The cardiovascular benefits of the SGLT2 inhibitors, used in type 2 diabetes, have been known for some time. But the players in the space are eyeing a new use: treating heart failure in patients both with and without diabetes.
Astrazeneca is the first to get a win here, today reporting that its DAPA-HF trial of Farxiga met its primary cardiovascular outcomes endpoint. But the group might not be able to enjoy its head start for long, with Lilly and Boehringer Ingelheim’s Jardiance set to yield results from similar studies soon.
Success in DAPA-HF should move Farxiga from just the realm of endocrinology and squarely into the cardiology space. "This is truly an indication that’s in the hands of cardiologists," Joris Silon, senior vice-president of Astra’s cardiovascular, renal and metabolism unit, told Vantage.
However, the biggest challenge for both products could be spurring uptake among cardiologists, who have so far been slow to embrace the SGLT2s (Calling all heart docs – your diabetes drugs need you, April 27, 2017).
|Looking beyond diabetes with the SGLT2 inhibitors|
|Trial name||Setting||Trial ID||Data|
|Dapa-HF||CV outcomes in HF with reduced ejection fraction||NCT03036124||Toplined Aug 2019|
|Determine-reduced||HF symptoms in pts with reduced ejection fraction||NCT03877237||Jan 2020|
|Determine-preserved||HF symptoms in pts with preserved ejection fraction||NCT03877224||Feb 2020|
|Dapa-CKD||Cardiorenal outcomes in chronic kidney disease||NCT03036150||Nov 2020|
|Deliver||CV outcomes in HF with preserved ejection fraction||NCT03619213||Jun 2021|
|Jardiance (Lilly/Boehringer Ingelheim)|
|Emperial-Reduced||HF symptoms in pts with reduced ejection fraction||NCT03448419||Sep 2019|
|Emperial-Preserved||HF symptoms in pts with preserved ejection fraction||NCT03448406||Oct 2019|
|Emperor-Reduced||CV outcomes in HF with reduced ejection fraction||NCT03057977||Jun 2020|
|Emperor-Preserved||CV outcomes in HF with preserved ejection fraction||NCT03057951||Oct 2020|
|Empa-Vision||Heart function in HF patients||NCT03332212||Apr 2020|
|Empa-Kidney||Cardiorenal outcomes in chronic kidney disease||NCT03594110||Jun 2022|
|Source: EvaluatePharma, clinicaltrials.gov.|
Jardiance is currently forecast to be the biggest SGLT2 by 2024; the product was the first in the class to show it could reduce cardiovascular events in diabetics, leading to an expanded label in December 2016.
Astra was much further behind with Farxiga, reporting results from its cardiovascular outcomes study, Declare-Timi, last year (AHA 2018 – Astrazeneca takes heart from partial Farxiga victory, November 11, 2018).
The product has only just got a cardiovascular outcomes label in diabetes in Europe, where it is branded Forxiga; Astra is expecting a decision in the US in the next couple of months. Farxiga’s second-quarter revenues fell short of analyst consensus and the drug will need a boost to meet forecasts for this year.
It is unclear whether this boost could come anytime soon. When asked about Farxiga’s traction among cardiologists, Mr Silon seemed to play down expectations, saying it was still early days.
Meanwhile, sales of another SGLT2 inhibitor, Johnson & Johnson’s Invokana, went backwards in the second quarter – but that drug has suffered after being linked with an increased risk of amputations, despite getting its cardiovascular label in the diabetes setting last year.
|A mixed quarter for the SGLT2s|
|Q2 2019 sales ($m)||Future sales ($m)|
|Invokana||Johnson & Johnson||177||189||-17%||726||465|
|*Alliance revenue; **At constant exchange rates|
|Source: EvaluatePharma, company releases.|
Still, the SGLT2 tide might finally be turning, Bernstein analysts believe, noting that the importance of treating heart failure in diabetics was a hot topic at the recent American Diabetes Association meeting.
But they added that it could take more time for cardiologists to consider SGLT2s part of the standard of care in the non-diabetic population, and that guideline changes would be needed to spur broader uptake of this class in heart failure.
Success in DAPA-HF should help, but the details will be important. All Astra is saying for now is that the study met its primary endpoint, a composite of cardiovascular death, hospitalisation for heart failure, or an urgent heart failure visit, with Farxiga plus standard of care versus standard of care alone.
Patients in the study had heart failure with reduced ejection fraction (HFrEF), which affects around half of heart failure patients.
The drug’s performance in diabetics versus non-diabetics will be worth watching, but the trial does not appear to be skewed towards the former. Around 40% of patients in DAPA-HF had type 2 diabetes, which is representative of the heart failure population according to Elisabeth Bjork, head of late-phase cardiovascular and metabolic development at Astra.
Full results will be presented at an undisclosed conference; the American Heart Association meeting, taking place in Philadelphia in November, could be a possibility.
DAPA-HF is not Astra’s only effort to extend Farxiga’s reach beyond diabetes. The company also has an outcomes trial ongoing in the tricky setting of heart failure with preserved ejection fraction, an indication that recently tripped up Novartis’s Entresto.
But the next studies of Farxiga to read out will be the Determine trials, assessing functional measures including the six-minute walk test.
Lilly and Boehringer’s programme with Jardiance looks eerily similar, and data from its comparable trials, called Emperial-Reduced and Emperial-Preserved, could be available by the end of this year; meanwhile Emperor-Reduced, which is analogous to DAPA-HF, is set to yield results in 2020.
So far, the cardiovascular benefit with the SGLT2s looks like a class effect. If the same is true outside diabetes, which seems likely, Astra will not have this space to itself for long.