Saturday , April 17 2021

Dapagliflozin Causes Heart Failure in Diabetes



CHICAGO – Dapagliflozin (Farxiga / Forxiga, AstraZeneca) showed a non-significant trend towards a decrease in adverse heart rate (MACE) but significantly reduced hospitalization for heart failure in the DECLARE-TIMI 58 trial in patients with type 2 diabetes.

This hearing was presented here at the American Scientific Sessions 2018 by lead author Stephen Wiviott, MD, Brigham and Women 's Hospital and Harvard Medical School, Boston, Massachusetts. It is also simultaneously published online on the Internet New England Medical Journal.

"What we saw in this trial is a theme similar to a large trial of sodium glucose inhibitor cotransporter-2 (SGLT2) – a significant reduction in hospitalization for heart failure and kidney events, "Wiviott commented to theheart.org | Medscape Cardiology.

"DECLARE-TIMI 58, however, is different from the others [cardiovascular outcomes] the trial in that case listed a much wider and healthier population including 10,000 patients without existing cardiovascular disease but with several risk factors, and 7,000 patients with existing cardiovascular disease. "

"We found that the benefits of dapagliflozin in heart failure were similar in patients with and without pre-existing cardiovascular disease, whereas the effect on MACE differed between these populations, without effect on the primary prevention group and the decreased tendency for those with secondary prevention.

"All three SGLT2-inhbitor trials have found a large effect at the end point of heart failure, and our trial adds to the literature known in that regard. But it also extends the benefits of heart failure to the primary prevention diabetes population," Wiviott said.

He added: "If we look at all experiments, empagliflozin shows the most benefits on MACE, but this is still less than the benefits of heart failure. I think after the DECLARE-TIMI 58 trial we can now say the biggest benefit of SGLT2 inhibitors is prevention of heart failure. and the reduction in major cardiovascular events is limited to patients with underlying cardiovascular disease. "

"The DECLARE TIMI-58 experiment also provides very convincing data about safety without signs of increased stroke, amputation, or bladder cancer," he added.

A large cardiovascular trial of newer type 2 diabetes drugs is being carried out to show safety after a mandate by the US Food and Drug Administration (FDA) in 2008 after concerns about CV damage with older type 2 diabetes drugs.

But so far, none of the eight results of the completed CV test have identified the risk of excessive CV from the drugs in question, and three have actually shown benefit.

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

Likewise, in the third study, LEADER, with gluconate-like protein 1 (GLP-1) gluconate injections which were injected once liraglutide (Victoza, Novo Nordisk), all patients with type 2 diabetes have established CV disease (CVD) or chronic kidney failure, or are aged 60 years and older with CVD risk factors.

DECLARE now adds to the list of studies that show cardiovascular benefits with new diabetes drugs, although the benefits are limited to the end point of heart failure and it does not show a similar decrease in MACE as well as other SGLT2 inhibitor trials, or LEADER. But this trial registered a lower population of patients with type 2 diabetes than in previous studies of cardiovascular outcomes.

There is no increase in amputation with Dapagliflozin on DECLARE

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

The primary safety outcome is a combined incidence of MACE, which is defined as CV death, myocardial infarction (MI), or ischemic stroke. The two primary co-efficacy endpoints are MACE and a combination of cardiovascular death or hospitalization for heart failure.

After an average follow-up of 4.2 years, the main safety outcomes met the criteria for noninferiority.

In terms of the two efficacy results, MACE was reduced numerically in the dapagliflozin group, but this finding was not significant. The CV death / heart failure hospitalization end points were significantly reduced. This is driven by lower rates of hospitalization for heart failure.

The primary secondary results were renal composites (≥40% decrease in estimated glomerular filtration rate to <60 mL / minute per 1.73 m2 body surface area, new end-stage kidney disease, or kidney death or CV). This 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 / hospitalized heart failure 4.9 5.8 0.83 (0.73 – 0.95)
Heart failure in the hospital 2.5 3.3 0.73 (0.61 – 0.88)
Death of CV 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 into patients with and those without cardiovascular disease, MACE was not significantly reduced with dapagliflozin in those with established disease, but there was no effect on those who did not have CVD.

Table 2. Results in Those Who Have and Without CVD (HR for Dapagliflozin)

Variable Hazard Ratio (95% Confidence Interval)
CVD There is no CVD
CV death / MI / stroke 0.90 (0.79 – 1.02) 1.01 (0.86 – 1.20)
CV death / hospitalized heart failure 0.83 (0.71 – 0.98) 0.84 (0.67 – 1.04)

In terms of side effects, diabetic ketoacidosis is more common with dapagliflozin (0.3% vs 0.1%), as well as genital infusion that leads to discontinuation or is considered serious (0.9% vs 0.1%). Wiviott notes that these two side effects are known as SGLT2 inhibitors.

He commented: "Our results also ensure that we do not see suggestions for increased amputation or stroke with dapagliflozin and this is the largest study of these agents with the longest follow-up."

