AHA 2018 – Astrazeneca takes heart from partial Farxiga victory

The Declare-Timi trial’s success was driven by a decrease in cardiovascular hospitalisations rather than deaths, but Astra put this down to the lower-risk population studied.


Astrazeneca’s Farxiga has become the third SGLT2 inhibitor to show a benefit on cardiovascular outcomes. But working out how the diabetes drug stacks up against its rivals – Lilly and Boehringer’s Jardiance, and Johnson & Johnson’s Invokana – is difficult.

On the face of it Farxiga looks to have fallen short of the competition with full results from the Declare-Timi trial, presented at the American Heart Association conference yesterday. But the picture is complicated by the fact that the companies chose to study slightly different populations of diabetes patients in their big outcomes studies.

Indeed, Astra believes that its decision to enrol mainly primary prevention patients might end up standing it in good stead. Around 60% of the 17,000 subjects in Declare-Timi were merely at risk of cardiovascular events, while the rest had had established cardiovascular disease.

By contrast, all patients in the Empa-Reg Outcome trial of Jardiance had both diabetes and cardiovascular disease, while the Canvas study of Invokana was split around 70:30 in favour of the secondary prevention population.

SGLT2 inhibitor cardiovascular outcomes trials
Product Company Trial Population Result
Farxiga Astrazeneca Declare-Timi, NCT01730534 60% primary prevention, 40% secondary prevention Non-inferior on MACE-3; 17% reduction in risk of CV death or hospitalisation
Jardiance Lilly/Boehringer Ingelheim Empa-Reg Outcome, NCT01131676 All secondary prevention 14% reduction in MACE
Invokana Johnson & Johnson Canvas, NCT01032629 30% primary prevention, 70% secondary prevention 14% reduction in MACE
Source: Company releases, Clinicaltrials.gov.

This might explain why Declare-Timi was unable to show a benefit on one of its co-primary endpoints, a composite of cardiovascular death, myocardial infarction or stroke – which are more likely to happen in sicker patients. Both Jardiance and Invokana demonstrated a 14% reduction in the risk of such events.

However, Astra was lucky – or wise – in that it added a co-primary endpoint to Declare-Timi before unblinding the study. This outcome, a composite of cardiovascular death or hospitalisation, hit significance, something that Astra had already disclosed (Astra not too timid to declare Farxiga victory, September 24, 2018).

Class effect?

At AHA yesterday the company gave more details. Treatment with Farxiga reduced the risk of cardiovascular death or hospitalisation by 17%; however, this was entirely driven by a benefit on the hospitalisation part of this endpoint, and there was no impact on cardiovascular death.

Elisabeth Björk, head of Astra’s cardiovascular, renal and metabolic division, was unconcerned, telling Vantage: “One possible reason is that our patient population was healthier than the population in the other [studies].”

As well as including primary prevention patients, the secondary prevention cohort was less sick than in other SGLT2 outcomes trials, she added. Declare-Timi excluded patients with a creatinine clearance, a measured of kidney function, of less than 60ml per minute.

“To us the most important finding is that you have this massive reduction of heart failure across this broad patient population; this is an everyday population that physicians are seeing,” Ms Björk concluded.

Also importantly, Declare-Timi did not find an increase in the rate of amputations, a problem that has dogged Invokana.

So Farxiga’s main competitor looks likely to be Jardiance. When asked how doctors might pick between the two, Danilo Verge, Astra’s vice-president of global medical affairs, replied: “If a doctor is forced to choose, based on available data, we can say we’re the only company that has data spanning the totality of diabetes populations.”

He added: “We can now say unequivocally that Farxiga should be considered in any patient with type 2 diabetes walking through the door of a GP’s office.”

But Astra is not stopping at patients with diabetes. The company also has ongoing trials of Farxiga in heart failure and kidney disease patients, regardless of whether they have diabetes or not, with the first data due in 2020.

Lilly and Boehringer also have active studies of Jardiance in heart failure irrespective of diabetes.

Jardiance and Invokana both have cardiovascular risk reduction on their labels. The results from Declare-Timi provide more evidence of a class effect. 

Moving outside diabetes: selected SGLT2 trials
Study Setting Trial ID Data due
Dapa-HF   Heart failure with reduced ejection fraction NCT03036124 2020
Deliver Heart failure with preserved ejection fraction NCT03619213 "2020 onwards"
Dapa-CKD Chronic kidney disease NCT03036150 2020
Emperial-Reduced Heart failure with reduced ejection fraction NCT03448419 2019
Emperial-Preserved Heart failure with preserved ejection fraction NCT03448406 2019
Emperor-Reduced Heart failure with reduced ejection fraction NCT03057977 2020
Emperor-Preserved Heart failure with preserved ejection fraction NCT03057951 2020
Source: Clinicaltrials.gov

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