Dapagliflozin Cuts Heart Failure in Diabetes


CHICAGO – Dapagliflozin (Pharyngitis, AstraZeneca) showed a non-significant trend towards a reduced rate of major adverse cardiac events (MACE), but significantly reduced hospitalization for heart failure in the DECLARE-TIMI 58 study in patients with type 2 diabetes.

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

"What we are seeing in this essay is a similar theme to other important tests of sodium-2 (SGLT2) cotransporter inhibitors – a significant reduction in hospitalization for heart failure and kidney events, "Wiviott commented. theheart.org | Medscape Cardiology.

"DECLARE-TIMI 58, however, differs from the other [cardiovascular outcomes] clinical trials that included a much broader and healthier population, including 10,000 patients without preexisting cardiovascular disease but with multiple risk factors as well as 7,000 patients with pre-existing cardiovascular disease. "

"We found that the benefit of dapagliflozin in heart failure was similar in those patients with and without preexisting cardiovascular disease, while the effect on MACE differed between these populations, with no effect on the primary prevention group and a tendency toward a reduction in those with secondary prevention.

"All three clinical trials of SGLT2 found a major effect on the outcome of heart failure, and our study adds to the known literature in this regard, but it also extends this benefit from heart failure to the diabetic population of primary prevention," said Wiviott.

He added, "If we looked at all the tests, empagliflozin showed the greatest benefit in MACE, but that was still less than the benefit of heart failure. I think after the DECLARE-TIMI 58 trial we can definitely say the biggest benefit of SGLT2 inhibitors are in the prevention of heart failure, and the reduction of major cardiovascular events is limited to patients with existing underlying cardiovascular disease. "

"The DECLARE TIMI-58 study also provides very reassuring data on safety, with no signs of stroke, amputation or bladder cancer," he added.

Major cardiovascular (CV) trials of new type 2 diabetes medications are being conducted to demonstrate safety following a US Food and Drug Administration mandate in 2008 after concerns about cardiovascular damage with older type 2 diabetes medications.

However, so far, none of the eight completed CV results have identified CV risk in excess of the medications in question, and three have actually shown benefit.

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

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

DECLARE now adds to this list of studies showing cardiovascular benefit with new diabetes medications although its benefits are restricted to the end point of heart failure and have not shown the same reductions in MACE as other studies with SGLT2 inhibitor, or LEADER. But this study involved a population at lower risk of patients with type 2 diabetes than in previous studies of cardiovascular outcomes.

No increase in amputations with Dapagliflozin in DECLARE

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

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

After an average follow-up of 4.2 years, the primary safety endpoint met the non-inferiority criteria.

In terms of the two efficacy results, the MACE were numerically reduced in the dapagliflozin group, but this result was not significant. The outcome CV hospitalization for death / heart failure was significantly reduced. This was driven by a lower rate of hospitalization for heart failure.

An important secondary outcome was a renal compound (≥ 40% decrease in estimated glomerular filtration rate to <60 mL / min by 1.73 m2 body surface area, new terminal renal disease, or death from renal or cardiovascular causes). This was also significantly reduced with dapagliflozin.

Table 1. DECLARE-TIMI 58: Main Results

Variable Dapagliflozin (%) Placebo (%) Risk rate (95% confidence interval)
Death CV / MI / stroke 8.8 9.4 0.93 (0.84 – 1.03)
CV death / hospitalization for heart failure 4.9 5.8 0.83 (0.73-0.95)
Hospitalization for heart failure 2.5 3.3 0.73 (0.61-0.88)
Death CV 2.9 2.9 0.98 (0.82 – 1.17)
Renal compound 4.3 5.6 0.76 (0.67-0.87)

After groups were separated in patients with and without established cardiovascular disease, ECAMs were not significantly reduced with dapagliflozin in those with established disease, but there was no effect in those without established CVD.

Table 2. Results in people with and without CVD (CF for Dapagliflozin)

Variable Risk rate (95% confidence interval)
Death CV / MI / stroke 0.90 (0.79 – 1.02) 1.01 (0.86 – 1.20)
CV death / hospitalization for heart failure 0.83 (0.71-0.98) 0.84 (0.67 – 1.04)

In terms of adverse events, diabetic ketoacidosis was more common with dapagliflozin (0.3% vs 0.1%), as were genital infections that led to discontinuations or were considered serious (0.9% vs 0.1%). Wiviott noted that these are both known side effects of SGLT2 inhibitors.

He commented, "Our results are also reassuring, since we do not see any suggestion of increased amputations or spills with dapagliflozin and this is the largest study of these agents with the longest follow-up."

"At the [EMPA-REG OUTCOMES] empagliflozin trial, stroke was 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 studies, we evaluated these results very carefully and found no evidence of any increase with dapagliflozin. "

"In the early studies on dapagliflozin, there was a small increase in bladder cancer with the drug, so the FDA determined that we had to do careful surveillance on DECLARE and found that the rate of bladder cancer was actually lower. this is comforting again and shows that observations in studies with small numbers are often due to chance, "he added.

