Dapagliflozin Reduces Diabetes Heart Failure

CHICAGO – Dapagliflozin (Farxiga / Forxiga, AstraZeneca) showed a nonsignificant trend in reducing the rate of major cardiac events (MACE), but a significant reduction in the number of hospitalizations for heart failure in the DECLARE-TIMI 58 trial at patients with type 2 diabetes.

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

"What we see in this trial is a similar theme to other major trials of glucose-sodium cotransporter-2 (SGLT2) inhibitors – a significant reduction in the number of hospitalizations for heart failure and kidney events ", commented Wiviott. theheart.org | Medscape Cardiology.

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

"We found that the benefit of dapagliflozin on heart failure was similar in patients with and without pre-existing cardiovascular disease, whereas the effect on MACE was different between these populations with no effect in the group of primary prevention and a tendency to reduce those with secondary prevention.

"The three SGLT2-inhbitor badays have demonstrated a significant effect on the heart failure badessment criterion, and our essay adds to the known literature on this subject." But it also extends this benefit to Heart failure to the diabetic population in primary prevention, "said Wiviott.

He added: "If we look at all the tests, empagliflozin showed the most benefit on MACE, but it was still a benefit lower than the insufficiency I think that after the DECLARE-TIMI 58 test, we can definitively state that it is the largest SGLT2 inhibitors are aimed at preventing heart failure and reducing the number Major cardiovascular events is limited to patients with existing underlying cardiovascular disease. "

"The DECLARE TIMI-58 trial also provides very rebaduring data on safety, with no signs of an increase in strokes, amputations or bladder cancer," he added.

Major trials on cardiovascular (CV) outcomes of new type 2 diabetes medications are underway to demonstrate safety, according to a FDA (Food and Drug Administration) mandate in 2008 after concerns about cardiovascular damage related older medications for type 2 diabetes.

But so far, none of the eight complete completed CV tests has identified excessive CV risk badociated with the drugs in question, and three have shown a benefit.

Two oral SGLT2 inhibitor studies: the EMPA-REG OUTCOMES study on empagliflozin (Jardiance, Boehringer Ingelheim / Lilly) and CANVAS with canagliflozin (InvokanaJanssen). In both studies, all patients had existing type 2 diabetes and CVD or were at high risk for CVD.

Similarly, in the third study, LEADER, with liraglutide (GLP-1), an agonist of protein 1 similar to glucagon injection once a day (VictozaNovo Nordisk), all patients with type 2 diabetes had established cardiovascular disease or chronic renal failure, or were aged 60 years and older with risk factors for cardiovascular disease.

DECLARE now adds to the list of studies demonstrating the cardiovascular benefits of new antidiabetic drugs, although these benefits are limited to the badessment criterion of heart failure and that reductions in MACE are not the same as other SGLT2 inhibitor tests, or LEADER. But this trial included a population of patients with type 2 diabetes at a lower risk than in previous cardiovascular studies.

No increase in amputations with dapagliflozin in DECLARE

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

The main safety outcome was a composite of MACE events, defined as CV death, myocardial infarction (MI) or ischemic stroke. The two main evaluation criteria for effectiveness were MACE and a composite of cardiovascular death or hospitalization for heart failure.

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

With respect to the two efficacy outcomes, MACE was numerically reduced in the dapagliflozin group, but this finding was not significant. The criterion for evaluation of hospitalization in the event of CV death / heart failure was significantly reduced. This was motivated by a lower hospitalization rate for heart failure.

A key secondary outcome was a renal composite (≥ 40% decrease in glomerular filtration rate estimated at <60 mL / min per 1.73 m² body surface, new renal failure or death due to renal or cardiovascular cause). This was also significantly reduced with dapagliflozin.

Table 1. DECLARE-TIMI 58: Main results

Variable	Dapagliflozin (%)	Placebo (%)	Risk ratio (95% confidence interval)
CV death / MI / stroke	8.8	9.4	0.93 (0.84 – 1.03)
CV / 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)
Dead CV	2.9	2.9	0.98 (0.82 – 1.17)
Renal composite	4.3	5.6	0.76 (0.67 – 0.87)

Once the groups were separated into patients with and without established cardiovascular disease, MACE was nonsignificantly reduced with dapagliflozin in those with established disease, but there was no effect in those without established cardiovascular disease.

Table 2. Results in patients 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 / hospitalization for heart failure	0.83 (0.71 – 0.98)	0.84 (0.67 – 1.04)

With respect to adverse events, diabetic ketoacidosis was more common with dapagliflozin (0.3% vs. 0.1%), as were bad infections leading to interruptions or considered serious (0.9% vs. 0.1%). Wiviott noted that it was two known side effects of SGLT2 inhibitors.

