's GLP-1 analogue Victoza (liraglutide) cut the risk of cardiovascular death by 22% in at-risk type 2 diabetic patients and reduced the risk of major cardiovascular event by 13% , in a study whose results were presented at the meeting of the American Diabetes Association (ADA) in New Orleans.

The Danish pharma announced positive results for this study three months ago. It is the second study to show the ability of a diabetes drug to reduce cardiovascular risk, after the EMPA-REG OUTCOME study carried out with Boehringer Ingelheim/Lilly's Jardiance (empagliflozin).

Following concern over the cardiovascular risk of thiazolidinedione class diabetes drugs, the U.S. Food and Drug Administration (FDA) had asked that all new diabetes drugs should be the subject of large studies verifying their safety of use at the cardiovascular level. So far, these studies have shown mixed results, with some finding no cardiovascular effect while others showed an increase in potential risk of heart failure and others unexpectedly showed a protective cardiovascular effect.

The LEADER study was presented at the ADA meeting on Monday in a dedicated two-hour session, in front of several thousand attendees who applauded the positive results a number of times.

This clinical trial enrolled 9,340 type 2 diabetics who either had coronary disease or chronic renal impairment, or were over the age of 60 and had cardiovascular risk factors. Liraglutide 1.8 mg was compared with a placebo, on top of optimal diabetes treatment.

After three years' monitoring, liraglutide reduced glycated haemoglobin by 0.4% - a modest result, but one which is explained by the fact that the patients were also receiving optimal diabetes treatment that could be modified as required during the study.

The study's primary endpoint was risk of cardiovascular death, myocardial infarction (MI) and stroke. This risk was reduced by 13%.

Risk of cardiovascular death fell 22%, and risk of all-cause death was reduced by 15%.

Liraglutide cut the risk of MI by 12% and risk of stroke by 11%.

Risk of hospitalisation for heart failure, which was increased in some gliptin studies and is consequently followed with interest, was reduced by 13% by liraglutide, said Steven Marso from Dallas University.

Johannes Mann of Erlangen University, Germany, added that renal events - essentially development of albuminuria - also fell 22%. On the other hand, there was no benefit concerning ophthalmological complications.

Apart from vascular events, the study authors looked at many other pathologies so as to ensure the drug was safe to use. The overall adverse event level was no different with liraglutide than with placebo. The only complications whose rate increased with liraglutide were gallstones and - as ever with GLP-1 drugs - gastrointestinal disorders. There was no elevation in risk of cancer - including pancreatic cancer - nor in risk of pancreatitis, despite pancreatic enzyme elevation.

The number of patients who had hypoglycaemic events was similar in the two groups. However, when the researchers analysed the total number of these, they noted a drop of 20%, and even 31% for more severe events. This was apparently linked to the fact that in the placebo group, to control glycaemic level adequately, doctors needed to prescribe a sulfonylurea or insulin more often, said Michael Nauck of the Bochum hospital in Germany.

In conclusion, professor John Buse from the University of North Carolina, Chapel Hill, tried to explain the difference between this study in which liraglutide reduced cardiovascular risk, and the ELIXA study, presented at the 2015 ADA meeting (APMMA 42836), which did not show a fall in risk with another GLP-1 analogue, Sanofi's Lyxumia (lixisenatide).

Although it is always tricky to compare studies indirectly, Buse did point out that the populations in these studies were different. The diabetic patients in ELIXA needed to have had an acute coronary event in the previous six months and were consequently in a more serious state than those in the LEADER study.

He also emphasised that the two molecules, though they have the same target, are very different in structure: like exenatide (AstraZeneca's Byetta and Bydureon), lixisenatide is derived from a substance in lizard saliva, whereas liraglutide is directly derived from GLP-1. Moreover, lixisenatide has a shorter half-life, of less than 24 hours.

He also pointed out that although liraglutide and empagliflozin both reduced cardiovascular risk, there are differences between them. The effect of empagliflozin mainly involved a reduction in cardiovascular deaths and did not show benefit concerning stroke, whereas with liraglutide there is also benefit on MI and stroke. The mechanisms behind the positive effects of the two molecules may differ.

Buse ended his presentation pointing out that although diabetes experts were enthusiastic about the results of the LEADER study, these should not be extrapolated to all patients: they only concern diabetics at high cardiovascular risk.

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