Cardiovascular outcomes in diabetes: changing the sea in therapy

Wiviott noted that these new type 2 diabetes medications took a long time to penetrate the market. "Currently, cardiologists do not prescribe these drugs often, but now we have several studies showing cardiovascular benefits, I think their use in the cardiology community will increase in both primary and secondary prevention patients with diabetes.

"These tests were initially performed to show cardiovascular safety, but they actually showed cardiovascular benefits, which was not expected, and so these drugs are turning into cardiovascular agents that also reduce blood sugar rather than diabetic drugs.

"This is a radical change, and studies are ongoing with SGLT2 inhibitors such as heart failure and renal prevention treatments in patients without diabetes."

"Research is also underway on the mechanism of action behind its beneficial effects, which is probably not due solely to the reduction of blood sugar," he added. "They affect the sodium / glucose transporter in the kidney so that the patient excretes sodium and glucose in the urine, but they also may have direct cardiac effects," he suggested.

Asked about how the different agents within the class compared, he said, "I would feel confident using any of these drugs. Instead of competing with the SGLT2 inhibitor, I recommend that when treating diabetic patients, any of the class proven cardiovascular and renal benefit would be preferable to older diabetes medications that did not demonstrate such benefits. "

Reducing Macrovascular and Microvascular Events: A Paradigm Shift

"I also think we are entering a paradigm shift in the treatment of diabetes. Everyone has so far been set to reduce blood sugar to reduce microvascular complications and there is nothing to differentiate between the various classes of [newer] drugs for diabetes but now we are starting to focus on reducing macrovascular complications (ie cardiovascular outcomes) as well. "

Designated Debater of the study, Javed Butler, MD, of the University of Mississippi Medical Center, Jackson, said DECLARE-TIMI 58 was a well-conducted study and included the largest proportion of diabetic patients without atherosclerotic CVD established from all inhibitor CV outcome assays of SGLT2.

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

"We are also seeing, from all the tests, that diabetic patients with underlying cardiovascular disease" taking these agents gain a benefit with ECAM, but that "this effect does not extend to patients without underlying cardiovascular disease."

Butler pointed out that heart failure is a very important end point for diabetic tests.

It is also known that we can reduce cardiovascular outcomes in diabetic patients by working with lifestyle – stopping smoking, reducing heart failure, and reducing heart failure. weight and blood pressure, etc. – but this does not seem to have the same effect on the risk of heart failure. "

"These tests have now conclusively demonstrated that diabetic patients with underlying cardiovascular disease, or multiple cardiovascular risk factors, should take these medications to reduce the risk of heart failure."

For theheart.org | Medscape Cardiology, Butler added: "The choice between individual inhibitors of SGLT 2 is difficult. The benefit of cardiovascular mortality with empagliflozin was very impressive – this is hard to ignore. The benefits of kidney and heart failure seem to be overlapping with all drugs. There was a small increase in amputations with canagliflozin. This may have been just a fluke and has not been seen with other SGLT2 inhibitors. "

"So we also have the GLP-1 agonist drugs, which have shown a clear benefit over the major adverse cardiovascular events, but appear to be neutral in the risk of heart failure. I think we can justify the use of both classes of agents in some cases . "

A more moderate view …

Others, however, are taking a more moderate view. One of them is David Nathan, MD, director of the diabetes center at Massachusetts General Hospital in Boston, Massachusetts. He commented to theheart.org | Medscape Cardiology: "These SGLT2 inhibitors reduce the risk of hospitalization for heart failure in diabetics or at increased risk of heart disease, but the absolute risk reduction is quite modest – about 1%. patients with established heart disease. "

It also points out that the adverse effects and costs of SGLT2 inhibitors need to be taken into account when their use is being considered.

"These drugs increase urine glucose excretion, which leads to urinary tract infections, and we might ask if they are really expensive diuretics – we would have the same effect with a low dose of furosemide or a thiazide diuretic with fewer effects and much lower cost smaller? "

Nathan also noted that the glycemic effects of dapagliflozin were modest with a 0.4% reduction in hemoglobin A1c (HbA1c) (decreasing HbA1c from 8.3% to 7.9%) in this study. "This is not enough to meet the FDA's usual minimum requirements for approval of a new diabetes drug."

"If these drugs are to be more appropriately treated as treatments for heart failure in patients with diabetes, rather than drugs to lower glucose per se, it's 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 donations and personal fees from Astra Zeneca and Bristol-Myers Squibb. Butler is a consultant to Astra Zeneca.

Scientific Sessions of the American Heart Association (AHA) 2018. Abstract no. 19485. Submitted on November 10, 2018.

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

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