Dapagliflozin Heart Failure Cuts in Diabetes

CHICAGO – Dapagliflozin (Farxiga / Forxiga, AstraZeneca) showed a significant decrease in the rate of adverse cardiac events (MACE) but significantly reduced hospitalization for heart failure in the DECLARE-TIMI 58 trial 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 in the New England Journal of Medicine.

"What we're seeing in this trial is a similar topic to other major trials of sodium glucose cotransporter-2 (SGLT2) inhibitors – a significant reduction in heart failure and renal events, "Wiviott commented to theheart.org | Medscape Cardiology.

"DECLARE-TIMI 58, however, differs from the other [cardiovascular outcomes] It has been reported that patients with pre-existing cardiovascular disease have more than 10,000 patients with pre-existing cardiovascular disease. "

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

"All three SGLT2-inhbitor trials have found a large effect on the heart failure endpoint, and they also suggest that this approach extends to the primary prevention of diabetic population," Wiviott said.

He added: "If we look across all the trials, we have the most benefit on MACE, but this was still less than the heart failure benefit." I think after the DECLARE-TIMI 58 trial we can definitely say the biggest benefit of the SGLT2 inhibitors is the prevention of heart failure, and the major cardiovascular events are limited to patients with existing underlying cardiovascular disease. "

"The DECLARE TIMI-58 trial also revealed the need for amputation, or bladder cancer," he added.

The large cardiovascular (CV) outcome trials of newer type 2 diabetes drugs are being conducted by the US Food and Drug Administration (FDA) in 2008.

But thus far, the results of this study have been shown to be beneficial.

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

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

DECLARE now adds to this list of studies showing cardiovascular benefit with new diabetes drugs, and its benefits as a result of this endpoint and it has not been reduced to as low as SGLT2-inhibitor trials, or LEADER. But this trial enrolled a lower-risk population of patients with type 2 diabetes than in previous cardiovascular outcomes 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 to dapagliflozin 10 mg daily or placebo on top of standard therapy.

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

After a mean follow-up of 4.2 years, the primary safety outcome is the criteria for noninferiority.

In terms of the two-way outcomes, MACE was numerically reduced in the dapagliflozin group, but this finding was not significant. The CV death / heart failure hospitalization was significantly reduced. This was driven by a lower rate of hospitalization for heart failure.

A key composite outcome was a renal composite (≥40% decrease in estimated glomerular filtration rate to <60 mL / min per 1.73 m² of body surface area, new end-stage renal disease, or death from renal or CV causes). This was also significantly reduced with dapagliflozin.

Table 1. DECLARE-TIMI 58: Main Results

Variable	Dapagliflozin (%)	Placebo (%)	Hazard Ratio (95% Confidence Interval)
CV death / MI / stroke	8.8	9.4	0.93 (0.84 – 1.03)
CV death / heart failure hospitalization	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)
Renal composite	4.3	5.6	0.76 (0.67 – 0.87)

MACE have been nonsignificantly reduced with dapagliflozin in those with established disease, but there is no effect in those without established CVD.

Table 2. Results with CVD (HR for Dapagliflozin)

Variable	Hazard 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 hospitalization	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%), and was more likely to be discontinued or considered to be serious (0.9% vs 0.1%). Wiviott noted that these are known from SGLT2 inhibitors.

He commented: "Our results are also reassuring in that we are not seeing any suggestion of an increase in amputations or strokes with dapagliflozin and this is the largest study of these agents with the longest follow-up."

"In the [EMPA-REG OUTCOMES] empagliflozin trial, stroke went into the wrong direction and in the CANVAS trial with canagliflozin there was an increased incidence of amputations in the treated group. Because of these observations in previous trials, we report these outcomes very carefully and find evidence of any increase with dapagliflozin. "

"In early studies of dapagliflozin, there was a small increase in the incidence of cancer with the drug in the FDA. dapagliflozin arm. "So this is reassuring again and shows that observations in studies with small numbers are often due to chance," he added.

CV Outcomes Trials 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 are not often prescribing these drugs, but now we have multiple studies showing cardiovascular benefits, I think their use in the cardiology community will grow in both primary and secondary prevention patients with diabetes.

"These trials were originally conducted to show cardiovascular safety, but they did show cardiovascular benefit, which was not expected, and it was more likely that they would reduce blood sugar rather than just diabetic drugs.

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

"Research is also ongoing on the mechanism of action for their beneficial effects, which is probably not less blood sugar lowering," he added. "They affect the sodium / glucose transport in the kidney so the patient excretes sodium and glucose in the urine, but they may also have direct cardiac effects," he suggests.

Asked how the different agents compared to the class compared, he said, "I would like to be confident that I would recommend that, when treating diabetic patients, any of the drugs in this Which of the following have been shown to be beneficial and which would have been better?

Reducing Macrovascular and Microvascular Events: A Paradigm Shift

"I also think of a difference in the treatment of diabetes. [newer] diabetes drugs, but we are starting to focus on reducing macrovascular complications (ie, cardiovascular outcomes) as well. "

Designated discussant of the study, Javed Butler, MD, University of Mississippi Medical Center, Jackson, said DECLARE-TIMI 58 was a well-conducted trial and included the highest proportion of diabetic patients with CVD of all the SGLT2 inhibitor CV findings trials .

"This trial shows the benefits of SGLT2 inhibitors in diabetic patients," he said.

"We are also seeing all the trials in which diabetic patients with underlying cardiovascular disease" who are taking these benefits, but that "does not extend to patients without underlying cardiovascular disease."

Butler stressed that heart failure is a very important endpoint for diabetic trials.

Heart failure "is always more common, than other adverse events in cardiovascular events in diabetes patients, and heart failure outcomes." We also know that we can reduce cardiovascular outcomes in diabetes patients by working on lifestyle – quitting smoking, reducing weight, and blood pressure, et cetera – but this does not seem to have the same effect on heart failure risk. "

"These trials have now conclusively demonstrated that diabetes patients with underlying cardiovascular disease, or with multiple cardiovascular risk factors, should be taking these drugs to lower their risk of heart failure."

to theheart.org | Medscape Cardiology, Butler added: "Choosing between the individual SGLT 2 inhibitor drugs is difficult. The cardiovascular mortality benefit with empagliflozin was very striking – that's hard to ignore. The renal and heart failure benefits seem to be overlapping with all the drugs. There was a small increase in amputations with canagliflozin. This may have been just luck and has not been seen with other SGLT2 inhibitors. "

"Then we have the GLP-1 agonist drugs, which show a clear benefit on the major adverse cardiovascular events, but seem to be neutral on heart failure risk. some cases. "

A More Tempered View …

Others, however, are taking a more tempered view. One of these is David Nathan, MD, director of the diabetes center at Massachusetts General Hospital, Boston, Massachusetts. He commented to theheart.org | Medscape Cardiology: "These SGLT2 inhibitors reduce the risk of heart failure hospitalization in patients with heart disease, but the risk of heart failure is greater than the risk of heart failure." Empagliflozin has shown better effects on major adverse cardiovascular events in patients with established heart disease. "

He also points out that the adverse effects of SGLT2 inhibitors are all considered when they are used.

"These drugs increase the excretion of glucose in the urine, which leads to an increase in the incidence of infection. effects and much lower cost? "

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

"Whether these medications should be more appropriately assessed for patients with diabetes, rather than glucose-lowering medications per se, is a not-so-subtle distinction that needs consideration," he concluded.

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

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

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

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