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Dapagliflozin cuts heart failure in diabetes


CHICAGO – Dapagliflozin (Farxiga / ForxigaIn the DECLARE-TIMI 58 study in patients with type 2 diabetes, AstraZeneca showed a significantly lower hospitalization time for heart failure, although the rate of major cardiological cardiovascular events (MACE) was lower.

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

""What we see in this study is a theme similar to other important studies of sodium glucose kotransporter-2 (SGLT2) inhibitors – a significant reduction in heart failure hospitalizations and renal events," Wiviott said. | Medscape Cardiology.

"DECLARE-TIMI 58 is different from the others. [cardiovascular outcomes] he enrolled a larger and healthier population that did not have pre-existing cardiovascular disease but involving 10,000 patients with more than one risk factor and 7000 patients with pre-existing cardiovascular disease.

We have found that the benefit of dapagiflozine in heart failure is similar in patients with and without pre-existing cardiovascular disease; whereas the effect on MACE was different among these populations, those without secondary effects in the primary protection group and with a tendency to decrease.

"All three SGLT2-inhitor studies have had a major impact on heart failure outcome, and our experiment contributed to the literature known in this regard. However, this also expands the benefit of this heart failure to primary prevention diabetic population." Said.

He added: "If you look at all trials, empagliflozin has the most benefit on MACE, but this is still less than the benefit of heart failure. In my opinion, after the DECLARE-TIMI 58 trial, the largest SGLT2 inhibitors are now on the prevention of heart failure and a reduction in major cardiovascular events. is limited to patients with underlying cardiovascular disease. "

Edi The DECLARE TIMI-58 study also provides very reassuring data on safety without indicating an increase in stroke, amputation, or bladder cancer, “he added.

More recent cardiovascular (CV) outcome studies of newer type 2 diabetes drugs have been carried out following an order issued by the US Food and Drug Administration (FDA) in 2008, following damages related to older type 2 diabetes medicines.

However, so far, none of the eight completed CV outcome trials have identified the risk of excess CV from these drugs, and all three have actually benefited.

Among them were two oral SGLT2 inhibitor studies: EMPA-REG OUTCOMES study with empagliflozin (Jardian by, Boehringer Ingelheim / Lilly) and canagliflozin with CANVAS (invoke untilJanssen). In both studies, all patients had type 2 diabetes and CVD present or had a high risk of CVD.

Similarly, in the third study, LEADER injected once daily with glucagon-like protein-1 (GLP-1) agonist liraglutide (Victoz toNovo Nordisk, CVD (CVD) or chronic renal failure in all patients with type 2 diabetes, or CVD risk factors at age 60 and older were detected.

DECLARE is now adding cardiovascular benefits with new diabetes medicines to this study list, but its benefits are limited to the endpoint of heart failure and have not shown the same reductions in MACE as other SGLT2-inhibitor assays or LEADER. However, this study recorded a lower population of type 2 diabetic patients with lower risk than previous cardiovascular outcome studies.

No Increase in Amputations with Dapagliflozin in DECLARE

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

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

After an average of 4.2 years of follow-up, the primary safety outcome met the criteria for inadequacy.

In terms of two efficiencies, MACE decreased numerically in the dapagiflozin group, but this finding was not significant. CV death / heart failure hospitalization end point significantly decreased. This was driven by a lower hospitalization rate for heart failure.

One key secondary result was a renal composite (≥ 40% reduction in estimated glomerular filtration rate, 1.73 m <60 mL / min.2nd body surface area, new end stage renal disease or renal or CV causes). This is significantly reduced by dapagliflozin.

Table 1. DECLARE-TIMI 58: Main Results

Variable Dapagliflozin (%) Placebo (%) Danger Rate (95% Confidence Interval)
CV measurement / 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 hospitalizations 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)

After the groups were separated with patients without cardiovascular disease, dapagliflozin and MACE did not significantly decrease in patients with established disease, but had no effect in those without CVD.

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

Variable Danger Rate (95% Confidence Interval)
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 side effects, diabetic infusions (0.1% vs 0.1%) that cause discontinuities or are considered to be serious, such as diabetes ketoacidosis dapagiflozine (0.1% vs. 0.3%) are more common. ) was. Wiviott noted that these are known side effects of SGLT2 inhibitors.

Verici Our results are reassuring because we haven't seen any suggestions on amplification or stroke increase with dapagiflozin. This is the largest study of these agents, the longest follow-up period. Bu

"In [EMPA-REG OUTCOMES] The empagliflozin assay went in the wrong direction and there was an increased incidence of amputation in the CANVAS trial in the treatment group with canopiflozin. Because of these observations in previous studies, we carefully evaluated these results and found no evidence of any increase with dapagiflozin. "

"In the early studies of dapagliflozin, there was a small increase in bladder cancer with the drug, so the FDA DECLARE experiment claimed that we had to do a careful surveillance for it, and the rate of bladder cancer turned out to be actually lower. The dapagliflozin handle. The number of observations in studies in numbers often shows that it depends on chance, "he added.

