Spurred on by the big win with dapagliflozin (Farxiga) in DAPA-HF last week, the sodium glucose cotransporter-2 (SGLT2) inhibitors appear poised for broader use in heart failure with reduced ejection fraction (HFrEF) and are even eyeing cases with preserved EF.
While some members of this type 2 diabetes drug class have a cardiovascular prevention indication, DAPA-HF turned the tables by suggesting diabetes status didn't matter for the heart failure benefit.
The DAPA-HF trial, reported Sept. 1 at the European Society of Cardiology meeting in Paris, showed that dapagliflozin lowered the risk of worsening heart failure and cardiovascular disease death by a relative 26% compared to placebo. The effect size was similar among patients with type 2 diabetes and without it (HRs of 0.75 and 0.73, respectively).
"So this is now a heart failure-protective, cardiovascular and all-cause mortality-reducing therapy for heart failure with reduced ejection fraction and joins other classes of drugs, like beta-blockers and aldosterone antagonists," Gregg Fonarow, MD, of the University of California Los Angeles, told 鶹ý.
Based on the overall cardiovascular benefits seen in the outcomes trials in diabetes, the American College of Cardiology recommended last year that cardiologists take a bigger role in prescribing these drugs.
However, a recent study found that endocrinologists prescribe 40% of SGLT2 inhibitors, while .
"These new findings make it clear that all physicians involved in the care of patients with heart failure should be prescribing these medications to eligible patients without contraindications," said Fonarow.
The only contraindications are in type 1 diabetes and in severe chronic kidney disease (eGFR <30) or end stage renal disease on dialysis, as those groups have been excluded from trials, Fonarow told 鶹ý.
Distinction in HF
For heart failure benefit, the SGLT2 inhibitors have risen to the top among type 2 diabetes medications. In a recent meta-analysis, SGLT2 drugs canagliflozin (Invokana) and empagliflozin (Jardiance) had a relative 44% greater reduction in heart failure risk than other drugs for type 2 diabetes when compared with placebo.
"As far as looking at other diabetic medications, it may be worthwhile, but, unfortunately until we know the mechanism of the cardiovascular benefit of SGLT2s, it may be premature," emphasized Albert Hicks, MD, MPH, of Baylor Scott & White Healthcare in Round Rock, Texas.
SGLT2 inhibitors impact cardiovascular disease by largely preventing heart failure rather than atherosclerotic events, said Donald Lloyd-Jones, MD, of Northwestern University Feinberg School of Medicine in Chicago. And "the reason they prevent heart failure for the most part is that they are good diuretics."
"Why do diuretics work in hypertension?" he said. "Because there are a lot of people who are symptomatic from their heart failure already and don't realize it. If you reduce their volume, you prevent their hospitalization from heart failure. That's exactly what the SGLT2 inhibitors are doing and why they have such a robust effect on heart failure."
But while the class does have good diuretic effects, that may not tell the whole story, argued Javed Butler, MD, MPH, of the University of Mississippi in Jackson.
"All the CV benefit seen with these agents probably cannot be attributed solely to diuretic effects, otherwise we would see the same with other 'usual' diuretics like furosemide [Lasix]," he told 鶹ý.
SGLT2 inhibitors are "probably not as efficient diuretics as furosemide but probably more than hydrochlorothiazides," Lloyd-Jones said. "I think they are going to have a role to play in diabetics and non-diabetics ultimately if we think they are at risk for HF."
He pointed to the fairly good safety profile of SGLT2 inhibitors in terms of hypoglycemia, although noting that urinary tract infections are the major safety issue.
"We might not need Lasix quite so much if we start treating our patient earlier with an SGLT2 inhibitor to treat their blood sugar or reduce their risk," he suggested. Furosemide has "problems of hypokalemia, hyponatremia, potential renal function problems if given too aggressively, so I think this will be a nice intermediate step for heart failure prevention."
All the Same?
Among the SGLT2 inhibitors, there does seem to be a class effect in heart failure but some may work better than others, noted Hicks. That's been the case with beta-blockers in heart failure, too, he pointed out.
"I believe we're going to see the same thing with SGLT2s, where some affect heart failure better than others," Hicks told 鶹ý.
Three of the four SGLT2 inhibitors approved for type 2 diabetes treatment have already reported out findings from the FDA-mandated cardiovascular outcomes trials, all with a primary endpoint of cardiovascular death, myocardial infarction, and stroke.
and found significant cardiovascular benefit, leading to cardiovascular prevention indications in type 2 diabetes for empagliflozin in 2016 and canagliflozin in 2018. Dapagliflozin's DECLARE-TIMI 58 trial was powered for superiority, but did not find it.
Heart failure hospitalization was included as a secondary or exploratory endpoint in all three trials:
- 27% reduction with dapagliflozin
- 35% reduction with empagliflozin
- 33% reduction with canagliflozin
The most recently approved SGLT2 inhibitor -- ertugliflozin (Steglatro), greenlit for type 2 diabetes treatment in 2017 -- is still awaiting results of its cardiovascular outcomes trial, . Completion of the trial is expected in December.
Coming Soon
"This is the first new class of drug in systolic heart failure for some years, and will undoubtedly lead to a change in guidelines and clinical practice," Martin Cowie, MD, of the Imperial College London in England, told 鶹ý after the DAPA-HF findings were presented.
Guidelines committees will, no doubt, wait until publication of the findings before making a move, Clyde Yancy, MD, MSc, of Northwestern University Feinberg School of Medicine in Chicago, told 鶹ý.
AstraZeneca declined to say whether it is seeking a heart failure indication outside of diabetes.
"In this case, the bar for the FDA may differ from that of the guidelines and in today's climate may well lead to an indication for SGLT2 inhibitor therapy in HF," Yancy noted, "meaning that DAPA-HF and the surfeit of other heart failure-related data in the SGLT2 inhibitor [class] may be sufficient to warrant a label indication."
For dapagliflozin, the next question is whether these HFrEF benefits might extend to HFpEF, which the will answer in 2021.
For empagliflozin, the is underway assessing cardiovascular death and heart failure hospitalization among patients with HFrEF, with expected completion in mid-2020. It also has a HFpEF trial, , to be completed in November 2020.
For ertugliflozin and canagliflozin, there are no major heart failure trials currently registered in ClinicalTrials.gov.
Even while awaiting the HFpEF data, those patients are candidates for it as long as they have type 2 diabetes, noted Fonarow.
After the "disappointing" near miss for sacubitril/valsartan (Entresto) in HFpEF in the PARAGON-HF trial at the ESC conference, Yancy predicted that studying a drug for HFpEF broadly might not be the right approach given the deep heterogeneity of the disease.
"I strongly suspect that SGLT2 inhibitor therapy will work (perhaps considerably) in some patients with HFpEF," but perhaps only in some as was the case with the subgroups that benefited in PARAGON-HF, he told 鶹ý.