Wednesday , June 23 2021

Dapagliflozin reduces heart failure in diabetes



CHICAGO – Dapagliflozin (Farxiga / Forxiga, AstraZeneca) showed an insignificant trend towards a reduced rate of major adverse events (MACE), but significantly reduced hospitalization for heart failure in the DECLARE-TIMI 58 test in patients with type 2 diabetes.

The trial was presented here at the American Heart Association (AHA) Scientific Sessions 2018 by leading author Stephen Wiviott, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. It was simultaneously published online in New England Journal of Medicine.

"What we see in this experiment is a similar theme for other major trials of sodium glucose cotransporter-2 (SGLT2) – a significant reduction in heart failure hospitalization and renal disease, Wiviott commented that theheart.org | Medscape cardiology.

"DECLARE-TIMI 58 differs from the other [cardiovascular outcomes] try to include a much wider and healthier population including 10,000 patients without existing cardiovascular disease but with several risk factors, as well as 7,000 patients with previous cardiovascular disease. "

"We found that the benefit of dapagliflozin against heart failure was similar in those with and without existing cardiovascular disease, whereas the effect on MACE differs between these populations without any effect in the primary prevention group and a trend towards the reduction of secondary prevention.

"All three SGLT2 inhabitant trials have found a major effect on the end of the heart failure, and our attempt adds the known literature in that regard, but it also expands this heart failure to the primary prevention diabetic population," says Wiviott.

He added: "If we look at all experiments empagliflozin showed the most benefit of MACE, but it was still less than the heart failure. I think after the DECLARE-TIMI 58 test we can now say the biggest benefit of SGLT2 inhibitors is aimed at to prevent heart failure and the reduction of the major cardiovascular events is limited to patients with existing underlying cardiovascular disease. "

"The DECLARE TIMI-58 test also provides very calming data about safety without signs of stroke, amputations or bladder cancer," he added.

The major cardiovascular outcome tests of newer Type 2 diabetes drugs are conducted to demonstrate safety following a mandate by the US Food and Drug Administration (FDA) 2008 after concerns about CV injury with older Type 2 diabetes drugs.

But so far none of the eight completed results in the trial have shown excessive CV risk from the current drugs, and three have actually shown benefits.

These included two studies of oral SGLT2 inhibitors: EMPA-REG OUTCOMES trial with empagliflozin (Jardiance, Boehringer Ingelheim / Lilly) and CANVAS with canagliflozin (Invokana, Janssen). In both studies, all patients had type 2 diabetes and existing CVD or had a high risk of CVD.

Similarly, in the third study, LEADER, with the injectable glucagon-like protein 1 (GLP-1) agonist liraglutide once daily (Victoza, Novo Nordisk), all patients with type 2 diabetes had established CV disease or chronic renal failure, or were 60 years of age and older with CVD risk factors.

DECLARE now adds this list of studies showing cardiovascular disease with new diabetes drugs, although the benefits are limited to the endpoint of the heart failure and did not show the same reductions in MACE as the other SGLT2 inhibitors or LEADER. However, this attempt enrolled a lower risk population of patients with type 2 diabetes than in the previous cardiovascular results studies.

No increase in amputations with dapagliflozin in DECLARE

For the DECLARE-TIMI 58 study, 17,160 patients with type 2 diabetes who had atherosclerotic CVD or multiple risk factors for CVD were randomly assigned dapagliflozin 10 mg daily or placebo in addition to standard therapy.

The primary safety outcome was a combination of MACE events, defined as CV death, myocardial infarction (MI) or ischemic stroke. The two co-effective endpoints were MACE and a composite of cardiovascular death or hospitalization for heart failure.

Following an average follow-up of 4.2 years, the primary safety score met the criteria for non-inferiority.

As regards the two efficacy results, MACE was numerically reduced in the dapagliflozin group, but this result was not significant. CV death / heart failure hospitalization endpoint was significantly reduced. This was driven by a lower hospital stay for heart failure.

An important secondary outcome was a renal composite (≥40% decrease in the calculated glomerular filtration rate to <60 ml / min per 1.73 m2 of the body surface area, new kidney disease at the final stage or death from kidney or CV causes). This was also significantly reduced with dapagliflozin.

Table 1. DECLARE-TIMI 58: Main Result

Variable Dapagliflozin (%) Placebo (%) Risk Ratio (95% confidence interval)
CV death / MI / stroke 8.8 9.4 0.93 (0.84-1.03)
CV death / heart failure hospital stay 4.9 5.8 0.83 (0.73 – 0.95)
Heart failure hospitalization 2.5 3.3 0.73 (0.61 – 0.88)
CV death 2.9 2.9 0.98 (0.82-1.17)
kidney Composite 4.3 5.6 0.76 (0.67 – 0.87)

After the groups were separated into patients with and those who had no established cardiovascular disease, MACE was non-significant with dapagliflozin in those with established disease, but there was no effect on those without established CVD.

Table 2. Results in those with and without CVD (HR for dapagliflozin)

Variable Risk Ratio (95% confidence interval)
CVD No CVD
CV death / MI / stroke 0.90 (0.79-1.02) 1.01 (0.86-1.20)
CV death / heart failure hospital stay 0.83 (0.71-0.98) 0.84 (0.67-1.04)

In the case of adverse events, diabetic ketoacidosis was more common with dapagliflozin (0.3% vs 0.1%), as well as gender infectors that led to interruptions or considered to be severe (0.9% vs. 0.1%). Wiviott noted that these two are known side effects of SGLT2 inhibitors.

He commented: "Our results are also calming because we did not see any suggestions for an increase in amputations or strokes with dapagliflozin and this is the largest study of these drugs with the longest follow-up."

