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Under the impetus of the great dapagliflozin (Farxiga) victory over DAPA-HF last week, the inhibitors of glucose and sodium-2 cotransporter (SGLT2) seem ready to be used more widely in cases of 39, heart failure with reduced ejection fraction (HFrEF) and are even preserved sight cases EF.
Although some members of this class of type 2 diabetes medications have an indication of cardiovascular prevention, DAPA-HF reversed the situation by suggesting that the status of diabetes did not matter for the first time. benefit from heart failure.
The DAPA-HF trial, announced on September 1 at the meeting of the European Society of Cardiology in Paris, showed that dapagliflozin decreased the risk of worsening heart failure and deaths by cardiovascular disease of about 26% compared to placebo. The size of the effect was similar in patients with and without type 2 diabetes (HR 0.75 and 0.73, respectively).
"It is therefore a protective treatment for heart failure, reduction of cardiovascular and all-cause mortality, combined with other classes of drugs, such as beta-blockers and aldosterone antagonists". said Gregg Fonarow, MD, of the University of California at Los Angeles, said MedPage today.
Based on the overall cardiovascular benefits seen in diabetes clinical trials, the American College of Cardiology last year recommended that cardiologists play a greater role in prescribing these drugs.
However, a recent study has shown that endocrinologists prescribe 40% of SGLT2 inhibitors, while cardiologists prescribe only 5%.
"These new findings clearly show that all physicians involved in the care of patients with heart failure should prescribe these drugs to eligible patients without contraindications," Fonarow said.
The only contra-indications concern type 1 diabetes and severe chronic renal failure (eGFR <30) or end-stage renal failure on dialysis, these groups having been excluded from clinical trials, explained Fonarow. MedPage today.
Distinction in HF
With respect to heart failure, SGLT2 inhibitors have emerged as the leading drug for type 2 diabetes. In a recent meta-analysis, SGLT2 drugs such as canagliflozin (Invokana) and empagliflozin (Jardiance ) resulted in a 44% lower risk of heart failure than other drugs for type 2 diabetes compared with placebo.
"With respect to other diabetes medications, it may be worthwhile, but unfortunately, until we know the mechanism of the cardiovascular benefits of SGLT2, it could be premature," Albert said. Hicks, MD, MPH, from Baylor Scott & White Healthcare. in Round Rock, Texas.
Inhibitors of SGLT2 have an impact on cardiovascular disease by largely preventing heart failure rather than atherosclerotic events, said Donald Lloyd-Jones, MD, of the Feinberg School of Medicine at Northwestern University in Chicago. And "the reason they are preventing heart failure for the most part is that they are good diuretics".
"Why do diuretics work in hypertension?" he said. "Because there are already many people symptomatic of their heart failure and do not realize it.If you reduce their volume, you avoid hospitalization for heart failure.It is exactly this what do SGLT2 inhibitors do and why they have such a robust effect on heart failure ".
But if the class has good diuretic effects, it may not tell the whole story, said Javed Butler, MD, MPH, of the University of Mississippi in Jackson.
"All of the CV benefits seen with these agents probably can not be attributed solely to diuretic effects, otherwise we would see the same thing with other" usual "diuretics like furosemide. [Lasix]," he said MedPage today.
Inhibitors of SGLT2 are "probably not as effective diuretics as furosemide, but probably more than hydrochlorothiazides," Lloyd-Jones said. "I think they're going to have a role to play in diabetics and non-diabetics if we think they're at risk for myocardial infarction."
He highlighted the relatively good safety profile of SGLT2 inhibitors in terms of hypoglycemia, while noting that urinary tract infections were the main safety concern.
"We may not need Lasix 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 with hypokalemia, hyponatremia, potential kidney function problems if it is administered too aggressively, so I think it will be an interesting intermediate step for the prevention of heart failure ".
All The same?
Among the SGLT2 inhibitors, there seems to be a class effect on heart failure, but some may work better than others, Hicks noted. This has also been the case with beta-blockers in heart failure, he said.
"I think we will see the same thing with SGLT2, where some affect heart failure better than others," said Hicks. MedPage today.
Three of the four SGLT2 inhibitors approved for the treatment of type 2 diabetes have already reported the results of the FDA-mandated cardiovascular effects tests, all of which have the primary endpoint of cardiovascular death, infarction. myocardium and stroke.
EMPA-REG and CANVAS have shown significant cardiovascular benefits, which led to cardiovascular prevention indications in type 2 diabetes associated with empagliflozin in 2016 and canagliflozin in 2018. The trial DECLARE-TIMI 58 from Dapagliflozin was optimized, but did not find it.
Hospitalization for heart failure 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 latest SGLT2-approved inhibitor – ertugliflozine (Steglatro), greenlit for the treatment of type 2 diabetes in 2017 – is still waiting for the results of his trial on cardiovascular effects, VERTIS CV. The completion of the trial is scheduled for December.
Coming soon
"This is the first new class of medication for systolic heart failure in recent years, and will undoubtedly result in a change in guidelines and clinical practice," said Martin Cowie, MD, from Imperial College London MedPage today after the presentation of the DAPA-HF results.
Clyde Yancy, MD, MSc, of the Feinberg School of Medicine at Northwestern University in Chicago, told the guidelines committees that they would be waiting for the results to be released to make their decisions. MedPage today.
AstraZeneca refused to say he was looking for an indication of heart failure outside of diabetes.
"In this case, the bar for the FDA may differ from that of the guidelines and, in the current climate, might well indicate SGLT2 inhibitor treatment in heart failure," noted Yancy, which means that DAPA-HF and cardiac overabundance related to failures in the SGLT2 inhibitor [class] may be sufficient to justify an indication on the label ".
For dapagliflozin, the next question is whether these HFrEF benefits could extend to HFpEF, to which the DELIVER trial will respond in 2021.
For empagliflozin, the EMPEROR-REDUCED trial is underway to evaluate hospitalization in the event of cardiovascular death and heart failure in patients with HFrEF, who should be completed by mid-2020. It also features an HFpEF trial, EMPEROR-PRESERVED, to be completed in November 2020.
For ertugliflozine and canagliflozin, there is currently no major trial on heart failure recorded in ClinicalTrials.gov.
Even while waiting for HFpEF data, these patients are candidates for this as long as they have type 2 diabetes, noted Fonarow.
After the "disappointing" disappointment of Sacubitril / Valsartan (Entresto) in HFpEF during the PARAGON-HF trial at the ESC conference, Yancy predicted that the study of a drug intended for HFpEF may not be the right approach given the profound heterogeneity of the disease.
"I strongly suspect that SGLT2 inhibitor therapy will work (perhaps considerably) in some patients with HFpEF," but perhaps in some cases, as was the case for the subgroups benefiting from PARAGON-HF, he said. MedPage today.
2019-09-12T18: 00: 00-0400
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