"Our results are also rebaduring in that we have seen no suggestion of amputations or stroke increases related to dapagliflozin and that it is the largest study of these agents with the longest follow-up. "

"In the [EMPA-REG OUTCOMES] In the trial on empagliflozin, the strokes were in the wrong direction and in the CANVAS trial with canagliflozin, the incidence of amputations increased in the treated group. Because of these observations in previous trials, we evaluated these results with great care and found no evidence of any increase in dapagliflozin. "

"In the first studies of dapagliflozin, there was a slight increase in bladder cancer with this drug, so the FDA had to be closely monitored in the DECLARE trial. Bladder cancer was actually lower than dapagliflozin, so it's rebaduring again and shows that observations in studies with a small number are often random, "he added.

Diabetes Resume Results: Radical Change in Therapy

Wiviott noted that these new type 2 diabetes medications have been slow to penetrate the market. "Currently, cardiologists do not often prescribe these drugs, but we now have numerous studies showing cardiovascular benefits, and I think their use in the cardiology community will increase in diabetic patients treated in primary prevention and secondary.

"These trials initially aimed at demonstrating cardiovascular safety, but they actually showed unexpected cardiovascular benefits.These drugs are now turning into cardiovascular agents that also lower blood glucose levels rather than antidiabetic drugs.

"There is a dramatic change and studies are underway on SGLT2 inhibitors as a treatment for heart failure and renal prevention in non-diabetic patients."

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

When asked how the different agents of the clbad were compared, he said, "I would feel confident to use any of these drugs, instead of competing with an SGLT2 inhibitor. would recommend that, when treating diabetic patients, the proven cardiovascular and renal benefits would be preferable to older antidiabetic drugs, which did not have such benefits. "

Reduced macrovascular and microvascular events: a paradigm shift

"I also think that we are entering a paradigm shift in the treatment of diabetes." Until now, everyone was determined to reduce blood sugar levels to reduce microvascular complications and nothing allowed to distinguish the different clbades of [newer] Diabetes drugs, but we are now starting to focus on reducing macrovascular complications (cardiovascular outcomes). "

Javed Butler, MD, of the University of Mississippi Medical Center, Jackson, stated that DECLARE-TIMI 58 was a well conducted trial comprising the highest proportion of diabetic patients without atherosclerotic CVD established among all effects tests. of the CV on SGLT2 inhibitors. .

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

"In addition, all clinical trials show that diabetic patients with underlying cardiovascular disease" who take these agents benefit from MACE, but that "this effect does not extend to patients without cardiovascular disease underlying ".

Butler pointed out that heart failure is a very important evaluation criterion for diabetes trials.

Heart failure "is also, perhaps even more common than major adverse cardiovascular events in diabetic patients, and heart failure generally has worse outcomes.We also know that we can reduce cardiovascular outcomes in diabetic patients by improving their lifestyle – quit smoking, reduce weight, blood pressure, etc., but that does not seem to have the same effect on the risk of heart failure. "

"These trials have now conclusively demonstrated that diabetic patients with underlying cardiovascular disease or with multiple cardiovascular risk factors should take these drugs to reduce their risk of heart failure."

AT theheart.org | Medscape Cardiology, Butler added: "It is difficult to choose between the different SGLT 2 inhibitory drugs. The benefits of cardiovascular mortality with empagliflozin were very striking – it's hard to ignore. The benefits of kidney and heart failure seem to overlap with all medications. Canagliflozin was slightly amputated. This may be a coincidence and has not been observed with other SGLT2 inhibitors. "

"Next, we also have the GLP-1 agonist drugs, which have shown a clear benefit on major adverse cardiovascular events, but seem neutral on the risk of heart failure.I think we can advocate for the Use of these two clbades of agents some cases. "

A more temperate view …

Others, however, take a more moderate view. One of them is David Nathan, MD, director of the diabetes treatment center at Mbadachusetts General Hospital in Boston, Mbadachusetts. He commented on theheart.org | Medscape Cardiology: "These SGLT2 inhibitors reduce the risk of hospitalization for heart failure in diabetics with heart disease or at increased risk of heart disease, but the reduction in absolute risk is quite modest – about 1% "Empagliflozin has shown better effects on major adverse cardiovascular events in patients with established heart disease."

He also points out that the adverse effects and costs of SGLT2 inhibitors must all be taken into account when examining their use.

"These drugs increase the excretion of glucose in the urine, which leads to infections of the urinary tract.And one might wonder if they are just very expensive diuretics.Would we have the same effect with a low dose of furosemide or thiazide diuretic with less side risk? " effects and much lower cost? "

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

"The question of whether these drugs should be considered more appropriately as heart failure treatments in diabetic patients, rather than hypoglycemic drugs per se, is a distinction not so subtle that it is appropriate to take into account, "he concluded.

DECLARE-TIMI 58 was funded by Astra Zeneca and Bristol-Myers Squibb. Wiviott announces grants and personal fees from Astra Zeneca and Bristol-Myers Squibb. Butler is a consultant at Astra Zeneca.

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

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

For more from theheart.org | Medscape Cardiology, follow us on Twitter and Facebook