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Dapagliflozin reduces heart failure in diabetes.



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Chicago – Dapagliflozin (Ax Cigar / Porsiga, AstraZeneca) showed a significant decrease in the rate of major adverse cardiac event (MACE) decline in the DECLARE-TIMI 58 trial in patients with type 2 diabetes, but significantly reduced hospitalization for heart failure.

This clinical trial was conducted by Stephen Stephen, senior author of the American Heart Association (AHA) Science Session 2018 Wiviott, MD, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Also online New England Medical Journal.

"What we are seeing at this trial is a significant reduction in cardiac arrest admission and kidney events, similar to other major tests of the sodium glucose cotransporter-2 (SGLT2) inhibitor, Wiviott theheart.org | Medscape Cardiology.

"But DECLARE-TIMI 58 is different from the others [cardiovascular outcomes] A clinical trial was conducted in which a much wider and healthy population was enrolled, including 10,000 patients with multiple cardiovascular events but no known cardiovascular disease and 7000 patients with existing cardiovascular disease.

"The benefits of dapagliflozin on heart attack are similar in patients with or without an existing cardiovascular disease, but the effect on MACE was different among these groups, not with the primary prevention group, and with those with secondary prevention.

"All three clinical trials with SGLT2 have had a major impact on heart failure endpoints," Wiviott said, "and this clinical trial expands this heart attack to prevent diabetes."

"When we look at all clinical trials, empagliflozin has the most benefit of MACE, but less than the benefits of cardiovascular disease." In a DECLARE-TIMI 58 clinical trial, SGLT2 inhibitors showed that the major cardiovascular event- Limited to patients with.

"The DECLARE TIMI-58 clinical trial offers very reassuring information about safety without the signs of stroke, amputation, or bladder cancer," he added.

The results of a large-scale cardiovascular (CV) trial of a new type 2 diabetes drug were conducted to demonstrate safety under the 2008 US Food and Drug Administration's (FDA) mandate due to concerns about CV damage to older type 2 diabetes drugs.

However, to date, none of the eight CV result trials have identified an excessive CV risk for the drug, and three have actually benefited.

This included two studies on oral SGLT2 inhibitors: EMPA-REG results using empagliflozinZadia, Boehringer Ingelheim / Lilly) and canvas and canagliflozin (Inkocana, Janssen). In both studies, all patients have Type 2 diabetes and existing CVD, or are at high risk for CVD.

Likewise, in a third study, once daily injection of the glucagon-like protein-1 (GLP-1) agonist liraglutide (VictozaAccording to Novo Nordisk, all patients with type 2 diabetes were 60 years of age or older with cardiovascular disease (CVD) or chronic renal failure or CVD risk factors.

DECLARE is added to this list to demonstrate cardiovascular effects on new diabetic medications, although its benefits to cardiac arrest endpoints are limited and do not show the same MACE reduction as other SGLT2 inhibitor trials or leaders. However, this trial had a lower risk of type 2 diabetes than did previous cardiovascular outcomes studies.

No increase in cleavage site with Dapagliflozin in DECLARE

In a DECLARE-TIMI 58 study, 17,160 patients with type 2 diabetes were randomly assigned to 10 mg of dapagliflozin or placebo.

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

After a mean follow-up of 4.2 years, the primary safety outcome met the non-inferiority criteria.

In terms of two efficacy results, MACE was numerically decreased in the dapagliflozin group, but this result was not significant. The CV death / heart failure hospitalization end point has decreased significantly. This occurred because of low hospitalization rates for heart failure.

The primary secondary outcome was a reduction in renal complex (less than 60 mL / min per 1.73 m estimated glomerular filtration rate of more than 40%2 New end stage renal disease, death due to kidney or CV cause). This was also significantly reduced by dapagliflozin.

Table 1. DECLARE-TIMI 58: Key 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 / 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)
Resume death 2.9 2.9 0.98 (0.82-1.17)
Kidney complex 4.3 5.6 0.76 (0.67-0.87)

After the team was separated from patients without cardiovascular disease and those without cardiovascular disease, MACE was significantly reduced to dapagliflozin in people with established disease but not to people without established CVD.

Table 2. Results with or without 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 / hospitalization for heart failure 0.83 (0.71-0.98) 0.84 (0.67 – 1.04)

For side effects, diabetic ketoacidosis was more common than dapagliflozin (0.3% vs. 0.1%) and genital infections were discontinued or considered serious (0.9% vs. 0.1%). Wiviott has been shown to be a known side effect of SGLT2 inhibitors.

"Our results have been a step of relief because we have not seen suggestions for cutting or stroke increases with dapagliflozin.

