Trulicity’s turn to show a cardiovascular benefit

Nowadays, diabetes drugs must show a cardiovascular benefit. New agents such as Jardiance and Victoza have set the bar, while specialists are increasingly recognising that most diabetics die of heart-related complications and not the elevated blood sugar that is the primary symptom of the disease.

Thus the Rewind outcomes trial of Lilly’s Trulicity, when it reads out later this year, will need to show a delay in cardiovascular death, heart attacks and strokes for the drug to maintain its edge over its rival GLP-1 agonist Victoza. The latter, Novo Nordisk's once-daily product, showed a 13% risk reduction, so a similar result will be sought from once-weekly Trulicity. This might also help keep Lilly's product ahead of newer offerings from the Danish group.

There is every reason to believe that Trulicity will yield a significant result. After all, uncontrolled blood sugar is linked to damage to blood vessels and nerves that control the heart, in turn leading to heart disease. The hypothesis that long-term blood sugar control will improve cardiovascular outcomes has been supported by the Leader trial of Victoza and the Empa-Reg Outcome trial of the SGLT2 inhibitor Jardiance.

But there is no guarantee that all will go well for Trulicity. It might instead follow in the footsteps of other diabetes agents that have not fared so well here. For example, the Canvas trial of Johnson & Johnson's SGLT2 inhibitor Invokana showed a reduced risk of cardiovascular events but an elevated risk of lower-limb amputations, demonstrating the danger of uncovering a previously undetected safety signal in a large outcomes trial.

Lilly will hope that Trulicity emerges unscathed on safety, but it also needs to show a cardiovascular benefit. Rewind has enrolled 9,900 patients at a higher risk of cardiovascular events, defined as those who have experienced an event, shown evidence of disease, or have at least two risk factors. Patients were randomised to take Trulicity or placebo on a background of oral glucose-lowering drugs or insulin.

The trial will end after 1,200 events have accrued – expected in the fourth quarter of 2018 – and the primary analysis will be a composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

Rivals

The most important comparison will be versus Victoza, as both drugs are in the GLP-1 agonist class. The Leader trial of Victoza read out in 2016, enabling Novo to add data showing a 13% reduction in the risk of cardiovascular events to its label (Novo slumps as Leader looks more like a follower, June 14, 2016).

Victoza is the biggest seller in the class, but Trulicity has been making up ground quickly thanks to its less frequent dosing. However, being able to market on cardiovascular benefit has been an advantage for Novo.

Still, Trulicity still has the chance to grab an edge here. In Leader, the benefit on the composite endpoint appeared to be driven by cardiovascular deaths, with no effect on non-fatal myocardial infarctions or strokes. Showing significance on all three parts of the composite endpoint would help Trulicity, especially as payers are keen to avert costly hospital stays resulting from heart attacks and strokes.

A finding of cardiovascular benefit would also be useful as Lilly prepares to face the challenge of Novo’s once-weekly injectable GLP-1 Ozempic, and the daily oral GLP-1 using Ozempic’s active ingredient, semaglutide. Ozempic’s own smaller cardiovascular outcomes trial, Sustain 6, merely showed no increased risk of death, stroke or heart attack – but no cardiovascular benefit.

The newer Novo agents will eventually need to try to show a benefit here to keep up. No specific outcomes trials related to the diabetic population have been filed with Clinicaltrials.gov, but the Danish company is preparing to recruit 17,000 people for the Select trial of Ozempic measuring heart attacks and strokes in obese and overweight patients with established heart disease. That study excludes patients with a history of diabetes or elevated glucose, however.

Interestingly, Novo has said it hopes that an upcoming cardiovascular outcomes trial of oral semaglutide, slated to start next year, will be enough for a cardiovascular indication for both that drug and Ozempic.

For now Novo has the upper hand with a cardiovascular benefit label already in the bag for Victoza. The baseline assumption for Trulicity will be a reduction in cardiovascular risk somewhere in the mid-teens, just as Victoza and Jardiance have been able to show, with no safety signal emerging. Falling short of this could blunt Trulicity’s growth prospects.