"IN [EMPA-REG OUTCOMES] The empagliflozin trial went wrong in the wrong direction, and in the CANVAS trial with canagliflozin there was an increased incidence of amputations in the treated group. Due to these observations in previous experiments, we evaluated these results very carefully and found no evidence at all with dapagliflozin. "

"In early studies of dapagliflozin, there was a slight increase in bladder cancer with the drug, so the FDA called for the need for careful monitoring for this in the DECLARE trial, and it was found that the bladder cancer rate was actually lower in dapagliflozinarm. Again, showing that observations in small-number studies often depend on chance, "he added.

Provincies in Diabetes: Sea Change in Therapy

Wiviott noted that these newer type 2 diabetes drugs have been slow to penetrate the market. "At present, cardiologists do not often prescribe these drugs, but now we have several studies showing cardiovascular benefits, I think their use in cardiological society will grow in both primary and secondary prevention patients with diabetes.

"These trials were originally performed to show cardiovascular safety, but they have actually shown cardiovascular benefit, which was not expected, and so these drugs are now converted into cardiovascular drugs that also reduce blood sugar rather than just diabetic drugs.

"It's a sea change, and studies are currently underway with SGLT2 inhibitors such as heart failure and renal disease treatment in patients without diabetes."

"Research is also underway on the mechanism of action behind their beneficial effects, which probably is not just due to the reduction of blood sugar," he added. "They affect the sodium / glucose transporter in the kidneys, so the patient secrete sodium and glucose in the urine, but they can also have direct cardiac effects," he suggested.

Asked how the different agents in the class compared, he said: "I would feel safe to use any of these drugs. Instead of competing for which SGLT2 inhibitor to use, I recommend that in the treatment of diabetic patients any of the drugs In this class that has proven cardiac and renal benefits would be preferable to older diabetic drugs, which have not shown such benefits. "

Reduce Macrovascular and Microvascular Events: A Paradigm Shift

"I also think we are entering into a paradigm change in the treatment of diabetes. So far, everyone has been subject to lowering blood sugar to reduce microvascular complications and nothing has been differentiated between the different classes of [newer] diabetes, but now we begin to focus on reducing macrovascular complications (ie cardiovascular outcomes) as well. "

The appointed researcher of the study, Javed Butler, MD, University of Mississippi Medical Center, Jackson, said that the DECLARE-TIMI 58 was a well-conducted study and included the highest proportion of diabetic patients without established atherosclerotic CVD of all SGLT2 inhibitor CV outcome tests.

"This attempt again demonstrates the benefits of SGLT2 inhibitors in diabetic patients in reducing the risk of heart failure and kidney problems," he said.

"We also see from all attempts together that diabetes patients with underlying cardiovascular disease" who take these drugs have an advantage on MACE, but that "this effect does not extend to patients without underlying cardiovascular disease."

Butler stressed that heart failure is a very important endpoint for diabetes attempts.

Heart failure "is the same or perhaps even more common than important negative cardiovascular disease in diabetic patients, and heart failure is usually poorer. We also know that we can reduce cardiovascular outcomes in diabetic patients by working on lifestyle – stop smoking, reduce weight and blood pressure , etc. – but it does not seem to have the same effect on the risk of heart failure. "

"These trials have now conclusively shown that diabetic patients with underlying cardiovascular disease or with multiple cardiovascular risk factors should take these medicines to lower the risk of heart failure."

To theheart.org | Medscape Cardiology, Butler added: "Choosing between the individual SGLT 2 inhibitor drugs is difficult. The cardiovascular mortality of empagliflozin was very striking – it is hard to ignore. The benefits of kidney and heart failure appear to be overlapping with all drugs. There was a slight increase in cannabliflozin amputations. This may have been the only chance and have not seen other SGLT2 inhibitors. "

"Then we also have GLP-1 agonist medications, which have shown a clear advantage in large negative cardiovascular diseases, but appear to be neutral at the risk of heart failure. I think we can make a case for use of both these classes of agents in some cases."

A more temperate view …

Others, however, take a more temperate view. One of these is David Nathan, MD, Head of the Diabetes Center at the Massachusetts General Hospital, Boston, Massachusetts. He commented theheart.org | Medscape cardiology: "These SGLT2 inhibitors reduce the risk of heart failure hospitalization in diabetic patients with or with increased risk of heart disease, but the absolute risk reduction is quite modest – about 1%. Empagliflozin has shown better effects on major cardiovascular disease in patients with established heart disease. "

He also points out that the negative effects and costs of SGLT2 inhibitors all need to be considered when considering their use.

"These drugs increase the excretion of glucose into the urine, leading to urinary tract infections. And we can ask if they are only very expensive diuretics – would we have the same effect with a low dose of furosemide or thiazide diuretic with fewer side effects and much lower cost? "

Nathan also pointed out that the glycemic effects of dapagliflozin were modest with a decrease in hemoglobin A1c (HbA1c) by 0.4% (HbA1c reduction from 8.3% to 7.9%) in this trial. "This is not enough to satisfy the usual minimum FDA requirements for the approval of a new diabetes medication."

"Whether these medications should be considered as heart failure treatments in diabetes patients, instead of glucose-lowering drugs in themselves, is a not so subtle distinction that needs to be considered," he concluded.

DECLARE-TIMI 58 was funded by Astra Zeneca and Bristol-Myers Squibb. Wiviott reports contributions and personal fees from Astra Zeneca and Bristol-Myers Squibb. Butler is a consultant for Astra Zeneca.

American Heart Association (AHA) Scientific Sessions 2018. Summary # 19485. Presented November 10, 2018.

N Engl J Med. Published online on November 10, 2018. Full text

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