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Dapagliflozin reduces heart failure in diabetes

CHICAGO – Dapagliflozin (Farxiga / Forxiga, AstraZeneca) demonstrated an insignificant trend at reduced Mace disease rates but significantly reduced hospitalization due to heart failure in the DECLARE-TIMI 58 study in type 2 diabetes patients.

The trial is presented here by 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 also released on the Internet at the same time New England Journal of Medicine.

"What we see in this study is similar to other major studies of sodium glucose colotransporter-2 (SGLT2) – a significant reduction in hospitalization of heart and kidney events, commented Wiviott | Medscape Cardiology.

"DECLARE-TIMI 58, however, differs from others [cardiovascular outcomes] because it has enrolled a wider and healthier population, including 10,000 patients without already existing cardiovascular disease but with multiple risk factors as well as 7,000 patients with already existing cardiovascular disease. "

"We found that the benefit of dapagliflozin on heart failure was similar to those with and without previous cardiovascular disease, while the effect on MACE differentiated between these populations without the effect of the primary prevention group and the trend of reducing those with secondary prevention.

"All three SGLT2 inhbitor studies have shown great effects on the end points of heart failure, and our trial adds well-known literature in this regard, but also extends this benefit of cardiac failure in a primary population's diabetic population," Wiviott said.

He added: "If we look at all the experiments, empagliflozin showed the greatest benefit to MACE, but it is still less beneficial for heart failure. I think that after hearing DECLARE-TIMI 58 we can say the biggest benefit of SGLT2 inhibitors are on prevention heart failure, and the reduction of major cardiovascular events is limited to patients with existing baseline cardiovascular disease. "

"The undiluted TIMI-58 examination also provides highly convincing safety data without any signs of stroke, amputation, or urinary bladder cancer," he added.

The implementation of major cardiovascular (CV) outcomes of newer type 2 diabetes medications is being carried out to demonstrate safety after the mandate of the US Food and Drug Administration (FDA) in 2008, after being concerned about the damage to older type 2 diabetes medicines.

However, none of the eight completed lifetime HP studies have identified a surplus of CV risk of the drugs in question, and three were actually beneficial.

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

Likewise, in the third LEADER study, a single daily glycagon-like glucagon-1 (GLP-1) agonist liraglutide (Victoza, Novo Nordisk), all patients with Type 2 diabetes had liver disease (CVD) or chronic kidney failure or were older than 60 years of age with CVD risk factors.

DECLARE now adds this list of studies showing cardiovascular benefit to new diabetes medications, though its benefits are limited to the end point of heart failure and has not shown the same decrease in MACE as other SGLT2 inhibitors or LEADER tests. However, this study included a lower risk population of type 2 diabetes patients than in previous cardiovascular outcomes studies.

There is no increase in amputation 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 at the top of the standard therapy.

The primary outcome of the safety was the composite MACE event, defined as the death of an animal, myocardial infarction (MI) or ischemic stroke. Two contemporary endpoint efficacy were MACE and composite cardiovascular deaths or hospitalization for heart failure.

After an average 4.2 years follow-up, the primary outcome of safety meets the criteria for non-inferiority.

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

The key secondary outcome was the kidney composite (≥40% reduction in estimated glomerular filtration rate at <60 mL / min to 1.73 m2 body surface area, new endoscopic kidney disease or death from renal or CV causes). This is also significantly reduced with dapagliflozin.

Table 1. FORM-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)
Hospitalization of death / heart CV 4.9 5.8 0.83 (0.73-0.95)
Treatment of heart failure 2.5 3.3 0.73 (0.61 to 0.88)
Death of an animal 2.9 2.9 0.98 (0.82-1.17)
Renal Composite 4.3 5.6 0.76 (0.67-0.87)

After the groups were separated on patients with and without those with cardiovascular disease, MACE significantly decreased with dapagliflozine in those with established disease but no effect on those without established CVD.

Table 2 Results of those with and without CVD (HR for Dapagliflozin)

variable Risk Ratio (95% confidence interval)
CV death / MI / stroke 0.90 (0.79-1.02) 1.01 (0.86-1.20)
Hospitalization of death / heart CV 0.83 (0.71 – 0.98) 0.84 (0.67-1.04)

In terms of side effects, diabetic ketoacidosis was more common in dapagliflozin (0.3% vs. 0.1%), as well as genital infections that resulted in interruption or severe (0.9% vs 0.1%). Wiviott should note that this is also the known side effects of SGLT2 inhibitors.

He commented: "Our results are also encouraging because we have not seen any suggestions for increased amputation or stroke with dapagliflozin and this is the largest study of these agents with the longest tracking."