KV Result Trials in Diabetes Patients: Change in Sea at Therapy

Wiviott stated that these new type 2 diabetes drugs are slow to enter the market. "Currently cardiologists are often unable to prescribe these medications, but now there are numerous studies showing cardiovascular benefits, I think the uses in the cardiology community will grow in patients with diabetes and primary and secondary prevention.

Dönüş These studies were initially performed to demonstrate cardiovascular safety, but in fact they showed unexpected cardiovascular benefits, and these drugs are now becoming cardiovascular agents that lower blood sugar, rather than diabetic drugs.

"It is a sea change and currently studies with SGLT2 inhibitors as heart failure and renal prevention therapies in non-diabetic patients."

Edi In addition, research is under way on the mechanism of action behind the beneficial effects that are not due to lowering blood sugar, inden he added. ”Patients affect the sodium / glucose carrier in the kidney, so that the patient excretes sodium and glucose in the urine, but can also have direct cardiac effects.“

He asked how different agents in the classroom were compared, “I feel safe using any of these drugs. I recommend this in any of these drugs, while treating diabetic patients, rather than competing on which SGLT2 inhibitor to use. The class with proven cardiovascular and renal benefit may be preferred to older diabetes medicines without such benefits. "

Reduction of macrovascular and microvascular events: Paradigm shift

Orum I also think that we are changing paradigm in the treatment of diabetes. Everyone has been fixed so far to lower blood sugar to reduce microvascular complications, and nothing has been done to differentiate between various classes. [newer] Diabetes drugs, but now we are beginning to focus on reducing macrovascular complications (ie, cardiovascular outcomes). "

Jackson, Mississippi Medical Center University, Javed Butler, MD Javed Butler, a determined argumentative of the research, said that DECLARE-TIMI 58 was a well-made trial, and all SGLT2 inhibitor CV results trials included the highest proportion of non-diabetic patients with resident atherosclerotic CVD.

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

"We also see diabetic patients with underlying cardiovascular disease," he says. "These effects are beneficial to MACE, but" this effect does not extend to patients who do not have underlying cardiovascular disease. "

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

Heart failure is equally or probably more common than major cardiovascular events in patients with diabetes, and heart failure usually has worse outcomes. We are working on the lifestyle – we know we can reduce cardiovascular outcomes in diabetic patients by giving up smoking. weight and blood pressure, but cetera – but it does not seem to have the same effect on the risk of heart failure. "

"These studies concluded that diabetic patients with underlying cardiovascular disease or multiple cardiovascular risk factors should take these drugs to reduce the risk of heart failure."

for | Medscape Cardiology, Butler added: "It is difficult to choose between individual SGLT 2 inhibitor drugs. The benefit of cardiovascular mortality with empagliflozin was striking – it is difficult to ignore. The benefits of kidney and heart failure seem to overlap with all drugs. There was a small increase in amputations with canagliflozin. This can only be a chance and not seen with other SGLT2 inhibitors. "

"We then have GLP-1 agonist drugs that have a significant benefit in the major cardiovascular events but seem to be neutral on the risk of heart failure. I think we can make a case for the use of both of these two agent classes."

A More Tempered Look Daha

Others, however, receive a more tempered opinion. One of them is David Nathan, director of the diabetes center at Massachusetts General Hospital in Boston, Massachusetts. Commented | Medscape Cardiology: "These SGLT2 inhibitors reduce the risk of heart failure hospitalization in patients with diabetes, or increase the risk of heart disease, but the absolute risk reduction is quite low – about 1%. Empagliflozin has shown better effects on major cardiovascular events in patients with established heart disease."

It also draws attention to the negative effects and costs of SGLT2 inhibitors when considering their use.

"These drugs increase the excretion of glucose in the urine that leads to urinary tract infections in the urine. And we could actually ask whether they are very expensive diuretics – can we achieve the same effect with a lower dose of furosemide or thiazide diuretics with less side effects and lower costs?"

In addition, Nathan was modest in this study with a reduction of dapagliflozin glycemic effects in hemoglobin A1c (HbA1c) by a reduction of 0.4% (reducing HbA1c from 8.3% to 7.9%). pointed out that. ”This is not enough to meet the usual minimal FDA requirements for approval of new diabetes medications.“

Ti Whether these drugs should be considered more appropriately for the treatment of heart failure in patients with diabetes is a very subtle distinction to consider, rather than glucose-lowering drugs on its own. “

It was funded by DECLARE-TIMI 58, Astra Zeneca and Bristol-Myers Squibb. Wiviott, Astra Zeneca and Bristol-Myers from Squibb report grants and personal fees. Butler is an adviser to Astra Zeneca.

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

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

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