"In [EMPA-REG OUTCOMES] Empagliflozin trials, strokes running in the wrong direction and in the CANVAS trial with canagliflozin there was an increase in the incidence of amputation in the treated group. Because of these observations in previous trials, we evaluated these results very carefully and found no evidence of an increase with dapagliflozin. "

"In a preliminary study of dapagliflozin, there was a small increase in bladder cancer with the drug so the FDA mandated that we carefully monitor this in the DECLARE trial and it turns out the bladder cancer rate is actually lower in the dapagliflozin arm. So this is convincing return and show that observations in studies with small numbers are often accidental, "he added.

CV Exam Results in Diabetes: Deep Sea Change in Therapy

Wiviott notes that newer type 2 diabetes drugs are slow to penetrate the market. "Currently cardiologists don't often prescribe these drugs, but now we have several studies that show cardiovascular benefits, I think their use in the cardiology community will grow well in patients with primary and secondary prevention with diabetes.

"This experiment was initially carried out to show cardiovascular safety, but they actually showed cardiovascular benefits, which were not expected, and these drugs are now turning into cardiovascular agents that also reduce blood sugar rather than just diabetes drugs.

"That is a sea change, and research is now underway with SGLT2 inhibitors as heart failure and preventive care of the kidneys in patients without diabetes."

"Research is also ongoing on the mechanism of action behind their beneficial effects, which may not only be due to a decrease in blood sugar," he added. "They affect the transport of sodium / glucose in the kidneys so that patients excrete sodium and glucose in the urine, but they may also have a direct heart effect," he suggested.

When asked how different agents in the class were compared, he said, "I would feel confident using these drugs. Instead of competing using SGLT2 inhibitors for use, I would recommend that, when treating diabetes patients, one of the drugs in this class which has proven cardiovascular and kidney benefits to be better for older diabetes drugs, which have not shown such benefits. "

Reducing Macrovascular and Microvascular Events: A Paradigm Shift

"I also think we are entering a paradigm shift in the treatment of diabetes. Everyone has so far improved blood sugar to reduce microvascular complications and nothing distinguishes between various classes [newer] diabetes medication, but now we are starting to focus on reducing macrovascular complications (for example, cardiovascular results) too. "

Appointed study discussant, 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 without establishing atherosclerotic CVD from all the results of the SGLT2 CV inhibitor test.

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

"We also saw from all joint trials that diabetic patients with underlying cardiovascular disease" who took this agent benefited from MACE, but that "this effect does not extend to patients without underlying cardiovascular disease."

Butler stressed that heart failure is a very important end point for diabetes testing.

Heart failure "is the same, or maybe even more, common than severe cardiovascular events in diabetic patients, and heart failure usually has worse outcomes. We also know that we can reduce cardiovascular outcomes in diabetic patients by working on lifestyle – quitting smoking, reduce weight, and blood pressure, etc. – but this does not seem to have the same effect on the risk of heart failure. "

"This trial now conclusively shows that diabetic patients with underlying cardiovascular disease, or with some cardiovascular risk factors, must use this drug to reduce their risk of heart failure."

For theheart.org | Medscape Cardiology, Butler added: "Choosing between SGLT 2 individual inhibitor drugs is difficult. The benefits of cardiovascular mortality with empagliflozin are very striking – difficult to ignore. The benefits of kidney and heart failure seem to overlap with all drugs. There is a small increase in amputation with canagliflozin. This may be just a coincidence and has not been seen with other SGLT2 inhibitors. "

"Then we also have GLP-1 agonist drugs, which have shown clear benefits in severe cardiovascular events but appear to be neutral in the risk of heart failure. I think we can make a case for the use of these two classes of agents in some cases."

More Tempered Display …

Others, however, take a more angry view. One of them is David Nathan, MD, director of the diabetes center at Massachusetts General Hospital, Boston, Massachusetts. He commented theheart.org | Medscape Cardiology: "These SGLT2 inhibitors reduce the risk of hospital heart failure in diabetics with, or at an increased risk of heart disease, but absolute risk reduction is quite simple – about 1%. Empagliflozin has shown a better effect on large cardiovascular events that are detrimental to patients. with established heart disease. "

He also pointed out that the detrimental effects and costs of SGLT2 inhibitors all need to be taken into account when their use is being considered.

"These drugs increase glucose excretion in urine, which leads to urinary tract infections. And we can ask if they are actually very expensive diuretics – are we going to get the same effect with low doses of furosemide or thiazide diuretics with fewer side effects and costs lower? "

Nathan also showed that the glycemic effect of dapagliflozin was simple with a 0.4% reduction in hemoglobin A1c (HbA1c) (decreasing HbA1c from 8.3% to 7.9%) in this trial. "This is not enough to meet the usual minimum FDA requirements for approval of new diabetes drugs."

"Whether these drugs should be more appropriately seen as treatments for heart failure in patients with diabetes, rather than glucose-lowering drugs, is a not-so-subtle difference that needs to be considered," he concluded.

DECLARE-TIMI 58 is 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 for Astra Zeneca.

American Heart Association (AHA) 2018 Scientific Session. Abstract no. 19485. Published November 10, 2018.

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

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