" [EMPA-REG OUTCOMES] In the empagliflozin trial, the stroke progressed in the wrong direction, and the CANVAS clinical trial with canagliflozin increased the incision rate in the treatment group. In our previous experiments, we observed these results very carefully and did not find any evidence of an increase using dapagliflozin. "

"In an earlier study of dapagliflozin, there was a slight increase in bladder cancer with drugs, and the FDA was instructed to carefully monitor the DECLARE clinical trial and actually had a lower percentage of bladder cancer, so this is a safe and small number of observations, "He added.

CV results in diabetes test: marine change in therapy

Wiviott noted that this new type 2 diabetes drug is slow to penetrate the market. "Currently, cardiologists do not prescribe these drugs, but they have several studies on cardiovascular disease, and the use of cardiovascular disease is likely to increase in both primary prevention and second prevention patients with diabetes.

"This trial was initially conducted to demonstrate cardiovascular safety, but in fact it has been turned into a cardiovascular drug that reduces blood sugar rather than a diabetes drug because it is not expected to have a cardiovascular effect.

"This is a change of the sea and is an SGLT2 inhibitor in patients without diabetes, and studies of heart failure and kidney prophylaxis are underway."

"The study is continuing on the mechanism behind the beneficial effects, not the blood sugar drop," he added. He said it affects the sodium / glucose transporter in the kidneys, so it excretes sodium and glucose in the urine but can directly affect the heart.

"It would be better to use this drug when treating diabetics rather than competing with SGLT2 inhibitors," he said. "Oral antidiabetic drugs whose class has proven cardiovascular and renal efficacy will be preferable to older antidiabetic drugs that do not have this benefit."

Reduced Macrovascular and Microvascular Events: Paradigm Shift

"We think that we are experiencing a paradigm shift in the treatment of diabetes. Everyone has been locked up to lower blood glucose levels to reduce microvascular complications, [newer] Although we focused on the development of diabetes therapies, we are now focusing on reducing cardiovascular complications (eg, cardiovascular disease). "

Dr. Jackson of the University of Mississippi Medical Center in Jackson, MD, said that DECLARE-TIMI 58 was a well-conducted study and the highest percentage of patients with diabetes without the atherosclerotic CVD of all SGLT2 inhibitor CV results. .

"This trial again showed the benefits of SGLT2 inhibitors to reduce the risk of heart attack and kidney problems for diabetics," he said.

"We also found that patients with diabetes who have cardiovascular disease benefit from MACE, but this effect does not extend to patients without cardiovascular disease," he said.

Butler emphasized that heart attack is a crucial endpoint in diabetes clinical trials.

Heart failure "is equal or even more common than the major cardiovascular events in diabetics, and heart attack usually produces worse results.In addition, we do not affect lifestyle habits, weight, blood pressure, etc. of diabetic patients, "

"In this trial, we concluded that diabetics with cardiovascular disease or multiple cardiovascular risk factors should take this drug to lower the risk of heart failure," he concluded.

on theheart.org | Medscape Cardiology, Butler "Choosing an SGLT 2 inhibitor is difficult. The cardiovascular mortality rate of empagliflozin is very surprising. It is difficult to ignore. The effects of kidney and heart attack seem to overlap with all medications. Cutting cut slightly increased with canagliflozin. This may just be an opportunity and was seen in other SGLT2 inhibitors. "

"We also use GLP-1 agonist drugs, which have a significant effect on cardiovascular events, but seem to be neutral to heart failure risk, I think we can use both of these drugs.

More dull look …

But others have a much cheerful view. One of these is David Nathan of the Massachusetts General Hospital's diabetes center in Boston, Massachusetts. He commented on. theheart.org | Medscape Cardiology: "Although this SGLT2 inhibitor reduces the risk of heart disease due to heart failure in diabetics, the absolute risk reduction is about 1%. Epagliflozin has a better effect on the patient's major cardiovascular events with established cardiovascular disease. "

He also noted that it should be considered when considering both the side effects and costs of SGLT2 inhibitors.

"These drugs increase urinary glucose excretion and cause urinary tract infections, and in fact they are very expensive diuretics. Can a small amount of furosemide or thiazide diuretic give less effect?"

Nathan noted that the blood sugar effect of dapagliflozin reduced hemoglobin A1c (HbA1c) by 0.4% (lowering HbA1c from 8.3% to 7.9%). "This is not enough to meet the usual minimum FDA requirements for approval of new diabetes drugs."

He concluded, "It is a subtle difference, not a consideration, whether or not it should be properly considered as a treatment for heart attack in diabetics, rather than the drug that lowers glucose."

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

American Heart Association (AHA) Science Session 2018. Abstract Number. 19485. Announcement November 10, 2018.

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

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