The cardiovascular benefit with the SGLT2 inhibitors looks like a class effect. The latest to succeed is Johnson & Johnson’s Invokana, which met its primary endpoint in an analysis of the Canvas and Canvas-R cardiovascular outcomes trials presented today at the American Diabetes Association meeting.
The 14% cardiovascular benefit seen with Invokana mirrors that observed with Lilly and Boehringer’s Jardiance in the Empa-Reg Outcome trial. But an increased risk of amputation could see Invokana lose market share to the other SGLT2s, particularly Jardiance, which already has a cardiovascular outcomes benefit on its label.
The integrated analysis of the Canvas and Canvas-R studies, published simultaneously in the New England Journal of Medicine, met its primary endpoint, a composite of cardiovascular mortality, nonfatal MI or nonfatal stroke, showing superiority to placebo with a p value of 0.0158.
Patients received background therapy for glycaemia and cardiovascular risks, which included insulins and statins. J&J plans to submit the Canvas data to the US FDA in September, so could get a cardiovascular benefit claim on its label at some time in 2018.
Invokana vs Jardiance
Nearly two years ago Jardiance showed a 14% reduction in the same composite primary endpoint in Empa-Reg Outcome (EASD – Lilly blooms with full Jardiance outcomes data, September 18, 2015). Most of the benefit was driven by a reduction in heart failure, and the trial did not find a significantly lower rate of myocardial infarction or stroke.
Canvas, meanwhile, found a similar magnitude of benefit across all three elements of the composite endpoint, reducing nonfatal MI by 15%, cardiovascular death by 13%, and nonfatal stroke by 10%. However, none of these measures met statistical significance alone, James List, head of Janssen’s cardiovascular & metabolism unit, told EP Vantage.
Mr List was keen to stress that the Canvas programme was longer and enrolled more patients than Empa-Reg Outcome. Perhaps this explains why Canvas and Canvas-R uncovered an increased risk of amputation with Invokana, which prompted an FDA safety alert in May.
An analysis of real-world FAERs data collected by Advera Health has suggested that amputation is not a big problem with the other SGLT2s, but again Invokana has had considerably more patient exposure than other products (Amputation risk adds another cut to Invokana, May 30, 2017).
Mr List would not comment on whether the amputation risk could be a class effect with SGLT2s, but did say that the signal was “not easy to find. It took a programme of this size to find it.”
EvaluatePharma sellside consensus sees Invokana remaining the top product in the class in 2022. This could change as analysts begin to take into account the amputation risk, but Mr List noted that J&J had informed doctors about the issue around a year ago, and “Invokana continues to be number-one SGLT2 inhibitor in the world”.
|Top three SGLT2 inhibitors by 2022|
|Product||Company||2022e sales ($bn)|
Invokana joins Jardiance and Novo Nordisk’s GLP-1 agonist Victoza in the league of diabetes products that have shown a cardiovascular benefit. Victoza reduced cardiovascular death and complications by 13% in the Leader study, but like Jardiance did not manage to show a significant benefit on nonfatal heart attack or stroke (Novo slumps as Leader looks more like a follower, June 14, 2016).
Lilly is already pushing on, today announcing the start of a new outcomes trial of Jardiance in chronic kidney disease patients both with and without diabetes, though it did not give any further details.
Meanwhile, the other SGLT2s are lagging behind both Jardiance and Invokana, with Astrazeneca not expecting cardiovascular outcomes data with Farxiga until 2019.
And Merck & Co and Pfizer do not even have approval for ertugliflozin, although they expect an FDA decision later this year. The companies reported at ADA that the project significantly reduced HbA1c in two phase III trials, Vertis Met and Vertis Sita; data from the Vertis CV outcomes study are due in 2019.
J&J will be relieved to have got a result in Canvas, but will have to hope that Invokana is not scuppered by its link with amputation.
|Integrated analysis met primary endpoint|
|Invokana||Credence||NCT02065791||Renal and CV outcomes; primary completion Jun 2019|
|Farxiga||Declare-Timi58||NCT01730534||Primary completion Apr 2019|
|Ertugliflozin||Vertis CV||NCT01986881||Primary completion Oct 2019|