"IN [EMPA-REG OUTCOMES] empagliflozin, the stroke was started in the wrong direction, and in the CANVAS trial with canagliflozin there was an increased amputation frequency in the treated group. Due to these observations in the previous trials, we have carefully evaluated these outcomes and found no evidence of any increase in dapagliflozin. "

"In earlier studies of dapagliflozin, the drug had a small increase in urinary bladder cancer so that the FDA had determined that we needed to make careful monitoring of it in the DECLARE trial and it was shown that the urinary bladder cancer rate was actually lower. Thus, it is again encouraging and shows that observations in studies with a small number are often a consequence of the case, "he added.

Examination of skin outcomes in diabetes mellitus: change of the sea in therapy

Wiviott noticed that these new type 2 diabetes medications slowly penetrate the market. "Currently, cardiologists often do not prescribe these medicines, but now we have more studies that show cardiovascular benefits, I think their use in the cardiology community will grow in both primary and secondary prevention of diabetes patients.

"These experiments were initially carried out to demonstrate cardiovascular safety, but they actually showed a non-expected cardiovascular benefit, so these drugs now turn into cardiovascular agents that also reduce blood sugar, not just diabetic medications.

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

"Research is also underway on the mechanism of action for their beneficial effects, which is probably not just about lowering blood sugar," he added. "They affect the sodium / glucose carrier in the kidney and the patient secretes sodium and glucose in the urine, but they may also have direct heart effects," he suggests.

When asked how different class agents were compared, he said, "I feel self-confident with any of these drugs. Instead of competing with the SGLT2 inhibitor, I recommend that any of the medications in this class that, when treating diabetic patients, have proven cardiovascular and renal benefit preferring older diabetes drugs that have not shown such benefits. "

Decline in Macrovascular and Microvascular Events: paradigm shift

"I also think that we are entering a paradigm shift in the treatment of diabetes. Everyone has been fixed to lowering blood sugar to reduce microvascular complications and there was nothing to distinguish between different levels [newer] but now we are starting to focus on reducing macrovascular complications (ie cardiovascular outcomes).

The corresponding study investigator, javel Butler of the University of Mississippi Medical Center, Jackson, said that DECLARE-TIMI 58 was well tested and included the largest share of diabetic patients without established atherosclerotic CVD for all CVLT2 inhibitor outcome studies,

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

"We have seen together all the experiments that diabetic patients with cardiovascular disease who take these drugs benefit from MACE, but that this effect does not apply to patients without baseline cardiovascular disease."

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

Heart failure "is the same or even more common than the major adverse cardiovascular event in patients with diabetes, and cardiac failure usually has poorer results. We also know that we can reduce cardiovascular outcomes in diabetic patients, working on lifestyle – body weight and blood pressure, etc. – but it does not work at the risk of heart failure. "

"These experiments have now definitely shown that patients with diabetes with cardiovascular disease or with multiple cardiovascular risk factors should take these medicines to reduce the risk of heart failure."

To | Medscape Cardiology, Butler added: "The choice between certain drugs with SGLT 2 inhibitors is difficult. Cardiovascular mortality with empagliflosine was very striking – it is difficult to ignore. It appears that benefits from kidney failure and heart failure overlap with all medications. There has been a slight increase in amputation with canagliflozin. This could be just a chance and not visible with other SGLT2 inhibitors. "

"Then we also have GLP-1 agonist drugs that have shown a clear benefit in the more adverse cardiovascular events, but they seem to be neutral at the risk of heart failure. I think we can make a case for using both of these class agents in some cases."

More abandoned view …

Others, however, take a more temperamental look. One of them is David Nathan, MD, Director of Diabetes Center at Massachusetts General Hospital, Boston, Massachusetts. He commented | Medscape Cardiology: "These SGLT2 inhibitors reduce the risk of heart failure in diabetic patients with increased risk of heart disease, but the absolute risk reduction is rather modest – about 1%." Empagliflozin has been shown to have a better effect on the major adverse cardiovascular events in patients with established heart disease. "

It also points out that the harmful effects and costs of SGLT2 inhibitors need to be taken into account in their application.

"These drugs increase the excretion of glucose in the urine, leading to urinary tract infections and we can only wonder if they are just expensive diuretics – whether to get the same low dose furosemide or thiazide diuretics with fewer side effects and much lower costs?"

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

"Whether these medicines should be appropriately treated as a cure for heart failure in diabetic patients instead of glucose lowering drugs is a subtle difference that needs to be considered," he concluded.

DECLARE-TIMI 58 funded Astra Zeneca and Bristol-Myers Squibb. Wiviott submits grants and personal fees from Astra Zeneca and Bristol-Myers Squibb. Butler is an Astra Zeneca consultant.

American Heart Association (AHA) Scientific Session 2018. Summary no. 19485 Presented on November 10, 2018.

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

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